Prodrugs: A Novel Approach of Drug Delivery

Rishabh Gaur

doi:doi:10.11648/j.ijpc.20241002.11

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Prodrugs: A Novel Approach of Drug Delivery

Rishabh Gaur^*

Published in International Journal of Pharmacy and Chemistry (Volume 10, Issue 2)

Received: 23 May 2024 Accepted: 15 June 2024 Published: 29 June 2024

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Abstract

In the last one-decade numbers of review and research, articles have been published on prodrugs. This shows the interest of researchers in prodrugs because of the advantages offered by them over other drug delivery systems. Prodrug design is a method to focus many of the issues that trouble drug discovery and development, such as solidity, virulence, solubility, permeability, and drug targeting. Prodrug design is an effective method for targeting medications by altering their physiochemical, pharmacological, or pharmacokinetic properties. Prodrugs account for about 10% to 14% of all drugs sanctioned worldwide. Prodrugs can be created for a variety of administration methods, including transdermal, oral, intravenous, and more. However, the oral route of administration is the most popular and preferable approach; hence, oral prodrugs are highlighted in this article. Our main objectives are to explain the fundamental ideas behind the prodrug strategy, give a rundown of successfully registered oral prodrugs, and evaluate the therapeutic gains made in contrast to the parent drug. In this review article, we have made an attempt to incorporate all the basic details of prodrugs like Introductions, classification, applications of prodrug design in diverse fields of drug development, and basic functional categories that are amenable to prodrug design are all covered in this article. Using electronic databases such Web of Science, Google Scholar, PubMed, Sci Finder, Reaxys, and Cochrane, a literature search was conducted to locate information.

Published in	International Journal of Pharmacy and Chemistry (Volume 10, Issue 2)
DOI	10.11648/j.ijpc.20241002.11
Page(s)	18-24
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Prodrugs, Development, Classification, Application, Functional Categories, Virulence

1. Introduction

The development of novel chemical entities with great pharmacological efficacy is made possible by potent contemporary drug discovery approaches, including combinatorial chemistry and high-throughput screening

[1]

. These methods have also brought about a new hurdle because many of the novel drug candidates still need to be chemically modified or use formulation technologies in order to attain adequate performance and effectively complete the demanding drug development process

[2]

. Chemical alterations can include adding salts for faster dissolution

[3]

or adding alkyl moieties to the drug's molecule to make it more lipophilic. However, these alterations may cause the drug to lose or have less pharmacological activity than the original compound

[4]

. To overcome physicochemical barriers, a variety of formulation strategies can be used

[5-7]

, albeit they may or may not be successful in achieving adequate drug delivery. An strategy using prodrugs may be able to overcome these challenges

[8]

, When describing chemicals that undergo biotransformation before having a pharmacological effect, Adrian Albert coined the word "prodrug" in 1958. He described these substances as "therapeutic agents that are inactive but can be converted into one or more active metabolites." Another name for the prodrug design approach is "drug latentiation".

Prodrugs are bioreversible, inactive drug derivatives that can change into their active parent drug inside of a person's body. The prodrug strategy is used to get around biopharmaceutical, pharmacokinetic, or pharmacodynamics barriers, such as poor chemical stability, solubility restrictions, a lack of site-specificity, extensive drug metabolism, passing through biological barriers, utilising endogenous metabolic pathways, toxicity, or compliance barriers (unacceptable taste/odor), all in favour of optimal oral bioavailability and a resulting therapeutic effect

[9]

. The prodrug technique is used to optimise recently discovered chemical entities as well as to enhance the qualities of medications that have already been put in to the market. In the last ten years, the Food and Drug Administration (FDA) of the United States has approved about 30 prodrugs (12% of all novel small-molecule entities). Prodrugs are thought to make up about 10% of all commercially marketed medications worldwide

[10]

A prodrug is a pharmacologically inactive molecule that transforms into an active drug by metabolic biotransformation before, during, and after abstraction, or at specific target sites inside the body. When describing chemicals that undergo biotransformation before having a pharmacological effect, Adrian Albert coined the word "prodrug" in 1958. He described these substances as "therapeutic agents that are inactive but can be converted into one or more active metabolites." Another name for the prodrug design approach is "drug latentiation"

[11, 12]

The prodrug technique used to be thought of as a last resort in the drug development process, but this is no longer the case, and now it is taken into consideration at the very beginning phases of drug research and development. In spite of the fact that creating a prodrug requires working with a novel chemical entity, the cost of producing a prodrug is lower than that of creating a novel drug. The quicker drug development process, which could ultimately result in time, money, and effort savings, is caused by the better performance (relative to the parent drug)

[13-21].

