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Among all the routes the oral drug delivery has been known for years as the most commonly used route of administration that have been explored for the systemic delivery. The oral route achieved such popularity because administration is easy as well as the traditional believed that when drug is administered orally of the drug is absorbed well as the food stuff. Gastrointestinal physiology depends the absorbtion of the drug irrespective of its physical form. Therefore for the development of oral delivery need varying extent of optimization. Therefore a fundamental understanding of various disciplines, including GI physiology, pharmacokinetics, pharmacodynamics, and formulation design is necessary to achieve a successful development of an oral pharmaceutical dosage form, for this an oral drug delivery system consist of a basic understanding of the following three aspects,
Physiochemical ,pharmacokinetic and pharmacodynamic characteristic of the drug.
Anatomy and physiological characteristics of GIT
Physiochemical characteristics and the drug delivery mode of the dosage form.
Gastro intestinal tract physical dimension and dynamics
0.1 - 0.2
50 min 8 hrs
2 -6 hrs 4 -9 hrs
2-6 hrs 3hr-3days
The oral route is the preferred route for chronic drug therapy. Numerous potent lipophilic drugs exhibit low oral bioavailability due to their poor aqueous solubility properties. This class of compounds explained by Amidon et.al as low solubility/high permeability class, dissolution in the environment lumen is the rate controlling step in the absorption process. Efforts are ongoing to enhance the oral bioavailability of lipophiliic drug in order to increase their clinical efficacy.
NOVEL APPROACHES FOR INCREASING BIOAVAILABILITY OF POORLY WATER SOLUBLE DRUGS
Oral route drug delivery is limited to those drug which are poorly water soluble and having less permeability across the gastric mucosa. Novel techniques which are employed for bioavailability enhancement of water insoluble drugs are the following,
SIZE REDDUCTION TECHNOLOGIES
Drug particle are reduced to micron or nano size by
MEDIA MILLING/ NANO CRYSTAL TECHNOLOGY
NANO SUSPENSION BY HOMOGENIZATION TECHNIQUE
1) HOMOGENIZATION IN WATER
2) HOMOGENIZATION IN AQUEOUS MEDIA
1) SPRAY FREEZING INTO LIQUID
BY USING SUPERCRITICAL FLUID TECHNOLOGY
1) RAPID EXPANSION OF SUPER CRITICAL SOLUTIONS (RESS)
2) ANTI SOLVENT PROCESS
GAS ANTI SOLVENT RECRYSTALIZATION
SUPERCRITICAL ANTI SOLVENT TECHNIQUE
PRECIPITATION WITH COMPRESSED FLUID ANTI SOLVENTS
3) SOLUTION ENHANCED DISPERSION WITH SUPERCRITICAL FLUID
1) MIXED MICELLES
2) POLYMERIC MICELLES
POROUS MICRO PARTICLE TECHNOLOGY
SOLID DISPERSION TECHNOLOGY
a) INSULIN GLASSES/ SUGAR GLASSESS
LIPID BASED DRUG DELIVERY SYSTEM
1) LIPID BASED EXCIPIENT
2) LIPID EMULSION TECHNOLOGY
SELF DISPERSING LIPID FORMULATION
a) SELF EMULSIFYING DRUG DELIVERY SYSTEM
b) SELF MICROEMULSIFYING DRUG DELIVERY SYSTEM
Lipid Based Delivery Systems
Lipid-based formulations showed an enhancement of oral absorption of lipophilic drugs due enhanced drug solubilisation, increased membrane permeability and lymphatic transport. Lipid-based formulations incorporating lipophilic drugs-such as cyclosporine (NeoralÂ®), ritonavir (NorvirÂ®) and saquinavir (FortovaseÂ®) achieved clinical and commercial successes.
The lipid based delivery systems comprises Lipid Solutions, Lipid Emulsions, Micro emulsion and Self Dispersing Lipid Formulations (SDLF). Bioavailability improvement with lipids occurs due to the solubilizaton of the hyrdopophibic drugs.
The first pass metabolism of the drug can be prevented by are administiring with lipids. The administration of the drug with lipid influences their way of absorption of the drug. The high lipophilicity of the formulation facilitates absorption into the intestinal lymphatic and then to the systemic circulation and thus the firstpass metabolism of the drug is prevented. The important step for the bioavailability enhancement for the lipid solutions is the digestion of lipids. By dissolving the drug in vegetable oil or by dissolving the drug in medium chain triglycerides, lipid solutions can be formulated.
