Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5320_Библиотеки_им_академика_М_И_Перельмана
.pdf
https://t.me/med1917
Pharmaceutical Dosage Forms and Drug Delivery
cisplatin with reduced renal toxicity, doxorubicin— an analog of daunomycin with lower cardiotoxicity,
and topotecan— an analog of camptothecin with lower toxicity. Synthesis of analogs of known drugs is
sometimes aimed at improving the targeting and pharmacokinetics of a drug. The tauromustine couples
a nitrosourea anticancer agent to a brain- targeting peptide. Synthesis of NMEs that are analogs of known
followed by synthesis and evaluation by using tools such as solid- state and combinatorial chemistry.
demonstrated anticancer activity.
1.1.1.1.3 Use of Animals
The use of animals in the production of various biologic products, including serum, antibiotics, and
hormones obtained from the endocrine glands of cattle, sheep, and swine, are life- saving drugs used daily
as replacement therapy.
1.1.1.2 Genetic Engineering
In addition to the use of whole animals, cultures of cells and tissues of animal and human origin are routinely used for the discovery and development of new drugs— both small molecules and biologicals, such
as vaccines. Drugs traditionally produced in animals are increasingly being synthesized using cell and
binant deoxyribonucleic acid (DNA) technology and monoclonal antibody production. Recombinant
DNA technology involves the manipulation of cellular DNA to produce desired proteins, which may
then be extracted from cell cultures for therapeutic use. Recombinant DNA technology has the potential
to produce a wide variety of proteins. For example, human insulin, human growth hormone, hepatitis B
vaccine, and interferon are produced by recombinant DNA technology.
A growing class of biologics is mAbs against cellular targets aimed for destruction, such as molecular
markers on tumors. mAbs target a single epitope, an antigen surface recognized by the antibody, against
natural polyclonal antibodies, which bind to different epitopes on one or more antigen molecules. This
production within cells of lower animals, mAbs are produced in cells of higher animals, sometimes in the
patient, to ensure the lack of patient immune reaction against these macromolecules on administration.
mAbs are used as anticancer therapeutics, in-home pregnancy testing products, and for drug targeting
marker to pregnancy because HCG is synthesized exclusively by the placenta.
1.1.1.3 Gene Therapy
Gene therapy is the process of correction or replacement of defective genes. It can potentially be used to
prevent, treat, cure, diagnose, or mitigate human disease caused by genetic disorders. Oligonucleotides
and small interfering ribonucleic acid (RNA) (siRNA) are used to inhibit aberrant protein production,
whereas gene therapy aims at expressing therapeutic proteins inside the body.
1.2 Collaborating Disciplines
New drug discovery and development is a long, complex process that involves multidisciplinary scientists
working together in diverse, interconnected, and interdependent teams that coordinate their activities
and where a decision by each team potentially affects every other team working on a given project.
A consistent feature of new drug discovery research is the cross- disciplinary progress and collaboration.
https://t.me/med1917
Drug Discovery
7
This interdisciplinary collaboration is partly accomplished by scientists working together in different
departments within a pharmaceutical or biopharmaceutical company. Each of these disciplines is responsible for one or more aspects of the drug discovery and development process as it moves along the pipeline. These functions are usually known by different names in different organizations but have common
underlying themes, such as discovery chemistry, discovery biology, preclinical development, toxicology,
pharmaceutical development, clinical development, analytical and bioanalytical sciences, regulatory
sciences, manufacturing operations, quality operations, and commercialization functions. This chapter
-
tribute to drug discovery.
1.2.1 Biology
tested in assays that may be conducted in vitro, ex vivo, or in vivo. These assays, for example, could be
target- binding assays for isolated receptors, cellular response assays in cell culture models, or animal
Figure 1.3) that help rank different
compounds in the development pipeline through various metrics of their effectiveness. New drug discovery research should meet multiple criteria, such as clinical novelty, commercial opportunities, unmet
clinical needs, and building intellectual property.
