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Perspectives on Physicochemical and In Vitro Profiling of Ophthalmic Ointments

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Abstract

Ophthalmic ointments are unique in that they combine features of topical drug delivery, the ophthalmic route and ointment (semisolid) formulations. Accordingly, these complex formulations are challenging to develop and evaluate and therefore it is critically important to understand their physicochemical properties as well as their in vitro drug release characteristics. Previous reports on the characterization of ophthalmic ointments are very limited. Although there are FDA guidance documents and USP monographs covering some aspects of semisolid formulations, there are no FDA guidance documents nor any USP monographs for ophthalmic ointments. This review summarizes the physicochemical and in vitro profiling methods that have been previously reported for ophthalmic ointments. Specifically, insight is provided into physicochemical characterization (rheological parameters, drug content and content uniformity, and particle size of the API in the finished ointments) as well as important considerations (membranes, release media, method comparison, release kinetics and discriminatory ability) in in vitro release testing (IVRT) method development for ophthalmic ointments.

Summary of the physicochemcial profiling and in vitro drug release testing (IVRT) for ophthalmic ointments.

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Abbreviations

API:

Active pharmaceutical ingredient

CA:

Cellulose acetate

DoE:

Design of Experiments

FDC:

Franz diffusion cell

FTIR:

Fourier-transform infrared

G’:

Storage modulus

G”:

Loss modulus

IVRT:

In vitro release testing

MCE:

Mixed cellulose ester

PES:

Polyethersulfone

PDMS:

Polydimethylsiloxane

PLM:

Polarized light microscopy

PTFE:

Polytetrafluoroethylene

PVDF:

Polyvinylidene fluoride

PXRD:

Powder X-ray Diffraction

Q1/Q2 equivalent:

Qualitative and quantitative sameness

RLD:

Reference listed drug

SDS:

Sodium dodecyl sulfate

USP:

US pharmacopeia

VDC:

Vertical diffusion cell

References

  1. Järvinen K, Järvinen T, Urtti A. Ocular absorption following topical delivery. Adv Drug Deliv Rev. 1995;16:3–19.

    Article  Google Scholar 

  2. Pal Kaur I, Kanwar M. Ocular preparations: the formulation approach. Drug Dev Ind Pharm. 2002;28:473–93.

    Article  Google Scholar 

  3. Greaves J, Wilson C, Birmingham A. Assessment of the precorneal residence of an ophthalmic ointment in healthy subjects. Br J Clin Pharmacol. 1993;35:188.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. FDA Orange Book. Url: https://www.accessdata.fda.gov/scripts/cder/ob/ (accessed: 08.12.18).

  5. Ueda CT, Shah VP, Derdzinski K, Ewing G, Flynn G, Maibach H, Marques M, Rytting H, Shaw S, Thakker K. Topical and transdermal drug products, Pharmacopeial Forum. 2009; pp 750–764.

  6. FDA U. Guidance for industry. Nonsterile semisolid dosage forms, scale-up and postapproval changes: chemistry, manufacturing, and controls; in vitro release testing and in vivo bioequivalence documentation. Center for Drug Evaluation and Research (CDER). 1997.

  7. Aldrich DS, Bach CM, Brown W, Chambers W, Fleitman J, Hunt D, et al. Ophthalmic preparations. US Pharmacopeia. 2013;39:1–21.

    Google Scholar 

  8. Xu X, Al-Ghabeish M, Rahman Z, Krishnaiah YS, Yerlikaya F, Yang Y, et al. Formulation and process factors influencing product quality and in vitro performance of ophthalmic ointments. Int J Pharm. 2015;493:412–25.

    Article  CAS  Google Scholar 

  9. Bao Q, Jog R, Shen J, Newman B, Wang Y, Choi S, et al. Physicochemical attributes and dissolution testing of ophthalmic ointments. Int J Pharm. 2017;523:310–9.

    Article  CAS  Google Scholar 

  10. Dong Y, Qu H, Pavurala N, Wang J, Sekar V, Martinez MN, et al. Formulation characteristics and in vitro release testing of cyclosporine ophthalmic ointments. Int J Pharm. 2018;544:254–64.

