Acta Ophthalmologica 2017 The physical properties of generic latanoprost ophthalmic solutions are not identical Miriam Kolko1,2 and Peter Koch Jensen1 1Department of Ophthalmology, Zealand University Hospital, Roskilde, Denmark 2Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark ABSTRACT. Purpose: To compare various characteristics of Xalatanâ and five generic the adjuvant solution (Cantor 1997; latanoprost ophthalmic solutions. Chambers 2012; Zore et al. 2013). This may affect factors such as pH, viscosity Methods: Drop size, volume, pH values, buffer capacity, viscosity, hardness of and buffer capacity and in turn phar- bottles and costs were determined. Drop sizes were measured in triplicates by macokinetics, bioavailability and tolera- micropipettes, and the number of drops counted in three separate bottles of each bility (Brechue & Maren 1993; Cantor generic product was determined. pH values were measured in triplicates by a 1997). Moreover, no regulations con- calibrated pH meter. Buffer capacity was exploited by titrating known quantities cerning bottle material, shape and col- of strong base into 2.5 ml of each brand and interpolated to neutral pH. ours exist. As patients with glaucoma Kinematic viscosity was determined by linear regression of timed gravity flow generally are elderly, a great proportion from a vertical syringe through a 21-G cannula. The hardness of the bottles was will suffer from rheumatic diseases and evaluated by gradually increasing tension on a hook placed around each bottle hence be dependent on manageable bot- until a drop was expelled reading the tension on an attached spring scale. tles. In addition, change in colour and Results: Drop sizes and the number of drops in the bottles varied significantly shape may confuse patients and thereby between the generic drugs. The control value of pH in the brand version influence their adherence. Over all, it is (Xalatanâ) was markedly lower compared to the generic latanoprost products. questionable whether the lack of require- Titration of Xalatanâ to neutrality required substantially more NaOH compared ments before introduction of new copy to the generic latanoprost products. Finally, the viscosity revealed a significant products is short-sighted. In 2011, the patent on the most com- variability between brands. Remarkable differences were found in bottle shapes, Ò mon drug against glaucoma, Xalatan bottle hardness and costs of the latanoprost generics. Conclusion: (Pfizer, Ballerup, Denmark), expired Generic latanoprost eye drops should not be considered identical to the (Stein et al. 2008; Kolko et al. 2015). original brand version as regards to drop size, volumes, pH values, buffer capacity, Since then, a number of copy products viscosity, hardnessofbottles and costs.Itis likely that these issuesaffect compliance have been released. Few studies have and intraocular pressure (IOP)-lowering effect. Therefore, re-evaluation of the compared the clinical effect of XalatanÒ requirements for introducing generic eye drops seems reasonable. to its generic products, named latano- prost ophthalmic solutions (Narayanas- Key words: generic drugs – glaucoma – latanoprost wamy et al. 2007; Egan et al. 2014; Golan et al. 2015). In general, concerns Synopsis: Generic latanoprost ophthalmic solutions are not identical concerning drop size, pH have been raised on the clinical effect values, viscosity and buffer capacities. Moreover, the bottle design and hardness varies although no longitudinal studies have significantly, thereby leading to critical variations in the handling of the generics. been performed. In turn, insight into glaucoma progression differences in Acta Ophthalmol. 2017: 95: 370–373 patients treated with generic equivalents ª 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd still remains to be exploited. Obviously, doi: 10.1111/aos.13355 comparative studies are costly and per- haps strict regulations with requirement Introduction Without doubt, they can produce cost for such would not be beneficial. How- savings for both patients and the ever, more readily requirements could be Generic eye drops are becoming a healthcare system. However, even statutory before acceptance of copy major part of treatment for glaucoma though generic drugs have the same products. In turn, simple properties such with the assumption that generics are active ingredients, they may differ with as drop size, volume, pH, buffer capac- exact copies of the original product. respect to inactive ingredients such as ity, viscosity, bottle colour and bottle 370 Acta Ophthalmologica 2017 design constitute features that are more recordings of successive 0.1 ml of grav- had significantly higher values in the range easily assessed. A recent study evaluated ity outflow from a vertical 1-ml syringe 6.70–6.82 (Fig. 1C). Furthermore, pH the stability of pH in different generic through a 21-G cannula into a water differences were found inbetween the formulations and found significant vari- bath (see Appendix s1). latanoprost generic drugs (Table 1). ability (Velpandian et al. 2015). It is Titration of 2.5 