Advantages of liposome-based delivery system

1
Advantages of liposome-based delivery system

• Boost efficiency of ocular drug delivery
• Delivery of hydrophilic or lipophilic drugs
• Delivery of DNA/peptide/protein
• Liposome encapsulation may reduce ocular
  irritation

2
Criteria set forth by Lippomix

• Within ocular pH range (6.8-7.6)
• Isotonic
• Stable over the long term
• Projection of Commercial Shelf Life
• Pharmaceutically Elegant

3
Formulation development

• Formulation prototypes (44)
• -Buffered (24)
• -Unbuffered (20)
• Formulations which meet criteria (11)
• Short term stability data (1 month _at_ RT)
• Summary
• Conclusions

4
Formulation prototypes

• Unbuffered Formulations
• 0.9 NaCl
• Phosphatidylcholine (PC)
• Diclofenac
• Benzalkonium or Benzethonium chloride

• Buffered Formulations
• Boric acid, pH 7.2
• Phosphatidylcholine (PC)
• Diclofenac
• Benzalkonium or Benzethonium chloride

5
Liposomal formulation (placebo)

• 0.1 (w/v) PC
• 0.9 (w/v) NaCl

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Anti-microbial agents

• Benzethonium chloride
• FDA approved for ophthalmic use
• Does not contain mercury
• Maximum concentration of 0.01 (w/v)

• Benzalkonium chloride
• Commonly used, FDA approved preservative for
  multiple-use ophthalmic products
• Does not contain mercury
• Maximum concentration of 0.013 (w/v)

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Unbuffered Formulations 0.9 NaCl (24)
(w/v) PC (n4) (w/v) Diclofenac (n6) (w/v) Benzalkonium chloride (n1) (w/v) Benzethonium chloride (n1)
0.3 0.3, 0.1, 0 0.013
0.3 0.3, 0.1, 0 0.01
0.1 0.3, 0.1, 0 0.013
0.1 0.3, 0.1, 0 0.01
0.1 0.08, 0.05, 0.02 0.01
0.1 0.1, 0.08, 0.05 0.01
0.08 0.08, 0.05, 0.02 0.01
0.05 0.08, 0.05, 0.02 0.01
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Recommended formulations Unbuffered (6)
Sample name (w/v) PC (w/v) Diclofenac (w/v) Benzethonium chloride Notes pH Size
B032201-8 0.3 0.1 0.01 Translucent/ clear 6.7 400 nm
B032201-10 0.1 0.1 0.01 Translucent/ clear 6.7 1-5um
B032801-1 0.1 0.08 0.01 Translucent/ clear 7.0 1-5um
B032801-2 0.1 0.05 0.01 Clear 6.7 1-5um
B032801-3 0.1 0.02 0.01 Clear 6.5 1-5um
B032801-5 0.08 0.05 0.01 Translucent/ clear 6.7 1-5um
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pH Stability- Unbuffered formulations

• No change in pH over a period of 30 days
• pH of all six samples was between 6.5-7.0

10
Particle size stability Unbuffered formulations

• No change in sample containing 0.3 PC and 0.1
  diclofenac up to 20 days.
• Five formulations increase in size after
  processing, but remain constant in size up to 20
  days.

11
Buffered Formulations 0.3 M Boric acid, pH 7.2
(20)
(w/v) PC (n4) (w/v) Diclofenac (n5) (w/v) Benzalkonium Chloride (n1) (w/v) Benzethonium Chloride (n1)
0.3 0.3, 0.1 0.013
0.3 0.3, 0.1 0.01
0.1 0.3, 0.1 0.013
0.1 0.3, 0.1 0.01
0.1 0.08, 0.05, 0.02 0.01
0.08 0.08, 0.05, 0.02 0.01
0.05 0.08, 0.05, 0.02 0.01
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Recommended formulationsBuffered (5)
Sample name (w/v)PC (w/v) Diclofenac (w/v) Benzethonium chloride Notes pH Size
W032201-4 0.1 0.1 0.01 Translucent 7.3 1-5 um
W032901-1 0.1 0.08 0.01 Translucent/ some settling 7.3 1-5 um
W032901-2 0.1 0.05 0.01 Translucent/ partial settling 7.3 1-5 um
W032901-4 0.08 0.08 0.01 Translucent/ some settling 7.3 1-5 um
W032901-5 0.08 0.05 0.01 Translucent/ settling greater than 4 7.3 1-5 um
13
pH Stability Buffered Formulations

• No change in pH over a 20 day period.
• pH of all five formulations ranges from 7.2-7.3.

14
Particle size stability Buffered Formulations

• During cooling of sample, all formulations
  shifted to a size 3 ?m.
• Microscopic estimates put the liposomes between
  1-5 ?m.
• The larger-sized particles appear to maintain
  their size over the short term.
• Once a sample equilibrates, there is no change in
  particle size.

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Summary of findings

• Formulations may be made buffered (boric acid) or
  unbuffered (NaCl).
• PC concentrations within 0.05-0.3 (w/v) produce
  formulations with greatest clarity.
• Diclofenac may be added at 0.02-0.1.
• Benzethonium chloride at 0.01 is the more
  suitable anti-microbial agent, with regard to
  formulation clarity.
• pH of recommended formulations is constant over
  the short term (30 days).
• Most formulations shift to a larger particle size
  after processing, but remain stable once
  equilibrated.

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Formulation Criteria

• Formulation clarity
• Free of ethanol/organic solvents
• Ability to include an anti-microbial agent
• Within ocular pH range (6.8-7.6)
• Isotonic
• Stable over the long term (1 month to date)
• Projection of Commercial Shelf Life
• Pharmaceutically Elegant

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Conclusion

• We can produce several liposome-based ophthalmic
  formulations of diclofenac.
• All formulations are sterile, contain an
  anti-microbial agent, no organic solvents, and
  are within ocular pH and tonicity.
• Furthermore, these formulations are stable with
  respect to clarity and pH .

18
Future developments

• Additional product opportunities
• Hydrophilic drugs
• Lipophilic drugs
• DNA/Proteins/Peptides
• Other disease states (glaucoma, seasonal allergic
  or bacterial conjunctivitis, dry eye, etc)

19
pH Stability-Unbuffered Formulations
20
pH Stability-Buffered Formulations