    Article  CAS  Google Scholar 

  11. Bhagurkar AM, Angamuthu M, Patil H, Tiwari RV, Maurya A, Hashemnejad SM, et al. Development of an ointment formulation using hot-melt extrusion technology. AAPS PharmSciTech. 2016;17:158–66.

    Article  CAS  Google Scholar 

  12. Bao Q, Shen J, Jog R, Zhang C, Newman B, Wang Y, et al. In vitro release testing method development for ophthalmic ointments. Int J Pharm. 2017;526:145–56.

    Article  CAS  Google Scholar 

  13. Rege PR, Vilivalam VD, Collins CC. Development in release testing of topical dosage forms: use of the enhancer cell™ with automated sampling. J Pharm Biomed Anal. 1998;17:1225–33.

    Article  CAS  Google Scholar 

  14. El Gendy AM, Jun H, Kassem AA. In vitro release studies of flurbiprofen from different topical formulations. Drug Dev Ind Pharm. 2002;28:823–31.

    Article  Google Scholar 

  15. Reichling J, Landvatter U, Wagner H, Kostka K-H, Schaefer UF. In vitro studies on release and human skin permeation of Australian tea tree oil (TTO) from topical formulations. Eur J Pharm Biopharm. 2006;64:222–8.

    Article  CAS  Google Scholar 

  16. Shekunov BY, Chattopadhyay P, Tong HH, Chow AH. Particle size analysis in pharmaceutics: principles, methods and applications. Pharm Res. 2007;24:203–27.

    Article  CAS  Google Scholar 

  17. Ali Y, Lehmussaari K. Industrial perspective in ocular drug delivery. Adv Drug Deliv Rev. 2006;58:1258–68.

    Article  CAS  Google Scholar 

  18. Bao Q, Burgess DJ. unpublished data. 2018.

  19. Yamamoto Y, Fukami T, Koide T, Suzuki T, Hiyama Y, Tomono K. Pharmaceutical evaluation of steroidal ointments by ATR-IR chemical imaging: distribution of active and inactive pharmaceutical ingredients. Int J Pharm. 2012;426:54–60.

    Article  CAS  Google Scholar 

  20. Konning G, Mital H. Sheabutter V: effect of particle size on release of medicament from ointment. J Pharm Sci. 1978;67:374–6.

    Article  CAS  Google Scholar 

  21. Pandey P, Ewing GD. Rheological characterization of petrolatum using a controlled stress rheometer. Drug Dev Ind Pharm. 2008;34:157–63.

    Article  CAS  Google Scholar 

  22. Barry B, Grace A. Rheological properties of white soft paraffin. Rheol Acta. 1971;10:113–20.

    Article  CAS  Google Scholar 

  23. Park E-K, Song K-W. Rheological evaluation of petroleum jelly as a base material in ointment and cream formulations with respect to rubbing onto the human body. Korea-Australia Rheol J. 2010;22:279–89.

    Google Scholar 

  24. Barry B, Grace A. Structural, rheological and textural properties of soft paraffins. J Texture Stud. 1971;2:259–79.

    Article  CAS  Google Scholar 

  25. Muynck C, Lalljie S, Sandra P, Rudder D, Aerde P, Remon JP. Chemical and physicochemical characterization of petrolatums used in eye ointment formulations. J Pharm Pharmacol. 1993;45:500–3.

    Article  Google Scholar 

  26. Faust HR, Casserly EW. Petrolatum and regulatory requirements, Penreco. NPRA International Lubricants & Waxes Meeting, November. Citeseer. 2003; pp. 13–14.

  27. Ahmed TA, Ibrahim HM, Ibrahim F, Samy AM, Fetoh E, Nutan MT. In vitro release, rheological, and stability studies of mefenamic acid coprecipitates in topical formulations. Pharm Dev Technol. 2011;16:497–510.

    Article  CAS  Google Scholar 

  28. Krishnaiah YS, Xu X, Rahman Z, Yang Y, Katragadda U, Lionberger R, et al. Development of performance matrix for generic product equivalence of acyclovir topical creams. Int J Pharm. 2014;475:110–22.

    Article  CAS  Google Scholar 

  29. Bao Q, Newman B, Wang Y, Choi S, Burgess D. In vitro and ex vivo correlation of drug release from ophthalmic ointments. J Controlled Release: Off J Controlled Release Soc. 2018;276:93–101.