Diagramatic representation of the steps in oral drug absorption of lipid-based formulations.
Lipid Emulsion Technology
The lipophilic drugs can be carried by using lipid emulsions. Their basic structure of the lipid emulsion is a neutral lipid core which is stabilized by a monolayer of amphiphilic. The stability of the emulsion can be increased by the addition of a non-ionic surfactant. The formulations can be formed by the application of high shear,impaction (homogenization, ultrasonication, etc.). Globule size of 100 nm and lesser can be obtained. The oral bioavailability of hydrophobic drugs can be increased by micro emulsion drug delivery system. microemulsion drug delivery system can be formulated by lipophilic solubilization technology (LST).
Lipid formulation classification system was documented by Pouton in 2000. According to their composition and the probable effect after dilution and digestion and their ability to prevent drug precipitation lipid based formulation are classified into four types
Oils without surfactants (e.g. tri-, di-and mono-glycerides)
Non-dispersing, requires digestion
Safe status; simple; excellent capsule compatibility
Formulation has poor solvent capacity unless drug is highly lipophilic
Oils and water insoluble surfactants
SEDDS formed without water soluble components
Unlikely to lose solvent capacity on dispersion
Turbid o/w dispersion (particle size 0.25-2 Âµm)
Oils, surfactants, co-solvents (both water insoluble & water soluble
SEDDS/SMEDDS formed with water soluble components
Clear or almost clear dispersion; drug absorption without digestion
Possible loss of solvent capacity on dispersion; less easily digested
Water-soluble surfactants and co-solvents (no oils)
Formulation disperses typically to form a micellar solution
Formulation has good solvent capacity for many drugs
Likely loss of solvent capacity on dispersion; may not be digestible
Classification System Lipid based Formulation
Lipid based formulation approaches, particularly the self micro emulsifying drug delivery system are well-known for their potential as substitute strategies for delivery of lipophilic drugs. The self dispersing lipid formulation is a new technique to conquer formulation problems hydrophobic drugs, to enhance the oral bioavailability of poorly absorbed drugs.
Self Dispersing Lipid Formulations (SDLF)
The formulation problems of various hydrophobic drugs can be solved by the SDLF. The SDLF can be formulated by using oil and a surfactant mixture. to this oily phase the drug is incorporated. This formulation are emulsified when mixed with an aqueous environment .The self-emulsification process will differ according to particular surfactant, co surfactant, oil ratios and the temperature at which self-emulsification takes place. The self-dispersed drug from SDLF is quickly distributed throughout the GIT as excellent droplets. The positively charged particles from SDLF penetrates deeper into the ileum because the mucosal lining is negatively chargeds. The formed droplets from SDLF are either positively or negatively charged. The greater bioavailability has been shown by cationic emulsion than an anionic emulsion.
SELFMICROEMULSIFYING DRUG DELIVERY SYSTEM
SMEDDS is one the method for improvement of oral bioavailability of lipophilic drug. SMEDDS formulations are isotropic combination of oil, a surfactant, co surfactant, and a drug that forms emulsion on mixing with water with little or no energy input. The basic principle of this system is the ability to form fine oil in water microemulsions under mild agitation subsequent dilution by aqueous phase. The peristaltic movement of the stomach and intestine make available the agitation in GIT, which is essential for self emulsification of SMEDDS. The rapid formation of microemulsion in the gastro intestinal tract keep the drug in a solubilized form and the droplets formed are small in size which offers a great interfacial surface area for drug absorption. Apart from solubilization the occurrence of lipid in formulation further helps to improve bioavailability by carrying out the drug absorption.
Self emulsifying drug delivery system that is type II and self micro emulsifying drug delivery system that is type III are well known formulation which offers greater oral bioavailability due to increased surface area, formed on dispersion. Therefore the formulation is independent on bile secretion for absorption . The rapid transport of hydrophobic drug into the blood can be achieved by SMEDDS. The SMEDDS can be administered by filling into hard or soft gelatin capsules.
METHODS OF PREPARATION OF SMEDDS
For the formulation of SMEDDS the following techniques can be used
APPLICATION OF HIGH SHEAR
CAVITATION OR IMPACTION
Homogenization is the technique of blending of mutually related substances or group of mutually related substances with or without addition of surfactant and co surfactant to obtain a suspension or emulsion. The co surfactant added will increase the stability of the formulation.