studies. The discovery biology group works closely with bioanalytical scientists, who get involved in
developing assays for compounds and physiological markers. The data generated by these functions are
FIGURE 1.3
illustrates the dose- dependent cytotoxic effect of drugs on cells cultured in vitro in cell culture dishes. Cell cultures that
are not exposed to the drug (I) grow to a hypothetical threefold, or 300%, of their initial numbers on culturing in a growth-
However, the cells exposed to the drug (II) have less number of viable cells on culture under similar conditions for the same
amount of time. The number of viable cells in the drug- exposed culture dish depends on the drug concentration in a manner
illustrated by curve II. The drug concentration, at which the viable cell count after culture remains the same as the initial,
GI50 (growth inhibition to 50% level). Similarly, the concentration of a drug that halves the viable cell count from its initial
50 (lethal concentration to 50% level). (With kind permission from Springer Science+
Business Media: Narang A.S., and Desai, D.S. (2009) Pharmaceutical perspectives of cancer therapeutics. In Anticancer
Drug Development
https://t.me/med1917
8
Pharmaceutical Dosage Forms and Drug Delivery
critically analyzed by pharmacokineticists and toxicologists to differentiate compounds for prioritization
for advancement to the next stages of the drug discovery and development process.
1.2.2 Chemistry
Working closely with the discovery biology function, the discovery chemists provide an array of puri-
of this function. This function is involved in identifying chemical compounds that may have drug- like
properties and would respond in desirable ways (such as agonists or antagonists) on chosen enzymes,
receptors, or other targets. The drug design roles of these scientists frequently involve molecular modeling of the target receptor and in silico assessments of receptor binding of potential chemical structures
in the pharmaceutical developability assessment of new drug candidates to identify lead compounds
laboratories.
The discovery chemistry group works closely with analytical scientists to assess the purity and iden-
in
vitro models. Working coherently, discovery chemistry and discovery biology functions shortlist a few
candidates that enter preclinical assessment and optimization.
1.2.3 Pharmaceutics
Preclinical pharmaceutical development involves the optimization of potential drug candidates for druglike properties. Development of pharmaceuticals comprises a diverse group of scientists that assess
pharmaceutical dosage form developability through a series of assessments of solubility as a function
as temperature and humidity, and polymorph stability. This function also undertakes pharmacokinetic
and toxicokinetic assessments, in close collaboration with discovery biology colleagues, in one or more
tion and dose escalation clinical studies. Pharmaceutical development scientists work closely with all
functions involved in drug characterization and administration to address three key aspects of any new
drug: stability, bioavailability, and manufacturability.
Preclinical optimization, discovery chemistry, and discovery biology functions work together as
a team. They may identify several molecules that go through developability assessments and are
compared against each other for an array of desirable physicochemical and biological properties. The
of desirable attributes while avoiding undesirable ones. Often, one or more backup candidates are
candidate.
1.2.4 Animal Toxicology
As drug candidates advance toward FIH, formal toxicological evaluation in animal species is initiated.
These studies are guided by the compound characteristics, target therapeutic areas, and biological
receptors, as well as regulations that govern toxicity assessment in the animal species. Typically, toxicity
is studied in two species— one rodent and one non- rodent— with an intent to identify target organs and
organ systems that may exhibit toxicities at higher doses. These studies involve increasing drug dosing
and exposures in the animal species until toxicity is observed and carefully documented. These studies
https://t.me/med1917
Drug Discovery
FIGURE 1.4
MTD represents the max-
imum tolerated dose for the cytotoxic agent. (With kind permission from Springer Science+ Business Media: Narang A.S.,
and Desai, D.S. (2009) Pharmaceutical perspectives of cancer therapeutics. In Anticancer Drug Development
9
frequently combine plasma concentration assessment and biomarker studies if a biomarker has already
Toxicologists, working with diverse teams of professionals, are involved in the design and conduct of
animal studies, as well as in the interpretation of observations. The goal of toxicological assessments is to
strategy for potential toxicities during clinical studies. Toxicology studies seek to identify a maximum
Figure 1.4, these can be different for different compounds, based on
1.2.5 Clinical Pharmacology
Although no clinical studies are carried out with test candidates during drug discovery stages, clin-
screened. Aspects of drug discovery that can impact later stages of drug development, such as the rele-
route or frequency of administration), are critically assessed.
1.2.6 Analytical and Bioanalytical Sciences
Analytical and bioanalytical sciences form the core indispensable component of all functions involved in
drug discovery and development. Analyses of drug content, purity, and any changes during storage are
ensure their identity, purity, and quality. The analytical methodologies utilized to ensure these attributes
could be spectroscopic or wet analytical techniques such as titrations and chromatography. For example,
an oral solid dosage form must be tested for drug content, purity, water content, and drug release. A parenteral biologic drug product must be tested for drug content, purity by different methods (charge or sizebased separation techniques), receptor binding, bioactivity, pH, osmolality, and structure/ isoforms. In
addition, all the starting (raw) materials, intermediates for synthesis, and excipients used in formulations
must be rigorously tested to ensure these attributes and consistent quality across different batches. The
https://t.me/med1917
10
Pharmaceutical Dosage Forms and Drug Delivery
assurance of maintenance of all quality attributes of the drug substance and drug product over the duration of storage (stability testing) utilizes analytical testing at various time points under different storage
conditions (such as temperature, humidity, and light exposure). These functions are carried out by analytical scientists.
