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Among all the route, the oral drug delivery has been known for years as it is 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 it is absorbed well as the food stuff.1,2 Gastrointestinal physiology effects the absorption of the drug irrespective of its physical form. Therefore for the development of oral drug 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.3
Table No: Gastro intestinal tract physical dimension
SURFACE AREA (m2)
0.1 - 0.2
50 min 8 hrs
2 -6 hrs 4 -9 hrs
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 are explained by Amidon et al., as low solubility/high permeability class. Efforts are ongoing to enhance the oral bioavailability of lipophiliic drugs in order to increase their clinical efficacy. 1,4
NOVEL APPROACHES FOR INCREASING BIOAVAILABILITY OF POORLY WATER SOLUBLE DRUGS1
Oral route drug delivery is limited to those drugs which are poorly water soluble and having less permeability across the gastric mucosa. Novel techniques which are employed for enhancement bioavailability of water insoluble drugs are the following:
SIZE REDUCTION TECHNOLOGIES1
Drug particles are reduced to micron or nano size by
Media Milling/Nano Crystal Technology
Nano suspension by homogenization technique
Homogenization in water
Homogenization in aqueous media
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
Porous micro particle technology
Solid dispersion technology
Insulin glasses/ sugar glasses
Lipid based drug delivery system
Lipid based excipient
Lipid emulsion technology
a. Microemulsion technology
b. Self dispersing lipid formulation
i. Self emulsifying drug delivery system
ii. Self microemulsifying drug delivery system
Lipid Based Delivery Systems1,5,6
Lipid-based formulations showed an enhancement of oral absorption of lipophilic drugs due to enhanced drug solubilisation, enhanced membrane permeability and lymphatic transport. Lipid-based formulations incorporating lipophillic drugs such as cyclosporine (Neoral®), ritonavir (Norvir®) and saquinavir (Fortovase®) achieved clinical and commercial success.
The lipid based delivery systems comprises Lipid Solutions, Microemulsion, Lipid Emulsions, and Self Dispersing Lipid Formulations (SDLF).
The first pass metabolism of the drug can be prevented by administering with lipids. The administration of the drug with lipid influences their way of absorption of the drug. The high lipophilicity of the formulation improves the absorption of the drug. Thus the firstpass metabolism of the drug is prevented. The important step for the bioavailability enhancement of 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.
Figure : Diagramatic representation of the steps in oral drug absorption of lipid-based formulations1.
Lipid Emulsion Technology1,7
The lipophilic drugs can be carried in lipid emulsions. The basic structure of the lipid emulsion is a neutral lipid core which is stabilized by a monolayer of amphiphilic lipid. The stability of the emulsion can be increased with the help 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 or 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.
Table No: Classification System Lipid based Formulation8
Oils without surfactants (e.g. tri-, di-and mono-glycerides)
Non-dispersing, requires digestion
Safe status; simple; excelent capsule compatibility
Formulation has poor solvent capasity unless drug is highly lipophilic
Oils and water insoluble surfactants
SEDDS formed without water soluble componets
Unlikely to lose solvent capacity on dispersion
Turbid o/w dispercion (particle size 0.25-2 µm)
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 capasity on dispersion; less easily digested
Water-soluble surfactants and co-solvents (no oils)
Formulation disperses typicaly to form a micellar solution
Formulation has good solvent capacity for various drugs
Likely loss of solvent capacity on dispersion; may not be digistible
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 of 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 is emulsified when mixed with an aqueous environment .The self-emulsification process will differ according to particular surfactant, co-surfactant, oil ratios. The self-dispersed drug from SDLF is quickly distributed throughout the GIT as excellent droplets. The positively charged particles from SDLF penetrate deeper into the ileum because the mucosal lining is negatively charged. The formed droplets from SDLF are either positively or negatively charged. The greater bioavailability has been shown by cationic emulsion than an anionic emulsion. 1,9,10
SELF MICROEMULSIFYING DRUG DELIVERY SYSTEM
SMEDDS is one of the methods for improvement of oral bioavailability of lipophilic drugs. SMEDDS formulations are isotropic combination of oil, 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 with subsequent dilution by an aqueous phase. The peristaltic movement of the stomach and intestine causes the agitation in GIT, which is essential for self emulsification of SMEDDS. The rapid formation of microemulsion in the gastro intestinal tract keeps 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 formulations which offer 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. 1,8,11,12,13
Figure No: Steps involved in SMEDDS absorption11
METHODS OF PREPARATION OF SMEDDS1
For the formulation of SMEDDS the following techniques can be used
Application of high shear
Cavitation or impaction
Microemulsion Formation Theories14
The three approaches used to clarify microemulsion formation and stability are
(i) Interfacial or mixed film theories
(ii) Solubilization theories
(iii) Thermodynamic treatments
Figure No: Microemulsion formulation14
The formation of oil droplets from the formulation is complied by an increace in the intrfacial 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,
DG = DA - 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 fre energy of formation of the system becomes null or in negative value.
