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Combining SPIO Fe3O4 nanoparticles with ultrasound imaging by QCT277


 Classification of liquids:-

            MONOPHASIC                                         BIPHASIC

USE        USE                      USE      LIQUID                        LIQUID

DRAUGHTS       Used in Oral    Used in other    Oral use   External use
DROPS             cavity      than oral cavity EMULSION    LINIMENTS
                                                  Parenteral         Oral      External
                                                                  SUSPENSION   LOTION
    Which are the novel innovations in
         liquid dosage forms??
•   Nanosuspensions in drug delivery
•   Nanoemulsions in drug delivery
•   Multiple emulsions in drug delivery
•   Self emulsifying drug delivery system
•   Self microemulsifying drug delivary system
•   Dry emulsion

      Recent innovation in suspension

• More than 40 per cent of the drugs coming from
  high-throughput screening are poorly soluble in
• There are number of formulation approaches to
  resolve the problems include micronization,
  solublization using co-solvents, use of permeation
  enhancers, oily solutions, surfactant dispersions, salt
  formation and precipitation techniques.
• Other techniques like liposome's, emulsions, micro
  emulsions, solid-dispersions and inclusion complexes
  using Cyclodextrins show reasonable success but
  they lack in universal applicability to all drugs.
              Method of preparation
1. Bottom Up technology(precipitation technique)

2. Top Up technology(disintegration technique)
A)Media Milling (Nanocrystals or Nanosystems)
B)Homogenization In Water (Dissocubes)
C)Homogenisation In Nonaqueous Media (Nanopure)
D)Combined Precipitation And Homogenization (Nanoedege)
E)Emulsification-solvent evaporation technique

                  Precipitation technique
Drug + solvent           solution         added to non-solvent which gives pptn

                 Rapid addition of a drug solution to an antisolvent

                       super saturation of the mixed solution

                 generation of fine crystalline or amorphous

 The NANOEDGE process (is a registered trademark of Baxter International
 Inc. and its subsidiaries) relies on the precipitation of friable materials for
 subsequent fragmentation under conditions of high shear and/or thermal
 energy .
 Precipitation of an amorphous material may be favored at high
 supersaturation when the solubility of the amorphous state is exceeded.
• Simple process
• Low cost equipment
• Ease of scale up

• Drug has to soluble at least in one solvent and
  that this solvent needs to be miscible with a
  non-solvent Growing of drug crystals needs to
  be limit by surfactant addition.
A) Media Milling (Nanocrystals or Nanosystems)
 Principle :
     The high energy and shear forces generated as a
   result of the impaction of the milling media with the
   drug provide the energy input to break the micro
   particulate drug into nano-sized particles.

      The milling medium is composed of glass,
   zirconium oxide or highly cross-linked polystyrene

   In batch mode, the time required to obtain dispersions
   with unimodal distribution profiles and mean
   diameters<200nm is 3060 min(51 hr).
Figure 1 Schematic representation of the media milling process   10
• Easy to scale up.
• Media milling is applicable to the drugs that are poorly soluble in
  both aqueous and organic media.
• High flexibility in handaling of large quantity of drug.
• Very dilute as well as highly concentrated nanosuspensions can be
  prepared by handling 1mg/ml to 400mg/ml drug quantity.
• Nanosize distribution of final nanosize products.

• Genaration of residue of milling media.
• Nanosuspensions contaminated with materials eroded from balls
   may be problematic when it is used for long therapy.
• The media milling technique is time consuming.
• Some fractions of particles are in the micrometer range.
• Scale up is not easy due to mill size and weight.

   B) Homogenization In Water (Dissocubes)

• R.H.Muller developed
  Dissocubes technology
  in 1999.
• The instrument can be
  operated at pressure    25µm
  varying from 100 –
  1500 bars (2800 –
  21300psi) and up to
  2000 bars with volume
  capacity of 40ml (for
  laboratory scale).
                                 3mm diameter

• In piston gap homogeniser particle size reduction is based on the cavitation
  principle. Particles are also reduced due to high shear forces and the collision of
  the particles against each other.

• According to Bernoulli’s Law the flow volume of liquid in a closed system per
  cross section is constant.