Bioanalytical sciences focus on analyses of drug content, metabolites, and any drug- related substances
(such as both the parent compound and prodrug in the case of prodrug administration) in both animal
often without rigorous separation— and the very low concentrations of the target compounds (often in
micromolar quantities). These analyses are typically carried out using highly sensitive analytical methods
such as high- performance or ultra- high- performance liquid chromatography (HPLC/ UPLC), followed by
tandem mass spectrometry (MS/ MS).
robust and reproducible performance across potentially multiple testing sites, laboratories, and personnel.
1.2.7 Regulatory Sciences
All drug products developed in modern biopharmaceutical settings are designed for global patient
populations. Government regulatory agencies that monitor and control (regulate) the commercialization and utilization of drug products vary by each country, as do their requirements for the testing and
commercializing of new drug products. As much harmonization of international regulations is being
advocated and implemented (e.g., by the International Council on Harmonisation [ICH]), each country
thus maintains its sovereign control over access to its markets and the requirements, which are often
subpopulation. The government regulatory agencies include, for example, the Federal Food and Drug
Administration (FDA) in the United States and the European Medicines Agency (EMA) for several coun-
To ensure access to new drug products to patient populations globally, regulatory scientists work in
the biopharmaceutical industry to proactively understand the regulations of the targeted markets. The
countries. With ever- evolving analytical methodologies, drug development paradigms, and accelerating
regulatory policy to evolve with the times.
1.3 Small- Versus Large- Molecule Paradigms
Based on their molecular size, drugs are typically divided into small and large in the contemporary
vernacular. Small- molecule drugs are typically low molecular weight compounds, such as acetaminophen and ibuprofen, with molecular weight typically being less than or equal to 400 Da. Large- molecule
different molecular, biopharmaceutical, and pharmacokinetic characteristics of compounds that fall in
-
lular or cell surface receptors. In contrast, while small hydrophobic drugs are able to permeate through
cell membranes and access intracellular targets. The drugs that fall between these two broad classes in
their properties can be a unique mix, with dominance of one or the other characteristic.
Although the overall requirements and goals for new drug development are similar between the small-
https://t.me/med1917
Drug Discovery
11
well as the pathway for these drug candidates. For the purpose of a general comparison, a typical small-
TABLE 1.1
Typical Differences in the Drug Discovery Process between Small- and Large- Molecule Drugs
Paradigm Property Small- Molecule Drugs Large- Molecule Drugs
Clinical or therapeutic Drug target They are both intracellular and
extracellular.
Target engagement They typically have very fast
receptor on- and- off rates.
This results in a close
temporal correlation of a
drug’s pharmacodynamics
and pharmacokinetics. Thus,
any desire for a reduction
in the dosing frequency of
a drug generally requires
the use of sustained- or
controlled- release drug
delivery technologies.
Early development Source of compounds Most small molecules are
synthetic in origin.
Animal toxicology studies They are usually carried out in
two species, one rodent and
one non-rodent.
Target engagement They have fast on/ fast off
rates, leading to drug
pharmacokinetics being
closely linked to drug
pharmacodynamics.
Typically, they are extracel-
lular or cell surface.
Antibodies can have very
slow off- rates on target
receptors, enabling longer
duration activity after
single dose administration.
This leads to a potential
disconnect between the
pharmacokinetics and
pharmacodynamics, since
receptor engagement can
be much longer than the
presence of drug in the
blood. Thus, the largemolecule drugs may have
once- a- week dosing,
without the need for
sustained- or controlledrelease drug delivery
technologies.
Usually, recombinant DNA
technology is utilized in cell
culture- based systems to
produce the large molecules.
They usually include a primate
species, such as monkeys,
since human sequences
for large- molecule drugs
generally elicit an immune
response in nonprimate
species.
They have fast on/ slow off
rates, leading to longer
target engagement and
action duration than the
dosing frequency.
