A Comprehensive Text Book on Self-emulsifying Drug Delivery Systems

Drug delivery through the oral route is perfect for both solid and liquid dosage forms. Notwithstanding numerous favorable circumstances, the improvement of the oral delivery route still speaks to an excellent test attributable to interesting curious physicochemical characteristics of lipophilic drug compounds and physiological barriers, such as gastrointestinal unsteadiness, pre-systemic metabolism and efflux pump. Upon oral intake, lipophilic drug in a dosage form is effortlessly taken by patients, passes the GIT via a tremendously versatile environment. Factors affecting solubilization are the size of particle, temperature, pressure, molecular size, nature of solute and solvent, polarity and polymorphs. Ways of enhancing oral bioavailability includeboth chemical modifications and formulation modifications. The chemical modification includes soluble pro-drug and salt formation. While formulation modification comprises of physical changes like size reduction, crystal habit modification, complexation (e.g. with β-cyclodextrin), solubilization with co-solvents or surfactants, drug dispersion with carriers (e.g. eutectic mixture, solid dispersion and polymeric carriers like micro/nanoemulsions, self-emulsifying drug delivery systems, liposomes, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers which are described briefly. A formulation approach is a preferable option to chemical modification approaches which may prompt the change in chemical structure and may have an impact on the pharmacological action. Particle size reduction is classified into two categories - mechanical micronization and engineered particle size control. Mechanical micronization includes jet milling, ball milling, high-pressure homogenization. Engineered particle size control includes the cryogenic method, spray freezing onto cryogenic fluids, spray freezing into cryogenic liquids, spray freezing into vapor over liquid, ultra-rapid freezing and cryogenic spray processes. Crystal engineering includes nanocrystals, solid dispersion, co-crystal formation, sonocrystallization, liquisolid technique, self-microemulsifying drug delivery systems and inclusion complex which are discussed in detail. This chapter highlights various methods for solubility enhancements with their merits and demerits.

Lipid-based formulations (LBFs) are an alluring alternative among novel drug delivery formulations that are used for the improvement in solubility and bioavailability of drugs that are impossible to dissolve because of their limited solubility in the gastrointestinal tract. As a controlled and targeted formulation, LBDDS includes the discharge of drugs in a controlled manner, high drug loading capacity (as compared to others), biodegradable and biocompatible, carrying capabilities for both lipophilic and hydrophilic drugs and excipients with less risk profile. The most imperative classification in novel drug delivery systems is LBFs including self-emulsifying lipid formulations, lipid solutions and lipid suspensions. Emulsions, microemulsion, nanoemulsion, liposomes, solid lipid nanoparticles, niosomes, lipospheres, ethosomes, self-emulsifying drug delivery system and selfmicroemulsifying drug delivery systems. GI lipid digestion is a mechanism of lipidbased drug delivery systems that is based on the dispersion of oil droplets to give a fine formulation of emulsion, hydrolysis of fatty acid esters with the help of enzymes at the emulsion water interface, desorption and dispersion of insoluble lipid products for absorption. Various mechanisms for upgrading the drug retention include improvement in dissolution/solubilization rate, the extension of gastric retention time; changes in the physical barrier role of the gastrointestinal tract, change in biochemical hindrance capacity of the GI tract, drug assimilation through the intestinal lymphatic system, all of these are discussed in detail. Lipid digestion, hydrophobic nature of the API and mean emulsion droplet sizes are various formulations factors that influence the bioavailability of drugs from LBDDS. Porter outlined seven regulations for the development of LBFs. This chapter highlights various types of lipid-based drug delivery systems with their benefits and drawbacks.

