Topical Micro-Emulsion of 5-Fluorouracil by a Twin Screw Processor-Based Novel Continuous Manufacturing Process for the Treatment of Skin Cancer: Preparation and In Vitro and In Vivo Evaluations

Ajinkya Nitin Nikam; Angela Jacob; Ruchira Raychaudhuri; Gasper Fernandes; Abhijeet Pandey; Vinay Rao; Sheikh F. Ahmad; Ananth S. Pannala; Srinivas Mutalik

doi:10.3390/pharmaceutics15092175

Topical Micro-Emulsion of 5-Fluorouracil by a Twin Screw Processor-Based Novel Continuous Manufacturing Process for the Treatment of Skin Cancer: Preparation and In Vitro and In Vivo Evaluations

Ajinkya Nitin Nikam, Angela Jacob, Ruchira Raychaudhuri, Gasper Fernandes, Abhijeet Pandey, Vinay Rao, Sheikh F. Ahmad, Ananth S. Pannala, Srinivas Mutalik

Research output: Contribution to journal › Article › peer-review

Abstract

5-Fluorouracil (5-FU), a BCS class III drug, has low oral bioavailability and is cytotoxic in nature causing severe systemic side effects when administered through the intravenous route. Topical drug delivery could potentially mitigate the systemic side-effects. Microemulsions (MEs) would be an apt solution due to enhanced partitioning of the drug to the skin. However, conventional methods for preparing MEs are inefficient since they are not continuous and are very tedious and time-consuming processes hence revealing the need for the development of continuous manufacturing technology. In our study, 5-FU MEs were prepared using a continuous manufacturing Twin Screw Process (TSP) and its efficiency in the treatment of skin cancer was evaluated. Water-in-oil MEs were prepared using isopropyl myristate as the oil phase and Aerosol OT and Tween 80 as the surfactants. The average particle size was observed to be 178 nm. Transmission electron microscopy was employed to confirm the size and shape of the MEs. FTIR study proved no physical or chemical interaction between the excipients and the drug. In vitro drug release using vertical diffusion cells and ex vivo skin permeation studies showed that the drug was released sustainably and permeated across the skin, respectively. In in vitro cytotoxicity studies, 5-FU MEs were accessed in HaCat and A431 cell lines to determine percentage cell viability and IC50. Skin irritation and histopathological examination implied that the 5-FU MEs did not cause any significant irritation to the skin. In vivo pharmacodynamics studies in rats suggested that the optimised formulation was effective in treating squamous cell carcinoma (SCC). Therefore, 5-FU MEs efficiently overcame the various drawbacks faced during oral and intravenous drug delivery. Also, TSP proved to be a technique that overcomes the various problems associated with the conventional methods of preparing MEs.

Original language	English
Article number	2175
Number of pages	18
Journal	Pharmaceutics
Volume	15
Issue number	9
DOIs	https://doi.org/10.3390/pharmaceutics15092175
Publication status	Published - 22 Aug 2023

Bibliographical note

Funding Information:
The authors are thankful to: (i) Vision Group on Science and Technology, Government of Karnataka, India (No.: GRD 778, K-FIST L1) for providing financial assistance, (ii) Manipal Academy of Higher Education (MAHE), Manipal, India for Dr TMA Pai Doctoral Fellowships to Ajinkya Nitin Nikam and Gasper Fernandes, and (iii) Council of Scientific and Industrial Research (CSIR), Government of India, New Delhi for Senior Research Fellowship to Ruchira Raychaudhuri. The authors acknowledge and extend their appreciation to the Researchers Supporting Project Number (RSPD2023R709), King Saud University, Riyadh, Saudi Arabia for funding this study. The authors are thankful to Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India and Steer Life Private Limited, Bangalore for providing the necessary facilities for this research work.

Publisher Copyright:
© 2023 by the authors.

Keywords

5-Fluorouracil
microemulsion
twin-screw processor
continuous manufacturing
skin cancer
squamous cell carcinoma (SCC)

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Nikam, A. N., Jacob, A., Raychaudhuri, R., Fernandes, G., Pandey, A., Rao, V., Ahmad, S. F., Pannala, A. S., & Mutalik, S. (2023). Topical Micro-Emulsion of 5-Fluorouracil by a Twin Screw Processor-Based Novel Continuous Manufacturing Process for the Treatment of Skin Cancer: Preparation and In Vitro and In Vivo Evaluations. Pharmaceutics, 15(9), Article 2175. https://doi.org/10.3390/pharmaceutics15092175

