Clinical Ophthalmology
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`Q OprmAccassFu||Te,<:Fu‘fictc
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`Dovepress
`upcll access to scicrltifit‘. and medical rcsc:|rc.ii
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`oR|G;NA[_ RESEARCH
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`Dose uniformity of topical corticosteroid
`preparations: difluprednate ophthalmic emulsion
`0.05% versus branded and generic prednisolone
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`acetate ophthalmic suspension I%
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`William Stringer‘
`Roy Bryant}
`Module 3 Pharma Services.
`St. Petersburg, Florida;
`2E"C°'“P335 Pharmaceutical
`Services. Norcross, Georgia, USA
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`_
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`Elggrjipg lgzlrlllizzfiwlnger
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`I25 5th St South, Suite 202K,
`5‘ Pet°'sb"r3' Fl‘ 3370 l‘ USA
`Tel +1 727 644 394:
`Email wstringer@module3pharma.com
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`Purpose: To compare the dose uniformity of difluprednate ophthalmic emulsion 0.05%
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`(Durezolii) with both branded and generic prednisolone acetate ophthalmic suspension 1%
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`under different simulated patient usage conditions.
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`Methods: Drug concentrations of difluprednate emulsion, branded prednisolone acetate
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`suspension (Pred Forte“) and generic prednisolone acetate suspension following three storage
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`conditions (upnght, then shaken; upright, not shaken; inverted, not shaken) were analyzed by
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`high performance liquid chromatography assay and results were reported as percent of declared
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`concentration. Two drops were dispensed every four hours four times daily.
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`Results: Regardless ofbottle orientation and shaking, all difluprednate emulsion concentrations
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`at each time point analyzed were within 15% of declared concentration. Both branded and
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`generic prednisolone acetate suspension concentrations varied substantially throughout the
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`study. For the bottle stored upright and not shaken, 46% of the branded concentrations were
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`not within 15% of declared concentration; for the bottle stored upright and shaken prior to use,
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`60% failed to meet this criterion. None ofthe branded concentrations from the inverted and not
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`shaken bottle was within 15% of declared concentration. Generic prednisolone concentrations
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`demonstrated the poorest dose unifonnity, with 96% of the concentrations from the inverted
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`and not shaken bottle not within 15% of declared concentration; 94% of the concentrations
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`from the upright and shaken bottle and 87% from the upright and not shaken bottle similarly
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`failed to meet this criterion.
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`Conclusions: Dose uniformity of Durezol emulsion was predictable in all simulated patient
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`usage conditions, whereas the drop concentrations of Pred Forte and generic prednisolone acetate
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`suspensions were highly variable throughout the study. Drop concentrations are more predictable
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`with Durezol emulsion than with either prednisolone acetate suspension.
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`Keywords: difluprednate, dose uniformity, emulsion, prednisolone acetate
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`Introduction
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`The dose uniformity of any ophthalmic medication is critically dependent on the
`homogeneity of the formulation. Most topical ophthalmic preparations containing
`lipid—solub1e and aqueous components are suspensions, in which the active drug is
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`suspended in an aqueous vehicle. Homogeneity is a concern for suspensions because
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`sedimentation and aggregation occurs upon storage of the medication.’ Because of a
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`suspensions tendency to settle over time, suspensions must be shaken prior to use in
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`order to redrsperse the drug throughout the contents ofthe bottle. The need for shaking
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`SENJU-MITSUBISHI 2090
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`Stringer and Bryant
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`Dovepress
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`suspension 1% (Fred Forte), and generic prednisolone acetate
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`ophthalmic suspension 1% (Falcon Pharmaceuticals Ltd) in
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`their originally manufactured containers were evaluated in
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`this study. Five mL of difluprednate was contained in a 5 mL
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`nominal volume bottle and 5 mL each ofbranded and generic
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`prednisolone acetate was contained in 10 mL bottles.
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`to achieve dose uniformity raises several potential concerns.
