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Stability of ophthalmic preparations

Practical therapeutics

Valérie Sautou, PhD, PharmD
Department of Pharmacy, G Montpied Hospital, Faculty of Pharmacy, University Clermont, Clermont-Ferrand, France

Hospital pharmacists are often required to prepare ophthalmic formulations (eye drops or injectable preparations) to overcome the lack of drugs marketed for the treatment or the prevention of certain eye diseases. To meet the high demand and/or to manage emergency treatment, pharmacists must carry stocks of these sterile preparations. To this end, they must define the optimal storage conditions, and this requires data on stability of the preparations.

To obtain these data, pharmacists need to either carry out their own stability study of the preparation or refer to the bibliographic references available on the subject. Providing a rigorous methodology is observed, the stability study will yield information adapted to the pharmacist's own preparation.

In carrying out a literature 
review, the pharmacist must interpret the data with caution and be careful in extrapolating. Indeed, the conservation of a preparation can vary depending 
on the storage conditions and on 
other factors such as formulation 
or packaging.

Interpreting the data from 
a stability study
It is important to consider the 
following parameters in the interpretation of stability data of an ophthalmic preparation:

  • The formulation of the preparation: nature of excipients, nature and concentration of active ingredient
  • The type of container: bottle or syringe
  • The constituent materials of bottles 
or syringes (glass, polyethylene, polypropylene, polycarbonate) and 
the closure systems (for example chlorobutyl stoppers)
  • The conditions of preparation (filtration, autoclaving)
  • The storage conditions (light, temperature).

The stability of an ophthalmic preparation is assessed by physical, chemical and, if appropriate, microbiological parameters. Assessment of physical stability combines a visual examination (in order to detect potential precipitates, crystals, troubles or colouration changes) and the research 
of non-visible particles. Analytical methods to study the chemical stability of the preparation must be chosen carefully and validated as methods that indicate stability.

To this end, separative techniques 
are the methods of choice because 
they can separate possible degradation products from the active ingredients themselves. The evaluation of the 
active ingredient concentration and the monitoring of degradation products over time is carried out by the determination of pH and osmolality.

If the preparation is a multi-dose 
form, or if the integrity of packaging cannot be guaranteed, it is also important to study the microbiological stability of the preparation.

Some clinical examples
The following examples concerning the stability of ophthalmic preparations made in hospital pharmacies demonstrate the importance of the different criteria presented above.

Sodium cefuroxime solutions for intra-cameral injections
The European Society for Cataract and Refractive Surgery recommended an intracameral injection of cefuroxime as prophylactic treatment of endophthalmitis in cataract surgery. Solutions containing 10mg/ml sodium cefuroxime are prepared in 0.9% sodium chloride or possibly in 0.2% sodium hyaluronate hydrogel. The stability of cefuroxime is temperature dependent and degradation of the active ingredient is seen after 48 hours at 25°C. At 4°C, the preparation is stable for at least 21 days and for three months in the freezer at -20°C.1 However, when the preparation is frozen, the choice of container and the conditions of thawing are very important. Indeed, during a conditioning in prefilled syringes, an analysis of the active ingredient after thawing shows an inhomogeneity of the antibiotic concentration in the syringe. The concentration decreases from the stopper to the plunger of the syringe. More than 40% of the active ingredient is lost in the last 0.1ml, knowing that the syringe contains 0.5ml solution.2 It is therefore necessary to ensure an efficient homogenisation of the prefilled syringes after thawing and a return to room temperature.