Whatever the method or goal, after prodrug consumption, it must go through an activation process in which the free parent drug is released, allowing the pharmacological effect to be applied (Figure 1).

Prodrugs can be created for a variety of administration methods, including transdermal, oral, intravenous, and more

[22]

. However, the oral route of administration is the most popular and preferable approach; hence, oral prodrugs are highlighted in this article. Our main objectives are to explain the fundamental ideas behind the prodrug strategy, give a rundown of successfully registered oral prodrugs, and evaluate the therapeutic gains made in contrast to the parent drug. Additionally, effective prodrug examples that are already on the market or have undergone clinical trials are provided, highlighting their advantages over the parent drug in terms of pharmacological, therapeutic, and clinical outcomes.

Download: Download full-size image

Figure 1. Fate of prodrug approach.

2. Classification of Prodrugs

Prodrugs can be categorized using a variety of different approaches. These might consist of those: (1) based on therapeutic categories, such as prodrugs for cardiovascular disease, anticancer, antiviral, antibacterial, and nonsteroidal anti-inflammatory conditions; (2) depending on the types of chemical linkages or moiety/carriers that bind to the active substance, such as esteric, glycoside, bipartite, and tripartite prodrugs, as well as enzymes that are driven by an antibody, gene, or virus; or (3) based on functional categories and employing deliberate strategies to overcome limitations of the active drug; for instance, prodrugs to enhance site specificity, prodrugs to avoid high first-pass metabolism, prodrugs to enhance absorption, and prodrugs to lessen side effects.

[23-26]

Table 1. Classification of Prodrugs.

Prodrug type	Site of Conversion	Subtypes	Tissue location of conversion	Example
Type I	Intracellular	A	Therapeutics target tissues/cells	Type IA: Acyclovir, 5-Flurouracil, L-Dopa, Zidovudine etc.
Type I	Intracellular	B	Metabolic Tissues (Liver, GI mucosal cell, lungs etc.)	Type IB: Cabamazepine, Carisoprodol, Heroin, Phenacetin, Sildinac, disulfide etc.
Type II	Extracellular	A	GI fluids	Type IIA: Lisdexamfetamine, Oxyphenisation, Sulfasalazine
		B	Systemic circulation and other Extracellular fluid comaprtments	Type IIB: Succinate, Divivefin, Bambuterol, Dihydropyridine etc.
		C	Therapeutic target tissues/cells	Type IIC: ADPEs, GDEPs, VDEPs

3. Prodrug Activation

Prodrug design is the activation process that, in order to achieve the therapeutic goal, efficiently and characterizedly releases the active parent drug from the prodrug. Prodrug activation can be based on chemical processes (such as oxido-reduction) or can occur through enzyme-mediated hydrolysis. Oxidoreductases, such as cytochrome P450, hydrolytic enzymes, such as carboxylesterases, phosphatases, and esterases, transferases, and lyases can all be used in prodrug activation

[27]

The various absorption barriers and subsequent sites of possible metabolism on the path to the systemic blood circulation provide considerable obstacles for oral prodrug delivery. Whether the prodrug will be activated before or after absorption and systemic circulation is a major concern with oral prodrugs

[28]

. Prodrugs are medicines that, once ingested by the body, become active. Prodrugs increase a medication's efficacy. They could also be made to prevent specific negative effects or toxicities. Prodrugs are crucial for creating novel pharmaceuticals

[29, 30]

Table 2. Prodrug formula and their therapeutic uses.

Prodrug

Chemical formula

Therapeutic Uses

Remdesivir

C₂₇H₃₅N₆O₈P

Coronavirus disease 2019 (COVID-19) in adults and adolescents with pneumonia requiring supplemental oxygen

[31, 32]

OBI-3424

C₂₁H₂₅N₄O₆P

Relapsed/refractory T-cell acute lymphoblastic leukemia, hepatocellular carcinoma, and castrate-resistant prostate cancer

[33-35]

Baloxavir marboxil

C₂₇H₂₃F₂N₃O₇S

Influenza

[36, 37]

Selexipag

C₂₆H₃₂N₄O₄S

Pulmonary arterial hypertension

[38]

Valacyclovir

C₁₃H₂₀N₆O₄

Herpesvirus

[39, 40]

Gabapentin enacarbil

C₁₆H₂₇NO₆

Restless leg syndrome, postherpetic neuralgia

[41, 42]

NUC-1031

C₂₅H₂₇F₂N₄O₈P

Advanced biliary tract cancer

[43, 44]

Tenofovir alafenamide

C₂₁H₂₉N₆O₅P

HIV/AIDS and chronic hepatitis B

[45, 46]

4. Objectives of Prodrug Design

4.1. Pharmaceutical Objectives

1) To ameliorate solvability (e.g., corticosteroids).