Microemulsion Formation Theories
The three approaches used to clarify microemulsion formation and stability are
(i) Interfacial or mixed film theoriesÂ
(ii) Solubilization theoriesÂ
(iii) Thermodynamic treatmentsÂ
Â Microemulsion Formation
The formation of oil droplets from the formulation is accompanied by an increase in the interfacial area, DA, and the interfacial energy DG.. TDS The entropy of dispersion of the droplets from the formulation. The following formula explains the free energy of formation,
DGÂ Â Â Â Â Â =Â Â Â Â Â Â Â Â Â DA -Â TDS
With the microemulsion formed from the formulation the interfacial tension can be sufficiently low that the interfacial energy becomes similar to the entropy of dispersion or even lesser than the entropy of dispersion of the particles.
Here the thermodynamic stability of microemulsions was explained why because the free energy of formation of the system becomes zero or negative.
Microemulsions are homogenous, transparent liquid suspensions of water and oil that are prepared and thermodynamically stable by the addition of relatively large amount of a surfactant and co-surfactant. Microemulsions droplets diameter are in the range of 10-200nm.
Microemulsions are homogenous, transparent liquid suspensions of water and oil that are prepared and thermodynamically stable by the addition of relatively large amount of a surfactant and co-surfactant. The microemulsions can be formulated by simple mixing of oil, water, surfactant and co surfactant. Classification of microemulsions can be done in two ways water in oil and oil in water. W/0 and O/W microemulsions are formulated by emulsifiers of HLB in the range 3-6, 8-18 respectively. Both the co surfactant and the surfactant together reduces the interfacial tension to extremely low and even transient negative values.
THREE TYPES MICROEMULISIONS
Oil in Water Microemulsion
Water in Oil Microemulsion
Characteristics Of Microemulsions
Particle size of microemulsion is less than 200 nm
Microemulsions are thermodynamically stable
Microemulsions are Optically clear
Microemulsions have increased surface area
Microemulsions possess high solubilizing capabilities
Advantages Of Microemulsion Based SystemsÂ
Microemulsions are thermodynamically stable.
Microemulsions can act as super solvents of drug.Â They can solubilize both lipophilic and lipophobic drugs.
The dispersed phase, hydrophobic or hydrophilic can act as a potential reservoir of hydrophobic or hydrophilic drugs, respectively.Â
The droplets in microemulsions diameter is under 0.22 mm; the sterilization is done by filtration technique.Â The small size of droplet in microemulsions , below 100 nm, yields extremely large interfacial area which makes release rapid into external phase.
similar microemulsions can carry both hydrophobic and hydrophilic drugs.
Microemulsions are simple to prepare and require no important energy contribution during formulation.Â
The microemulsion delivery systems can improve the effectiveness of a drug, and thus the total dose can be reduced and thus side effects can be reduced.
Disadvantages of Microemulsion
concentration of surfactant and co-surfactant needed is more for stabilizing the nanodroplets.
solubilizing capacity is less for high-melting substances. Harmless surfactant must be used.
The stability of microemulsion is effected by temperature and pH, that is from patients to patients the therapeutic effect may vary.
Comparison with Emulsions and MacroemulsionsÂ
Â Â Emulsions
In emulsions spherical droplets of one phase dispersed into the other.
They change between droplet like swollen micelles to bicontinuous structure.
Droplet diameter: 1 - 20 mm.
Droplet diameter 10 - 200 nm.
Most emulsions are opaque (white) because droplets is larger than wavelength of light and most oils refractive indices is higher than water.
Microemulsions are translucent because droplet diameter are less than Â¼ of the wavelength of light.
in Ordinary emulsion droplets exist as individual entities until coalesance
Micro emulsion droplet may disappear within a fraction of a second.
They remain stable for long periods of time. They are kinetically stable and thermodynamically unstable.
Emulsions are lyophobic.
This are on the borderline between lyophobic and lyophilic colloids.
Powerful agitation is needed for their formation.
Generally formulated by mild mixing of ingredients.
Phase Behaviour Studies
By using ternary phase diagram the phase behaviour of microemulsion systems can be studied. In each corner of the diagram 100 percentage concentration of the particular components is represented.
Normally, pharmaceutical microemulsions comprises co surfactant and/or drug.Â A large number of drug molecules may themselves effect in phase behavior characteristics.
Characterization Of SMEDDS
Characterization of microemulsions can be done by various techniques.Â The characterization of microemulsions is a hard task as well as the limitations associated because of the complexity, variety of structures and components involved in these systems. The physicochemical properties of microemulsions can be found out by matching studies.Â Useful information can be obtained by finding out In the macroscopic level viscosity, conductivity.
