Delivery Of Low Soluble Drugs Biology Essay

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Poor solubility in gastro intestinal fluids remains a great barrier for drug absorption and bio availability for the compounds of class II in Biopharmaceutical classification system. Highly efficacious drugs are hydrophobic attributing to it penetration to reach the target and receptor binding property ,yet remains poorly water soluble which forms the rate limiting step for absorption. The drug delivery systems which mainly focus on delivering drugs of low solubility have been emphasized and importance associated with each system is highlighted.


Lipophilic or poorly water soluble drugs pose major problems in delivery of many drugs , significantly reducing the bioavailability of the drug and resulting in high inter patient variability. Also low soluble drugs limit the choice of technologies and pose formulation obstacles. Selection of appropriate salt form (solid) and pH (liquids) are important factors to be considered while formulating a polar drug (Michael Hite et al, 2003). Solubility of drugs can be increased by many conventional methods which include co solvents, surfactants, cremophor etc.. Most of these methods have drawbacks which limited their use. Few novel drug delivery systems like lipid based systems, liposomes, micro emulsions, micelles, cyclodextrins etc... are showing promising results for delivery of low soluble drugs (Lukyanov et al, 2004) The following review presents the discussion about various delivery systems which successfully deliver the low soluble drugs. The lipid base drug delivery system which form a major class, the polymeric micelles and the novel approach of supercritical fluid technology are briefly discussed. The targeted delivery of poorly soluble anti cancer drugs by mixed micelles is also discussed in the review.

Key Words: Self emulsifying system, Micelles, Amphiphlic micelles, Immunomicelles Super Critical Fluids, rapid expansion of supercritical fluid, Encapsulation.


As the conventional methods like co solvents and surfactants might cause precipitation on diluting with aqueous solutions and surfactants cannot act below critical micellar concentration, other delivery systems based on lipids came into light.


Lipids can affect the oral bio availability of the drugs by altering the properties like dissolution rate, solubility, drug protection from enzymatic and chemical degradation in oil droplets. The three different lipid systems are:

Simple Solutions

Self emulsifying drug delivery system

Solid self emulsifying drug delivery systems (BoTang , 2008).


Low soluble drugs can be delivered by dissolving the drug in a mixture of 2 or more excipients like triglyceride oil, co-surfactants etc.. Drugs blended with oil solutions are rapidly digested to free fatty acids by solubilisation to colloidal dispersion in bile lecithin mixed micelles (Pouton et al, 2000). The solubility of DDT has been enhanced in simple micelle system of bile salt sodium cholate to a greater extent. Maximum solubility enhancement of Clofazamine was observed with fatty acid (oleic acid) bile salt micelle. Naturally occurring mixed micelles and synthetic cremophor EL micelles showed a similar 4 -5 fold solubility enhancement for saquinavir and DDT. (Driscoll et al, 2007).


Spontaneous lipid droplets are formed in these formulations when drug is added to the excipients. Excipient selection, its ratio and aqueous dilution can affect the droplet formation. Self emulsification is enhanced by formation of optimum concentration of drug, oil, surfactant, and co-surfactant (Hauss et al, 2007). SEDD systems prove more effective for drugs which possess adequate solubility or mixture of oil and surfactant (Odeberg et al, 2003))

Chain length in triglycerides and the lipid volume administered with drug, affects the solubility of the drug (BoTang, 2008).

Poorly water soluble drugs were found to behave differently in similar vehicles. Therefore, data about individual compound is required to further develop the delivery system. More intrinsic studies on how the physiological environment, incorporation of bioactive excipients and complete data of the drug in relation to bio chemical process occurring in gut should to be carried out for successful delivery of low soluble drugs (Driscoll et al, 2007). Self emulsifying formulations showed better solubility than their non-self emulsified counterparts in only few cases. Proper mechanisms should be identified by which self emulsification might influence solubilisation (Hauss, 2007).

This is a new approach which utilises thermo softening binder (fatty acids, alcohols) and produces pellets under high shear. Dispersions of Diazepam prepared using these binders had greater solubility than neat diazepam (Hauss, 2007).


Polymeric micelles can be hydrophilic, hydrophobic or amphiphilic.


Formation of polymeric micelles by self association of amphiphlic polymers act as promising drug carriers for the low soluble drug delivery. Amphphilic micelles containing both hydrophilic and hydrophobic blocks have been used frequently to deliver drugs of low water solubility. Polymeric micelles have a very low CMC concentration and hence do not dissociate easily. Drugs encapsulated in polymeric micelles have high stability and are retained in parenteral administration (Lukyanov, 2004). Lipid moieties used as hydrophilic blocks cause high hydrophobic interaction in micelle core due to 2 hydrocarbon chains that add to the stability of the micelle. Smaller the size of the micelle, the more efficient is its ability to penetrate tumour cells (Torchilin, 2003).