Microemulsions are homogenous, transparent liquid suspensions of water, oil, surfactant and co-surfacant. Microemulsions droplets diameter are in the range of 10-200nm.
Microemulsions are homogenous, transparent liquid suspensions of water, and oil, 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 which are having HLB value in the range of 3-6 and 8-18 respectively. Both the co-surfactant and the surfactant together reduce the interfacial tension to extremely low and even transient negative values.
Figure No: Microemulsion Technology14
THREE TYPES MICROEMULISIONS14
Oil in Water Microemulsion
Water in Oil Microemulsion
Figure No : Types of microemulsion 14
Characteristics Of Microemulsions14,18
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 Systems14,19,20,21
Microemulsions are thermodynamically stable.
Microemulsions can act as super solvents of drug. 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.
The droplets in microemulsions diameter is under 0.22 mm. The sterilization is done by filtration technique. The smal 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.
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 Microemulsion14,22
More Concentration of surfactant and co-surfactant is needed 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, so that from patients to patients the therapeutic effect may vary.
Figure No: Comparison with Emulsions and Macroemulsions
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. A large number of drug molecules may themselves effect in phase behaviour characteristics.14,23,24
Figure No: 6 Ternary Phase Diagram14
Characterization Of SMEDDS14,23,24,25
Characterization of SMEDDS can be done by various techniques. The characterization of SMEDDS is a hard task as well as the limitations associated because of the complexity. The physicochemical properties of SMEDDS can be found out by matching studies. 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 of 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 scatering, smallâˆ’angle neutron scattering, and static as well as dynamic light scattering.
NUCLEAR MAGNETIC RESONANCE STUDIES
By using NMR techniques the structure and dynamic of microemulsions can be observed. Self-diffusion study of the particles can be done by means of different tracer techniques, generally radio labelling, suply information on the mobility of the components.
The interfacial tension of the formulation depends on the formation and the propertes of microemulsion. The formation and the properties of microemulsion can be studied by measuring the ultra low values of interfacial tension which are correlated with phase behaviour. The instrument used for measurement is spinning drop apparatus.
Highly conductance has been observed in O/W microemulsion where the external phace 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.
ELECTRON MICROSCOPE CHARACTERIZATION
Transmission Electron Microscopy and Scanning electron microscopy, 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 it is showing.
DETERMINATION OF SELF EMULSIFICATION TIME
Emulsification time is the most important parameter for SMEDDS and microemulsion formulation. By determining the emulsification time, grading of the formulated SMEDDS can be done.
IN VITRO DRUG RELEASE STUDIES
The release profile of the drug from the formulated SMEDDS was studied by carrying out in vitro dissolution.
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 SMEDDS1,8,11,24
Improved oral bioavailability enabling reduction in dose.
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 GIT.
Decreased variability including food effects.
Prevention of sensitive drug substances.
In SMEDDS, the lipid matrix interacts readily with water and the formed microemulsion droplets disperse the drug to the gastrointestinal mucosa and makes accessible for absorption and shows an increase in AUC. Increased bioavailability and Cmax is observed with many drugs when presented in SMEDDS.
Fine oil droplets are rapidly emptyed 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.
Using SMEDDS, Peptides can be delivered and thus enzymatic hydrolysis of peptides in GIT can be prevented.
When polymer is incorporated in composition of SMEDDS it gives prolonged release of drug.
The dissolution and permeability of SMEDDS formulation is increased due to the presence of small size of drugs.
From SMEDDS, drug is delivered to the lymphatic system and thus bypass first pass metabolism.
In SMEDDS, drug is loaded in the inner phase and thus the protection of the drug from hydrolysis by enzymes in the GI tract is prevented, and their by it reduces pre systemic clearance in the GI mucosa and hepatic first-pass metabolism.
DRAWBACK OF SMEDDS1,8,11
For the evaluation of SMEDDS and other lipid-based formulations the lack of good predicative in vitro models is a main drawback for assessment of the formulation. The in vitro model needs further development and validation before its strength can be evaluated. Further development will be based on in vitro and
in vivo correlations and therefore different prototype lipid based formulations need to be developed and tested in vivo in a suitable animal model.