Descriptive Terms Of Solubility Biology Essay
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The process of solubilization involves the breaking of inter-ionic or intermolecular bonds in the solute, the separation of the molecules of the solvent to provide space in the solvent for the solute, interaction between the solvent and the solute molecule or ion. (Shinde A. J., 2007)
Factors affecting solubility
The solubility depends on the physical form of the solid, the nature and composition of solvent medium as well as temperature and pressure of system. (James K., 1986)
Particle size of solid influences the solubility because smaller the particle size more is surface area to volume ratio and larger surface area allows a greater interaction with the solvent.
If the solution process absorbs energy then the solubility will be increased as the temperature is increased. If the solution process releases energy then the solubility will decrease with increasing temperature. Generally, an increase in the temperature of the solution increases the solubility of a solid solute. A few solid solutes are less soluble in warm solutions. For all gases, solubility decreases as the temperature of the solution increases.
For gaseous solutes, an increase in pressure increases solubility and a decrease in pressure decrease the solubility. For solids and liquid solutes, changes in pressure have practically no effect on solubility.
Nature of the solute solvent
Figure 1: Process of solubilization (Adopted from Reference Shinde A. J., 2007)
Therapeutic effectiveness of a drug depends upon ability of the dosage form to deliver the medicament to its site of action at a rate and amount sufficient to bring out the desired pharmacological response. Bioavailability is one of the principal pharmacokinetic properties of drugs, is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as oral), its bioavailability decreases (due to incomplete absorption or first-pass metabolism). The measurement of the amount of the drug in the plasma at periodic time intervals indirectly indicates the rate and extent at which the active pharmaceutical ingredient is absorbed from the drug product and becomes available at the site of action. Bioavailability is expressed as either absolute or relative bioavailability. (Brahmankar D. M., et al., 2009 and Thakkar H., et al., 2010)
Absolute bioavailability and Relative bioavailability
When the systemic availability of a drug administered orally is determined in comparison to its administration, it is called as absolute bioavailability. It is denoted by symbol F. Its determination is used to characterize a drug's inherent absorption properties from the e.v. site. Intravenous dose is selected as a standard because the drug is administered directly into the systemic circulation (100% bioavailability) and avoids absorption step. Intramuscular dose can also be taken as a standard if the drug is poorly water soluble. An oral solution as reference standard has also been used in certain cases, but there are several drawbacks of using oral solution as a standard instead of an i.v. dose. (Brahmankar D. M., et al., 2009)
Relative or comparative bioavailability
When the systemic availability of a drug after oral administration is compared with that of an oral standard of the same drug (such as an aqueous or non aqueous solution or a suspension), it is referred to as relative or comparative bioavailability. It is denoted by symbol Fr. In contrast to absolute bioavailability; it is used to characterize absorption of a drug from its formulation. F and Fr are generally expressed in percentage. (Brahmankar D. M., et al., 2009)
Factors Influencing Bioavailability
Bioavailability of drug is influenced by the drug, dosage form and the interaction of these with the complex environment of the absorption site. For orally administered compound many factors including GI anatomy and physiology, bacterial, mucosal and hepatic metabolism may affect absorption. The possible contributing of all of these factors must be considered when examining drug absorption, when interpreting the results of bioavailability studies and when designing drugs and dosage forms to optimize absorption characteristics to achieve desired therapeutic goals. (Welling P. G., et al., 2006).
Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation, such factors may include:
Physicochemical properties of the drug (hydrophobicity, pKa, solubility)
he drug formulation (immediate release, excipients used, manufacturing methods, modified release - delayed release, extended release, sustained release, etc.)
Whether the drug is administered in a fed or fasted state
Gastric emptying rate
Enzyme induction/inhibition by other drugs/foods
Interactions with other drugs (e.g. antacids, alcohol, nicotine)
Interactions with other foods (e.g. grapefruit juice, pomello, cranberry juice)
Transporters: Substrate of an efflux transporter (e.g. P-glycoprotein)
Health of the gastrointestinal tract
Intestinal motility-alters the dissolution of the drug and degree of chemical degradation of drug by intestinal microflora.
Enzyme induction/inhibition by other drugs/foods
Individual Variation in Metabolic Differences
Age: In general, drugs are metabolized more slowly in fetal, neonatal, and geriatric populations
Phenotypic differences, enterohepatic circulation, diet, gender
Each of these factors may vary from patient to patient (inter-individual variation), and indeed in the same patient over time (intra-individual variation) (Thakkar H., et al., 2010).
Methods for enhancement of bioavailability
As per definition of bioavailability, drug with poor bioavailability is one with poor aqueous solubility and/or slow dissolution rate in biological fluids and poor permeability through the biomembrane owing to inadequate partition coefficient or lipophilicity or large molecular size such as that of protein or peptide drugs. Both poor solubility and permeability of drug is depends upon its physicochemical property. (Brahmankar D. M., et al., 2009)
Biopharmaceutical Classification System (BCS)
Based on intestinal permeability and solubility of drugs, Amidon et al., developed Biopharmaceutical Classification System (BCS) which classify drugs into one of the four groups. (Table 2).
Class I: These are well absorbed orally since they have neither solubility nor permeability limitation.
Class II: Shows variable absorption owing to solubility limitation.
Class III: also shows variable absorption owing to permeability limitation.
Class IV: are poorly absorbed orally owing to both solubility and permeability limitation.
Table 2: Biopharmaceutical Classification System
Abacavir, Acetaminophen, Acyclovir, Amitryptyline, Antipyrine, Atropine, Bucspirone, Caffeine, Captopril, Chloroquine, Chlorpheniramine, Cyclophosphmide, Desipramine, Diazepam, Dilitiazem, Diphenhydramine, Disopyramide, Doxepin, Doxycycline, Enlapril, Ephedrine, Ergonovine, Ethambutol, fluoxetine, Glucose, Imipramine, Ketorolac, Ketoprofen, Labetolol, Levodopa, Levofloxacin, Meperidine, Metoprolol, Metronidazole, Midazolam, Minocycline, Misoprostol, Nifedipine, Phenobarbital, Phenylalamine, Prednisolone, Primaquine, Promazine, Propranolol, Quinidine, Rosiglitazone, Salicylic acid, Theophylline, Zidovudine. Risperidone.