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`First, the type, intensity, and duration of shaking behavior
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`vary among people, and no studies have identified the shaking
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`characteristics required for optimal redispersibilityf Second,
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`in a study ofcorticosteroid preparations, Apt et al determined
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`that patient compliance with shaking instructions was only
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`37%? Third, even with “optimal” shaking, suspensions
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`may potentially have poor homogeneity due to formulation
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`issues with particle size, caking, and agglomeration. Each
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`of these issues may contribute to a lack of dose uniformity,
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`which produces the potential for decreased efficacy with
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`lower—than-expected dosing or increased safety concerns
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`with higher-than-expected dosing.
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`Technologic advances have now provided ophthalmic
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`preparations consisting ofoil in water emulsions, with the drug
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`molecule dissolved in the oil phase and aqueous-compatible
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`surfactants providing emulsion stability, obviating the need
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`for shal_<ing prior to use. Thus, emulsion formulations have
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`improved dose uniformity compared with suspensions.
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`Ophthalmic emulsions were first introduced nearly a decade
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`ago, with the commercial availability oftwo dry eye products,
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`ie, over—the—counter (OTC) Refresh Endurali (Allergan, Inc.,
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`Irvine, CA) and prescription formula Restasis® (Allergan,
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`Inc.). Since that time, another artificial tear product with a
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`lipid emulsion formulation, the OTC Soothe® XP Emollient
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`eye drops (Bausch and Lomb, Rochester, NY), has been
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`introduced. Difiuprednate ophthalmic emulsion 0.05%
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`(Durezol®, Alcon Laboratories, Inc., Fort Worth, TX) is the
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`only other ophthalmic lipid emulsion commercially available
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`in the US. This corticosteroid was approved by the US Food
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`and Drug Administration in 2008 for tl1e_treatment of pain
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`and inflammation associated with ocular surgery.‘
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`In order to verify the expected dose uniformity of the
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`difiuprednate emulsion, the concentration of difiuprednate
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`was measured under varying simulated patient conditions.
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`It was also compared with two active controls, branded
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`prednisolone acetate ophthalmic suspension 1% (Pred Forte“;
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`Allergan, Inc., Irvine, CA), one of the most commonly
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`used formulations of ophthalmic prednisolone in the US,
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`and generic prednisolone acetate ophthalmic suspension
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`1%. Prednisolone acetate is indicated for the treatment of
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`steroid—responsive inflammation of the palpebral and bulbar
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`conjunctiva, cornea, and anterior segment of the globe.5
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`Methods
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`Test articles
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`Commercially available difluprednate ophthalmic emulsion
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`0.05% (Durezol), branded prednisolone acetate ophthalmic
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`Table I Study design evaluating the effect on ophthalmic steroid
`dose uniformity of varying simulated patient usage conditions,
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`specifically bottle storage orientation and shaking
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` Test article Storage orientation Shaking
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`Pred Forte®
`Upright
`No
`Upright
`_ Yes
`Inverted
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`Upright
`No
`Upright
`Yes
`Inverted
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`Upright
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`Upright
`Yes
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`Inverted No
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`Dure2o|*'°
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`Generic prednisolone
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`Study procedure
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`This study evaluated the effects of bottle orientation during
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`storage and the presence or absence of shaking on the
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`uniformity of dispensed drops. Three bottles of each test
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`article were stored in a defined orientation for l2 hours, ie,
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`two bottles of each test article were stored upright and one
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`each was stored inverted. Following storage, one of the two
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`upright bottles of each test article was shaken for five seconds
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`using a wri st-action mechanical shaker at six cycles/sec, with
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`an amplitude of 0.7 cm (Table 1). After shaking the two test
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`article bottles, two drops of all nine bottles were dispensed
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`into a tared glass vial. The drug concentration of the drops
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`was analyzed by high performance liquid chromatography
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`(HPLC), and results were reported as percent of declared
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`concentration. The assay for determining difluprednate
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`concentration was a specific, stabi1ity—indicating, normal-
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`phase HPLC method. The procedure used gradient elution
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`and ultraviolet detection. The assay method in the monograph
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`for prednisolone acetate ophthalmic suspension in the US
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`Phannacopeia was used for determining prednisolone acetate
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`concentration. A slight modification in sample preparation
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`was made and validated to account for the small sample
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`size used in this study. In all cases, HPLC instrumentation
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`fi'om Waters Corporation (Milford, MA) was utilized. The
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`dispensing protocol was repeated three times at four—l1our
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`intervals each day to simulate four times daily patient dosing.
