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Classification of liquids:-

LIQUIDS

MONOPHASIC BIPHASIC

ORAL USE

EXTERNAL USE

PARENTERAL SPECIAL USE

Used in Oral cavity

Used in other than oral cavity

LIQUID IN LIQUID

SOLIDS IN LIQUID

Oral useEMULSION

External useLINIMENTS

Parenteral OralSUSPENSION

ExternalLOTION

SOLUTIONDRAUGHTSDROPSLINCTUSESSYRUPSELIXIRS

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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

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Recent innovation in suspension

• More than 40 per cent of the drugs coming from high-throughput screening are poorly soluble in water.

• 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.

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Method of preparation1. 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

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Precipitation technique

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.

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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 solids.

Advantage:• Simple process• Low cost equipment• Ease of scale up Disadvantage• 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.

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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 resin.

In batch mode, the time required to obtain dispersions with unimodal distribution profiles and mean diameters<200nm is 3060 min(51 hr).

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Figure 1 Schematic representation of the media milling process 10

Advantages• 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.

Disadvantages• 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.

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B) Homogenization In Water (Dissocubes)

• R.H.Muller developed Dissocubes technology in 1999.

• The instrument can be operated at pressure varying from 100 – 1500 bars (2800 –21300psi) and up to 2000 bars with volume capacity of 40ml (for laboratory scale).

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3mm diameter

25µm

Principle:-

• 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 temperature.

• 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.

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Advantage• 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

administration.

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

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Application

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

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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 EvaluationC) Evaluation for surface-modified Nanosuspensions 1.Surface hydrophilicity 2. Adhesion properties 3. Interaction with body proteins

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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 drugs.

• 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.

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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

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Evaluation of SEDDS:

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

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Application

• 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.

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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• droplet size between

100 and 300 nm • Oil phase 40-50%

SMEDDS

• droplet size < 50 nm • Oil phase <20%

•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.

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ADVANTAGES OF SMEDDS:• 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 effects:

Several research papers specifying that, the performance of SMEDDS is independent of food and, SMEDDS offer reproducibility of plasma profile are available.

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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.

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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 solutions.

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

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Introduction

• 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.

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Application

• 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

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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 LIPOSOMS.

• NJ –TRI K indusry & its perant company Kemira have launched a new nano-based gel for skin care .In that NE is carrier system .

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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 pathogen.

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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.

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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 control.

• The study was developed to evaluate the potential of NEs for increasing the solubility and the in vitro transdermal delivery of carvedilol.

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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 aceclofenac.

• 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 control.

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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 drug.

• 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 phase.

• particle size range of 90-120 nm and zeta potential ranging from 134 mV to 245 mV.

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Self-nanoemulsifying drug delivery systems

• The research project was done to develop a self-nanoemulsifying drug delivery system (SNEDDS) for non-invasive delivery of protein drugs.

• Eg. Fluorescent-labeled beta-lactamase (FITC-BLM), a model protein, was loaded into SNEDDS through the solid dispersion technique.

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MULTIPAL EMULSION

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Introduction • 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 detail.

• 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.

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Preparation Multiple emulsions, either W/O/W or O/W/O

emulsions, are generally prepared using a 2-step procedure.

• 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.

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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. 40

• 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.

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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.

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methylene chloride containing PLA (0.50g)hydrophobic SPIO Fe3O4nanoparticles (0.5g)+

W/O microbubble emulsion

& deionized water (1 ml)Tween 80 (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.

Preparation of multiple emulsion microbubbles

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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.

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Homogenization and membrane emulsification

Dropwise extrusion through a syringe

Recovery and lyophilization.

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Reference1. Suryakanta Nayak et.al., Nanosuspension:A novel drug delivery system,

Journal of Pharmacy Research 2010, 3(2),pp.241-246.2. V. B. Patravale et.al., Nanosuspensions: a promising drug delivery

strategy jpp,2004,56,pp.-827 – 8403. Jiraporn CHINGUNPITUK, Nanosuspension Technology for Drug Delivery

Walailak J Sci & Tech 2007; 4(2) pp. 139-153.4. Shah P et.al., Nanoemulsion: A Pharmaceutical Review, Sys Rev Pharm ,

January-June 2010 ,Vol 1 , Issue 1,pp.24-32.5. Fang Yang et.al., Multiple emulsion microbubbles for ultrasound

imaging, www.sciencedirect.com, Materials Letters 62 (2008) pp.121–124

6. Fabienne Cournarie et.al., Insulin-loaded W/O/W multiple emulsions, European Journal of Pharmaceutics and Biopharmaceutics 58 (2004) pp.477–482

7. Ritesh B. Patel, Self-Emulsifying Drug Delivery Systems, Jul 2, 20088. Eiichi Toorisaka et.al, An enteric-coated dry emulsion formulation for

oral insulin delivery Journal of Controlled Release 107 (2005) pp.91–969. 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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