Amiodarone, Atorvastatin, Azithromycine, Carbamazepine, Carvedilol, Chlorpromazine, Ciprofloxancin, Cyclosporine, Danazol, Dapsone, Diclofenac, Digoxine, Erythromycin, Flurbiprofen, Glyburide, Griseofulvin, Ibuprofen, Indinavir, Indomethacin, Itraconazole, Ketoconazole, Lansoprazole, Lovastatin, Mebendazole, Naproxen, Nelfinavir, Ofloxacin, Oxaprozin, Phenazopyridine, Phenytoin, Piroxicam, Raloxifene, Ritonavir, Saquinavir, Sirolimus, Spironolactone, Tacrolimus, Talmolol, Tamoxifen, Terfenadine, Telmisartan, Verapamil hydrochloride, Warfarin,
Acyclovir, Amiloride, Amoxicillin, Atenolol, Atropine, Bisphosphonates, Captopril, Cefazolin, Cetrizine, Cimetidine, Ciprofloxacin, Cloxacillin, Dicloxacillin, Erythromycin, Famotidine, Fexofenadine, Ganciclovir, Lisinopril, Metformin, Methotrexate, Nadolol, Pravastatin, Penicillins, Tetracyline, Trimethoprim, Valsartan, Zalcitabinne
Amphotericin B, Chlorthalidone, Chlorothiazide, Colistin, Ciprofloxacin, Furosemide, Hydrochlorothiazide, Mebandazole, Methotrexate, Neomycin.
BCS Class boundaries
Class boundary parameters (i.e., solubility, permeability, and dissolution) are for easy identification and determination of BCS class.
Solubility: A drug substance is considered highly soluble when the highest dose strength is soluble in 250 mL or less of water over a pH range of 1-7.5 at 37 °C.
Permeability: A drug substance is considered highly permeable when the extent of absorption in humans is greater than 90% of an administered dose, based on mass-balance or compared with an intravenous reference dose.
Dissolution: A drug product is considered rapidly dissolving when 85% or more of the labeled amount of drug substance dissolves within 30 min using USP Apparatus 1 or 2 in a volume of 900 mL or less of buffer solutions. (Reddy B. B. K., et al., 2011)
There are three approaches in overcoming bioavailability problems are:
It involves modification of formulation, manufacturing process or physicochemical properties of drug without changing chemical structure.
It involves alteration of pharmacokinetic of drug by altering its chemical structure by developing new chemical entity with desirable feature or prodrug design.
In which route of drug administration is changed such as changing from oral to parenteral route.
Pharmacokinetic approach has many drawbacks such as expensive, time consuming, repetition of clinical studies and long time of regulatory approval. Hence pharmaceutical approach is mainly aimed at altering the biopharmaceutical properties of drug by using one of the following ways:
By enhancing drug solubility or dissolution rate:
Supercritical fluid recrystallization
Spray freezing into liquid
Evaporative precipitation into aqueous solution
Use of surfactants
Use of salt forms
Use of precipitation inhibitors
Alteration of pH of drug microenvironment
Use of amorphous, anhydrates, solvates and metastable polymorphs
Selective adsorption on insoluble carriers
Molecular encapsulation with cyclodextrin
By enhancing drug permeability across biomembrane
By enhancing drug stability
Use of metabolism inhibitors
By Gastrointestinal retention
Methods of Assessing Bioavailability
The bioavailability of a drug substance formulated into a pharmaceutical product is fundamental to the goals of dosage form design and essential for the clinical efficacy of the medication. Thus, bioavailability testing, which measures the rate and extent of drug absorption, is a way to obtain evidence of the therapeutic utility of a drug product. Bioavailability determinations are performed by drug manufacturers to ensure that a given drug product will get the therapeutic agent to its site of action in an adequate concentration. Bioavailability studies are also carried out to compare the availability of a drug substance from different dosage forms or from the same dosage form produced by different manufacturers. There are two categories of method used for quantitative evaluation of bioavailability, pharmacokinetic method and pharmacodynamic method. (Chereson R. (1996) and Brahmankar D. M., et al., 2009)
This method is based on assumption that, pharmacokinetic profile reflects therapeutic effectiveness of drug. Hence these are indirect methods. The two major pharmacokinetic methods are:
Plasma level-time studies/ blood level studies
Blood level studies are the most common type of human bioavailability studies, and are based on the assumption that there is a direct relationship between the concentration of drug in blood or plasma and the concentration of drug at the site of action. By monitoring the concentration in the blood, it is thus possible to obtain an indirect measure of drug response. Following the administration of a single dose of a medication, blood samples are drawn at specific time intervals and analyzed for drug content. A profile is constructed showing the concentration of drug in blood at the specific times the samples were taken. The parameters such as AUC, Cmax, Tmax, etc are noted.
Urinary excretion studies
An alternative bioavailability study measures the cumulative amount of unchanged drug excreted in the urine. These studies involve collection of urine samples and the determination of the total quantity of drug excreted in the urine as a function of time. These studies are based on the premise that urinary excretion of the unchanged drug is directly proportional to the plasma concentration of total drug. Thus, the total quantity of drug excreted in the urine is a reflection of the quantity of drug absorbed from the gastrointestinal tract. (dXu/dt)max, (tu)max and Xuâˆž are three major parameters in urinary excretion data obtained with a single dose study.
This method is complementary to pharmacokinetic approaches and it involves direct measurement of drug effect on a physiological process as a function of time. The two pharmacodynamic methods involve determination of bioavailability from:
Acute pharmacological response:
When bioavailability measurement by pharmacokinetic methods is difficult, inaccurate and non reproducible, an acute pharmacological effect such as change in ECG or EEG readings, pupil diameter, etc is related to the time course of a given drug. Bioavailability then can be determined by construction of pharmacological effect-time curve as well as dose-response graph.
Therapeutic response method:
Theoretically this is most definite method. This method is based on observing the clinical response to a drug formulation given to patients suffering from disease for which it is intended to be used.
In-Vitro Dissolution and Bioavailability
The term commonly used to describe correlation between some physicochemical property of a dosage form and the biological availability of the drug from that dosage form is in-vitro in-vivo correlation (IVIVC). Specifically, it is felt that if such a correlation could be established, it would be possible to use in-vitro data to predict a drug's in-vivo bioavailability. This would considerably reduce, or in some cases, completely eliminate the need for bioavailability tests. The desirability for this becomes clear when one considers the cost and time involved in bioavailability studies as well as the safety issues involved in administering drugs to healthy subjects or patients. It would certainly be preferable to be able to substitute a quick, inexpensive in-vitro test for in-vivo bioavailability studies. Hence best available tool today which can at least quantitatively assure about biological availability of a drug from its formulation is its in-vitro dissolution test.