Vancomycin
Eye drops and solutions for intravitreal injections of vancomycin are widely used at differing concentrations ranging from 10–50mg/ml in various solvents (5% glucose; 0.9% sodium chloride; water). Their stability has been validated up to six months in the freezer at -20°C.3–5 Once thawed, vancomycin is degraded after eight days at 4°C and after 48 hours at 25°C.6 Crystalline degradation products without antibiotic activity are observed.7 The ocular toxicity of these degradation products is unknown. This crystallisation is pH dependent, so one may wonder if there is no risk of crystal formation upon contact with the vitreous, whereas the stability of the solution has been validated

Ticarcillin
Ticarcillin is a penicillin used in bacterial keratitis because of its broad spectrum activity against Pseudomonas aeruginosa and Proteus. Ticarcillin eye drops at concentrations of 5–6mg/ml are prepared in hospital pharmacies. Studies by Calvez et al8 and Blondeel et al9 have assessed the stability of ticarcillin ophthalmic solutions. The methodology of these studies was similar in terms of formulation, containers and storage conditions but Calvez et al kept the preparations before analysis whereas Blondeel et al opened them twice a day to simulate the administration of ticarcillin in the eyes of the patient. The repeated opening of the bottles accelerated the degradation of the antibiotic. At 4°C ticarcillin eye drops are stable for seven days if the bottles are opened, and for 
16 days if they remain closed. In practice, the fortified antibiotic eye drops can 
be administered four times per day or once every hour. Taking into account 
the conditions of use of the eye drops 
is crucial in stability studies.

Cyclosporine eye drops
Cyclosporine administration is very effective in immunological diseases of the cornea, conjunctive or uvea (for example vernal keratoconjunctivis, Sjögren's syndrome, Actinic prurigo). Moreover, cyclosporine is widely used in cases of corneal transplantation where there 
is a high risk of rejection. The eye drop formulations are varied and some stability studies have been performed.10–12 The effects of differing container constituents (for example glass, polyethylene) have been studied but none of these studies focused on the compatibility of cyclosporine with the PVC material of the dropper fitted on 
the glass bottle. Cyclosporine is absorbed significantly by PVC, so it is important 
to consider this during the use of cyclosporine eye drops. Pending interaction studies, polyethylene containers seem to be suitable for storing cyclosporine.

Conclusion
The examples above demonstrate the influence of different parameters, such 
as the type of formulation and storage conditions, together with the type 
of use, in the stability of an opthalmic formulation.

It is important that stability studies 
are well done and reflect hospital practice. However, there is, as yet, no methodological referential taking into account these different criteria. The 
ICH guidelines13 provide a basic template but are more adapted to industrial production than to preparation in hospitals. Under the auspices of the Société Française de Pharmacie Clinique and the Groupe d'Evaluation et de Recherche sur la Protection en Atmosphère Contrôlée, a group of hospital pharmacists have decided to work on the subject with the goal of establishing rigorous methodological guidelines for carrying out stability studies for hospital preparations.

References

  1. Uhart M et al. Int J Pharm 2010;398:14–20
  2. Bontemps C et al. SNPHPU Congress 2009;Reims http://www.infostab.com/publications_comp_list.php (accessed 16 May 2011)
  3. Chédru-Legros V et al. Cornea 2010;29(7):807–11
  4. Chédru-Legros V et al. J Fr Ophtalmol 2007;30(8):807–13
  5. Sautou-Miranda V et al. Int J Pharm 
2002;234(1-2):205–12
  6. Maillot-Pysczek V et al. Hopipharm Congress 2010;Vittel http://www.infostab.com/upload/files/6b60ec90657b26c15b6f7fb06aa89c8f70b... (accessed 16 May 2011)
  7. Barbault S et al. J. Pharm Clin 1999 ;18:183–89
  8. Calvez O et al. Pharm Hosp 2007;42(171):171–76
  9. Blondeel S et al. Can J Hosp Pharm 2005;58(2):65–70
  10. Fiscella RG et al. J Ocul Pharmacol Ther 1996;12(1):1–4
  11. Lallemand F et al. Eur J Pharm Sci 2005;26(1):124–29
  12. Chast F et al. J Fr Ophtalmol 2004;27(6):567–76
  13. ICH. Stability testing of new drug substances and products Q1A(R2), 2003. http://private.ich.org/LOB/media/MEDIA419.pdf (accessed 15 May 2011)

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