Quality control parameters for suspensions include particle size, particle size distribution, particle shape, zeta-potential, viscosity, physicochemical stability, particle settling rates, sedimentation volume, degree of flocculation, stability with respect to time/temperature/relative humidity, syringeability, and endotoxin content. ICH and FDA guidelines should be followed in developing suspension formulations.

18.3.2.2  In Situ Forming Suspensions, Selection of Drug Form for Suspension, and Polymeric Microparticle Suspension

In situ forming suspensions and selection of drug form:  An interesting method of treating the diseases is the use of in situ suspension formulation (Pedersen et al. 2008). A brief description of these formulations is worth mentioning, at this juncture. Poor physical stability and sterilization issues confound the manufacturing of microparticulate-based injectables for posterior segment. Advances in the research field are focused on overcoming these problems by designing a liquid preformulation which upon injection forms a particulate depot in contact with the tissue fluids. For developing such in situ depot-forming formulations, different excipients are used which might possess varying toxicologic potential depending on the site of administration. Also, injection into aqueous body fluid compartments might minimize the local toxic effects of hydrophilic excipients by dilution and rapid clearance into the systemic circulation. In these in situ suspension forms, the drugs will precipitate and form suspensions, which are in a physical form similar to that used in the preformed aqueous suspensions. Further, suspensions of highly soluble salt form of drugs can be prepared by converting them to less-soluble base form. Using this approach, (Durairaj et al. 2009) a suspension dosage form was prepared with less soluble diclofenac acid obtained by acidification of sodium salt of diclofenac. Following intravitreal injection, diclofenac acid prolonged the vitreous half-life and sustained delivery to the retinal tissues when compared with diclofenac sodium solution. In this study, rabbit vitreal half-life increased from 2.9 hours for diclofenac sodium to 24 days with diclofenac acid suspension.

In situ forming suspensions offer the advantage of solution drug formulation and the associated simple manufacturing process including sterilization by filtration. Following in vivo administration as a solution, these dosage forms transform to suspensions at the site of administration. In situ forming suspensions have been developed for transscleral delivery of drugs such as rapamycin, tacrolimus, everolimus, and pimecrolimus (2, 3). In these formulations, drug molecules (e.g., 2% w/w for rapamycin) were dissolved in solvents like ethanol (e.g., 4% w/w) and polyethylene glycol 400 (e.g., 94% w/w) and injected subconjunctivally or intravitreally for sustained drug delivery. A drug depot is formed as the drug molecule precipitates due to diffusion and dilution of the solvent. Characterization of such formulations included (a) in vitro assessment of sclera permeability, (b) rate and extent of drug release from the depot formed after solvent removal, (c) local tolerability of the formulation at the site of injection, (d) accelerated and long-term stability of drug in the solvent matrix, (e) viscosity of the formulation for ease of injection, (f) isotonicity,

(g) sterility, and (h) uniformity of each injection removed from a multi-dose vial. A variation of this technology is to use slow-release polymers along with drug in a solvent system.

In situ forming suspensions can also be prepared by exploiting changes in pH of the surrounding environment. For a formulation of a VEGFR-2 inhibitor, PF337210, Khamphavong et al. (2010) prepared a solution of the drug at pH 3.3, which is below its pKa. When injected into the vitreous humor, the drug precipitated as the pH of the surrounding environment increased toward physiological pH. Gupta et al. (2010) prepared an in situ forming gel-suspension of forskolin, wherein the drug was suspended in a solution of polycarbophil and poloxamer 407 mixture at pH 4.4. As the pH of the formulation increased toward physiological pH, a liquid to gel transition occurred, trapping the suspended drug particles in the gel. These formulations were characterized for rheological changes with (a) change in pH, (b) isotonicity of the liquid and gel forms, (c) sterility, (d) in vitro release, (e) extent of drug precipitation, (f) dose recovery from the gel, and (g) accelerated and long-term stability studies of formulation in liquid and gel forms.

Polymeric microparticles:  Microparticles prepared using biodegradable polyester polymers are being explored for their use in sustaining drug delivery following intravitreal injection. Triamcinolone acetonide (TA) microspheres were investigated for the treatment of diabetic macular edema in patients (Lavinsky et al. 2008). A single microsphere injection equivalent to 1 mg TA was able to reduce central macular thickness and improve visual acuity for up to 12 months (Cardillo et al. 2006). Microparticle suspensions have also been prepared for another steroid drug, dexamethasone (Barcia et al. 2009), wherein 20–53 mm microparticles were injected intravitreally into a rabbit eye using a 25-guage needle.

In an effort to develop a sustained microparticle delivery system of TG0054 for neovascular disorders, Shelke et al. (2011) prepared poly(L-lactide) microparticles of 7.6 mm diameter. The microparticles were injected into rabbit eyes using a 27-guage needle. A single microparticle injection was able to sustain back of the eye drug delivery for at least 3 months. The microparticle suspension was prepared in sterile phosphate buffer (PBS) saline pH 7.4, with an osmolality of ~300 mOsm/kg. Microparticle suspensions were characterized for (a) particle size of the suspension,

(b) syringeability, and (c) residual organic solvent content. Microparticle preparations such as this require gamma irradiation for end-stage sterilization. Further, they can be supplied as dry, lyophilized powder along with a reconstituting solution for mixing just prior to injection.

18.3.2.3  Clinical Studies on Safety

The data on safety of back of the eye suspension formulations is slowly accumulating. There are more than 30 peer-reviewed publications that evaluated triamcinolone acetonide for the treatment of ophthalmic diseases and conditions, primarily based on Kenalog-40. None of the studies met all of the FDA’s criteria for adequate and well-controlled study design with adequate duration of assessment (³1 year).