Problems and Breakthroughs of Bioavailability Enhancement Techniques
There are many more methods used to enhance solubility, dissolution rate and hence bioavailability. But these methods have their own limitations. Salt formation of neutral compounds is not feasible and synthesis of weak acid and weak base salts may not always be practical. Moreover, the salts that are formed may convert back to their original acid or base forms and lead to aggregation in the gastrointestinal tract. Particle size reduction may not be desirable in situations where handling difficulties and poor wettability are experienced for very fine powders. To overcome these drawbacks, various other formulation strategies have been adopted including the use of cyclodextrins, nanoparticles, solid dispersions and permeation enhancers. Indeed, in some selected cases, these approaches have been successful. (Gursoy R. N., et al., 2004)
The major disadvantages of solid dispersion are related to their instability. Several systems have shown changes in crystallinity and a decrease in dissolution rate with aging. The crystallization of ritonavir from the supersaturated solution in a solid dispersion system was responsible for the withdrawal of the ritonavir capsule (Norvir, Abboft) from the market. Moisture and temperature have more of a deteriorating effect on solid dispersions than on physical mixtures. Some solid dispersion may not lend them to easy handling because of tackiness. (Dixit A. K., 2012)
In pH adjustment technique there is risk for precipitation upon dilution with aqueous media having a pH at which the compound is less soluble. Intravenously this may lead to emboli, orally it may cause variability. Also tolerability and toxicity (local and systemic) related with the use of a non physiological pH and extreme pHs. As with all solubilized and dissolved systems, a dissolved drug in an aqueous environment is frequently less stable chemically compared to formulations crystalline solid. The selected pH may accelerate hydrolysis or catalyze other degradation mechanisms. In particle size reduction technique; due to the high surface charge on discrete small particles, there is a strong tendency for particle agglomeration. Developing a solid dosage form with a high pay load without encouraging agglomeration may be technically challenging. Technically, development of sterile intravenous formulations is even more challenging. Complexation of drugs with cyclodextrins also have some drawbacks such as potential toxicity issue, regulatory and quality control issue related to presence of ligand may add complication and cost to the development process. (Vemula V. R., et al., 2010)
Lipid based drug delivery
In recent years, greatly interest has paying attention on lipid-based formulations to improve the oral bioavailability of poorly water soluble drug. Lipid formulations for oral administration of drugs generally consist of a drug dissolved in a blend of two or more excipients, which may be triglyceride oils, partial glycerides, surfactants or co-surfactants. Lipid formulations are a diverse group of formulations which have a wide range of properties. These result from blending of up to five classes of excipients, ranging from pure triglyceride oils, through mixed glycerides, lipophilic surfactants, hydrophilic surfactants and water-soluble co solvents. (Pouton C. W., 2000)
An ideal oral lipid-based dosage form must meet a number of demands: (Cannon J. B., 2011)
It should solubilize therapeutic amounts of the drug in the dosage form.
It should maintain adequate drug solubility over the entire shelf-life of the drug product (generally 2 years) under all anticipated storage conditions.
It should provide adequate chemical and physical stability for the drug and formulation components.
It must be composed of approved excipients in safe amounts.
Once ingested, it should facilitate dispersion of the dosage form in the intestinal milieu and maintain drug solubilization in the dispersed form.
It should adapt to the digestive processes of the GI tract such that digestion either enhances or maintains drug solubilization.
It should present the drug to the intestinal mucosal cells such that absorption into the cells and into the systemic circulation is optimized.
Lipid formulation classification system
The Lipid Formulation Classification System (LFCS) was introduced by Pouton C. W. as a working model in 2000 (Pouton C. W. 2000) and an extra 'type' of formulation (Type IV) was added in 2006 (Pouton C. W. 2006). In recent years the LFCS has been discussed more widely within the pharmaceutical industry to seek a consensus which can be adopted as a framework for comparing the performance of lipid-based formulations. (Pouton C. W., et al., 2008).
Table 3: Lipid Formulation Classification System
III A SEDDS
III B SMEDDS
Oils: triglycerides or mixed mono and diglycerides
Water-insoluble surfactants (HLB < 12)
Water-soluble surfactants (HLB > 12)
(e.g. PEG, proylene glycol, transcutol)
Particle size of dispersion (nm)
Significance of aqueous dilution
Solvent capacity unaffected
Some loss of solvent capacity
potential loss of solvent capacity
loss of solvent capacity
Significance of digestibility
Not crucial but likely to occur
Not crucial but may be inhibited
Not required and not likely to occur
May not be digestible
Self Micro Emulsifying Drug Delivery System
Self-emulsifying drug delivery systems (SEDDS) or selfemulsifying oil formulations (SEOF) 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. Upon mild agitation followed by dilution in aqueous media, such as GI fluids, these systems can form fine oil-in-water (o/w) emulsions or microemulsions (SMEDDS). Self-emulsifying formulations spread readily in the GI tract, and the digestive motility of the stomach and the intestine provide the agitation necessary for self-emulsification. SEDDS typically produce emulsions with a droplet size between 100 and 300 nm while SMEDDS form transparent microemulsions with a droplet size of less than 50 nm. When compared with emulsions, which are sensitive and metastable dispersed forms, SEDDS are physically stable formulations that are easy to manufacture. Thus, for lipophilic drug compounds that exhibit dissolution rate-limited absorption, these systems may offer an improvement in the rate and extent of absorption and result in more reproducible blood-time profiles. (Gursoy R. N., et al., 2004 and Kohli K., et al., 2010)
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: In emulsification process the free energy (âˆ†G) associated is given by the equation:
Where, âˆ†G is the free energy associated with the process (ignoring the free energy of mixing), N is the number of droplets of radius r and ó represents the interfacial energy. The two phases of emulsion tend to separate with time to reduce the interfacial area, and subsequently, the emulsion is stabilized by emulsifying agents, which form a monolayer of emulsion droplets, and hence reduces the interfacial energy, as well as providing a barrier to prevent coalescence. (Reiss H., 1975, Craig D. Q. M., et al., 1995 and Kohli K., et al., 2010 )
It was also suggested that, in case of SMEDDS, the free energy of formation is very low and positive or even negative which results in thermodynamic spontaneous emulsification. It has been suggested that self emulsification occurs due to penetration of water into the Liquid Crystalline (LC) phase that is formed at the oil/surfactant-water interface into which water can penetrate assisted by gentle agitation during self-emulsification. After water penetrates to a certain extent, there is disruption of the interface and a droplet formation. This LC phase is considered to be responsible for the high stability of the resulting nanoemulsion against coalescence. (Shah I., 2011)
Upon aqueous dilution the drug remains in the oil droplets or as a micellar solution since the surfactant concentration is very high in such formulations. (Pouton C. W., et al., 2008) The drug in the oil droplet may partition out in the intestinal fluid as shown in Figure 2. (Shah I. 2011)
Figure 2: Mechanism of drug partitioning in SMEDDS (Adopted from Reference Shah I. 2011)
Advantages and Disadvantages of SMEDDS (Shukla J. B., et. al., 2010)
Improvement in oral bioavailability
Dissolution rate dependant absorption is a major factor that limits the bioavailability of numerous poorly water soluble drugs. The ability of 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 enable more efficient drug transport through the intestinal aqueous boundary layer and through the absorptive brush border membrane leading to improved bioavailability. Khoo S. M showed that the lipid-based formulations of halofantrine base afforded a six- to eight-fold improvement in absolute oral bioavailability relative to previous data of the solid halofantrine HCl tablet formulation. (Khoo S. M. et al., 1998)
Ease of manufacture and scale-up
Ease of manufacture and scale- up is one of the most important advantages that make SMEDDS unique when compared to other drug delivery systems like solid dispersions, liposomes, nanoparticles, etc., dealing with improvement of bio-availability. SMEDDS require very simple and economical manufacturing facilities like simple mixer with agitator and volumetric liquid filling equipment for large-scale manufacturing. This explains the interest of industry in the SMEDDS.