• The reduction in diameter from 3mm to 25µm leads to increase in dynamic
  pressure and decrease of static pressure below the boiling point of water at room

• Due to this water starts boiling at room temperature and forms gas bubbles,
  which implode when the suspension leaves the gap (called cavitation) and normal
  air pressure is reached.

• The size of the drug nanocrystals that can be achieved mainly depends on factors
  like temperature, number of homogenization cycles, and power density of
  homogeniser and homogenization pressure.

• Ease of scale-up and little batch-to-batch variation (Grauetal2000).
• It does not cause the erosion of processed materials.
• Very dilute as well as highly concentrated nanosuspensions can be
  prepared by handling 1mg/ml to 400mg/ml drug quantity.
• Narrow size distribution of the nano particulate drug Present in the final
  product (Muller&Bohm1998).
• It is applicable to the drugs that are poorly soluble in both aqueous and
  organic media.
• It allows aseptic production of nanosuspensions for parentral

• Preprocessing like micronization of drug is required.
• High cost instruments are required that increases the cost of dosage form.

•   Parenteral administration
•   Peroral administration
•   Ophthalmic drug delivery
•   Pulmonary drug delivery
•   Target drug delivery
•   Topical formulations

    Evaluation of nanosuspensions:–

A) In-Vitro Evaluations
        1. Particle size and size distribution
        2. Particle charge (Zeta Potential)
        3. Crystalline state and morphology
        4. Saturation solubility and dissolution velocity
B) In-Vivo Evaluation
C) Evaluation for surface-modified Nanosuspensions
        1.Surface hydrophilicity
        2. Adhesion properties
        3. Interaction with body proteins

     Self emulsifying drug delivery system
• Self-emulsifying drug delivery systems (SEDDSs) have gained exposure
  for their ability to increase solubility and bioavailability of poorly soluble

• SEDDSs are mixtures of oils and surfactants, sometimes containing
  cosolvents, and can be used for the design of formulations in order to
  improve the oral absorption of highly lipophilic compounds.

• SEDDSs emulsify spontaneously to produce fine oil-in-water emulsions
  when introduced into an aqueous phase under gentle agitation.

The self-emulsifying process is depends on:
• The nature of the oil–surfactant pair
• The surfactant concentration
• The temperature at which self-emulsification occurs.

            Mechanism of self-emulsification
• According to Reiss, self-emulsification occurs when the entropy
  change that favors dispersion is greater than the energy required to
  increase the surface area of the dispersion. The free energy of the
  conventional emulsion is a direct function of the energy required to
  create a new surface between the oil and water phases and can be
  described by the equation:

  DG = free energy
  N =number of droplets
  r= redius
  s= interfacial energy
               Evaluation of SEDDS:

•   Visual assessment
•   Turbidity Measurement
•   Droplet Size
•   Zeta potential measurement
•   Determination of emulsification time

• The system has the ability to form an oil-in-water
  emulsion when dispersed by an aqueous phase
  under gentle agitation.
• SEDDSs present drugs in a small droplet size and
  well-proportioned distribution, and increase the
  dissolution and permeability.

        SMEDDS are defined as isotropic mixtures of natural or synthetic oils,
solid or liquid surfactants, or alternatively, one or more hydrophilic solvents and
co-solvents/surfactants that have a unique ability of forming fine oil-in-water
(o/w) micro emulsions upon mild agitation followed by dilution in aqueous
media, such as GI fluids.
   SEDDS                                   SMEDDS
  • droplet size between                  • droplet size < 50 nm
     100 and 300 nm
                                          • Oil phase <20%
  • Oil phase 40-50%

  •When compared with emulsions, which are sensitive and metastable
  dispersed forms, SMEDDS are physically stable formulations that are easy
  to manufacture.

  •The SMEDDS mixture can be filled in either soft or hard gelatin capsules.

• Improvement in oral bioavailability:
  SMEDDS to present the drug to GIT in solubilised and micro emulsified
   form (globule size between 1-100 nm) and subsequent increase in
   specific surface area
  E.g. In case of halofantrine approximately 6-8 fold increase in BA of
   drug was reported in comparison to tablet formulation.

• Ease of manufacture and scale-up:
  Ease of manufacture and scale up is one of the most important
  advantage that makes SMEDDS unique when compared to other drug
  delivery systems like solid dispersions, liposomes, nanoparticles, etc.,
  dealing with improvement of BA.