(continued)
https://t.me/med1917
12
Pharmaceutical Dosage Forms and Drug Delivery
TABLE 1.1 (Continued)
Typical Differences in the Drug Discovery Process between Small- and Large- Molecule Drugs
Paradigm Property Small- Molecule Drugs Large- Molecule Drugs
Pharmaceutical
development
Interspecies scaling and
prediction of human dose
Molecular identity Small molecules have very
Key toxicological risks Off- target toxicity is
Physicochemical properties Most contemporary small-
Characterization techniques Robust and precise
Product presentation A solid dosage form for oral
They are usually based on
dose per unit body weight.
precise identity, down to the
atomic level.
usually the most common
observation with smallmolecule new chemical
entities (NCEs).
molecular NCEs are
hydrophobic, crystalline
compounds.
substances, metabolites, and
impurities with mechanism
of their formation guides
drug product development.
administration is the most
common or targeted product
presentation for most small
molecules.
They are usually based on
dose per unit body surface
area.
to characterize down to
the atomic level. Normal
levels of variation may
exist within a pool of
antibodies, for example,
without affecting stability
or activity. Multiple clones
are sometimes used during
early development, of
which one clone may later
be selected for commercial
development.
Off- target toxicities are
less likely with antibody
drugs. Immunogenicity
throughout drug product
development.
Most large- molecule drugs,
such as antibodies, are
hydrophilic drugs in
solution or amorphous
matrices with other
excipients.
Complex analytical methods
usually provide bulk
characterization rather
than exact identity at the
atomic level. Comparability
characterization between
batches used in clinical
studies is often used as
a criterion of uniformity
across a product’s clinical
development and life cycle.
A ready- to- use parenteral solu-
tion presentation is the most
common or targeted product
presentation for most largemolecule drugs.
https://t.me/med1917
Drug Discovery
FIGURE 1.5 A typical process train for a biologic- manufacturing operation showing cell culture in progressively increasing
through a series of operations yielding the target protein of interest. (From )
13
1.3.1 Preclinical Discovery and Toxicology Assessment
Large- molecule drugs are typically produced in cell culture systems by utilizing recombinant DNA
technology. In contrast, most small- molecule drugs are synthetic compounds produced using one of the
laboratory’s high- throughput manufacturing technologies. The synthetic chemistry utilized for the generation of small- molecule drugs is based on the principles of organic chemistry and reaction kinetics.
The utilization of cell culture for biological manufacturing is based on increasing the scale of cell culture in bioreactors in what is termed upstream manufacturing operations. In contrast, the downstream
manufacturing operations focus on purifying the target protein of interest (harvesting) from the cells
(Figure 1.5).
The preclinical toxicology assessment of antibody therapeutics is typically carried out in primates to
ensure relative tolerance to human sequences and closeness of animal physiology with the human physiology that is being targeted. In addition, more than one clone of the antibody may be tested in animal
species in certain cases in the early stages of development. In the case of small molecules, a very precise
crystalline form of a highly pure compound is usually tested in the animal species to allow scaling of the
observations to human administration.
1.3.2 Pharmaceutical Development
Small- and large- molecule drugs are inherently different in that the typical small molecules are hydrophobic, crystalline, well- characterized compounds. In contrast, the typical large molecules are hydrophilic species that exist in solution. A particular batch of an antibody may not be exactly uniform in
all the molecules that exist in the solution. Antibody product presentations are usually a solution,
whereas preferred product presentations for small molecules are typically in some solid- state dosage
form intended for oral administration. The ready- to- use solution presentations of antibodies are typ-
administration. In certain cases, to ensure maximum product stability, antibodies may be lyophilized
in the presence of excipients to present a solid dosage form in a sterile vial for reconstitution before
administration.
https://t.me/med1917
14
1.3.3 Clinical Development
Pharmaceutical Dosage Forms and Drug Delivery
bodies and small- molecule drugs. Small- molecule drugs typically have fast on/ off rates of target receptor
occupation. This results in their target activity being closely linked to the pharmacokinetics or the drug
concentration at the site of action. However, for the antibody therapeutics, the molecular target- off rates
are longer. This results in bioactivity being observed long after the drug has cleared the plasma. This can
result in a longer duration of action and less frequent need for repeat administration of the drug.