Reduction in inter-subject and intra-subject variability and food effects
There are several drugs which show large inter-subject and intra-subject variation in absorption leading to decreased performance of drug and patient non-compliance. Food is a major factor affecting the therapeutic performance of the drug in the body. SMEDDS are a boon for such drugs. Several research papers specifying that, the performance of SMEDDS is independent of food and, SMEDDS offer reproducibility of plasma profile are available. (Kohsaku K. et al., 2002)
Ability to deliver peptides that are prone to enzymatic hydrolysis in GIT
One unique property that makes SMEDDS superior as compared to the other drug delivery systems is their ability to deliver macromolecules like peptides, hormones, enzyme substrates and inhibitors and their ability to offer protection from enzymatic hydrolysis. The intestinal hydrolysis of prodrug by cholinesterase can be protected if Polysorbate 20 is emulsifier in micro emulsion formulation. (Cortesi R. et. al., 1997)
No influence of lipid digestion process
Unlike the other lipid-based drug delivery systems, the performance of SMEDDS is not influenced by the lipolysis, emulsification by the bile salts, action of pancreatic lipases and mixed micelle formation. SMEDDS are not necessarily digested before the drug is absorbed as they present the drug in micro-emulsified form which can easily penetrate the mucin and water unstirred layer.
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
SMEDDS not only offer the same advantages of emulsions of facilitating the solubility of hydrophobic drugs, but also overcomes 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.
Microemulsions formed by the SMEDDS exhibit good thermodynamics stability and optical transparency. The major difference between the above microemulsions and common emulsions lies in the particle size of droplets. The size of the droplets of common emulsion ranges between 0.2 and 10 Î¼m, 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. 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.
One of the obstacles for the development of SMEDDS and other lipid-based formulations is the lack of good predicative in vitro models for assessment of the formulations.
Traditional dissolution methods do not work, because these formulations potentially are dependent on digestion prior to release of the drug.
This in vitro model needs further development and validation before its strength can be evaluated.
Further development will be based on in vitro - in vivo correlations and therefore different prototype lipid based formulations needs to be developed and tested in vivo in a suitable animal model.
The drawbacks of this system include chemical instabilities of drugs and high surfactant concentrations in formulations (approximately 30-60%) which irritate GIT.
Moreover, volatile co solvents in the conventional self-microemulsifying formulations are known to migrate into the shells of soft or hard gelatin capsules, resulting in the precipitation of the lipophilic drugs.
The precipitation tendency of the drug on dilution may be higher due to the dilution effect of the hydrophilic solvent.
Formulations containing several components become more challenging to validate.
Formulation approach of SMEDDS
188.8.131.52 Components of SMEDDS
With a large variety of liquid or waxy excipients available, ranging from oils through biological lipids and hydrophobic and hydrophilic surfactants to water-soluble cosolvents, there are many different combinations that could be formulated for encapsulation in hard or soft gelatin or mixtures that disperse to give fine colloidal emulsions. The following points should be considered in the formulation of a SEDDS: (i) the solubility of the drug in different oil, surfactants and cosolvents and (ii) the selection of oil, surfactant and cosolvent based on the solubility of the drug and the preparation of the phase diagram. The backbone of SMEDDS formulation comprises lipids, surfactants and cosolvents. The right concentration of the above three decides the self-emulsification and particle size of the oil phase in the emulsion formed. (Gupta R. N., et al., 2009) These ingredients are discussed below:
Active Pharmaceutical Ingredient (API)
Active Pharmaceutical Ingredient
Lipid based compound forms a potential platform for improving oral bioavailability of drug especially those belonging to BCS class II and IV. A important indication of potential utility of lipid based formulation can be obtain by assessing drug lipophilicity (Log P) and its solubility in pharmaceutically accepted lipid excipients. Another indicator of potential success of lipid based formulation is the observance of strong positive food effect when the drug is administer with fatty meal as opposed to dosing in the fasting SMEDDS usually provide advantage of increased drug loading capacity as the solubility of poorly water soluble drugs with intermediate partition coefficient (2< Log P<4) are typically low in natural lipid and much greater in surfactant, co-surfactant. Other indications are dose of drug should not be high, drug should be oil soluble, melting point should not be high. (Pouton C. W., et al., 2008, Kohli K., et al., 2010 and Patel M. J., et al., 2010)
Oils play a critical role in SMEDDS because it is responsible for solubilization of the hydrophobic drug, aiding in self-emulsification and moreover contributes to the intestinal lymphatic transport of the drug. The emulsification property of the oil is said to be dependent on the molecular structure of the oil. (Kimura M., et al., 1994) The oil represents one of the most important excipients in the SMEDDS formulation not only because it can solubilize marked amounts of the lipophilic drug or facilitate selfemulsification but also and mainly because it can increase the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract depending on the molecular nature of the triglyceride. Both long and medium chain triglyceride oils with different degrees of saturation have been used for the design of self-emulsifying formulations. Furthermore, edible oils which could represent the logical and preferred lipid excipient choice for the development of SMEDDS are not frequently selected due to their poor ability to dissolve large amounts of lipophilic drugs. Modified or hydrolyzed vegetable oils have been widely used since these excipients form good emulsification systems with a large number of surfactants approved for oral administration and exhibit better drug solubility properties. They offer formulative and physiological advantages and their degradation products resemble the natural end products of intestinal digestion. Novel semisynthetic medium chain derivatives, which can be defined as amphiphilic compounds with surfactant properties, are progressively and effectively replacing the regular medium chain triglyceride oils in the SEOFs. (Gursoy R. N., et al., 2004, Patel M. J., et al., 2010)
Examples: Acconon CC 400, Acconon E, Acconon Sorb-20, Acrysol K 140, Brij 30, Brij 90 Campul GMO, Campul MCM, Caprol ET, Capryol 90, Captex 355, Carprofen, Castor oil, Corn oil, Cotton seed oil, Ethyl oleate, Imwitor 742, Labrafac CC, Labrafac Lipophile, Labrafac PG, Labrafi l 1944 CS, Labrafil M, Labrafil M 2125 CS, Labrasol, Labrfac CM-1O, LabrafacLipophil WL 1344, Lauroglycol 90, Lauroglycol FCC, Miglylol 812, Olive oil, Peanut oil, Peceol, Plurol oleique, Sefsol ET, Sesame oil, Solutol, Solutol HS, Soybean oil, Sunflower oil, Triacetin, Paraffin oil, Neobee M5, etc.
