Grasp the lifeline of new drug research and development from a macro perspective

The research and development of new drugs is a long, expensive and risky activity, generally may take more than ten years, 1-2 billion US dollars of investment, like thousands of troops crossing a single wooden bridge full of uncertainty and hardship, and finally the birth of a new drug, as shown in the figure below, although a candidate compound into clinical trials still has a probability of failure
of more than 90%.
From the perspective of new drug development in recent years, even the drugs of Me Too or Me Better, I feel that the faster the clinical advancement, the earlier it will fail
.
For the progress of new drug research and development, the earlier it is promoted, the earlier the risks can be discovered, so as to avoid the discovery of great defects and greater losses
in the later stage of clinical research.
An early declaration of failure may not be a bad thing
either.

Cited from Reference 1

The ultimate goal of new drug development is to market early, and when pharmaceutical companies come, they can recover their costs as soon as possible to avoid generic drugs coming too quickly; For patients, they can also receive treatment early and avoid the torment
of illness.
How to promote the development of new drugs faster is a huge problem, which requires the joint cooperation of different research departments in research and development to formulate practical research and development strategies
.
In fact, we have also seen some pharmaceutical giants make some changes
in research and development strategies.

In 1988, a literature disclosing the causes of drug development failures showed that about 39% of drugs failed
due to poor biopharmaceutical properties (PK and bioavailability).
Before the early 1990s, the drug development process was largely one-way
.
The drug discovery stage pays more attention to whether the drug molecule is a ligand that has a strong interaction with the protein target
.
Promising molecules will be studied
in vivo pharmacokinetics (PK), efficacy and safety in animals.
When the candidate compound enters the development stage, the physicochemical properties of the compound are characterized and the early formulation process is studied, and a drug product
with certain stability, manufacturability and exhibits optimal PK (i.
e.
, absorption, distribution, metabolism and excretion) in the human body is prepared.
After filing the IND, the product will undergo clinical trials in humans, after which the development team turns its attention to the manufacturing process
that will eventually produce the drug on a commercial scale.
This one-way model of drug discovery is called Development 1.
0
.
The main feature of this development mode is that the candidate compound molecule has not been characterized by physicochemical properties and it has been confirmed that it will be developed later, even if its stability is poor, solubility is low, and bioavailability is low in the real development stage, the data has been unchangeable, and the raw rice is cooked and
matured.
Development teams sometimes have to bite the bullet to develop development strategies, and of course poor molecular properties lead to the inevitable creation
of inferior drug products.
Many clinical programs are delayed, or worse, fail
completely.
Most drug candidates are not stillborn throughout the development process, where the low water solubility of the compounds has become a disaster
.
Insoluble drugs are becoming more common and may be related to the following aspects:

Combinatorial chemistry and high-throughput screening modalities may have played a role
in the application of new drug screening, typically in non-aqueous media (or mixed solvent media).

The quest for enhanced potency, coupled with the understanding that receptor binding is at least partially mediated by hydrophobic interactions, further amplifies the possibility that
drug candidates have limited water solubility.

Explore unprecedented drug targets, some of which are associated with intracellular signaling pathways, lipid processing architecture, or highly lipophilic endogenous ligands, to expand the production
of highly lipophilic, poorly water-soluble drug candidates.

With the exploration of the root causes of the collapse of new drug development caused by Development 1.
0, the exploratory drug development model - Development 2.
0
will continue.
Scientists' core competencies in preclinical development—including physical chemistry, process chemistry, engineering, pharmacy, and materials science—are brought to the discovery stage
.
Before determining the individual molecular structure, preclinical experts will study physicochemical and biopharmaceutical properties and even assess manufacturability and scale-up potential, with drug properties requiring attention as shown in Figure 2
.
Only then can a compound enter the full-scale preclinical development stage
.
In other words, the transition from discovery to development becomes bidirectional: the molecule moves forward into development as before—but first, the expertise gained downstream is fed back to the discovery team and decided not to proceed
at the (or not long ago) candidate selection phase.

Figure 2 Common properties of compound molecules (cited from Reference 2)

Development 2.
0 opens up a two-way communication between discovery and development teams, helping to discover candidate compounds
that can achieve a balance between structure-activity relationship (SAR) and structure-property relationship (SPR).
Recently, many companies have begun to scale
up these studies through high-throughput, miniaturized, or automated physicochemical screening during the lead and lead optimization phases of discovery.
A wide range of properties of candidate compounds are characterized, including physicochemical, biological, and PK, toxicity
.
The properties of the acquired drugs will be characterized, and these drug data can infer the possibility and difficulty of their subsequent development based on some drug-like rules, such as Lipinski's famous "Rule of 5", druggability and biopharmaceutical classification system
.

The rule of five, also known as the Lipinski rule, reads as follows: A small molecule drug should have the following properties:

1.
Molecular weight less than 500;

2.
The number of hydrogen bond donors is less than 5;

3.
The number of hydrogen bond receptors is less than 10;

4.
The partition coefficient of lipid water is less than 5;

5.
The number of rotatable keys does not exceed 10.

If a compound violates 2 or more of the five rules of the class drug, the likelihood of the compound becoming an oral drug is lower
.

Biopharmaceutical Classification System (BCS)

Fig.
3 Constructing a biopharmaceutical classification system
for drug solubility and permeability.