PHASE BEHAVIOR STUDIES
The boundaries of the different phases can be studied with the help Phase diagram. The effectiveness of different surfactants can be found out from Phase behaviour studies.
SCATTERING TECHNIQUES FOR MICROEMULSIONS CHARACTERIZATION
study of microemulsions can be done by Smallâˆ’angle Xâˆ’ray scattering (SAXS), smallâˆ’angle neutron scattering (SANS), and static as well as dynamic light scattering.
NUCLEAR MAGNETIC RESONANCE STUDIES
By using nuclear magnetic resonance techniques the structure and dynamics of microemulsions can be observed. Self-diffusion study of the particles can be done by means of different tracer techniques, generally radio labeling, supply information on the mobility of the components.Â
The interfacial tension of the formulation depends the formation and the properties of microemulsion. The formation and the properties of microemulsion can be studied by measuring the ultra low values of interfacial tension are correlated with phase behavior. The instrument used for measurement is spinning drop apparatus.
Microemulsion formulation may contain the presence of rodâˆ’like or wormâˆ’like reverse micelle.Â The presence of type of micelle present in the formulation can be found out from Viscosity measurements.
Highly conductances has been observed in O/W microemulsion where the external phase is water, but W/O type microemulsion wont show. The detection of phase inversion phenomena explains the nature of the continuous phase and this determination can be done by the electrical conductivity measurements.
(H) ELECTRON MICROSCOPE CHARACTERIZATION
Transmission Electron Microscopy (TEM) and Scanning electron microscopy (SEM), captures secondary electron produced from the sample surface and is captured by camera. From this the morphological character of the formulation can be explained.
VISUAL ASSESSEMENT OF SELF MICROEMUSIFICATION
The formulated SMEDDS can be graded on the basis of visual assessment that is from which type of appearance is it showing.
DETRMINATION OF SELF EMULSIFICATION TIME
Emulsification time is the most important parameter for SMEDDS and microemulsion formulation. By determining the emulsification time the formulated SMEDDS can be graged.
IN VITRO DRUG RELEASE STUDIES
By carrying out the in vitro drug release studies the release profile of the drug from the formulated SMEDDS was studied.
CLOUD POINT MEASUREMENT
The determination of the cloud point of the formulation explains that up to which temperature the formulation is stable.
For checking the stability of the formulated SMEDDS the stability studies was carried out under different temperature cycles.
ADVANTAGES OF SMEDDS
improved oral bioavailability enabling reduction in
extra consistent temporal profiles of drug absorption
Selective targeting of drug(s) towards specific absorption window in GIT
Protection of drug(s) from the host environment in gut
Recreased variability including food effects.
Prevention of sensitive drug substances.
In SMEDDS, the lipid matrix interacts readily with water, and the formed the emulsion droplets will deliver the drug to the gastrointestinal mucosa in the dissolved state readily accessible for absorption and shows an increase in AUC , bioavailability and C max is observed with many drugs when presented in SMEDDS.
Fine oil droplets empty rapidly from the stomach and promote wide distribution of drug throughout the intestinal tract and thereby minimizing irritation frequently encountered with extended contact of drugs and gut wall
Ease of manufacture and scale up is one of the most important advantage that make SMEDDS unique when compared to other drug delivery system like solid dispersion, liposomes, nanoparticles etc.
peptides that are processed to enzymatic hydrolysis in GIT can be delivered by SMEDDS
When polymer is incorporated in composition of SMEDDS it gives prolonged release of
The dissolution and permeability of SMEDDS formulation is increased due to the presence of drugs in a small droplet size and well-proportioned distribution.
From SMEDDS drug is delivered to the lymphatic system can bypass first pass metabolism.
In SMEDDS drug is loaded in the inner phase Thus protect drugs against hydrolysis by enzymes in the GI tract and reduce the pre systemic clearance in the GI mucosa and hepatic first-pass metabolism.
DRAWBACK OF SMEDDS
One of the obstacles for the development of self micro emulsifying drug delivery systems
(SMEDDS) and other lipid-based formulations is the lack of good predicative in vitro models for
assessment of the formulation. Traditional dissolution methods do not work because these formulations potentially are dependent on digestion prior to release
of the drug. To mimic this, in vitro model simulating the digestive processes of the duodenum has been developed. This in vitro model needs further
development and validation before its strength can be evaluated. Further development will be based on invitro in-vivo correlations and therefore different prototype lipid based formulations need to be
developed and tested in vivo in a suitable animal model.