Non-ionic surfactants with a relatively high hydrophilic-lipophilic balance (HLB) are most widely used in SMEDDS. The commonly used emulsifiers are various solid or liquid ethoxylated polyglycolyzed glycerides and polyoxyethylene 20 oleate (Tween 80). Safety is a major determining factor in choosing a surfactant. Emulsifiers of natural origin are preferred since they are considered to be safer than the synthetic surfactants. However, these excipients have a limited self-emulsification capacity. Non-ionic surfactants are less toxic than ionic surfactants but they may lead to reversible changes in the permeability of the intestinal lumen. Usually the surfactant concentration ranges between 30 and 60 % w/w in order to form stable SEDDS. It is very important to determine the surfactant concentration properly as large amounts of surfactants may cause GI irritation. (Gursoy R. N., et al., 2004) The surfactants used in these formulations are known to improve the bioavailability by various mechanisms including: improved drug dissolution, increased intestinal epithelial permeability, increased tight junction permeability and decreased / inhibited p-glycoprotein drug efflux. (Shah N. H., et al., 1994) However, the large quantity of surfactant may cause moderate reversible changes in intestinal wall permeability or may irritate the GI tract. The effect of formulation and surfactant concentration on gastrointestinal mucosa should ideally be investigated in each case. (Gupta R. N., et al., 2009)
Most single-chain surfactants do not lower the oil-water interfacial tension sufficiently to form microemulsions nor are they of the correct molecular structure. Further under certain condition, a combination of oil, water and surfactant will result in a phase where there are orderly planes of oil and water separated by monomolecular layer of surfactant. This type of phase is known as liquid crystal (lamellar phase). Liquid crystals formation can be detected by large increase in viscosity. Co-surfactant is added to further lower the interfacial tension between the oil and water phase, fluidize the hydrocarbon region of the interfacial-film, and to influence the film curvature. (Patel M. J., et al., 2010) In SMEDDS, generally co-surfactant of HLB value 10-14 is used. Hydrophilic co-surfactants are preferably alcohols of intermediate chain length such as hexanol, pentanol and octanol which are known to reduce the oil water interface and allow the spontaneous formulation of micro emulsion. (Gupta R. N., et al., 2009)
Examples of Surfactants and co-surfactants: Campul MCM C8, Capryol 90, Carbitol, Cremophor EL, Cremophor RH 40, Crodamol EO, Crodamol GTCC, D-alpha Tocopheryl polyethylene glycol 1000 succinate (TPGS), Emulsifier OP, Ethoxylated polyglycolysed glycerides, Gelucire® 44/14, Glycerine, Glycerol, Hexanol, Labrafac PG, Labrafil 2609 WL, Labrafil M 2125 Cs, Labrafil M1944 Cs, Labrasol, Lauroglycol FCC, Lauroglycol FCC, Maisine 35-1 (glyceryl monolinoleate), Octanol, Oleic acid, PEG 200, PEG 400, Pentanol, Plurol Oleique, Plurol Oleique CC 497, Polaxamer 188, Polaxamer 407, Polysorbate 80, Propylene glycol, Solutol HS 15, Span 20, Span 80, Transcutol, Transcutol HP, Transcutol P, Tricaprylin, Tween 20, Tween 60, Tween 80, etc.
Organic solvents such as, ethanol, propylene glycol (PG), and polyethylene glycol (PEG) are suitable for oral delivery, and they enable the dissolution of large quantities of either the hydrophilic surfactant or the drug in the lipid base. These solvents can even act as co-surfactants in microemulsion systems. On the other hand, alcohols and other volatile co-solvents have the disadvantage of evaporating into the shells of the soft gelatin, or hard, sealed gelatin capsules in conventional SEDDS leading to drug precipitation. Thus, alcoholâˆ’free formulations have been designed, but their lipophilic drug dissolution ability may be limited. (Gursoy R. N., et al., 2004) Addition of an aqueous solvent such as Triacetin, (an acetylated derivative of glycerol) for example glyceryl triacetate or other suitable solvents act as co-solvents. (Gupta R. N., et al., 2009)
Additional material can be added to alter the consistency of the emulsions; such materials
include tragacanth, cetyl alcohol, stearic acids and /or beeswax. (Gupta R. N., et al., 2009)
If the therapeutic agent is subject to enzymatic degradation, enzyme inhibitors can be added to the composition of SMEDDS. (Shinde G., et al., 2011)
Enzyme inhibitors are:
Inhibitors that are not based on amino acids. e. g. P-aminobenzamidine, FK-448, Cosmostat mesylate, Sodium glycocolate.
Amino acids and modified amino acids e.g. aminoboronine derivatives and n-acetylcysteine.
Peptides and modified peptides e.g. Bacitracin, antipain, leupeptin, amastatin.
Polypeptide protease inhibitors e.g. Apratinin, Bowman-Birk inhibitor, Soyabeen trypsin inhibitor, Chicken egg white trypsin inihibitor.