A further application of the solubility-permeability relationship for oral drug absorption is the Biopharmaceutical Classification System (BCS)
originally developed by Amedon et al.
The principle of BCS is well described elsewhere for the solubility and permeability of drug molecules
.
According to BCS, Class I molecules are those that have both high solubility and high permeability (so oral absorption may rarely be problematic); Class II compounds are those with low solubility and high permeability (where solubility is the main limit of absorption); Class III compounds have high solubility but low permeability (absorption is limited by membrane permeation rather than solubility); Class IV compounds are compounds
with poor solubility and poor permeability that limit drug absorption.
(Cited from Reference 3)

The discovery team is characterizing the compounds, helping to identify compounds entering the development phase and getting early access to possible issues
in compound development.
Nonetheless, preclinical and late-stage clinical development can present problems
that early development specialists may not recognize.
For example, it is well known that it is difficult for experts to accurately predict the biopharmaceutical properties of human beings before clinical trials, even if there are theories that want to predict the absorption of first-time human clinical drugs, such as PKPB, DCS, etc
.
, through the results of in vitro and animal experiments.
There is an exponential gap between the development of early preparations of new drugs and the batch volume of commercial production in the later stage, and it is impossible to predict many problems
that the product may encounter in scale-up.

While pharmaceutical companies that adopted Development 1.
0 have spent huge efforts trying to develop untapped molecules, in vain; But is it possible to avoid this by adopting the Development 2.
0 model? The two-way communication of Development 2.
0 still has its drawbacks: Promising molecules—for example, those that may have high binding affinity and specificity for their targets—are eliminated
due to poor stability, biopharmaceutical properties, or amplification potential.
Some of these failures may be premature
.

The advent of Development 2.
0 has led pharmaceutical R&D teams to rethink the rationality of the drug development process, but it is still not comprehensive.

Drug information obtained by preclinical and early development teams should be expanded to include each stage
of drug development.
Policymakers should not only be able to recognize whether molecules can be easily made into pharmaceutical formulations, but should also be able to identify the huge role of other solid-state forms in the development of new drugs, that is, to bring poorly druggable drugs back into the
R&D track through changes in solid-state forms.
These require decision-makers to be able to estimate biopharmaceutical properties and prepare
in advance for any difficulties in scaling up production.
In short, R&D management must be transformational
.
They must pay attention to the many evolutions that a molecule in the discovery stage must undergo before reaching its target – as it is formulated, manufactured, stored, administered, absorbed, metabolized, and transported
.
They must ask:

Can such molecules make it to every subsequent stage of its life cycle, not just for early clinical formulation development?

Which solid-state development form (e.
g.
crystalline or amorphous) is chosen for development to guarantee absorption in vivo?

Development of pharmaceutical ingredients into capsules or tablets?

How can the molecule of the drug change during shelf life?

How is the drug molecule absorbed, distributed, metabolized and excreted in the human body?

Can the pharmaceutical formulation be mass-produced?

Information about a drug acquired during the development phase will serve all phases of drug development up to human administration, a translational drug development process known as Development 3.
0
.
Development 3.
0 is a process
that reduces the likelihood of therapeutically promising compounds being wasted by designing downstream developability.
There is an urgent need for such a radical rethinking
of the relationship between discovery and development.
Development 3.
0 reduces the potential for surprises in downstream development, enabling management teams to make the most prudent and informed decisions
about which molecules to move forward.
Development 3.
0 also prevents promising molecules from failing
in the first place.
In some cases, early understanding of late-stage development issues may bring medicinal chemists back to the discovery
of compounds.
In other cases, Development 3.
0 has rescued promising compounds that would otherwise be phased out, such as potent compounds with poor water solubility, which could still become clinically viable if
they could be developed in other solid forms, including polymorphic, eutectic, and amorphous dispersions.
Some of the issues in developability may be corrected during preclinical development, and of course, as to whether Development 3.
0 is the best drug development model, I believe that with the continuous development of science and technology, new models will emerge
.

Brief summary:

New drug research and development is a particularly large project, which has involved so many people and departments that it is necessary to formulate appropriate research and development strategies to promote the rapid development
of new drugs.
From the above, we can also know that the new drug development model is also crossing the river by feeling the stones, not overnight, constantly summarizing experience and lessons in practice, and then starting
again.
In the new historical period, we believe that more high-tech will emerge, apply in the journey of new drug development, to promote the development of new drugs, try to learn and apply, try to accept new things, try to encourage innovation, try to innovate or revolution
.
After working, I can't help but feel that the domestic new drug research and development infrastructure still has a long way to go
.
I can't help but ask, do domestic top-level pharmaceutical enterprises have top-level R&D teams, top-level management teams, top-level strategies and tactics, top-level talent management methods, top-level .
.
.
? Hahaha.
.
.
Having been working for so long, I feel quite watery
.
The above is mainly compiled and translated from reference 4, if there is anything inappropriate, please also check the original text
.

Conclude with a poem in the dream of the red chamber:

The paper is full of absurd words, a bitter tear.

Duyun author is stupid, who understands the taste?

References:

1.
Why 90% of clinical drug development fails and how to improve it?

2.
Drug-like Properties Concepts Structure Design and Methods; from ADME to Toxicity

3.
Strategies to Address Low Drug Solubility in Discovery and Development

4.
Pharmaceutical Amorphous Solid Dispersions