    Article  CAS  Google Scholar 

  30. Shah VP, Elkins J, Hanus J, Noorizadeh C, Skelly JP. In vitro release of hydrocortisone from topical preparations and automated procedure. Pharm Res. 1991;8:55–9.

    Article  CAS  Google Scholar 

  31. Saitoh I, Takagishi Y. Effect of temperature on bleeding and drug release from a liquid droplet dispersion ointment. Biol Pharm Bull. 1995;18:326–9.

    Article  CAS  Google Scholar 

  32. Shah VP, Elkins JS. In-vitro release from corticosteroid ointments. J Pharm Sci. 1995;84:1139–40.

    Article  CAS  Google Scholar 

  33. Mura P, Nassini C, Proietti D, Manderioli A, Corti P. Influence of vehicle composition variations on the in vitro and ex vivo clonazepam diffusion from hydrophilic ointment bases. Pharm Acta Helv. 1996;71:147–54.

    Article  Google Scholar 

  34. Zatz JL, Varsano J, Shah VP. In vitro release of betamethasone dipropionate from petrolatum-based ointments. Pharm Dev Technol. 1996;1:293–8.

    Article  CAS  Google Scholar 

  35. Flynn GL, Shah VP, Tenjarla SN, Corbo M, DeMagistris D, Feldman TG, et al. Assessment of value and applications of in vitro testing of topical dermatological drug products. Pharm Res. 1999;16:1325–30.

    Article  CAS  Google Scholar 

  36. Müller-Goymann C, Alberg U. Modified water containing hydrophilic ointment with suspended hydrocortisone-21-acetate–the influence of the microstructure of the cream on the in vitro drug release and in vitro percutaneous penetration. Eur J Pharm Biopharm. 1999;47:139–43.

    Article  Google Scholar 

  37. Nallagundla S, Patnala S, Kanfer I. Comparison of in vitro release rates of acyclovir from cream formulations using vertical diffusion cells. AAPS PharmSciTech. 2014;15:994–9.

    Article  CAS  Google Scholar 

  38. Tiffner KI, Kanfer I, Augustin T, Raml R, Raney SG, Sinner F. A comprehensive approach to qualify and validate the essential parameters of an in vitro release test (IVRT) method for acyclovir cream, 5%. Int J Pharm. 2018;535:217–27.

    Article  CAS  Google Scholar 

  39. Ayres JW, Laskar PA. Diffusion of benzocaine from ointment bases. J Pharm Sci. 1974;63:1402–6.

    Article  CAS  Google Scholar 

  40. Bottari F, Di Colo G, Nannipieri E, Saettone M, Serafini M. Influence of drug concentration on in vitro release of salicylic acid from ointment bases. J Pharm Sci. 1974;63:1779–83.

    Article  CAS  Google Scholar 

  41. Chowhan Z, Pritchard R. Release of corticoids from oleaginous ointment bases containing drug in suspension. J Pharm Sci. 1975;64:754–9.

    Article  CAS  Google Scholar 

  42. Bottari F, Di Colo G, Nannipieri E, Saettone M, Serafini M. Release of drugs from ointment bases II: in vitro release of benzocaine from suspension-type aqueous gels. J Pharm Sci. 1977;66:926–31.

    Article  CAS  Google Scholar 

  43. Behme RJ, Kensler TT, Brooke D. A new technique for determining in vitro release rates of drugs from creams. J Pharm Sci. 1982;71:1303–5.

    Article  CAS  Google Scholar 

  44. Takamura A, Ishii F, Noro SI, Koishi M. Physicopharmaceutical characteristics of an oil-in-water emulsion-type ointment containing diclofenac sodium. J Pharm Sci. 1984;73:676–81.

    Article  CAS  Google Scholar 

  45. Ong JT, Manoukian E. Release of lonapalene from two-phase emulsion-type ointment systems. Pharm Res. 1988;5:16–20.

    Article  CAS  Google Scholar 

  46. Velissaratou A, Papaioannou G. In vitro release of chlorpheniramine maleate from ointment bases. Int J Pharm. 1989;52:83–6.

    Article  CAS  Google Scholar 

  47. Kumar P, Sanghvi P, Collins CC. Comparison of diffusion studies of hydrocortisone between the Franz cell and the enhancer cell. Drug Dev Ind Pharm. 1993;19:1573–85.

