Development of a Cysteamine ophthalmic in situ Gelling System

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Development of a Cysteamine ophthalmic in situ
Gelling System
Dr Olufemi Rabiu
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Cystinosis ophthalmic symptoms

• Rare autosomal recessive condition.
• Characterised by excessive cystine accumulation
  within lysosomes of various cells in the body.
• Symptoms renal Fanconi syndrome, growth
  retardation, corneal erosions, blurred vision and
  photophobia.

Untreated
Treated
(Gahl, Thoene et al. 2002)
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Cysteamine topical treatment

• Oral therapy (cysteamine hydrochloride) has no
  effect on ocular symptoms.
• Topical cysteamine drops have been developed and
  in use since 1986.
• Current UK formulation (0.55) is produced by
  the pharmacy-manufacturing unit at Guys and St.
  Thomas NHS Foundation Hospital.
• Recommended frequency of administration is hourly
  during the initial treatment phase followed by
  four to six times a day
• POOR PATIENT COMPLIANCE

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Aim of the project
Increased residence time in the eye

• Develop a formulation to reduce the frequency of
  administration using the concept of in situ
  gelling system.

Increased Bioavailability
Reduced dosing frequency
IMPROVED COMPLIANCE
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In situ gelling systems
Liquid Drops
Gel

• Ions
• Gellan gum
• Alginate

• pH
• Carbomers
• Chitosan

Combinations of polymers

• Temperature
• Poloxamer
• HPMC, MC

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In situ gelling systems

• Various concentration of combinations of
  temperature sensitive polymers with moderate
  mucoadhesive capacity were further tested
• HPMC
• Poloxamer 407/Poloxamer 188
• Poloxamer 407/Poloxamer 188/ HPMC

Mechanism of temperature induced gelation
Cellulose derivatives
Poloxamer
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Evaluation of the formulations

• Rheology
• ? in vitro behaviour of the gel
• Viscosity
• RT (25C) / 34C
• Undiluted / Diluted with simulated tear fluid
  (STF) or water (257)
• Shear rates
• Low 10s¹ (squeezing out of bottle)
• Medium 100s¹ (normal blinking)
• High 200s¹ (fast blinking)
• Oscillation
• mimic behaviour once in the eye at 34C diluted
  with STF, with blinking

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Evaluation of the formulations

• Dialysis Bag Method
• ? In vitro cysteamine drug release

• Dialysis membrane bag
• (cut off 12,000-14,000 Da).
• Immersed in STF at 34C under gentle
• magnetic stirring
• Sampling done at over 8 hours
• Drug content assayed by iodometric titration
  
• (validated method)

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Characterisation of ophthalmic preparations

• pH physiological
• Good dropability 42 ul
• Non Newtonian viscoelastic flow type not
  deformed after application of stress (blinking),
  good tolerance because of blinking adaptation,
  not easily drained
• Good comparison with commercially available (in
  situ) gels (eg for dry eyes and tear deficiency
  etc)

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Slower cysteamine release gels
N3
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Conclusion

• Ternary combination of 2 Poloxamers and HPMC in
  higher concentrations were found to be suitable
  to prolong the release of cysteamine while
  maintaining good rheological profiles.
• Future Lab Studies
• Further In Vitro drug release studies
• on Franz Diffusion Cells
• 2. Mucoadhesion assessment
• 3. In vivo evaluation of permeation and kinetic
  release of cysteamine in cornea of Rabbits
• And then Clinical trial

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Any question?

• Acknowledgments to
• CRN for the funding
• B Lawal MPharm, S Lalji MPharm, U Lingam MSc, C
  Tuleu
• The School of Pharmacy, University of London, UK
• R Sekhri, W Vant Hoff, K Nischal
• Great Ormond Street Hospital Trust for Children

THANK YOU FOR YOUR ATTENTION!