1. Composite Polysaccharide Hydrogels
An Innovative Approach for Sustained Release of Hydrophobic Drugs
Dr. Elinor Josef1,2, Keren Delmar2, Havazelet Bianco-Peled2,3
1Inter-Departmental Program for Biotechnology, 2The Russell Berrie Nanotechnology Institute, 3Department of Chemical Engineering. Technion-Israel Institute of Technology
8th International Conference and Exhibition on
Pharmaceutics & Novel Drug Delivery Systems
March 07-09, 2016 Madrid, Spain

2. Motivation How to use hydrogels to deliver hydrophobic drugs?
Hydrogels have many advantages as drug delivery vehicles:
Biocompatible
Tunable release patterns
Injectable
Environmental sensitive systems
Can encapsulate proteins and DNA
Ideal for oral and mucosal delivery
Vashist et al. J. Mater. Chem. B, 2014,2,
On the down side, hydrogels cannot easily be used as delivery matrices for hydrophobic drugs, that now constitute over 40% of new developed drugs.

3. Microemulsions
Microemulsions are often used to solubilize hydrophobic moieties for transdermal drug delivery.
M. J Lawrence et al. , Advanced drug delivery reviews (2000)
Microemulsions are thermodynamically stable dispersions of oil and water, stabilized by a surfactant film.
Microemulsions can’t be used for oral/mucosal sustained release

4. Composite Hydrogels
Hypothesis: Drug loading will increase due to its higher solubility in the oil droplets, while the cross-linked hydrogel matrix could be readily used as a solid controlled delivery system. 4

5. System Design Challenges Stable polymer-microemulsion mixture.
Empirical formulation only.
Use of biocompatible ingredients:
Hydrocarbon oils are not acceptable.
Limited number of surfactants.
Many of the co-surfactants are long chain alcohols which are not biocompatible. Short chain alcohols could cause phase separation upon dilution
Incorporation of the drug.
Composite hydrogel
Stable polymer-microemulsion mixture.
Crosslinking of the polymer.

6. Microemulsion Tween-80 Span-20 IPM (Isopropyl Ketoprofen (KT)
C64H124O26
1310 gr/mol
Span-20
C18H34O6
346 gr/mol
IPM (Isopropyl
Myristate)
C17H34O2
270 gr/mol
Ketoprofen (KT)
C16H14O3
254 gr/mol 6

7. Formation of the Microemulsion
Cryo-TEM
Dynamic Light Scattering
100nm
Diameter [nm] ± stdev
ME φ=2.8%
11.6±0.8
ME φ=1.4%
9.8±0.5
ME φ=0.9%
9.9±0.4
ME-KT φ=2.8%
8.9±0.7
ME-KT φ=1.4%
10.3±0.2
ME-KT φ=0.9%
10.5±0.6
φ – Surfactants Concentration
ME- Microemulsion
ME-KT- Microemulsion with Ketoprofen
Josel et al., Acta Biomaterialia, 6(12),

8. Structure of the Microemulsion
Small angle X-ray scattering (SAXS) curves of ME and ME-KT with φ=2.8% (upper curve) and 1.4%.
Φ= Surfactants concentration
ME- Microemulsion.
ME-KT- Microemulsion with ketoprofen.
Parameter ME
φ=2.8%
φ=1.4%
ME-KT
Rc [nm]
4.4 ± 0.05
4.6 ± 0.07
4.5 ± 0.06
4.3 ± 0.1
Rshell [nm]
5.7 ± 0.04
5.6 ± 0.07
6.0 ± 0.04
Shell density
[el/nm3]
53 ±2
81 ± 8
69 ± 4
43 ± 3 σ
0.6 ±0.02
0.6 ± 0.02
0.7 ± 0.02
0.7 ± 0.04 Rc
Rshell
Drug is located in the shell

9. Hydrogel Ca Biocomaptable Easy cross-linking Mucoadhesive
L-guluronic acid (G) D-mannuronic acid (M) Ca
Biocomaptable
Easy cross-linking
Mucoadhesive

10. Composite hydrogels Alginate gels crosslinked with Calcium ions
Alginate 25 mg/ml
Ca-EGTA 15 mM
Ketoprofen 1 mg/ml
No Drug
With Drug
With Drug in ME
Alginate-ME
Calc.
Alginate + ME
]nm-3[
SAXS curves of alginate-ME gel with 7.5mM and 15mM Ca-EGTA
Alginate ME

11. Ketoprofen Release Profiles
Time to 20% Release
Ketoprofen in Alginate Composite Hydrogel
Alginate 25 mg/ml, Ca-EGTA 5.5, 7.5, 20 mM
Time to 50% Release

12. Release from Composite Hydrogels
Time to 20% Release
Time to 50% Release
Crosslinker: Calcium 7.5 mM
Crosslinker: Calcium 20 mM
Release rate can be varied by changing the gel composition (network structure)

13. Release from Composite Hydrogels
Release from composite hydrogels with the same alginate hydrogel
5 “empty” MEs
Progesterone in 3 MEs
Progesterone , vitamin D, and empty ME
Nile Red, different concentrations
Release rate does not depend on the exact ME composition, the drug type or its concentration
Josel et al., Acta Biomaterialia, 9(11),

14. Alginate Sponges
Self-microemulsifying Drug Delivery Systems
Droplets are preserved after a drying – rehydration cycle
Josef & Bianco-Peled, Int J Pharm 458(1), , 2013

15. Limitations of alginate composite hydrogels
Release is completed within few hours
Disintegrates in buffer
Idea: positively charged hydrogel, anionic microemulsion

16. Chitosan hydrogels Chitosan has been reported to be non-toxic
biocompatible
biodegradable
antimicrobial and antifungal properties
Making it an ideal candidate for controlled release applications

17. Crosslinking of chitosan
20 hours
Before swelling, 20 hour gelation pH=5
pH=4.0
pH=4.5
pH=5.0
pH=5.5
90 hours
Swollen chitosan (1% w/v) hydrogels crosslinked with genipin (0.1% w/v)
K. Delmar and H. Bianco-Peled, Carbohydrate Polymers 127, 28-37, 2015

18. Release from chitosan composite hydrogels
Release in water
Nile Red
Curcumin
pH=5.5
pH=4.0
Release rate depends on the exact ME composition
Faster release from the highly crosslinked hydrogels
K. Delmar and H. Bianco-Peled, Carbohydrate Polymers 136, , 2016.

19. Release from chitosan composite hydrogels
Release in PBS buffer
Nile Red
Curcumin
pH=5.5
pH=4.0
Release rate depends on the exact ME composition
Release is faster in PBS

20. Swelling of chitosan composite hydrogels

21. Swelling of chitosan composite hydrogels

22. FTIR analysis

23. Conclusions
Composite hydrogels were successfully designed. Addition of drug resulted in a clear gel with no visible precipitations.
Microemulsion droplets exist in the composite hydrogel.
The system showed potential as a drug delivery vehicle.

24. Acknowledgments

25. Thank you for your attention
Haifa, Israel