• Reduction in inter-subject and intra-subject variability and food
   Several research papers specifying that, the performance of SMEDDS is
  independent of food and, SMEDDS offer reproducibility of plasma
  profile are available.
Ability to deliver peptides that are prone to enzymatic hydrolysis
                                in GIT:
• SMEDDS ability to deliver macromolecules like peptides, hormones,
  enzyme substrates and inhibitorsand their ability to offer protection
  from enzymatic hydrolysis.

No influence of lipid digestion process:
• SMEDDS is not influenced by the lipolysis, emulsification by the bile
  salts, action of pancreatic lipases and mixed micelle formation.

Increased drug loading capacity:
• SMEDDS also provide the advantage of increased drug loading capacity
  when compared with conventional lipid solution as the solubility of
  poorly water soluble drugs with intermediate partition coefficient (2<log
  P>4) are typically low in natural lipids and much greater in amphilic
  surfactants, co surfactants and co-solvents.

             Advantages of SMEDDS over emulsion:
•   The drawback of the layering of emulsions after sitting for a long time SMEDDS can be easily
    stored since it belongs to a thermodynamics stable system.

•   The size of the droplets of common emulsion ranges between 0.2 and 10 μm, and that of
    the droplets of microemulsion formed by the SMEDDS generally ranges between 2 and 100
    nm (such droplets are called droplets of nano particles).

•   Since the particle size is small, the total surface area for absorption and dispersion is
    significantly larger than that of solid dosage form and it can easily penetrate the
    gastrointestinal tract and be absorbed.
•   So, The bioavailability of the drug is therefore improved.

•   SMEDDS offer numerous delivery options like filled hard gelatin capsules or soft gelatin
    capsules or can be formulated in to tablets whereas emulsions can only be given as an oral

•   Emulsion can not be autoclaved as they have phase inversion temperature, while SMEDDS
    can be autoclaved.

• Nano emlsion are submicron sized, the thermodynamically stable
  isotropic system in which two immiscible liquid (water and oil) are
  mixed to form a single phase by means of an appropriate
  surfactants or its mix with a droplet diameter approximately in the
  range of 0.5-100 um. Nanoemulsion droplet sizes fall typically in
  the range of 20-200 nm and show narrow size distributions.

•   NE in cosmetics
•   NE in mucosal vaccines system.
•   Antimicrobial NE.
•   NE in non-toxic disinfectant cleaner.
•   NE in cancer therapy & in targeted drug delivery.
•   NE in various disease condition.
•   NE formulations for improve oral delivery of poorly
    soluble drugs.
•   NE as a vehicle for TDDS.
•   Solid SNEDS as a platform tech. for formulation of
    poorly solubal drugs

     Nanoemulsion in cosmetics
• They can form a optimum dispersion of active
  ingrediant .
• Due to their lipophilic interior,NEs are more
  suitable for trasport of lipophilic drug then
• NJ –TRI K indusry & its perant company
  Kemira have launched a new nano-based gel
  for skin care .In that NE is carrier system .

          Antimicrobial NE
• Antimicrobial NEs are oil-in-water droplets
  that range from 200 to 600 nm. They are
  composed of oil and water and are stabilized
  by surfactants and alcohol.
• This fusion is enhanced by the electrostatic
  attraction between the cationic charge of the
  emulsion and the anionic charge on the

   NE in cancer therapy & in targeted drug delivery.
• In order to achieve absorption of Paclitaxel , formulatad in NE increase the
  BA of 70.62% .

• Inhibition of P-glycoprotein efflux by D-tocopheryl polyethyleneglycol 1000
  succinate and labrasol would have contributed to the enhanced peroral
  bioavailability of PCL.

• Camptothecin is a topoisomerase I inhibitor that acts against a broad
  spectrum of cancers. However, its clinical application is limited by its
  insolubility, instability, and toxicity .

