Docstoc

Linker-based non-toxic microemulsions

Document Sample
Linker-based non-toxic microemulsions Powered By Docstoc
					         Linker-based non-toxic
             microemulsions

                     Edgar Acosta
Thu Nguyen, Jeffrey H. Harwell and David A. Sabatini

                          O
                          U
                  University of Oklahoma
         Institute for Applied Surfactant Research
                                    Motivation
Why non-toxic microemulsions?
Drug delivery
Ketoprofen - Lecithin, butanol, Span 80, medium chain triglycerides (MCT)
Amphotericin B - Lecithin, IPM, BRIJ-96V
Flurbiprofen - Lecithin, ethyl oleate, ethanol, PEG

Cosmetic formulations
Retinol - Lecithin, IPM, Tweens 60 & 80, butanol, PPG
Non-irritant formulations
Formulation with natural products

Cleaning technologies
Environmentally friendly - “Green solvents”
Cleaners with enhanced biodegradation profile           Transdermal lidocaine Delivery

                                                                                O
                                                                                U
 Performance of microemulsion systems
       Drug and Cosmetic                          Cleaners and solvent
          Formulations                               replacements
Pros:                                        Pros:
•Faster delivery (transdermal and oral)      •No VOCs
•Low energy for emulsification               •Cleaning of organic and inorganic
•Higher permeation through membranes         contaminants
•Size is tunable (~10 nm typical)            •Biodegradable
•Low viscosity (in certain formulations)     •Non-harmful compounds
                                             •Aqueous-based
Cons:
•Potential toxicity of the surfactants and   Cons:
cosurfactants: especially ionic              •Cost of surfactant - limited solubilization
surfactants and short/medium chain           capacity of organic compounds vs
alcohols                                     organic solvents
•Complexity of formulation                   •Complexity of formulation, special for a
                                             variety of oils that can be present in
                                             stains.

                                                                                     O
                                                                                     U
                       Hypothesis
 By using the “linker” formulation approach to produce
 microemulsions we can obtain microemulsions with oils
 relevant to drug and cosmetic delivery, and cleaning
 applications using non-toxic surfactants and cosurfactants

                        Objectives
• Produce a Lecithin-based microemulsion system with oils of
interest in drug delivery and cosmetic and cleaning
applications using non-toxic linker molecules
• Characterize the microemulsion system using solubilization
studies, phase diagrams, viscosity and interfacial tension
•Investigate the role of active pharmaceutical solutes (e.g.
lidocaine) on microemulsion phase behavior                     O
                                                               U
                                      Microemulsion Fundamentals

     •Ultralow interfacial tension (reduce capillary forces)
     •Maximum oil solubilization capacity




                                                                                                         Solubilization ml/g AMA
                                                                                                     3
                                                  I                     III                II
                                                                                                     2
                                              Type I              Type III             Type II
         Interfacial Tension, mN/m




                                                                                                     1

                                         1                                                           0
                                              2          3          4              5   6         7
                                                                          % NaCl
                                       0.1

                                      0.01

                                     0.001
                                                      Increasing Salinity
                                     0.0001

Tetrachloroethylene (PCE) - 4% Sodium dihexyl sulfosuccinate (AMA) - NaCl
                           phase behavior study                                                                                    O
                                                                                                                                   U
                    Why Combined Linker
                     Microemulsions?

•Combined linkers => Achieves




                                     $/m^3 to solubilize 20%
success (I.e. middle phase)                                    600
                                                               500
•Oils for detergency =>Long Chain                              400




                                             of oil
                                                               300
•Combined linker => Saves                                      200
money($$$…)                                                    100
                                                                 0
•Able to use non-toxic ingredients                                   C2HCl 3 C2Cl 4    C6 C10 C14 C18
                                                                                      Oil phase
•Desirable phase behavior (no                                   AMA 4%           AMA 4%+ combined linker
precipitate or liquid crystals)
                                                                                                        O
                                                                                                        U
                          Linker Microemulsions

                                                               Water side of the interface
Lipophilic linker accumulates
    at palisade layer and          Surfactant Aerosol-MA®
    increases interfacial                 SO Na                  SO Na
                                                                   3       SONa            SO Na
                                                                                             3     SONa
                                            3
          thickness               O                    O             O
                                                                             3
                                                                                   O           O
                                                                                                     3
                                              O

                                      O   O       H        O     O                     O   O       H
                                                   O                                                O
Hydrophilic linker Coadsorb
O/W interface and increase                                        Hydrophilic linker
      interfacial area                                                SMDNS

                                                                  Oil side of the interface
 Combined linker behaves
 as a assembled surfactant      Lipophilic linker Dodecanol                                Combined linker