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abstract = "5-Fluorouracil (5-FU), a BCS class III drug, has low oral bioavailability and is cytotoxic in nature causing severe systemic side effects when administered through the intravenous route. Topical drug delivery could potentially mitigate the systemic side-effects. Microemulsions (MEs) would be an apt solution due to enhanced partitioning of the drug to the skin. However, conventional methods for preparing MEs are inefficient since they are not continuous and are very tedious and time-consuming processes hence revealing the need for the development of continuous manufacturing technology. In our study, 5-FU MEs were prepared using a continuous manufacturing Twin Screw Process (TSP) and its efficiency in the treatment of skin cancer was evaluated. Water-in-oil MEs were prepared using isopropyl myristate as the oil phase and Aerosol OT and Tween 80 as the surfactants. The average particle size was observed to be 178 nm. Transmission electron microscopy was employed to confirm the size and shape of the MEs. FTIR study proved no physical or chemical interaction between the excipients and the drug. In vitro drug release using vertical diffusion cells and ex vivo skin permeation studies showed that the drug was released sustainably and permeated across the skin, respectively. In in vitro cytotoxicity studies, 5-FU MEs were accessed in HaCat and A431 cell lines to determine percentage cell viability and IC50. Skin irritation and histopathological examination implied that the 5-FU MEs did not cause any significant irritation to the skin. In vivo pharmacodynamics studies in rats suggested that the optimised formulation was effective in treating squamous cell carcinoma (SCC). Therefore, 5-FU MEs efficiently overcame the various drawbacks faced during oral and intravenous drug delivery. Also, TSP proved to be a technique that overcomes the various problems associated with the conventional methods of preparing MEs.",

keywords = "5-Fluorouracil, microemulsion, twin-screw processor, continuous manufacturing, skin cancer, squamous cell carcinoma (SCC)",

author = "Nikam, {Ajinkya Nitin} and Angela Jacob and Ruchira Raychaudhuri and Gasper Fernandes and Abhijeet Pandey and Vinay Rao and Ahmad, {Sheikh F.} and Pannala, {Ananth S.} and Srinivas Mutalik",

note = "Funding Information: The authors are thankful to: (i) Vision Group on Science and Technology, Government of Karnataka, India (No.: GRD 778, K-FIST L1) for providing financial assistance, (ii) Manipal Academy of Higher Education (MAHE), Manipal, India for Dr TMA Pai Doctoral Fellowships to Ajinkya Nitin Nikam and Gasper Fernandes, and (iii) Council of Scientific and Industrial Research (CSIR), Government of India, New Delhi for Senior Research Fellowship to Ruchira Raychaudhuri. The authors acknowledge and extend their appreciation to the Researchers Supporting Project Number (RSPD2023R709), King Saud University, Riyadh, Saudi Arabia for funding this study. The authors are thankful to Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India and Steer Life Private Limited, Bangalore for providing the necessary facilities for this research work. Publisher Copyright: {\textcopyright} 2023 by the authors.",

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doi = "10.3390/pharmaceutics15092175",

language = "English",

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Nikam, AN, Jacob, A, Raychaudhuri, R, Fernandes, G, Pandey, A, Rao, V, Ahmad, SF, Pannala, AS & Mutalik, S 2023, 'Topical Micro-Emulsion of 5-Fluorouracil by a Twin Screw Processor-Based Novel Continuous Manufacturing Process for the Treatment of Skin Cancer: Preparation and In Vitro and In Vivo Evaluations', Pharmaceutics, vol. 15, no. 9, 2175. https://doi.org/10.3390/pharmaceutics15092175

Topical Micro-Emulsion of 5-Fluorouracil by a Twin Screw Processor-Based Novel Continuous Manufacturing Process for the Treatment of Skin Cancer: Preparation and In Vitro and In Vivo Evaluations. / Nikam, Ajinkya Nitin; Jacob, Angela; Raychaudhuri, Ruchira et al.
In: Pharmaceutics, Vol. 15, No. 9, 2175, 22.08.2023.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Topical Micro-Emulsion of 5-Fluorouracil by a Twin Screw Processor-Based Novel Continuous Manufacturing Process for the Treatment of Skin Cancer

T2 - Preparation and In Vitro and In Vivo Evaluations

AU - Nikam, Ajinkya Nitin

AU - Jacob, Angela

AU - Raychaudhuri, Ruchira

AU - Fernandes, Gasper

AU - Pandey, Abhijeet

AU - Rao, Vinay

AU - Ahmad, Sheikh F.

AU - Pannala, Ananth S.

