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Can formulation and drug delivery reduce attrition during drug discovery and development-review of feasibility, benefits and challenges.

Basavaraj S, Betageri GV - Acta Pharm Sin B (2014)

Bottom Line: Drug discovery and development has become longer and costlier process.The fear of failure and stringent regulatory review process is driving pharmaceutical companies towards "me too" drugs and improved generics (505(b) (2)) fillings.The formulation and drug delivery technologies are suitable for addressing various issues contributing to attrition are discussed in detail.

View Article: PubMed Central - PubMed

Affiliation: Western Centre for Drug Development, Western University of Health Sciences, Pomona, CA 91766, USA.

ABSTRACT
Drug discovery and development has become longer and costlier process. The fear of failure and stringent regulatory review process is driving pharmaceutical companies towards "me too" drugs and improved generics (505(b) (2)) fillings. The discontinuance of molecules at late stage clinical trials is common these years. The molecules are withdrawn at various stages of discovery and development process for reasons such as poor ADME properties, lack of efficacy and safety reasons. Hence this review focuses on possible applications of formulation and drug delivery to salvage molecules and improve the drugability. The formulation and drug delivery technologies are suitable for addressing various issues contributing to attrition are discussed in detail.

No MeSH data available.


Representative diagram of blood brain barrier and major pathways of drug transport across the BBB. Modified from Ref. 100.
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f0015: Representative diagram of blood brain barrier and major pathways of drug transport across the BBB. Modified from Ref. 100.

Mentions: The number of people suffering from CNS disorders is on increasing trend, yet very few drugs getting approved for the treatment. Staggering 35% of total disease burden in the Europe is from CNS disorders93. The global burden from CNS diseases is expected to rise to 14% in 202094. It has been reported that most of the CNS drug development efforts (99%) are directed towards finding new molecule, only meager 1% of efforts are on delivery of molecules to brain95. The main problem encountered in the delivery of drugs to brain is the presence of various barriers in the brain which prevent entry of drugs, other chemicals and toxins. The main barrier is BBB. The BBB is situated at brain and blood interface, is mainly composed of brain vascular endothelial cells and is barely penetrated (Fig. 3). Other cells, such as pericytes, astrocytes and neuronal cells, also play an important role in the functioning of BBB. Main function of BBB is to maintain homeostasis of the brain. The other barriers, blood-cerebrospinal fluid (CSF) barrier, blood-spinal barrier, choroid plexus and brain-CSF barrier also restrict movement of drug molecule into brain96–98. The molecules with favorable physicochemical properties will reach the brain. The molecular weight, log P, polar surface area and charge play the important role in brain permeation of drugs99. The ideal drug candidate should have MW<450 Da, log P 1.5–2.5, polar surface are of 65–70 Å2. The molecules bearing positive charge at pH 7–8 and those with tertiary nitrogen in the structure will have greater BBB permeability99.


Can formulation and drug delivery reduce attrition during drug discovery and development-review of feasibility, benefits and challenges.

Basavaraj S, Betageri GV - Acta Pharm Sin B (2014)

Representative diagram of blood brain barrier and major pathways of drug transport across the BBB. Modified from Ref. 100.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4590717&req=5

f0015: Representative diagram of blood brain barrier and major pathways of drug transport across the BBB. Modified from Ref. 100.
Mentions: The number of people suffering from CNS disorders is on increasing trend, yet very few drugs getting approved for the treatment. Staggering 35% of total disease burden in the Europe is from CNS disorders93. The global burden from CNS diseases is expected to rise to 14% in 202094. It has been reported that most of the CNS drug development efforts (99%) are directed towards finding new molecule, only meager 1% of efforts are on delivery of molecules to brain95. The main problem encountered in the delivery of drugs to brain is the presence of various barriers in the brain which prevent entry of drugs, other chemicals and toxins. The main barrier is BBB. The BBB is situated at brain and blood interface, is mainly composed of brain vascular endothelial cells and is barely penetrated (Fig. 3). Other cells, such as pericytes, astrocytes and neuronal cells, also play an important role in the functioning of BBB. Main function of BBB is to maintain homeostasis of the brain. The other barriers, blood-cerebrospinal fluid (CSF) barrier, blood-spinal barrier, choroid plexus and brain-CSF barrier also restrict movement of drug molecule into brain96–98. The molecules with favorable physicochemical properties will reach the brain. The molecular weight, log P, polar surface area and charge play the important role in brain permeation of drugs99. The ideal drug candidate should have MW<450 Da, log P 1.5–2.5, polar surface are of 65–70 Å2. The molecules bearing positive charge at pH 7–8 and those with tertiary nitrogen in the structure will have greater BBB permeability99.

Bottom Line: Drug discovery and development has become longer and costlier process.The fear of failure and stringent regulatory review process is driving pharmaceutical companies towards "me too" drugs and improved generics (505(b) (2)) fillings.The formulation and drug delivery technologies are suitable for addressing various issues contributing to attrition are discussed in detail.

View Article: PubMed Central - PubMed

Affiliation: Western Centre for Drug Development, Western University of Health Sciences, Pomona, CA 91766, USA.

ABSTRACT
Drug discovery and development has become longer and costlier process. The fear of failure and stringent regulatory review process is driving pharmaceutical companies towards "me too" drugs and improved generics (505(b) (2)) fillings. The discontinuance of molecules at late stage clinical trials is common these years. The molecules are withdrawn at various stages of discovery and development process for reasons such as poor ADME properties, lack of efficacy and safety reasons. Hence this review focuses on possible applications of formulation and drug delivery to salvage molecules and improve the drugability. The formulation and drug delivery technologies are suitable for addressing various issues contributing to attrition are discussed in detail.

No MeSH data available.