2) To ameliorate chemical constancy (e.g., dopamine).

3) To ameliorate organoleptic properties (e.g., chloramphenicol palmitate is a sparingly resolve prodrug of chloramphenicol, which is practically flavorless due to its low aqueous solubility as well as it is hydrolyzed to active chloramphenicol by the action of pancreatic lipase).

4) To decrease annoyance and ache.

4.2. Pharmacokinetic Objectives

1) To ameliorate articulate (oral) absorption or permeability and thus multiply bioavailability (ampicillin, epinephrine).

2) To decrease first pass metabolism (propanolol).

3) To improve saturation by non oral routes.

4) To provide organ or tissue selective delivery of active agent.

4.3. Pharmacodynamics Objectives

1) To avoid adverse effects or toxicities.

2) To mask reactive species to improve its corrective index.

3) To improve site specificity (i.e., that the site of action of an active drugs rather nonspecific such as anticancer agents)

[47, 48]

5. Prodrugs Approved

Prodrugs are roughly 10% of all pharmaceuticals that are marketed worldwide. The FDA has approved at least 30 prodrugs since 2008. Seven prodrugs were authorized in 2015 after six were approved in 2017. Examples of recently approved prodrugs are such as dabigatran etexilate (approved in 2010), gabapentin enacarbil (2011), sofosbuvir (2013), tedizolid phosphate (2014), isavuconazonium (2015), aripiprazole lauroxil (2015), selexipag (2015), latanoprostene bunod (2017), benzhydrocodone (2018), and tozinameran (2020). Stdies are still going on are new prodrugs

[49]

6. Liposome Encapsulated Prodrugs Development

Prodrugs (drugs conjugated to pro-carriers) are inactive substances that can be converted into biologically active drugs in vivo by chemical or enzymatic processes. Prodrugs are used to enhance the parent drug's pharmacological, physicochemical, and ADME (absorption, distribution, metabolism, and excretion) properties. Prodrug techniques can facilitate drug preparation and administration, boost medication effectiveness, increase site specificity, and/or lessen toxicity. Today, prodrug approaches are used in the early stages of drug research

[50]

Liposomal prodrug formulations have a number of important benefits, such as high drug loading efficiency, increased drug availability, controllable drug release, and a reduced tendency to aggregate following encapsulation. Prodrug-based liposomes have an advantage over other kinds of liposomal medications in that they can intelligently react to specific stimuli and release the required medicines. After years of research and development, numerous prodrug-based liposomes with various chemical alterations have come into existence as corresponding stimuli, including those from the internal tumour microenvironment (TME) (such as pH, redox environment, enzyme and hypoxic, etc.) and the external environment (such as light, heat, ultrasound, magnetic field, etc.)

[51, 52]

7. Merits and Demerits

Liposomes are exceptional drug delivery systems because they preserve the encapsulated materials from physiological deterioration

[53]

, increase the drug's half-life, regulate drug molecule release

[54]

, and have great biocompatibility and safety. Production cost is high liposomal products examples: Arikayce, Shingrix, Vyxeos, Onivyde, Marqibo, Doxil Caelyx etc.

Download: Download full-size image

Figure 2. Structure of prodrug-based nanocarriers.

8. Limitations of Prodrug Design

Unexpectedly hazardous metabolite formation from the entire prodrug. The inert carrier formed after prodrug cleavage might also undergo a hazardous metabolite transformation. A essential cell component may be consumed by the prodrug during its activation stage, depleting it. Prodrugs are chemically altered forms of pharmacologically active agents that have little to no biological activity. These prodrugs must be transformed in vivo to release the actual medication

[55-58]

9. Conclusion

One of the most promising methods for boosting the therapeutic efficacy and/or mitigating the side effects of pharmacologically active agents is the prodrug strategy. This approach works through a variety of mechanisms, such as improved permeability and bioavailability, tissue-targeted delivery, increased solubility, and stability. As a result, prodrugs are emerging as a cutting-edge paradigm for drug discovery. Even with the amazing advancements in prodrug design, further research is obviously required, particularly in the early phases of drug development, to ensure that prodrugs reach the state of art and become a standard component of contemporary pharmacotherapy.