    Article  Google Scholar 

  48. Collins CC, Little AC, Sanghvi PP, Hofer H, Swon JE. Transdermal cell test matter volume-adjustment device. Google Patents 1995.

  49. Petró É, Paál T, Erős I, Kenneth A, Baki G, Csóka I. Drug release from semisolid dosage forms: a comparison of two testing methods. Pharm Dev Technol. 2015;20:330–6.

    Article  Google Scholar 

  50. Chattaraj S, Kanfer I. ‘The insertion cell’: a novel approach to monitor drug release from semi-solid dosage forms. Int J Pharm. 1996;133:59–63.

    Article  CAS  Google Scholar 

  51. Chattaraj S, Swarbrick J, Kanfer I. A simple diffusion cell to monitor drug release from semi-solid dosage forms. Int J Pharm. 1995;120:119–24.

    Article  CAS  Google Scholar 

  52. Chattaraj S, Kanfer I. Release of acyclovir from semi-solid dosage forms: a semi-automated procedure using a simple plexiglass flow-through cell. Int J Pharm. 1995;125:215–22.

    Article  CAS  Google Scholar 

  53. Olejnik A, Goscianska J, Nowak I. Active compounds release from semisolid dosage forms. J Pharm Sci. 2012;101:4032–45.

    Article  CAS  Google Scholar 

  54. Naik P, Shah SM, Heaney J, Hanson R, Nagarsenker MS. Influence of test parameters on release rate of hydrocortisone from cream: study using vertical diffusion cell. Dissolut Technol. 2016;23:14–20.

    Article  CAS  Google Scholar 

  55. Kregar ML, Dürrigl M, Rožman A, Jelčić Ž, Cetina-Čižmek B, Filipović-Grčić J. Development and validation of an in vitro release method for topical particulate delivery systems. Int J Pharm. 2015;485:202–14.

    Article  Google Scholar 

  56. Sesto Cabral ME, Ramos AN, Cabrera CA, Valdez JC, González SN. Equipment and method for in vitro release measurements on topical dosage forms. Pharm Dev Technol. 2015;20:619–25.

    Article  CAS  Google Scholar 

  57. Marques MR, Loebenberg R, Almukainzi M. Simulated biological fluids with possible application in dissolution testing. Dissolution Technol. 2011;18:15–28.

    Article  CAS  Google Scholar 

  58. Higuchi T. Rate of release of medicaments from ointment bases containing drugs in suspension. J Pharm Sci. 1961;50:874–5.

    Article  CAS  Google Scholar 

  59. Shah VP, Elkins JS, Williams RL. Evaluation of the test system used for in vitro release of drugs for topical dermatological drug products. Pharm Dev Technol. 1999;4:377–85.

    Article  CAS  Google Scholar 

  60. Siepmann J, Peppas NA. Higuchi equation: derivation, applications, use and misuse. Int J Pharm. 2011;418:6–12.

    Article  CAS  Google Scholar 

  61. Xu X, Al-Ghabeish M, Krishnaiah YS, Rahman Z, Khan MA. Kinetics of drug release from ointments: role of transient-boundary layer. Int J Pharm. 2015;494:31–9.

    Article  CAS  Google Scholar 

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Acknowledgements and Disclosures

Funding for this project was made possible by a Food and Drug Administration grant (1U01FD005177–01). The views expressed in this review do not reflect the official policies of the U.S. Food and Drug Administration or the U.S. Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government. Dissolution equipment support from Sotax Corporation is highly appreciated. The authors are grateful to Dr. Louis Tisinger (application specialist, Agilent Technologies) and Mr. Keegan A. McHose (product specialist, Agilent Technologies) for FTIR-imaging test support.

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  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, 06269, USA

    Quanying Bao & Diane J. Burgess

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  1. Quanying Bao
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  2. Diane J. Burgess
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Correspondence to Diane J. Burgess.

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Guest Editors: Hovhannes J Gukasyan, Shumet Hailu, and Thomas Karami

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Bao, Q., Burgess, D.J. Perspectives on Physicochemical and In Vitro Profiling of Ophthalmic Ointments. Pharm Res 35, 234 (2018). https://doi.org/10.1007/s11095-018-2513-3

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