Complexing agent e.g. EDTA, EGTA, Phenanthroline, Hydroxychinoline.
Inert polymer matrix representing from 5 to 40% of composition relative to the weight, which is not ionizable at physiological pH and being capable of forming matrix are used for the formulation of sustained release SMEDDS. The polymer matrix after ingestion, in contact with GI fluid, forms a gelled polymer making it possible to release the micro emulsified active agent in a continuous and sustained manner by diffusion. Examples are hydroxypropylmethyl cellulose and ethyl cellulose. (Shinde G., et al., 2011)
184.108.40.206 General selection criteria for excipients in SMEDDS
Self-emulsification has been shown to be specific to the nature of the oil/surfactant pair; the surfactant concentration and oil/surfactant ratio; and the temperature at which self-emulsification occurs. In support of these facts, it has also been demonstrated that only very
specific pharmaceutical excipient combinations could lead to efficient self-emulsifying systems. (Rahman M. A., et al., 2012) Following are some factors which affect choice of excipients in SMEDDS:
Regulatory issues-irritancy, toxicity, knowledge and experience
Morphology at room temperature (i.e. melting point)
Self-dispersibility and role in promoting self-dispersion of the formulation
Digestibility, and fate of digested products
Purity, chemical stability
Cost of goods
Toxicity is an independent issue, and is important with regard to the choice of surfactants. Water-insoluble surfactants penetrate and fluidize biological membranes and water-soluble surfactants have the potential to solubilise membrane components. All surfactants are potentially irritant or poorly tolerated as a result of these non-specific effects. There is a considerable literature on the interaction of surfactants with biological systems and published toxicity data gives an indication of differences between surfactants. In general terms cationic surfactants are more toxic than anionic surfactants which in turn are more toxic than non-ionic surfactants. Lipid-based delivery systems usually only include non-ionic surfactants so it is pertinent to compare the toxicity of non-ionic surfactants. In general bulky surfactants such as polysorbates or polyethoxylated vegetable oils are less toxic than single-chain surfactants, and esters are less toxic than ethers (which are non-digestible). Non-ionic surfactants are generally considered to be acceptable for oral ingestion, and the emergence of several successful marketed products has given the industry confidence in lipid-based products. The oral and intravenous LD50 values for most non-ionic surfactants are in excess of 50 g/Kg and 5 g/Kg respectively, so 1 g surfactant in a formulation is well-tolerated for uses in acute oral drug administration. (Pouton C. W., et al., 2008)
A range of industrial nonionic surfactants were screened using subjective visual assessment by Pouton and Wakerly for their ability to form self-emulsifying systems with medium-chain
and long-chain triglycerides. The most efficient systems were formed by surfactants with predominantly unsaturated acyl chains. Amongst these the most efficient were oleates with HLB values of approximately 11. Sorbitan esters (e.g. Polysorbate 85) or ethoxylated triglycerides (e.g. Tagat TO) were usually more efficient than fatty acid ethoxylates, probably because the latter are more polydisperse since they usually contain mono- and di-esters. (Pouton C. W., et al., 1997)
220.127.116.11 Construction of Pseudo Ternary Phase Diagram
Phase diagram is needed to be established for systematic study of micro emulsion composition. From these, the extent of micro emulsion region can be identified and its relation to other phases can be established. The pseudo-ternary phase diagrams can be constructed by water titration method. As quaternary phase diagram (four component system) is time consuming and difficult to interpret, pseudo ternary phase diagram is constructed to find out the different zones including microemulsion zone, in which each corner of the diagram represents 100% of the particular components. Pseudo-ternary phase diagrams of oil, water, and co-surfactant/surfactants mixtures are constructed at fixed cosurfactant/surfactant weight ratios. Phase diagrams are obtained by mixing of the ingredients, which shall be pre-weighed into glass vials and titrated with water and stirred well at room temperature. Formation of monophasic/ biphasic system is confirmed by visual inspection. In case turbidity appears followed by a phase separation, the samples shall be considered as biphasic. In case monophasic, clear and transparent mixtures are visualized after stirring; the samples shall be marked as points in the phase diagram. The area covered by these points is considered as the microemulsion region of existence. (Jha S. K., et al., 2011)
Hypothetical Phase Diagram
Figure 3: Hypothetical Phase Diagram (Adopted from Reference Patel M. R., et al.)
18.104.22.168 Evaluation of SMEDDS
Visual assessment may provide important information about the self-emulsifying property of the SMEDDS and about the resulting dispersion. Estimation of the efficiency of the self-emulsification can be done by evaluating the rate of emulsification and particle size distribution. Turbidity measurement to identify efficient self-emulsifying can be done to establish whether the dispersion has reached equilibrium rapidly and in reproducible time. (Pouton C. W., 1985, Craig D. Q. M., et al., 1993, Craig D. Q. M., et al., 1995 and Gupta R. N., et al., 2009)
Droplet polarity and droplet size are important emulsion characteristics. Polarity of oil droplets is governed by the HLB value of oil, chain length and degree of un-saturation of the fatty acids, the molecular weight of the hydrophilic portion and concentration of the emulsifier. A combination of small droplets and their appropriate polarity (lower partition coefficient o/w of the drug) permit acceptable rate of release of the drug. Polarity of the oil droplets is also estimated by the oil/water partition coefficient of the lipophillic drug. (Shah N. H., et al., 1994 and Gupta R. N., et al., 2009)
Size of the emulsion droplet is very important factor in self-emulsification / dispersion performance, since it determine the rate and extent of drug release and absorption. The Coulter nano-sizer, which automatically performs photon correlation analysis on scattered light, can be used to provide comparative measure of mean particle size for such system. This instrument detects dynamic changes in laser light scattering intensity, which occurs when particle oscillates due to Brownian movement. This technique is used when particle size range is less than 3µm, size range for SMEDDS is 10 to 200 nm. (Pouton C. W., 1985, Craig D. Q. M., et al., 1995 and Gupta R. N., et al., 2009)
For sustained release characteristic, dissolution study is carried out for SEMDDS. Drugs known to be insoluble at acidic pH can be made fully available when it is incorporated in SMEDDS. (Gupta R. N., et al., 2009)
Solid Self Micro Emulsifying Drug Delivery System (S-SMEDDS)