1.4 Contemporary Drug Discovery Case Studies
Drug discovery often happens through an unpredictable path that depends on deep expertise and close
collaboration among various disciplines. This section highlights some contemporary examples of drug
1.4.1 Statins
Pathway 1 to the discovery of this class of cholesterol- lowering drugs— a subject of 13 Nobel prizes—
1987 and was followed by the commercialization of semisynthetic (simvastatin and pravastatin) and syn-
The intertwined pathway to the discovery of these drugs starts with the discovery of cholesterol in
1784 from gallstones by the French chemist Francois Pelletier. The proof of the structure of cholesterol was established in the early twentieth century. Cholesterol was linked to atherosclerosis in 1910 by
plaques. This was followed by an experimental production of atherosclerosis in rabbits by the consump-
attacks in several large families in 1939. A genetic understanding of this phenomenon, now known as
Meanwhile, the complex 30- enzyme biochemistry of cholesterol’s synthesis and regulation of metabolism was elucidated in the 1950s. With the cholesterol synthetic pathway known and the connection to
human disease fairly plausible, several companies invested in research on molecules that would block
one or more of these steps through the synthesis of analogs of natural substrates. Some of these drugs,
were effective in reducing cholesterol levels but had serious side effects due to the accumulation of
inhibited the 3- hydroxy- 3- methylglutaryl coenzyme A (HMG CoA) reductase enzyme, citrinin, a key
enzyme in the cholesterol synthetic and metabolic regulatory pathway, was isolated from mold in 1971,
and the second compound, compactin, was isolated in 1972. The preclinical and clinical results with
compactin in the 1970s inspired compactin was also isolated from mold Penicillium citrinum chemists
tial suspicion of carcinogenicity of this class of compounds based on observations in dogs at high doses.
1.4.2 Immuno- Oncology
Immuno- oncology drugs started transforming the clinical treatment of cancer for a wide spectrum of
patients with the regulatory approval and commercialization of the following humanized recombinant
https://t.me/med1917
Drug Discovery
15
mAbs: ipilimumab (Yervoy®) by Medarex, Inc., and Bristol- Myers Squibb, Co. (BMS), targeting the
(Keytruda®) by Merck and nivolumab (Opdivo®) by BMS, both targeting the programmed cell death
cross- functional development but also the necessity of continuous evolution of drug discovery and devel-
• Immunotherapy agents are unique in that they do not directly attack the tumor but rather mobilize
the body’s innate and adaptive immunity. The contemporary clinical new cancer drug development
paradigm was based on the historical experience with chemotherapy drugs, whereby reduction in
tumor size was a measured endpoint and clinical success was measured in terms of progressionfree survival (PFS). An increase in tumor size during clinical trial over a relatively short period
of time, about two months, would typically lead to cessation of dosing with the experimental
drug. In the clinic, the immunotherapy drugs take longer to reach the time- to- event endpoint, with
delayed separation of survival curves. They also produced unique immune- related adverse effects
that were reversible and clinically manageable. The clinical success of ipilimumab was a result of
-
ical trial of another immunotherapy agent, the anti- CTLA4 mAb tremelimumab, which operated
with the chemotherapy paradigm of clinical development, failed to demarcate itself in the clinic to
gain regulatory approval.
• Host immunity, which is consequential to tumor treatment, was observed and experimented with
tumors in the nineteenth century. American surgeon William Coley observed clearance of cancer
on intratumoral injection of bacterial broth in some cases. The discovery of immune checkpoints to
tumor progression in the twentieth century, the cloning of the CTLA4 gene in 1987, and the demonstration of the value of immune checkpoint inhibitors in cancer treatment in mouse models in the
1990s provided impetus to the discovery of immune checkpoint modifying drugs.
• Antibodies for human use long suffered from immune rejection until progressive development
from polyclonality to monoclonality, and humanization through recombinant DNA technologies
made possible the development of therapeutic antibodies that would not elicit an immune response.
•
characterization of physicochemical properties and structural features. The number, type, and quantity of size and charge variants of these large- molecule drugs are often used for purity assessment
instead of exact chemical structures of compounds. The development paradigms deviate from the
conventional small- molecule drugs in utilizing comparability among clinical batches instead of
absolute chemical purity as a benchmark during drug development.
an entirely new class of drugs.
1.5 Artificial Intelligence (AI) in Drug Discovery
AI refers to the process by which machinery or computers simulate human intelligence. Typically, their
operation involves training on an enormous amount of pre- trained models, examining the data for trends
and relationships, and subsequently generating predictions based on these trends.
1.5.1 How Is AI Being Used in Drug Design?
As discussed in the earlier sections, current medicinal chemistry methods rely heavily on a hit- and- miss
approach and large- scale testing techniques. These methods make drug discovery a time- consuming and
Соседние файлы в папке Библиотека им академика М.И. Перельмана