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`On days 0, 5, l0, and 15, the drug concentrations from each
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`ofthe four time points were analyzed. On the other days, data
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`from the first and fourth time points were analyzed.
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`Dovepress
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`Results
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`Dose uniformity of difluprednate and prednisolone
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`When upright bottles were shaken slowly for five seconds
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`prior to dispensing, difluprednate emulsion concentrations
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`were consistently near 100% of declared concentration, with
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`the range of concentrations varying 8.1% (Figure 2). The
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`branded prednisolone acetate suspension concentrations were
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`primarily higher than 100% ofthe declared concentration, with
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`the initial concentration 312.0% of declared concentration;
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`only two data points were below 100%, but the lowest
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`reached only 51.0% of declared concentration. In contrast,
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`generic prednisolone acetate concentrations were primarily
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`below 100% through day 14, with most time points below
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`70% of declared concentration. From day 15 and beyond,
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`only three time points were below 100%, with concentra-
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`tions on the final two days spiking to 504.6% of declared
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`concentration.
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`Figure 3 illustrates that the inverted bottle of difluprednate
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`emulsion, not shaken prior to dispensing, approximated
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`declared concentration throughout the study, with a high
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`of 103.5% and a low of 96.2%. The branded prednisolone
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`acetate suspension produced concentrations above the
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`declared concentration (up to 201.4%) for the first two days,
`after which concentrations dropped below 100%, with values
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`ranging from 80.1% to 10.7% of declared concentration.
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`The generic prednisolone acetate suspension followed a
`similar pattern, with most time points in the first three days
`
`far above 100% of declared concentration, afier which they
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`dropped far below 100%. None of the time points for the
`
`
`- - 0 - - Pred Forte®
`—I— Durezol®
`_‘_
`Generic prednisolone
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`The dose uniformity of all three steroid preparations after
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`upright bottle storage and no shaking prior to dispensing is
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`shown in Figure 1. The percentage of declared concentration
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`ofthe difiuprednate emulsion was near 100% at 97.6% (40/41)
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`of the data points for this test condition. The percentage of
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`declaied concentration of the branded prednisolone acetate
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`suspension was more variable over time, ranging from 20.5%
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`to 181.4%. At day 0, prednisolone concentrations were
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`greater than the declared concentration, but then ‘dropped
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`below declared concentration and did not consistently reach
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`concentrations greater than 100% until day 5. Concentrations
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`remained primarily above 100% through day 7, then were near
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`or below 100% through day 1 1, at which time concentrations
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`remained consistently above 100% until the bottle was
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`emptied on day 14. On days 0, 5 and 10, when data from
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`all four time points were analyzed, branded prednisolone
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`concentrations were lowest at the first time point and peaked
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`at the third or fourth time point; each of these data series
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`showed substantial intraday variability, with day 5 containing
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`both the lowest (20.5%) and the highest (181.4%) concentra-
`tions. The generic prednisolone acetate concentrations were
`
`the most varied of all the steroid preparations, ranging from
`
`7.0% to 231.5% of declared concentration. Most time points
`
`prior to day 13 were less than 100% of declared concentration,
`
`whereas each time point at day 14 and beyond was greater
`than 100%, ranging from 123.6% to 231.5%.
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`9 1
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`0
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`1
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`3
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`4
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`5
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`6
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`7
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`8
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`0
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`11
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`12
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`13
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`14
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`15
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`16
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`17
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`18
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`Percentofdeclaredconcentration
`
`Figure I Dose uniformity of difluprednate emulsion and prednisolone acetate suspensions with upright storage orientation and no shaking of CGnl:El1l'5.