• The NEs were prepared using liquid perfluorocarbons and coconut oil as the
  cores of the inner phase. These NEs were stabilized by phospholipids and/or
  Pluronic F68 (PF68). The NEs were prepared at high drug loading of
  approximately 100% with a mean droplet diameter of 220-420 nm.        32
     Nanoemulsions as a vehicle for
         transdermal delivery
• NEs have great potential for transdermal drug
  delivery of aceclofenac.
• The NEs of the system containing ketoprofen
  evidenced a high degree of stability. Ketoprofen-
  loaded Nes enhanced the in vitro permeation
  rate through mouse skins as compared to the
• The study was developed to evaluate the
  potential of NEs for increasing the solubility and
  the in vitro transdermal delivery of carvedilol.
    Nanoemulsions as a vehicle for
        transdermal delivery
• From in vitro and in vivo data, it was
  concluded that the developed NEs have great
  potential for transdermal drug delivery of
• The NEs of the system containing ketoprofen
  evidenced a high degree of stability &
  enhanced the in vitro permeation rate
  through mouse skins a compared to the

Nanoemulsion formulations for improved oral
delivery of poorly soluble drugs

• NE formulations were developed to enhance oral
  bioavailability of hydrophobic drugs.
• Paclitaxel was selected as a model hydrophobic
• The oil-in-water (o/w) NEs were made with pine
  nut oil as the internal oil phase, egg lecithin as
  the primary emulsifier, and water as the external
• particle size range of 90-120 nm and zeta
  potential ranging from 134 mV to 245 mV.
  Self-nanoemulsifying drug delivery
• The research project was done to develop a
  self-nanoemulsifying drug delivery system
  (SNEDDS) for non-invasive delivery of protein
• Eg. Fluorescent-labeled beta-lactamase (FITC-
  BLM), a model protein, was loaded into
  SNEDDS through the solid dispersion


•   Multiple emulsions are complex polydispersed systems where both oil in water and
    water in oil emulsion exists simultaneously which are stabilized by lipophillic and
    hydrophilic surfactants respectively.

•   The ratio of these surfactants is important in achieving stable multiple emulsions.

•   Among water-in-oil-in-water (w/o/w) and oil-in-water-in-oil (o/w/o) type multiple
    emulsions, the former has wider areas of application and hence are studied in great

•   It finds wide range of applications in controlled or sustained drug delivery, targeted
    delivery, taste masking, bioavailability enhancement, enzyme immobilization, etc.

•   Multiple emulsions have also been employed as intermediate step in the
    microencapsulation process and are the systems of increasing interest for the oral
    delivery of hydrophilic drugs, which are unstable in gastrointestinal tract like proteins
    and peptides.

•   With the advancement in techniques for preparation, stabilization and rheological
    characterization of multiple emulsions, it will be able to provide a novel carrier
    system for drugs, cosmetics and pharmaceutical agents.

  Multiple emulsions, either W/O/W or O/W/O
  emulsions, are generally prepared using a 2-step
• For W/O/W emulsions, the primary emulsion (W/O) is
  first prepared using water and a low-HLB surfactant
  solution in oil. In the second step, the primary emulsion
  (W/O) is reemulsified in an aque-ous solution of a high-
  HLB surfactant to produce a W/O/W multiple emulsion.
• The first step is usually carried out in a high-shear device
  to produce very fine droplets. The second emulsification
  step is carried out in a low-shear device to avoid
  rupturing the multiple droplets.

Multiple emulsion microbubbles for ultrasound imaging
        (Materials Letters 62 (2008) 121–124 )
  • Air or N2 or perfluorocarbon only encapsulated microbubbles which
    are currently used have lower efficiency and short imaging time.

  • So the novel contrast agents with a higher efficiency are required.

  • To achieve this objective, the strategy that we have explored
    involves the use of superparamagnetic iron oxide (SPIO) Fe3O4
    nanoparticles multilayer emulsion microbubbles.

  • This multilayer structure consists of three layers.

  •   The core is poly-D, L-lactide (PLA) encapsulated N2 nanobubble
      with the SPIO nanoparticles forming oil-in-water (W/O) layer.

  • The outermost is water-in-oil-in-water ((W/O)/W) emulsion layer
    with PVA solution.
• An overall diameter of around 2μm–8μm.

• On the one hand, the stable gas encapsulated microstructure can
  provide a high scattering intensity resulting in high echogenicity, On
  the other hand, SPIO nanoparticles have shown the potential of
  high resolution sonography.

• So the multiple emulsion microbubbles with SPIO can have double
  action to enhance the ultrasound imaging.

•    Besides, because SPIO can also serve as magnetic resonance
    imaging (MRI) contrast agents, such microstructure may be useful
    for multimodality imaging studies in ultrasound imaging and MRI.