Targeted drug delivery of low soluble drugs using polymeric micelles is a novel area of exploration. This depends on enhanced permeability and retention effect. Pathological processes which are associated with the temperature increase or acidosis can be exploited as target where the micelles are disintegrated to release the drug at the site of interest (Lukyanov, 2004). Immunomicelles are special targeting drugs that are used to target tumours. Micelle encapsulation of drug greatly improves bio availability and prevents its degradation from biological environment and alters the distribution and other pharmacokinetic properties. (Valdimir, 2003). Micelles not only deliver the drug, but also retain the morphology of drug and protect the encapsulated form of drug when administered parenterally (Lukyanov, 2004)

Another targeting approach is attaching a vector molecule like antibody, peptide to drug which has specificity to the ligand at the site of interest. Antibodies specific to antigens in brain cells are attached to the micelles of conjugated fatty acids. Thus micelles get accumulated in the brain . The antibodies used were Fab fragments of antibodies and micelles were prepared from PEG-PE (Lukyanov, 2004)

Figure 1

(Source: Anatoly N. Lukyanov, Valadimir P. Torchlin (2004), Micelles from lipid derivatives of water soluble polymers as delivery systems for poorly soluble drugs, Advance Drug delivery Reviews. 56, 1273-1289)


Hydrophobically modified polysaccharides based micelles have been employed to increase the aqueous solubility of drug. Paclitaxel, poor water soluble anti cancer drug, the aqueous solubility was enhanced up to 5000 times by incorporating into hydrophobic core of mixed micelles (Gaucher, 2010).


Two approaches are followed:

This involves direct dissolution of drug and polymer in water when polymeric material is not very hydrophobic.

This involve dissolving drug with polymer which in turn is dissolved in common organic solvent followed by slow displacement of solvent with water by various techniques like dialysis. This method is followed when drug and polymer are water insoluble (Gaucher, 2010)

According to Valdimir, there is no proper explanation given regarding the covalent attachment of various antibodies to polymeric micelles (valdimir, 2003).

Though the micelles have proved to improve the solubility of various drugs, the stability studies and the in vitro â€" in vivo correlation data is insufficient and not yet clear as the in vivo environment offers various conditions which affect the micelles. A clear research needs to be carried out into the mechanisms governing these factors (Gaucher, 2010).


A novel approach followed for improving dissolution of drugs is super critical fluid system. Drugs are micronized using SCF technology with carbon dioxide. SCF technology needs no organic solvents or no heating to form fundamental particles. Carbon dioxide has been widely used SCF due to its very low critical point and toxicity (Okamoto,2006)


Solvent for drug substance

Anti solvent for precipitation

Medium for other fluid techniques (J.Jung, 2001).

The methods involved are:


Extracting a solute that is dissolved in SCF when it expands under reduced pressure is RESS. Composites can also be produced using the process (Jose Cocero, 2009).

A modification in this process involves usage of anti solvent for the polymer that can also be used as co solvent for the SCF solubility improvement. Organic co solvents are used for efficient production as pharmaceutical products are not normally very soluble SC- Carbon dioxide (Sauceau,2005).

A major problem associated with RESS is the difficulty in controlling the loading of the composites due to the rapid precipitation (S-DYeo, 2005)


This method involves pumping of super critical carbon dioxide into solvent of drug and allowed to expand and extract solvent resulting in precipitating of materials (Jai, 1998)

The dissociation studies of Phenytoin from super critical composite particles are as shown in figure 2.

Fig. 2 Dissolution profiles of phenytoin from SCF composite particles with phenytoin and PVP at a ratio of 1:2 in SGF with 1% SLS. SCF12c, SCF12s, andPM12 stand for SCF particles from the coacervate method, the solution method,and the physical mixture of the drug and PVP, respectively.

(Source: Tekehiko Yasuji, Hirofuni Takeuchi, Yoshaiaki kawashima (2008), Particle design of poorly water soluble drug substances using super critical fluid technologies, Advanced Drug Delivery Review 60, 388-398)

The versatility of Super critical fluid has been increased by combination of SCF with other techniques like emulsifying and use of special equipment methods like spray drying, freeze drying etc.. (Majerik, 2007).


It is a lipid based system which contains dry emulsion. The dispersed phase in these emulsions, have been encapsulated in either water soluble (sugar) or insoluble solid carrier (magnesium alumina metasilicate). Higher stability and flexible storage conditions are the advantages of these dry emulsions

The exact mechanism by which these dry emulsions act to improve solubility is yet to be found. The dissolution and pharmacokinetic profile of Class II can be improved by the combination of high solubilising effect of lipids and high stability of silica nano particles which form the silica lipid hybrid microcapsules Lecithins or triglycerides have been used as lipid content for the formulation of SLH microcapsules .The SLH has a better solubility and hence bio availability than other dosage forms like emulsions. Suspensions or solutions (Angel Tan, 2009).


The low solubility of drugs is associated with low therapeutic efficacy affecting drug absorption and bio availability to a larger extent. Various conventional methods involving particle size reduction, recrystallization, co solvency, surfactants etc... had drawbacks which limited their use. Development of novel delivery systems aimed at delivering the drugs with low solubility. The lipid based formulations include many systems like liposomes, simple solutions, self emulsifying systems which enhanced the solubility of drugs to many fold. Lipid based formulations act as good carriers and easily penetrate the lipoidal membrane. Micelles are one of the best approaches for drug targeting to tumour cells. Enhancement of Penetration and Retention (EPR) effect of the micelles allow its accumulation in tumour cells. The drug loading capacity, retention property, drug discharge on administering orally made micelles an effective delivery system. Solvent properties can be determined in super critical fluids enhanced the solubility of drugs. Once the drug is solubilised in SC fluids, it can be easily recrystallized at reduced particle size which in turn, sufficiently enhances solubility.