In recent years, selfâ€emulsifying and selfâ€microemulsifying drug delivery systems (SEDDS and SMEDDS) have shown a reasonable success in improving oral bioavailability of poorly water soluble and lipophilic drugs. SEDDS and SMEDDS are normally prepared either as liquids or encapsulated in soft gelatin capsules, which have some shortcomings especially in the manufacturing process, leading to high production costs. Moreover, these dosage forms may be inconvenient to use and incompatibility problems with the shells of the soft gelatin are usual. Incorporation of a liquid selfâ€emulsifying formulation into a solid dosage form may combine the advantages of SEDDS with those of a solid dosage form and overcome the disadvantages of liquid formulations described above. (Kumar A., et al., 2010)
The primary reason to formulate SMEDDS in a solid form is to consolidate the advantages of liquid SEDDS with convenience of solid oral dosage forms. Oral solid dosage form following advantages:
Low production cost
Convenience of process control
High stability and reproducibility and
Better patient compliance
22.214.171.124 Solidification techniques
The main techniques for transforming liquid and semi-solid formulations into solid lipid-based particles or granules are spray-cooling, spray drying, adsorption onto solid carriers, melt granulation, melt extrusion, super-critical fluid based methods and high pressure homogenization (to produce solid lipid nanoparticles (SLN) or nanostructured lipid carriers (NLC)). (Katteboina S., et al., 2009)
Capsule filling with liquid and semisolid selfemulsifying formulations
Capsule filling is the simplest and the most common technique for the encapsulation of liquid or semisolid SE formulations for the oral route. For semisolid formulations, thre are four steps: (Kumar A., et al., 2010 and Shukla J. B., et. al., 2010)
Heating of the semisolid excipient to at least 20°C above its melting point
Incorporation of the active substances (with stirring)
Capsule filling with the molten mixture and
Cooling to room temperature (Cole E. T., et al., 2008)
For liquid formulations, it involves twoâ€step process:
Filling of the formulation into the capsules
Sealing of the body and cap of capsule, either by banding or by microspray sealing (Janin V., et al., 2008)
Spray cooling, also referred to as spray congealing, is a process whereby the molten formula is sprayed into a cooling chamber and, upon contact with the cooling air, the molten droplets congeal and re-crystallize into spherical solid particles that fall to the bottom of the chamber and can subsequently be collected as fine powder. The fine powder may then be used for development of solid dosage forms such as tablets or capsules. (Janin V., et al., 2008 and Katteboina S., et al., 2009) Equipment like rotary, pressure, two-fluid or ultrasonic atomizers are available to atomize the liquid mixture and to generate droplets. (Rodriguez L., et al., 1999)
Essentially, this technique involves the preparation of a formulation by mixing lipids, surfactants, drug, solid carriers, and solubilisation of the mixture before spray drying. The solubilized liquid formulation is then atomized into a spray of droplets which are introduced into a drying chamber; the volatile phase (water contained in an emulsion) evaporates, forming dry particles under controlled temperature and airflow conditions. The atomizer, the temperature, the most suitable airflow pattern and the drying chamber design are selected according to the drying characteristics of the product and powder specifications. Spray drying has been employed to prepare dry emulsions by removing water from an ordinary emulsion containing a water-soluble solid carrier. (Katteboina S., et al., 2009) Like spray cooling, the microparticles obtained by spray drying may be dry filled into hard shell capsules or alternatively compressed into tablets. (Janin V., et al., 2008) The solid SMEDDS was prepared by spray drying the liquid SMEDDS in a laboratory spray dryer, using dextran as a solid carrier for nimodipine. (Yi T., et al., 2008)
Adsorption to solid carriers
Free flowing powders may be obtained from liquid SMEDDS by adsorption onto solid carriers. The adsorption process is simple and involves addition of the liquid formulation onto the carrier of choice by mixing in a blender. The carriers used for this purpose include calcium silicate, magnesium aluminometasilicate, silicon dioxide, or carbon nanotube. These carriers should be selected for their ability to adsorb a great quantity of liquid excipients (to allow for a high drug loading and high lipid exposure) and for the flowability of the mixture after adsorption. The resulting free flowing powder may then be filled directly into capsules or alternatively mixed with suitable excipients before compression into tablets. The process is simple, requires minimal (if any) investment in equipment and facilitates formulation of tablets. The down side of this formulation technique however, may be the reduced drug loading capacity in the final dosage form. This is due initially to dilution of the lipid formulation during mixing with the solid carrier and subsequent dilution by addition of excipients to obtain compressible mixtures for tableting. (Janin V., et al., 2008) A significant benefit of the adsorption technique is good content uniformity as well as the possibility for high lipid exposure: up to 70% w/w of SMEDDS may be adsorbed on to suitable carriers. (Ito Y., et al., 2005) At present, colloidal silicon dioxide is widely used as a adsorbing agent for various drugs like ketoprofen, ezetimibe, and Siramesine hydrochloride. It has been reported that porous polystyrene beads can be used as carriers for a self-emulsifying system containing loratadine. Silicone dioxide has been used as an adsorption carrier for ketoprofen. It is also currently used in formulations of drugs like ketoprofen, ezetimibe, siramesine hydrochloride, and gentamicin. (Katteboina S., et al., 2009)
Melt granulation or pelletization is a one step-process allowing the transformation of a powder mix (containing the drug) into granules or spheronized pellets. The technique necessitates high shear mixing in presence of a meltable binder which may be sprayed in molten state onto the powder mix as in classic wet granulation process. This is referred to as "pump-on" technique. Alternatively, the binder may be blended with the powder mix in its solid or semi-solid state and allowed to melt (partially or completely) by the heat generated from the friction of particles during high shear mixing-referred to as "melt-in" process. The melted binder forms liquid bridges with the powder particles that shape into small agglomerates (granules) which can, by further mixing under controlled conditions transform to spheronized pellets. (Janin V., et al., 2008)
Melt extrusion/extrusion spheronization:
Melt extrusion is a solventâ€free process that allows high drug loading (60%) (Janin V., et al., 2008), as well as content uniformity. Extrusion is a procedure of converting a raw material with plastic properties into a product of uniform shape and density, by forcing it through a die under controlled temperature, product flow, and pressure conditions. The size of the extruder aperture will determine the approximate size of the resulting spheroids. The extrusion-spheronization process is commonly used in the pharmaceutical industry to make uniformly sized spheroids (pellets). (Kumar A., et al., 2010) This approach has been successfully applied to 17Î²-estradiol and two model drugs (methyl and propyl parabens) with surfactants such as sucrose monopalmitate (Surfhope® D-1616), lauroyl polyoxylglycerides (Gelucire®â„¢ 44/14) and polysorbate 80 (Tween® 80). (Huelsmann S., et al., 2000)