`
`Time (days)
`
`

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`Dovepress
`Stringer and Bryant
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`C 500 ----------
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`.3 500
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`0 400
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`--c-- Preci Forte®
`—I— Durezo|®
`-— -A~ Generic prednisolone
`—
`—
`
`-
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`g 300
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`E 200
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`‘E 100
`E 0
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`0
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`1
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`2
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`3
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`5
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`6
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`T
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`8
`
`10
`
`11
`
`12
`
`13
`
`14
`
`_
`
`I
`
`
`m—
`i
`
`
`1
`iTim
`
`
`r
`
`r
`l
`
`,'
`i‘
`," ‘U1
`
`
`
`
`1:.
`F
`
`‘i
`
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`
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`\
`
`\ 2
`‘
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`16
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`I
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`I
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`18
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`19
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`" *
`.0 «O-‘,1-9
`” ’
`
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`
`I
`\
`\ IA‘,-‘Ki
`Y
`
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`
`15
`
`
`1
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`17
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`
`As shown in Table 2, difiuprednate emulsion concentration
`
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`
`
`remained within 15% ofdeclared concentration at each time
`point analyzed and under all conditions tested. In contrast,
`
`branded prednisolone acetate suspension concentrations
`met this criterion for 54% of the upright and not shaken
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`
`ii
`5i
`_n. _ .3. _,¢.,..c.,...
`i
`m
`‘P. _...’'f
`’ *
`A
`h
`v
`H
`‘
`
`
`
`
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`
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`A R , \ ‘A \
`i
`_‘f
`‘
`I
`\.‘
`.'
`‘K I §,*\‘,""“
`A‘ /A__‘’
`\‘/ VI
`\‘
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`4
`9
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`Time (days)
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`Figure 2 Dose uniformity of difluprednace emulsion and prednisolone acetate suspensions with uprigl-it storage orientation after 5 seconds of shaking of contents.
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`Generic prednisolone acetate concentrations were within
`final 10 days of the experiment reached greater than 20% of
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`declared concentration.
`15% of declared concentration for only 4%—l3% ofthe time
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`points, depending on the condition tested. Measurement of
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`drug concentrations within 10% of declared concentration
`remained nearly identical for difluprednate emulsion, with
`
`only one datum point from the upright and not shaken bottle
`
`
`outside this range (98% of the data points were within
`
`10% of declared concentration). One hundred percent of
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`concentrations analyzed from the other two diflupred-
`nate bottles were within 10% of declared concentration.
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`Pred romeo
`--—I-- Durezo|®
`— -1-— Generic prednisolene
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`time points and 40% of the upright and shaken time points.
`None of the prednisolone acetate concentrations from the
`
`inverted bottle was within 15% of declared concentration.
`
`800
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`700
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`600
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`500
`
`concentration
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`400
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`300
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`200
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`100
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`10
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`11
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`12
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`13
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`14
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`15
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`16
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`17
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`18
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`19
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`20
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`Time (clays)
`
`Figure 3 Dose uniformity of difluprednate emulsion and prednisolone acemte suspensions with inverted storage orientation and no shaking of contents.
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`Usage condition
`
`Pred Forte”
`
`
`Durezolg
`
`
`Table 2 Percentage of data points within l5% of declared
`concentration
`
`
`
`Generic
`
`
`prednisolone
`
`
`
`I395
`6%
`4%
`
`Upright, not shaken
`Upright. shaken
`Inverted. not shaken
`
`54%
`40%
`0%
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`100%
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`l00%
`I 00%
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`Discussion
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`Dose uniformity of difluprednate and prednisolone
`Dovepress
`
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`difluprednate remained near 100% of declared concentration
`
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`with little variability. Only one datum point was not within
`
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`10% of declared concentration, and this was likely an outlier,
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`as evidenced by the fact that the other 40 data points from this
`
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`testing condition were within 4.2% ofdeclared concentration.