Abbreviations

IC	Intracellular
US	United States
FDA	Food and Drug Administration
EC	Extracellular
TME	Tumour Microenvironment

Author Contributions

Rishabh Gaur is the sole author. The author read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

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Gaur, R. (2024). Prodrugs: A Novel Approach of Drug Delivery. International Journal of Pharmacy and Chemistry, 10(2), 18-24. https://doi.org/10.11648/j.ijpc.20241002.11

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@article{10.11648/j.ijpc.20241002.11,
  author = {Rishabh Gaur},
  title = {Prodrugs: A Novel Approach of Drug Delivery
},
  journal = {International Journal of Pharmacy and Chemistry},
  volume = {10},
  number = {2},
  pages = {18-24},
  doi = {10.11648/j.ijpc.20241002.11},
  url = {https://doi.org/10.11648/j.ijpc.20241002.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijpc.20241002.11},
  abstract = {In the last one-decade numbers of review and research, articles have been published on prodrugs. This shows the interest of researchers in prodrugs because of the advantages offered by them over other drug delivery systems. Prodrug design is a method to focus many of the issues that trouble drug discovery and development, such as solidity, virulence, solubility, permeability, and drug targeting. Prodrug design is an effective method for targeting medications by altering their physiochemical, pharmacological, or pharmacokinetic properties. Prodrugs account for about 10% to 14% of all drugs sanctioned worldwide. Prodrugs can be created for a variety of administration methods, including transdermal, oral, intravenous, and more. However, the oral route of administration is the most popular and preferable approach; hence, oral prodrugs are highlighted in this article. Our main objectives are to explain the fundamental ideas behind the prodrug strategy, give a rundown of successfully registered oral prodrugs, and evaluate the therapeutic gains made in contrast to the parent drug. In this review article, we have made an attempt to incorporate all the basic details of prodrugs like Introductions, classification, applications of prodrug design in diverse fields of drug development, and basic functional categories that are amenable to prodrug design are all covered in this article. Using electronic databases such Web of Science, Google Scholar, PubMed, Sci Finder, Reaxys, and Cochrane, a literature search was conducted to locate information.
},
 year = {2024}
}

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TY  - JOUR
T1  - Prodrugs: A Novel Approach of Drug Delivery

AU  - Rishabh Gaur
Y1  - 2024/06/29
PY  - 2024
N1  - https://doi.org/10.11648/j.ijpc.20241002.11
DO  - 10.11648/j.ijpc.20241002.11
T2  - International Journal of Pharmacy and Chemistry
JF  - International Journal of Pharmacy and Chemistry
JO  - International Journal of Pharmacy and Chemistry
SP  - 18
EP  - 24
PB  - Science Publishing Group
SN  - 2575-5749
UR  - https://doi.org/10.11648/j.ijpc.20241002.11
AB  - In the last one-decade numbers of review and research, articles have been published on prodrugs. This shows the interest of researchers in prodrugs because of the advantages offered by them over other drug delivery systems. Prodrug design is a method to focus many of the issues that trouble drug discovery and development, such as solidity, virulence, solubility, permeability, and drug targeting. Prodrug design is an effective method for targeting medications by altering their physiochemical, pharmacological, or pharmacokinetic properties. Prodrugs account for about 10% to 14% of all drugs sanctioned worldwide. Prodrugs can be created for a variety of administration methods, including transdermal, oral, intravenous, and more. However, the oral route of administration is the most popular and preferable approach; hence, oral prodrugs are highlighted in this article. Our main objectives are to explain the fundamental ideas behind the prodrug strategy, give a rundown of successfully registered oral prodrugs, and evaluate the therapeutic gains made in contrast to the parent drug. In this review article, we have made an attempt to incorporate all the basic details of prodrugs like Introductions, classification, applications of prodrug design in diverse fields of drug development, and basic functional categories that are amenable to prodrug design are all covered in this article. Using electronic databases such Web of Science, Google Scholar, PubMed, Sci Finder, Reaxys, and Cochrane, a literature search was conducted to locate information.