                                                                                                        O
                                                                                                        U
                                            Materials
                                            +N
                                                     O       -O
                                                                  Surfactant: Purified egg-yolk lecithin
                              OH   OH                             Lipophilic linker: Span 80
 Water                       OH                      O   P   O
                                                                  Hydrophilic linker: AG6206




                                   OH
                               O
                                            O
               OH                                O




                                        O
                              O




                                                         O
                    O


                                                                  Oils: Hexane, decane, hexadecane,
          OH



                        OH



 Oil                                                              squalene, isopropyl myristate, ethyl
                        AG-6206                                   oleate
                    O
               O




                                                                  Electrolyte: NaCl
                        Hexyl                                     Active: Lidocaine (anesthetic)
SPAN-80                 Glucoside

Sorbitol                                Lecithin
monooleate
                                        phosphatidyl choline
                                        - dioleate
                                                                                                 O
                                                                                                 U
        Selecting Linkers with Improved
     Environmental and Toxicological Profile

Lipophilic linker - Span 80          Surfactant - Lecithin       Hydrophilic linker -
                                                                 Hexyl glucoside




          II     III   I
                                                Alkyl Glucoside Scan (AG)
               Hexane, 25ºC                     Type II - III - I transition
   4.5% 4.65 4.70 4.75        4.8%              High solubilization capacity
    AG %AG %AG %AG             AG
                                                Less sensitive to electrolyte
   4% NaCl, 4% Span 80, 2% Lecithin
                                                                                 O
                                                                                 U
   Phase behavior of Isopropyl myristate
          (IPM) microemulsion
       Formulation: Lecithin/Span 80 = 1/1, Scan of AG-6206




             %Lecithin in water, Le/Span80=1/1
                                                 10
                                                 9
                                                                  IV
                                                 8
                                                 7
                                                 6
                                                 5
                                                 4
                                                                       II           I
                                                 3
                                                 2                            III
                                                 1
                                                 0
                                                      0.5   1       1.5       2         2.5   3
                                                                AG-6/Le weight ratio

Narrow TypeIII region - only 12% total surfactant (Lecithin + Span 80
    + AG6206) concentration to achieve single phase (Type IV)                                     O
                                                                                                  U
         Formulation of Single Phase (Type IV)
              non-toxic microemulsions

              Not a single phase yet, also                                      Formulation: Lecithin/Span 80 =
              uses 26% 1-propanol (in water)
                                                                                    1/1, Scan of AG-6206
              Langmuir 1998, 14, 3506-3511
                        % wt. Lecithin in water




                                                        AG6206/Lecithin ratio
            25                                    3                              More Hydrophobic oils =>
                                                  2.5                               higher surfactant
            20
                                                  2
                                                                                  concentrations & less
            15                                                                       hydrophilic linker
                                                  1.5
            10
                                                  1
             5                                    0.5                            Combined linker approach
             0                                    0                                    for lecithin-based
                                                                                     microemulsion more
               de te
       op De e
                     ne

             xa sta



                      e
              Sq ane
                     n




                   len
                   ne
                   xa
                  ca




                                                                                 efficient than alcohol-based
         He yri

                  c
                yle




                 ua
                He



               M
              th




                                                                                          formulations
                                                                                                                O
           oe




          yl
        lor




                                                                                                                U
      ch




     pr
   tra




 Iso
Te
      Effect of Formulation Conditions
      Formulation: Lecithin/Span 80 = 1/1, Scan of AG-6206,
            Lecithin aqueous concentration = 4% wt.

                                        2.5




            Fraction AG-6206/Lecithin
                                                        Isotonic solution, 0.9% NaCl
                                         2              Saline solution, 4% NaCl

                                        1.5

                                         1

                                        0.5

                                         0
                                              Hexane   Decane Hexadecane Isopropyl
                                                                         Mirystate




Increase in electrolyte concentration => slightly less AG required
 The system does not behave like ionic microemulsion systems
                                                                                       O
                                                                                       U
          Effect of Formulation Conditions
          Formulation: Lecithin/Span 80 = 1/1, Scan of AG-6206




             %Lecithin in water, Le/Span80=1/1
                                                 10
                                                  9
                                                                  IV                   Phase behavior @ 25C
                                                  8
                                                                                       Phase behavior @ 40C
                                                  7
                                                  6
                                                  5
                                                  4
                                                                                   I
                                                  3          II
                                                  2                          III
                                                  1
                                                  0
                                                   0.5   1             1.5   2         2.5      3
                                                             AG-6/Le weight ratio

Increase in Temperature => slightly less AG required, more robust systems
    The system does not behave like nonionic microemulsion systems                                            O
                                                                                                              U
       Formulation Properties: Viscosity and
              Characteristic length
           Formulation: Lecithin/Span 80 = 1/1, Scan of AG-6206,
            Data obtained from single phase Type (IV) systems
                                 Viscosity, cpoise
                      0   20     40     60      80   100     120
      Pure PEG-400
           Pure IPM
           Squalene
 IPM-microemulsion
        Hexadecane                                                      φoφ wV
                                                               ξ* = 6
            Decane                                                       ms as
            Hexane
Tetrachloroethylene
                      0   50   100 150 200 250 300           350
                          Characteristic length, Angstroms