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`These results were reproduced in multiple additional runs
`
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`conducted under similar conditions using other difluprednate
`
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`lots (data not shown). In contrast, both branded and generic
`
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`prednisolone acetate suspensions varied substantially in all
`
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`three simulated patient usage conditions, with none of them
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`showing consistent approximation of declared concentration.
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`Concentrations from the branded prednisolone acetate bottle
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`stored upright with no shaking prior to use varied consider-
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`ably throughout the study, alternating between very high
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`and low concentrations. Even prednisolone acetate drops
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`dispensed on the same day differed dramatically, with the
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`largest variability exhibited on day 5, ie, 20.5% at the first
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`time point compared with 181.4% at the last time point.
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`Concentrations from the generic prednisolone acetate bottles
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`demonstrated the largest variability, ranging from 224.5%
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`for the upright and not shaken bottle to 720.8% for the
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`inverted bottle.
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`The dose uniformity of difluprednate can be attributed to
`
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`its emulsion formulation. Because the concentration of drug
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`throughout the bottle is consistent, it is not subject to bottle
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`storage orientation. Moreover, difluprednate emulsion does
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`not require shaking of the contents in order to resuspend
`
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`the drug within its vehicle. In contrast, prednisolone acetate
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`is required to be shaken prior to use because of its poor
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`homogeneity upon storage? In the current study, however,
`
`
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`shaking the prednisolone acetate bottles, either branded or
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`generic, prior to dispensing did little to improve the dose
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`uniformity, as shown in Figure 2. In this data set, only 40%
`
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`of the time points from the branded prednisolone and 6%
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`from the generic prednisolone had concentrations within
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`15% of declared concentration. Of interest is the dilference
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`in the effect ofshaking between the branded prednisolone and
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`generic prednisolone products. Overall, very low concentra-
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`tions in the generic prednisolone bottle were observed through
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`day 15, while the branded product exhibited overall higher
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`concentrations with much less variability. In most cases, a
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`lower dispensed drug concentration of generic prednisolone
`was observed on the first dose of each day compared with
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`Branded prednisolone acetate concentrations within 10%
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`0% for the inverted bottle. Generic prednisolone acetate
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`concentrations within 10% of declared concentration were
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`and shaken bottle, and 0% for the inverted bottle.
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`This study compared two corticosteroid suspensions with
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`a corticosteroid formulated in an emulsion. Suspensions
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`have a well characterized tendency to settle, agglomerate,
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`homogeneity and allow potential dosing inconsistencies.
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`One approach to reduce these dosing errors is to shake the
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`contents prior to use in an attempt to redisperse the drug;
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`another approach is to formulate the drug as an emulsion
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`rather than a suspension. Emulsions are produced by
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`dissolving the active drug molecule within the oil phase of
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`acts as a stabilizer, preventing the oil droplets from coalescing
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`and allowing aqueous compatibility.“ Thus, emulsions create
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`homogeneous dispersions that are not subject to sedimenta-
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`tion or aggregation. Empirically, emulsions have been shown
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`as demonstrated by a pharmacokinetic study conducted in
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`rabbits, in which a corticosteroid emulsion showed a 4. 1 —fold
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`higher area under the curve (AUC) in aqueous humor and a
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`formulated as a suspension.’ A similar relationship between
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`emulsion and suspension formulations was reported by
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`Inoue et al in another pharmacokinetic animal study, in which
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`the corticosteroid emulsion produced an aqueous humor
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`concentration that was 40% higher than the corticosteroid
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`suspension?
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`The current study illustrates the predictability in dose
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`uniformity of difluprednate ophthalmic emulsion 0.05%
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`compared with prednisolone acetate suspension 1%. Regard-
`less ofthe simulated patient usage conditions (upright versus
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`inverted storage, shaking prior to use versus no shaking),
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`the final dose of each day. This suggests that with enough
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`agitation, the generic prednisolone will eventually disperse
`uniformly in the bottle. It is possible that the type, intensity,
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`or duration ofthe mechanical shaking performed in this study
`was not adequate to resuspend the drug fully, but this cannot
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`,au’
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`Dovepress
`Stringer and Bryant
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`be evaluated because no studies have been published that
`Acknowledgment
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`determine optimal shaking parameters. Nonetheless, these
`Jennifer Klem, PhD provided medical writing assistance.