ml XalatanÒ to neu- obvious that such variation will affect trality required 70.4 Æ 0.4 nmol NaOH Statistical analysis adherence and possibly the effect of the compared to the generic latanoprost given medication. Drop size, volume, All statistical analyses were performed products, which required within the buffer capacity and viscosity are other in GraphPad Prism 6.0 software range 28.1–33.7 nmol NaOH (Fig. 1D). factors that will influence the amount of (GraphPad Software, La Jolla, CA, The viscosity in one of the generic drug that enters the surface of the eye. USA), and p-values less than 0.05 were products latanoprost (Stada) revealed a Moreover, increased tear volume and considered significant. All data are significant higher value compared to drainage through the nasolacrimal sys- expressed as means Æ SD, and differ- the other tested generics (Fig. 2A). tem will dilute the drug (Ariturk et al. ences between conditions were analysed Significant viscosity differences were 1996), and low retention time will using ordinary one-way analysis of furthermore observed between latano- decrease the penetration of the cornea variance (ANOVA) followed by Tukey’s prost Actavis and latanoprost Teva as and conjunctiva (Ahmed et al. 1987). multiple variance comparisons test. well as between latanoprost Pfizer and Finally, bottle hardness affects the deliv- latanoprost Teva (Fig. 2A). ery of the drug reaching the eye surface Results The average force to release three (Moore et al. 2016). In spite of an subsequent drops varied significantly increasing number of generic eye drops, Drop sizes and volume varied signifi- between XalatanÒ and the generic only limited studies have evaluated these cantly between the brand version (Xala- latanoprost drugs (Fig. 3B, Table 2). Ò factors in the increasing range of gener- tan ) and the generic latanoprost XalatanÒ required the least pressure to ics. In this study, we evaluated five products in the range of 40–46 ll the mid-bottle to release a drop. Over all, different latanoprost generics and com- (Fig. 1). The number of drops in each differences were found for hardness in the pared them to the brand name, XalatanÒ generic bottle varied between 92 and 111 range of 1.8–2.7 kg for release of the first drops (Fig. 1A), and the drop volume drop (Fig. 3B, Table 2). Successive drops Materials and Methods ranged between 40 and 46 ll (Fig. 1B). required more tension: +22 Æ 7% and The control value of pH in the brand +37 Æ 13% for release of the second and Ò Five generic brands of latanoprost oph- version (Xalatan ) was 5.99 Æ 0.01, third drops, respectively, whereupon the thalmic solutions available in Denmark whereasthegenericlatanoprostproducts from Pfizer, Actavis, Sandoz, Stada (Herlev, Denmark) and Teva were included and compared to XalatanÒ The drop size of the contents was measured in triplicates by micropipettes, and the number of drops counted in three separate bottles of each product. Mea- surements of pH values were performed by a calibrated pH meter. Three indepen- dent measurements were performed in three separate bottles. The measurements were repeated to confirm the results. The hardness of the bottles was eval- uated with a spring scale attached to a hook that conformed to bottle curvature. The hook was carefully centred on each bottle perpendicular to the axis. Tension was gradually increased, and the levels for release of three successive drops in free air wererecorded.Subsequently,totaltension was released and the evaluations were repeated three times on three independent bottles for each generic. Titrations of 2.5 ml of each brand were performed by adding known quan- Fig. 1. The number, size of drops, pH and neutralization of latanoprost generics varies significantly. (A) The average number of drops is shown with SD error bars (n = 3). (B) The tities of 1 M NaOH and interpolated to n = neutral pH = 7.4 by a nonlinear logistic average drop volume is shown with SD error bars ( 3). (C) Triplicate mean values of pH in latanoprost generics ÆSD (n = 6, p < 0.0001, ordinary one-way ANOVA followed by Tukey’s regression fit using Microsoft Excel multiple comparisons analysis is outlined in Table 1). (D) Amount of 1M NaOH required for Solver (Lyngby, Denmark). titration of 2.5 ml drug to neutrality. Mean values are shown ÆSD (n = 3, ****p < 0.0001, Kinematic viscosity was determined ordinary one-way ANOVA). Multiple comparisons analysis shows no significant differences by linear regression of split-time inbetween the generic drugs. *p < 0.05, **p < 0.001, ***p < 0.0001. 371 Acta Ophthalmologica 2017 Table 1. pH values vary between latanoprost generics. Condition Difference p Xalatan versus Actavis À0.77 **** Xalatan versus Pfizer À0.77 **** Xalatan versus Sandoz À0.72 **** Xalatan versus Stada À0.70 **** Xalatan versus Teva À0.84 **** Actavis versus Pfizer 0.00 ns Actavis versus Sandoz 0.06 * Actavis versus Stada 0.07 ** Actavis versus Teva À0.06 * Pfizer versus Sandoz 0.06 * Pfizer versus Stada 0.07 ** Pfizer versus Teva À0.06 * Sandoz versus Stada 0.02 ns Sandoz versus Teva À0.12 **** Stada versus Teva À0.14 **** Fig.