2 - Principles of Pharmaceutical Preformulation and Formulation

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Principles of pharmaceutical pre-

formulation and formulation
Formulation: technique and approaches that have to be set up to generate the
medicine from the drug.
Before of that, we have to find out the main feature of the drug that can be
generated. These studies are important because it can reveal the risks during the
formulation.
These studies are mostly carried out by the “inventors” or discovers of the drug.
Aim of the pharmaceutical pre-formulation
For example: very thin powder can flow very easily in the pipes, or if the powder has
porosity, dictated by density. For protein the information is more complex:
- pI
- Melting point
- Structure
- Etc…
In terms of PK ADME, pre-formulation aims to predict, we can study in vitro the
metabolism: if we want, we can adopt a method of pool of enzymes present in the
liver, or the use of microsome, we add the drug and with an analytical tool (LC-mass)
and with this we can understand if the drug has been degraded.
When we refer to dosage form, we have some peculiar properties:
- Shape
- Texture (matrix type)
- Stability (usually two years)
- Availability: fraction of drug that go into solution
- Bioavailability: fraction of the drug/dose that reaches the bloodstream
- Compliance: dosage regimen, and acceptability by patient
- Therapeutic efficacy
The first two features describe the type of dosage form.
Factors affecting the therapeutic efficacy of a drug

- Physic-chemical and biological properties of the drug
o Activity power
o Specificity of action
o Pharmacodynamics
o Legislative class of therapeutic drug: the drug will be labelled within a
legislative therapeutic class according to Ministry of Health
o Therapeutic index: ration between the dose that dives the minimal
biological activity and the dose that start to generate toxic effects
o Availability, pharmacokinetics (ADME)
o Stability
o Self-targeting: some drugs can reach easily their target. For example,
alendronate sodium table osteoporosis agents specifically accumulate in
the bone, helping it in regenerating, or benzodiazepines, that can easily
reach the brain
- Route of administration: it accords to the previous properties, and it’s necessary
for an effective therapeutic outcome
o Structure and composition of biological membrane to be permeated
o Physiological and pathological conditions of the administration site
 Pathologies can affect administration
o Absorption site surface: since we have a barrier and we have to cross it:
the larger the barrier, the bigger the absorption (intestine area = 250-
300m2)
o Site of activity: systemic and local, the first one is referred to the blood
circulation, the second one is referred to a specific localized area
o Effect of local conditions at the site of administration
o Impact on the processes of excretion and clearance: in some barriers we
have some mechanisms of excretion, for example given by the presence
of P-glycoprotein
Administration routes
Three main classifications:
- Enteral: they enter in contact with the external environment
o Sublingual: used to treat diseases that need very quick on-set
o Oral
o Rectal
- Parenteral
o Intravascular
o Intramuscular
o Cutaneous
- Others
o Organ
o Intracavitary
o Transcutaneous
Transmucosal
- Pharmaceutical dosage form
o The stability of the drug depends on this (protein or antibody solutions)
o Availability
o Bioavailability
o Stability at the site of administration before absorption
o Controls where the drug is absorbed
o Can promote or delay absorption
o Can target to specific site of action
o Favor patient compliance
Criteria for the selection of pharmaceutical dosage form

- Administration route
- Physic-chemical features of the drug. In some cases, certain dosage forms are
excluded
- Biopharmaceutical features of the drug. When features are poor, the
bioavailability can be “modulated” by choosing suitable dosage forms. A
biopharmaceutical feature could be the permeability of the drug, so we prepare
an in vitro system similar to the in vivo one, or also the logP
- Required onset of the drug effect
- Treatment type
- Therapeutic window: this is important since it defines the minimum
concentration for the therapeutic effects and the minimum concentration for
toxic ones
0210
Protein delivery
New protein drug delivery methods are expected to further increase patient
compliance and expand its applications into several disease therapeutic markets. The
biotech molecules are the most difficult to administer.
Brief history of protein delivery:
- 1982: recombinant human insulin was the first recombinant protein to be
licensed
- 2005: >90 recombinant proteins
- 2009: first biosimilar ever approved in Japan → Human growth hormone
- 2023: >400 types of licensed proteins drugs are already commercialized and
nearly 1300 are undergoing clinical trials
Therapeutic applications of proteins

- Anemia (induced by chemotherapy)
- Autoimmune diseases
- Cancer and Multiple sclerosis
- Arthritis
- Psoriasis
- Cardiology
- Diabetes (insulin and new polypeptides)
- Hormone replacement
- Hepatitis Metabolic disorders
- Reproductive medicine
Biosimilar medicine
A biosimilar medicine is a medicine which is like a biological medicine that has already
been authorized (the ‘biological reference medicine’).
FDA definition: Biosimilar or Biosimilarity means: that the biological product is highly
similar to the reference product notwithstanding minor differences in clinically inactive
components; and there are no clinically meaningful differences between the biological
product and the reference product in terms of safety, purity, and potency of the
product.
When the generic drugs have “biotechnological” identity, we call them biosimilars:
- It’s impossible to guarantee the exact chemical and structural identity of the
originator: tools for their production are not available from the market because
generally they belong uniquely to the producer who put the drug on the market
- There’s not absolute equivalence
Features:
- Biosimilars and biological reference medicines are used at the same dose to
treat the same disease
- Name, appearance and packaging of a biosimilar differ to the originator
The general requirements for biosimilars are:
- Immunogenicity: not required by general drugs
- PK and PD: they have to be the same. The PD has not to be the same for
general drugs
The Public Health Service Act requires that a 351(k), that is the licensure pathway
which permits a biosimilar biological product to be licensed, application include,
among other things, information demonstrating biosimilarity based upon data derived
from:
- Analytical studies
- Animal studies
- Clinical study or studies
o Immunology assessments
o PD or PK assessments
o Others
These are enough to demonstrate the:
o Safety
o Purity
o Potency
EMA regulation for approval of biosimilars
For the authorization of a new biosimilar, comparing them to the originators,
assessments have to be done for:
- Comparative quality studies
o Analytical: physical + chemical properties
o Functional: biological/pharmacological activity
- Comparative non-clinical studies
o Pharmacodynamic
o Toxicology
- Comparative clinical studies
o Pharmacokinetic/pharmacodynamic
Features of therapeutic proteins

- Size
o 100-500 times larger than classic drugs
o Cannot be completely characterized by physico-chemical methods
- Structural heterogeneity
- Immunogenicity
- Relatively high biological activity
- Relatively unstable
The factors that affect therapeutic activity of proteins are:
- The gene and the promoter used for cell transfection
- Host cell transfected to produce the protein
- Culture conditions
- Purification
- Formulation
- Storage and handling
- Unknown factors

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2409

Principles of pharmaceutical pre-

Aim of the pharmaceutical pre-formulation

Factors affecting the therapeutic efficacy of a drug

Criteria for the selection of pharmaceutical dosage form

Therapeutic applications of proteins

Features of therapeutic proteins

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