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`results suggest that the effect of shaking on the resuspension
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`Disclosure
`of prednisolone acetate should be fiirther evaluated.
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`WS was an employee of Sirion Therapeutics, Inc., during the
`The inverted bottles of prednisolone acetate, which
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`generation of these data. Sirion Therapeutics sold the rights
`were not shaken prior to use, demonstrated the greatest
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`to market difluprednate ophthalmic emulsion 0.05% to Alcon
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`concentration variability of all suspension bottles tested.
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`Laboratories in March 2010. Roy Bryant is COO of Encom-
`Initially, both the branded and generic prednisolone acetate
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`concentrations from the inverted bottles were greater than the
`pass Pharmaceutical Services, lnc, who was paid a consulting
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`fee by Sirion Therapeutics, Inc. to perform this study. No
`declared concentration. However, by day 3, concentrations
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`other conflicts of interest existed for either author.
`rapidly dropped below declared concentration, not reaching
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`above 50% of declared concentration for the final l0 days
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`of either suspension. This pattern of dose variability
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`(increased concentrations at early time points followed by
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`low concentrations later) is consistent with settling occurring
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`within the tip ofthe bottle, allowing for highly concentrated
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`drops to be dispensed initially until the majority of the drug
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`has been depleted from the bottle, resulting in little drug
`dispensed at later time points. The discrepancy between the‘
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`dose variability of prednisolone acetate suspension in this
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`study and the dose uniformity exhibited by difluprednate
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`emulsion suggests that the clinical use of difluprednate may
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`' produce more predictable efficacy and safety.
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`Conclusion
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`The dose uniformity of difluprednate ophthalmic emulsion
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`0.05% was highly predictable in all simulated patient usage
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`References
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`l. Diestelhorst M, Kwon KA, Suverkrup R. Dose uniformity of ophthalmic
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`suspensions. J Caramel‘ Refract Snrg. l998;24(5):6'.o‘2—677.
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`2. Deicke A, Suverkrup R. Dose uniformity and redispersibility of phar-
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`maceutical suspensions. l: Quantification and mechanical modelling
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`of human shaking behaviour. Eur J Pharm Biopfmrm.
`l999;48(3):
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`225-232.
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`3. Apt L, Henrick A, Silverman LM. Patient compliance with use of
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`topical ophthalmic corticosteroid suspensions. Am J Opfttlzalmol. E979;
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`87(2):2l0—2l4.
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`4. Durezol“ [Package insert]. Tampa FL. Sirion Therapuetics, Inc.; 2008.
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`5. Pred Forte“ [Package insert]. Irvine CA. Allergan, Inc.; 2004.
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`6. Jamal KN, Callanan DG. The role of difluprednate ophthalmic emulsion
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`in clinical practice. Clin Oplarltalmal. 2009;3:38i—390.
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`7. Yamaguchi M, Yasueda S, Isowaki A, et al. Formulation of an
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`ophthalmic lipid emulsion containing an anti-inflammatory steroidal
`drug, difluprednate. Int! Phat-m. 2005;30l(l—2):l2l—l28.
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`8. Inoue J, Yamaguchi M, Sakaki H, et al. Preclinical pharmacokinetics
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`of difluprednate ophthalmic emulsion. 2007 Annual Meeting of the
`Association for Research in Vision and Ophthalmology. Foster 2651.
`Fort Lauderclale, Florida, USA, 2007 May 6-10.
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`conditions, confirming that this product is not dependent
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`on bottle shaking. The drop concentration of both branded
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`and generic prednisolone acetate suspension 1% was
`highly variable over the duration of the study and across
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`patient usage conditions. Shaking did not improve the dose
`uniformity of these products.
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`Clinical Ciphthalmology
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`Pubiish your work in this journal
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`Clinicai Ophthalmology is an international, peer-reviewed journal
`covering all subspecialties within ophthalmology. Key topics include:
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