AU - Mutalik, Srinivas

N1 - Funding Information: The authors are thankful to: (i) Vision Group on Science and Technology, Government of Karnataka, India (No.: GRD 778, K-FIST L1) for providing financial assistance, (ii) Manipal Academy of Higher Education (MAHE), Manipal, India for Dr TMA Pai Doctoral Fellowships to Ajinkya Nitin Nikam and Gasper Fernandes, and (iii) Council of Scientific and Industrial Research (CSIR), Government of India, New Delhi for Senior Research Fellowship to Ruchira Raychaudhuri. The authors acknowledge and extend their appreciation to the Researchers Supporting Project Number (RSPD2023R709), King Saud University, Riyadh, Saudi Arabia for funding this study. The authors are thankful to Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India and Steer Life Private Limited, Bangalore for providing the necessary facilities for this research work. Publisher Copyright: © 2023 by the authors.

PY - 2023/8/22

Y1 - 2023/8/22

N2 - 5-Fluorouracil (5-FU), a BCS class III drug, has low oral bioavailability and is cytotoxic in nature causing severe systemic side effects when administered through the intravenous route. Topical drug delivery could potentially mitigate the systemic side-effects. Microemulsions (MEs) would be an apt solution due to enhanced partitioning of the drug to the skin. However, conventional methods for preparing MEs are inefficient since they are not continuous and are very tedious and time-consuming processes hence revealing the need for the development of continuous manufacturing technology. In our study, 5-FU MEs were prepared using a continuous manufacturing Twin Screw Process (TSP) and its efficiency in the treatment of skin cancer was evaluated. Water-in-oil MEs were prepared using isopropyl myristate as the oil phase and Aerosol OT and Tween 80 as the surfactants. The average particle size was observed to be 178 nm. Transmission electron microscopy was employed to confirm the size and shape of the MEs. FTIR study proved no physical or chemical interaction between the excipients and the drug. In vitro drug release using vertical diffusion cells and ex vivo skin permeation studies showed that the drug was released sustainably and permeated across the skin, respectively. In in vitro cytotoxicity studies, 5-FU MEs were accessed in HaCat and A431 cell lines to determine percentage cell viability and IC50. Skin irritation and histopathological examination implied that the 5-FU MEs did not cause any significant irritation to the skin. In vivo pharmacodynamics studies in rats suggested that the optimised formulation was effective in treating squamous cell carcinoma (SCC). Therefore, 5-FU MEs efficiently overcame the various drawbacks faced during oral and intravenous drug delivery. Also, TSP proved to be a technique that overcomes the various problems associated with the conventional methods of preparing MEs.

AB - 5-Fluorouracil (5-FU), a BCS class III drug, has low oral bioavailability and is cytotoxic in nature causing severe systemic side effects when administered through the intravenous route. Topical drug delivery could potentially mitigate the systemic side-effects. Microemulsions (MEs) would be an apt solution due to enhanced partitioning of the drug to the skin. However, conventional methods for preparing MEs are inefficient since they are not continuous and are very tedious and time-consuming processes hence revealing the need for the development of continuous manufacturing technology. In our study, 5-FU MEs were prepared using a continuous manufacturing Twin Screw Process (TSP) and its efficiency in the treatment of skin cancer was evaluated. Water-in-oil MEs were prepared using isopropyl myristate as the oil phase and Aerosol OT and Tween 80 as the surfactants. The average particle size was observed to be 178 nm. Transmission electron microscopy was employed to confirm the size and shape of the MEs. FTIR study proved no physical or chemical interaction between the excipients and the drug. In vitro drug release using vertical diffusion cells and ex vivo skin permeation studies showed that the drug was released sustainably and permeated across the skin, respectively. In in vitro cytotoxicity studies, 5-FU MEs were accessed in HaCat and A431 cell lines to determine percentage cell viability and IC50. Skin irritation and histopathological examination implied that the 5-FU MEs did not cause any significant irritation to the skin. In vivo pharmacodynamics studies in rats suggested that the optimised formulation was effective in treating squamous cell carcinoma (SCC). Therefore, 5-FU MEs efficiently overcame the various drawbacks faced during oral and intravenous drug delivery. Also, TSP proved to be a technique that overcomes the various problems associated with the conventional methods of preparing MEs.

KW - 5-Fluorouracil

KW - microemulsion

KW - twin-screw processor

KW - continuous manufacturing

KW - skin cancer

KW - squamous cell carcinoma (SCC)

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DO - 10.3390/pharmaceutics15092175

M3 - Article

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ER -

Topical Micro-Emulsion of 5-Fluorouracil by a Twin Screw Processor-Based Novel Continuous Manufacturing Process for the Treatment of Skin Cancer: Preparation and In Vitro and In Vivo Evaluations

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Bibliographical note

Keywords

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