• Combining SPIO Fe3O4 nanoparticles with ultrasound imaging
  technique may be more attractive in ultrasound molecular imaging
  and also may provide a dramatic increase in resolution over
  conventional clinical diagnostic ultrasound scanners.
    Preparation of multiple emulsion microbubbles

•    The methylene chloride organic solution (10.00ml) was prepared
    containing PLA (0.50g) and hydrophobic SPIO Fe3O4 nanoparticles
    (0.5g) at 25°C.
•    To generate the first W/O microbubble emulsion, 1.00mL deionized
    water and a few Tween 80 (about 1.00ml) were added to the
    organic solution and sonicated continuously by ultrasound probe at
    100W with constant purging using a steady (4ml/min) stream of N2
    gas for 5min.
•   The W/O microbubble emulsion is brown and visibly homogeneous.
•    The dissociated Fe3O4 can be separated from the first emulsion
    microbubbles solution under an external magnetic field.
•   The first W/O microbubble emulsion was then poured into a 1%
    PVA(w/v) solution and mixed mechanically for 2h to form(W/O)/ W
    multiple emulsion microbubbles and to eliminate the organic
    solution. After reaction, the final emulsion became milk-white.

                  Preparation of multiple emulsion microbubbles
                                                    hydrophobic SPIO Fe3O4
   methylene chloride containing PLA (0.50g)   +    nanoparticles (0.5g)

                               W/O microbubble emulsion      +
                                                   Tween 80 (1 ml) & deionized water (1 ml)
   sonicated continuously by ultrasound probe at 100W with constant purging using a steady
                             (4ml/min) stream of N2 gas for 5min

                      brown and visibly homogeneous W/O emulsion

           poured into a 1% PVA(w/v) solution and mixed mechanically for 2h

                               eliminate the organic solution.

(W/O)/ W multiple emulsion microbubbles is ready and the final emulsion became milk-white.
                        Dry emulsion
• A novel oral dosage formulation of insulin consisting of a surfactant, a
  vegetable oil, and a pH-responsive polymer has been developed. First, a
  solid-in-oil (S/O) suspension containing a surfactant–insulin complex
  was prepared.

• Solid-in-oil-in-water (S/O/W) emulsions were obtained by
  homogenizing the S/O suspension and the aqueous solution of
  hydroxypropylmethylcellulose phthalate (HPMCP).

•   A microparticulate solid emulsion formulation was successfully
    prepared from the S/O/W emulsions by extruding them to an acidic
    aqueous solution, followed by lyophilization.

• The insulin release from the resultant dry emulsion responded to the
  change in external environment simulated by gastrointestinal
  conditions, suggesting that the new entericcoated dry emulsion
  formulation is potentially applicable for the oral delivery of peptide and
  protein drugs.

Homogenization and membrane emulsification

Dropwise extrusion through a syringe

Recovery and lyophilization.

1.   Suryakanta Nayak, Nanosuspension:A novel drug delivery system,
     Journal of Pharmacy Research 2010, 3(2),pp.241-246.
2.   V. B. Patravale, Nanosuspensions: a promising drug delivery
     strategy jpp,2004,56,pp.-827 – 840
3.   Jiraporn CHINGUNPITUK, Nanosuspension Technology for Drug Delivery
     Walailak J Sci & Tech 2007; 4(2) pp. 139-153.
4.   Shah P, Nanoemulsion: A Pharmaceutical Review, Sys Rev Pharm ,
     January-June 2010 ,Vol 1 , Issue 1,pp.24-32.
5.   Fang Yang, Multiple emulsion microbubbles for ultrasound imaging,, Materials Letters 62 (2008) pp.121–124
6.   Fabienne Cournarie, Insulin-loaded W/O/W multiple emulsions,
     European Journal of Pharmaceutics and Biopharmaceutics 58 (2004)
7.   Ritesh B. Patel, Self-Emulsifying Drug Delivery Systems, Jul 2, 2008
8.   Eiichi Toorisaka, An enteric-coated dry emulsion formulation for oral
     insulin delivery Journal of Controlled Release 107 (2005) pp.91–96
9.   Anand U. Kyatanwar et al. Self micro-emulsifying drug delivery system
     (SMEDDS) : Review Journal of Pharmacy Research 2010, 3(1),pp.75-83


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