Biomedical Engineering Reference
In-Depth Information
The following overview primarily focuses on CMC aspects
of ophthalmic formulations as a roadmap for developmental
scientists.
3 CMC of Ophthalmic Drug Substance (DS)
3.1 Ocular Drug
Candidate
Developability Criteria
A critical aspect in formulation development is to assess the
druggability of the molecule of interest. Physicochemical properties
such as solubility, lipophilicity, ionic charge, molecular size, and
polar surface area contribute to drug penetration through ocular
tissues [
5
-
9
]. Topically applied drugs that penetrate through the
cornea by passive diffusion usually proceed via either transcellular
or paracellular pathway. Partition coefficient (log P) of the drug
molecule has significant impact on drug penetration through cor-
nea. Compounds with log P between 1 and 3 showed maximum
penetration. Molecular weight and size of the drug molecule also
plays a role in penetration through different ocular tissues due to
different cutoff molecular weight of ocular tissues. For example,
molecular weight cutoff for cornea is at approximately 500 Da,
whereas for conjunctiva and sclera are approximately 40 and
150 kDa, respectively. Therefore, higher molecular weight mole-
cules would more likely be absorbed in conjunctiva and sclera
compared to cornea [
9
-
16
].
The ionization constant is an important parameter in ocular
absorption of acidic and basic drugs. Although both the ionizable
and the unionized forms of the drug may diffuse across ocular
membranes, it is predominantly the unionized form that deter-
mines the extent of ocular drug absorption (bioavailability). There-
fore, from a drruggability perspective, it is important to select
functional groups that maximize the unionized fraction at physio-
logical pH without compromising other attributes such as solubil-
ity, stability and potency. The salt form of the drug molecule can
also play a significant role in ocular bioavailability as well as comfort
after instillation.
A salt form of the drug may be considered to improve or
modify the solubility or aqueous dissolution rate. Identification
and selection of the best physical form from developability view-
point are critical to avoid issues at a later time. Physical form and
salt screening at this stage is an important step to identify the most
stable form that can go to the product development [
17
-
20
].
Therefore, judicious selection of salt form is essential.
In some cases prodrug approach may be considered in drug
candidate selection if there is a need to modulate certain physico-
chemical properties that cannot be resolved by physical methods.
Prodrugs can have substantially better bioavailability and solubility
characteristics than the parent compound. For example, prodrugs
of various prostaglandins showed substantial higher bioavailability