Supercritical fluid based methods
Lipids may be used in supercritical fluid based methods either for coating of drug particles, or for producing solid dispersions. The coating process entails dispersing the drug particles as powder in a supercritical fluid containing one or more dissolved coating materials. The solubility of the coating material(s) is sustained initially by elevated pressure and temperature conditions. The coating process is subsequently facilitated by a gradual reduction in pressure and temperature leading to reduced solubility of the coating material in the supercritical fluid allowing gradual deposition onto the drug particles, to form coating layer(s). The supercritical fluid of choice is supercritical carbon dioxide. The process for obtaining solid particles entails dissolving the drug and lipid-based excipient(s) in an organic solvent such as methanol and then in a supercritical fluid, followed by lowering the temperature and pressure conditions to reduce their solubility in the fluid. Examples of lipid-based or lipid-related excipients that have been studied with this process for controlled-release applications include glyceryl trimyristate (Dynasanâ„¢114) and stearoyl polyoxylglycerides (Gelucire® 50/02). (Janin V., et al., 2008 and Katteboina S., et al., 2009)
Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC)
SLN and NLC are two types of submicron sized particles between 50-1000 nm composed of physiologically tolerated lipid components which are in the solid state at room temperature. These submicron carriers can be classified according to their inner structure: SLN have a solid core while NLC have a liquid core. The classic components of SLN are glyceryl dibehenate (Compritol® 888 ATO) as solid lipid matrix and poloxamers 188 (Pluronic® F68) or polysorbates 80 (Tween® 80) as surfactant. (Janin V., et al., 2008 and Katteboina S., et al., 2009)
126.96.36.199 Dosage form of S-SMEDDS
Various dosage forms of S-SMEDDS are as listed below: (Shukla J. B., et. al., 2010)
Self-emulsifying sustained/controlled-release tablets
Self-emulsifying sustained/controlled-release pellets
Self-emulsifying solid dispersions
Self-emulsifying sustained-release microspheres
188.8.131.52 Self-emulsifying sustained/controlled-release system
SMEDDS can also be formulated to give sustained release dosage form, by adding inert polymeric matrix, which is not ionizable at physiological pH, and dispersed in the self-micro emulsifying system before ingestion. The polymer matrix (after ingestion) in contact with GI fluid forms a gelled polymer making it possible to release the micro emulsified active agent in a continuous and sustained manner by diffusion. (Gupta R. N., et al., 2009)
It is possible to prepare a solid self-micro emulsifying formulation for oral poorly water-soluble drug by spray drying, using a water soluble solid carrier. It was also suggested that different solid carrier resulted in different droplet size of reconstituted micro emulsions, which has been shown to have an important influence on the drug release from S-SEF. Thus, it could be surmised that spray-dried S-SEF using solid carrier material with different effect on controlling the drug release could behave differently in the drug release pattern. (Tahara K., et al., 1995, Vyas S. P., et al., 2002 and Yi T., et al., 2008)
Yi T., et al. developed a controlled release system based on self-microemulsifying mixture aimed for oral delivery of poorly water-soluble drug. HPMC-based particle formulations were prepared by spray drying containing a model drug (nimodipine) of low water solubility and hydroxypropylmethylcellulose (HPMC) of high viscosity. This investigation has shown that it is possible to control the release of a poorly water-soluble drug from the solid self micro emulsifying formulation by employing high viscosity HPMC as solid carrier to modify the drug release. Hydroxy propyl methylcellulose (HPMC) is the most important hydrophilic carrier material used widely as matrices for oral controlled-release formulations. Upon contact with aqueous media, hydration takes place and HPMC matrices form a gel layer to achieve controlled drug release. (Yi T., et al., 2008)
Figure 4: Potential structures of (a) the spray-dried controlled-release S-SEF particle and (b) the spray-dried HPMC particle without self-emulsifying mixtures (Adopted from Reference Yi T., et al., 2008)
Biopharmaceutical aspects of SMEDDS (Shah I., 2001 and Kumar A., et al., 2010)
The ability of lipids and/or food to enhance the bioavailability of poorly waterâ€soluble drugs has been comprehensively reviewed and the interested reader is directed to these references for further details. (Humberstone A. J., et al., 1997) Although incompletely understood, the currently accepted view is that lipids may enhance bioavailability via a number of potential mechanisms, including:
Alterations (reduction) in gastric transit: thereby slowing delivery to the absorption site and increasing the time available for dissolution. (Porter C. J. H., et al., 2001)
Increase in effective luminal drug solubility: The presence of lipids in the GI tract stimulates an increase in the secretion of bile salts (BS) and endogenous biliary lipids including phospholipid (PL) and cholesterol (CH), leading to the formation of BS/PL/CH intestinal mixed micelles and an increase in the solubilization capacity of the GI tract. However, intercalation of administered (exogenous) lipids into these BS structures either directly (if sufficiently polar), or secondary to digestion, leads to swelling of the micellar structures and a further increase in solubilization capacity.
Stimulation of intestinal lymphatic transport: For highly lipophilic drugs, lipids may enhance the extent of lymphatic transport and increase bioavailability directly or indirectly via a reduction in firstâ€pass metabolism. (Porter C. J. H., et al., 1997)
Changes in the biochemical barrier function of the GI tract: It is clear that certain lipids and surfactants may attenuate the activity of intestinal efflux transporters, as indicated by the pglycoprotein efflux pump, and may also reduce the extent of enterocyteâ€based metabolism. (Benet L. Z., et al., 2001)
Changes in the physical barrier function of the GI tract: Various combinations of lipids, lipid digestion products and surfactants have been shown to have permeability enhancing properties. For the most part, however, passive intestinal permeability is not thought to be a major barrier to the bioavailability of the majority of poorly waterâ€soluble, and in particular, lipophilic drugs.
Effect of oils on the absorption: Such formulations form a fine oilâ€inâ€water emulsion with gentile agitation, which may be provided by gastrointestinal motility. A SES also improves the reproducibility of the plasma level-time profile. Various physiological mechanisms have been proposed to explain the effect of oils on the absorption of waterâ€insoluble compounds, including altered gastrointestinal motility, increased bile flow and drug solubilization, increased mucosal permeability, enhanced mesenteric lymph flow, and increased lymphatic absorption of water insoluble drugs and bioavailabilit
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