    All Microemulsion systems had low viscosity except for isopropyl
         myristate (IPM) but still substantially lower than common
         pharmaceutical solvent polyethylene glycol (PEG-400)
Size of the aggregates are in the target zone for microemulsion delivery
                                                                                 O
                                                                                 U
          Formulation Properties: Interfacial
               Tension and Rigidity
            Formulation: Lecithin/Span 80 = 1/1, Scan of AG-6206,
              Data obtained from Type (III) systems, 2% Lecithin
                                      Interfacial Tension, mN/m
                          0.E+00 1.E-03 2.E-03 3.E-03 4.E-03 5.E-03 6.E-03
                   Squalene

          Isopropyl Mirystate
                Hexadecane
                     Decane
                     Hexane
         Tetrachloroethylene

                                0   0.5     1    1.5     2    2.5    3   3.5
                                       Interfacial Rigidity (Er), KBT

                 The IFT increases for more hydrophobic oils
                The interfacial rigidity is higher for IPM systems
Potential Interaction between the ester group of the oil and lecithin molecules
                                                                               O
                                                                               U
           Formulation with Lidocaine

      Formulation: Lecithin/Span 80 = 1/1, Scan of AG-6206,
        Data obtained from single phase (Type IV) system
           Property of formulation      Isopropyl       Isopropyl Myristate +
                                      Myristate alone         Lidocaine
           Lidocaine wt% (of total         0.0%                 10.0%
                   volume)
            Lecithin wt% (of total         3.8%                 4.5%
                   volume)
           Span 80 / Lecithin ratio         1.0                  1.0

          AG-6202 / Lecithin ratio          1.5                  1.4

            Viscosity, centipoise         28 cp                 43 cp
          Characteristic length ξ*,       18 nm                13 nm
                    nm



Solubilize twice the lidocaine compared to commercial formulations
Higher surfactant concentration and higher viscosity than IPM only
The formulations were obtained with non-irritant, non toxic additives
                                                                                O
                                                                                U
           The role of lecithin in non-toxic
                    formulations
         Formulation: Span 80/Lecithin = 1/1 & 2/1, Scan of AG-
        6206, Data obtained from single phase (Type IV) system

                 Property of          Span 80/Lecithin =   Span 80/Lecithin =
                 Formulation                 1/1                  2/1
              Lecithin wt% (total           3.8%                 2.8%
                   volume)
              Span 80 / Lecithin              1                    2
                     ratio
              AG 6206 / Lecithin             1.5                 1.33
                     ratio
             Viscosity, centipoise          28 cp                11 cp

             Characteristic length,        18 nm                 20 nm
                     nm



Lecithin increases viscosity and tendency to form liquid crystals, specially
          with ester oils like IPM, methyl oleate and tryglicerides
Reducing lecithin content improves viscosity, solubilization efficiency and
                    cost, but a minimum is required
                                                                                O
                                                                                U
 Lecithin-based versus alkyl sulfosuccinate-
based microemulsions: solubilization capacity

                                320
                                300                                              Formulation: Lecithin/Span 80
                                280
                                260                                              weight ratio = 1/1, 0.9% NaCl,
     Characteristic length ξ*   240
                                220
                                200
                                180
                                160
                                140
                                120
                                100                                                  Formulation: 4% AMA, 0.18
                                 80
                                 60                                                   M oleyl alcohol, 0.18 M
                                 40                                                           SMDNS
                                 20
                                  0
                                      -5    0      5      10     15     20      25
                                           Oil Equivalen Alkane Number (EACN)




     Lecithin - based linker microemulsions are more efficient
           than anionic surfactants alkyl sulfosuccinate                                                   O
                                                                                                           U
  Lecithin-based versus alkyl sulfosuccinate-
based microemulsions: electrolyte concentration

                                       Formulation: Lecithin/Span 80                                           Formulation: 4% AMA, 0.18 M
                                       weight ratio = 1/1, 0.9% NaCl                                           oleyl alcohol, 0.18 M SMDNS




                                                                               S*, NaCl wt% in aqueous
                                                                                                                    High concentration of Brine
Hexyl Glucoside / Lecithin




                              3
                                                                                                                     Phase separation before




                                                                                solution at optimum.
                             2.5                                                                         100            contacting with oil
       weight ratio




                              2
                             1.5
                                                                                                         10
                              1
                             0.5
                                                                                                          1
                              0
                                   0        5      10      15      20     25                                   -5   0     5    10    15    20

                                        Oil Equivalent Carbon number (EACN)          Equivalent Alkane Carbon Number (EACN)



