Biomedical Engineering Reference
In-Depth Information
dosing at reasonable dose volumes and adequate DS (and excipient)
stability over the proposed shelf life and storage temperature.
If no pH provides adequate solubility to allow for small-dose
volumes, excipients that enhance solubility of the DS may allow
formulation of a solution that otherwise has insufficient solubility.
Solubility studies should be conducted with the solubilizing system
to determine if solubility enhancement is possible. If solubility
enhancement of the API is not possible and resulting dose volumes
will be too high, a solution formulation will not be possible. Like-
wise, if no pH provides adequate stability then a topical ocular
solution may not be possible.
Gel formulations can be of two types: one that gels upon instilla-
tion in the eye, and the other type that is a high-viscosity gel and
somewhat similar to ointment. Incorporation of stimuli-sensitive
polymers in solution dosage form can provide a formulation that
is a solution at ambient conditions. However, under appropriate
stimuli; it undergoes phase change giving a viscous gel. Stimuli
can be of various types such as temperature (poloxamer), ions
(gelrite, alginic acid and its derivatives), complexation (borate/
pH), pH (cellulose acetate phthalate), and lysozyme (xanthan
gum). These formulations have better dispensing characteristics
compared to highly viscous formulation. Moreover, they provide
longer residence time compared to solution. Two currently mar-
ketedproductsweredevelopedthatarebasedonthisapproach.
Timoptic XE
®
uses Gelrite (gellan gum), whereas timolol gel-
forming solution (TGFS) uses xanthan gum. As an alternative to
ointment, high-viscosity semisolid gel preparation of
an antiglaucoma drug was developed by Alcon. This product
(Pilopine HS
®
Gel) showed higher bioavailability compared to
solution [
19
,
20
].
4.1.2 Gel
With extensive use of high-throughput screening new chemical
entities with fewer drugs like properties are being identified.
These compounds, which fall in BCS class II and IV category,
have very poor aqueous solubility, and therefore cannot be formu-
lated as a solution dosage form. Other dosage form such as suspen-
sion was often explored to achieve a pharmaceutically acceptable
alternative. A suspension formulation is a coarse dispersion of insol-
uble solid particles of a drug substance in an aqueous vehicle
containing a suitable amount of surfactant, preservative, buffering,
and tonicity agents. The particle size of the suspension may vary
from nanometer to micrometer range depending on the situation.
Although development of suspension formulation is more complex
and challenging than solution, ophthalmic suspension formulations
can provide higher bioavailability by prolonging residence time of
formulations in precorneal area and therefore may be desirable.
In those cases suspensions satisfy two critical attributes: (1) the
4.1.3
Suspension