VL  - 10
IS  - 2
ER  -

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Author Information

Rishabh Gaur

Department of Pharmacology, Roorkee College of Pharmacy, Roorkee, India

Contact Email

http://orcid.org/0000-0003-4707-6371

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APA Style

Gaur, R. (2024). Prodrugs: A Novel Approach of Drug Delivery. International Journal of Pharmacy and Chemistry, 10(2), 18-24. https://doi.org/10.11648/j.ijpc.20241002.11

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ACS Style

Gaur, R. Prodrugs: A Novel Approach of Drug Delivery. Int. J. Pharm. Chem. 2024, 10(2), 18-24. doi: 10.11648/j.ijpc.20241002.11

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AMA Style

Gaur R. Prodrugs: A Novel Approach of Drug Delivery. Int J Pharm Chem. 2024;10(2):18-24. doi: 10.11648/j.ijpc.20241002.11

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@article{10.11648/j.ijpc.20241002.11,
  author = {Rishabh Gaur},
  title = {Prodrugs: A Novel Approach of Drug Delivery
},
  journal = {International Journal of Pharmacy and Chemistry},
  volume = {10},
  number = {2},
  pages = {18-24},
  doi = {10.11648/j.ijpc.20241002.11},
  url = {https://doi.org/10.11648/j.ijpc.20241002.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijpc.20241002.11},
  abstract = {In the last one-decade numbers of review and research, articles have been published on prodrugs. This shows the interest of researchers in prodrugs because of the advantages offered by them over other drug delivery systems. Prodrug design is a method to focus many of the issues that trouble drug discovery and development, such as solidity, virulence, solubility, permeability, and drug targeting. Prodrug design is an effective method for targeting medications by altering their physiochemical, pharmacological, or pharmacokinetic properties. Prodrugs account for about 10% to 14% of all drugs sanctioned worldwide. Prodrugs can be created for a variety of administration methods, including transdermal, oral, intravenous, and more. However, the oral route of administration is the most popular and preferable approach; hence, oral prodrugs are highlighted in this article. Our main objectives are to explain the fundamental ideas behind the prodrug strategy, give a rundown of successfully registered oral prodrugs, and evaluate the therapeutic gains made in contrast to the parent drug. In this review article, we have made an attempt to incorporate all the basic details of prodrugs like Introductions, classification, applications of prodrug design in diverse fields of drug development, and basic functional categories that are amenable to prodrug design are all covered in this article. Using electronic databases such Web of Science, Google Scholar, PubMed, Sci Finder, Reaxys, and Cochrane, a literature search was conducted to locate information.
},
 year = {2024}
}

Copy | Download

TY  - JOUR
T1  - Prodrugs: A Novel Approach of Drug Delivery

AU  - Rishabh Gaur
Y1  - 2024/06/29
PY  - 2024
N1  - https://doi.org/10.11648/j.ijpc.20241002.11
DO  - 10.11648/j.ijpc.20241002.11
T2  - International Journal of Pharmacy and Chemistry
JF  - International Journal of Pharmacy and Chemistry
JO  - International Journal of Pharmacy and Chemistry
SP  - 18
EP  - 24
PB  - Science Publishing Group
SN  - 2575-5749
UR  - https://doi.org/10.11648/j.ijpc.20241002.11
AB  - In the last one-decade numbers of review and research, articles have been published on prodrugs. This shows the interest of researchers in prodrugs because of the advantages offered by them over other drug delivery systems. Prodrug design is a method to focus many of the issues that trouble drug discovery and development, such as solidity, virulence, solubility, permeability, and drug targeting. Prodrug design is an effective method for targeting medications by altering their physiochemical, pharmacological, or pharmacokinetic properties. Prodrugs account for about 10% to 14% of all drugs sanctioned worldwide. Prodrugs can be created for a variety of administration methods, including transdermal, oral, intravenous, and more. However, the oral route of administration is the most popular and preferable approach; hence, oral prodrugs are highlighted in this article. Our main objectives are to explain the fundamental ideas behind the prodrug strategy, give a rundown of successfully registered oral prodrugs, and evaluate the therapeutic gains made in contrast to the parent drug. In this review article, we have made an attempt to incorporate all the basic details of prodrugs like Introductions, classification, applications of prodrug design in diverse fields of drug development, and basic functional categories that are amenable to prodrug design are all covered in this article. Using electronic databases such Web of Science, Google Scholar, PubMed, Sci Finder, Reaxys, and Cochrane, a literature search was conducted to locate information.

VL  - 10
IS  - 2
ER  -

Copy | Download