                      Lecithin-based microemulsions can be formulated with low electrolyte
                             concentration compared to anionic alkyl sulfosuccinates                                                         O
                                                                                                                                             U
                         Summary
• Using a linker-based mixture of Lecithin, Hexyl Glucoside
  (AG6206) and Sorbitol monoleate (Span 80) can produce
  alcohol-free nontoxic microemulsion systems
• Scans of AG6206 offered narrow middle phase regions which
  are slightly affected by electrolyte or temperature.
• Formulations with the active ingredient Lidocaine offers high
  solubility with less viscosity than PEG-400 solvent.
• Lecithin tends to increase viscosity and promote the formation
  of liquid crystals, specially with ester oils
• Lecithin-based linker microemulsions are more efficient and
  require less electrolyte than anionic alkyl sulfosuccinate
  systems

                                                              O
                                                              U
                  Future Work

          Optimize concentration of Lecithin
 Formulate systems for Methyl oleate and tryglicerides
           Drug permeation/irritation studies
       Microemulsion enhanced biodegradation
         Detergency and hard-surface cleaning
System characterization - DLS, SANS, NMR self diffusion
                      Effect of pH




                                                     O
                                                     U
                                           References
•Malmsten, M. "Microemulsions in Pharmaceuticals" in Handbook of Microemulsion Science and Technology.
Editor: P. Kumar. Marcell Dekker, Inc. 1999, p. 755-772
•Engstroem, S. and Larsson, K. "Microemulsions in Foods" in Handbook of Microemulsion Science and Technology.
Editor: P. Kumar. Marcell Dekker, Inc. 1999, p. 789-796
•Lawrence M. J. and Rees, G. D. "Microemulsion-based media as novel drug delivery systems". Adv. drug delivery
rev. 45, 2000, p. 89-121
•Salager J.L.; Graciaa, A; Lachaise, J. "Improving Solubilization in Microemulsion with Additives. Part III: Lipophilic
Linker Optimization". J. Surfactant Detergents. 1, 1998, p. 403.
•Uchiyama, H; Acosta, E.; Sabatini, D.A.; Harwell J.H. "Supersolubilization in Chlorinated Hydrocarbon
Microemulsions: Solubilization Enhancement by Lipophilic and Hydrophilic Linkers". Ind. Eng. Chem. Res. 39(8),
2000, p. 2704.
• Acosta, E.; Uchiyama, H.; Sabatini, D.A.; Harwell, J.H. "The Role of Hydrophilic Linkers". J. Surfactants
Detergents. 5, 2002, p.151.
• Acosta, E.; Uchiyama, H.; Tran, S.; Sabatini, D.A.; Harwell, J.H. "Formulating Chlorinated Hydrocarbon
Microemulsions Using Linker Molecules". Environ. Sci. Technol. 36, 2002, p. 4618
•Acosta, E. Mai P.D. , Harwell J.H.; Sabatini D.A. "Linker-Modified Microemulsions for a Variety of Oils and
Surfactants". Journal of Surfactant and Detergents. 2003, 6(4) 353-363.
• Kahlweit M.; Busse, G.; Faulhaber, B. "Preparing Microemulsions with Lecithins ". Langmuir. 11, 1995, p. 1576-
1583
• Kahlweit M.; Busse, G.; Faulhaber, B. "Preparing Microemulsions with Alkyl Monoglucosides and the Role of n-
Alkanols ". Langmuir. 11, 1995, p. 3382-3387
• Corswant, C. V.; Olsson, C.; Soderman O. "Microemulsion based on Soybean Phosphatidylcholine and


                                                                                                                 O
Isopropylmyristate-Effect of Addition of Hydrophilic Surfactants". Langmuir. 14, 1998, p. 6864-6870.
• Acosta, E .J.; Harwell, J.H.; Sabatini, D.A. "Self-Assembly in Linker Modified Microemulsions". Submitted to
Journal of Colloid and Interface Science. July 2003.
                                                                                                                 U
 Institute for Applied Surfactant Research
                  Sponsors
Akzo Nobel Chemicals Inc.      ICI Americas Inc.
Albemarle Corporation          Kerr-McGee Corp.
Amway Corporation              Lubrizol Corporatio
Colgate-Palmolive              Nikko Chemicals
Clorox company                 Phillips Petroleum Company
Dial Corporation               Pilot Chemical Company
Dow Chemical Company           Procter & Gamble Company
DowElanco                      Reckitt Benckiser North America
E.I. Dupont de Nemours & Co.   Schlumberger Technology Corp.
Halliburton Services Corp.     Shell Chemical Company
Henkel Corporation             Sun Chemical Corp.
Huntsman Corporation           Unilever Inc.
Witco Corporation
                                                            O
                                                            U

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:48
posted:8/22/2011
language:English
pages:23