SMEDDS (Type III B systems) are isotropic mixtures of oils, surfactants, co-solvents and co-surfactants that have the capability to create fine o/w microemulsions upon mild stirring followed by dilution in the aqueous phase. They have captured due attention because of their high transparency, high solubilization capacity, thermodynamic stability and simple production method. They also improve oral assimilation and eradicate food effects. There has been an upheaval over the most recent two decades in the usage of microemulsion systems in an assortment of pharmaceutical, chemical and industrial processes. The use of self-microemulsion in pharmaceuticals, as cosmetics agents, for analytical purposes, in biotechnology, as enzymatic reactions, for immobilization of protein, bioseparations and chemical sensor have been described briefly. Oral, topical, parenteral, oculars and pulmonary deliveries are the general routes of drug administration for LBDDS that are discussed in detail. The oral route includes SE capsule, SE sustained/controlled release tablet/capsule/ pellets, SE solid dispersions. This chapter highlights various benefits, drawbacks, selection of ingredients and the applications of self-emulsification in various fields such as cosmetics, analysis, bioseparation and so on.

The key thought in choosing suitable ingredients for any lipid-based formulations (LBFs) is the identification of an ingredient or their combination that can keep the whole drug dose in solubilized form for oral administration. The chief ingredients in LBFs are lipids, surfactant and co-surfactant that are described in detail. These components are meant for achieving the maximum drug loading, minimal time for self-emulsification and small size of globule in the gastric environment for obtaining maximum assimilation, lessening variation in the emulsion globule size and preventing or minimizing drug degradation. Generally, a low dose of the drug is appropriate for SMEDDS. Lipids are an important component in SMEDDS because they are responsible for fluidization of intestinal cell membrane, solubilization of hydrophobic drugs, enhancing the dissolution rate and solubility in GI fluids, protection of the drug from chemical and enzymatic degradation. Surfactants play an important role in enhancing the solubility of a hydrophobic drug in oil, dispersion of liquid vehicle in GIT fluids, improving bioavailability by increasing permeability, avoiding the precipitation of drug in GI lumen and prolonging the existence of drug moiety in a solubilized form that results in its effective assimilation. But, a few surfactants are orally acceptable. The combination of ionic and non-ionic surfactants is very effective for improving the degree/area of the micro-emulsion region. It plays an important role in the synergetic effect in critical micelle concentration. A high amount of surfactant is essential to diminish interfacial tension adequately, which can cause gastric irritation, otherwise. That is why; co-surfactants of HLB value 10-14 are added to reduce their concentration. They are added in combination with surfactants to provide sufficient flexibility to interfacial film, dissolve a greater quantity of either hydrophobic drug or hydrophilic surfactant in the lipidic base and decreasing the interface of oil/water. They help in dissolving a large amount of surfactant or drug in lipid base, assisting the dispersion process, decreasing the amount of surfactant in the formulation and performing an action of co-surfactant in microemulsion system. This chapter highlights the various categories of ingredients that are used in the formulation of SMEDDS and their marketed products.

The gastrointestinal tract is abundantly provided with both lymphatic and blood vessels. In this way, material or drugs that are retained over the small intestinal epithelial cells can conceivably go through either lymphatic or blood vessels. The larger parts of drugs or compounds are transported into blood vessels because of a high flow rate (500-overlay), greater than that of intestinal lymph. Lymphatic transport of drugs will occur when the drug is profoundly lipophilic (log P >5) and demonstrates high solubility in TGs (>50mg/ml). Type of lipid, co-administered lipid substance, and level of unsaturation of lipid can alter the degree of lymphatic drug transportation. Biopharmaceutical issues such as increment in the rate of disintegration and dissolvability in the intestinal fluids, shieldthe drug from chemical and enzymatic degradation in the oil globules. The development of lipoproteins favor lymphatic transportation of highly hydrophobic drugs. The food impact is gathered throughout the ongoing decades, and it depends on the various components emerging from physiology, dosage form, and physicochemical features. The dietary lipids that occur in the food also play a role as solubilizers for drugs and consequently experience the lipid digestion by gastric and pancreatic lipases, similar to the mechanism depicted for LBFs to create different micellar species. A variety of in vitro models can act as a substitute to in vivo models for the investigation of lymphatic drug transport. In the intestinal permeability model, caco-2 cells are utilized to estimate the intracellular lipoproteinlipid assembly. Animal models are used to investigate the direct estimation of the drug via lymphatic drug transport by cannulation of the intestinal lymphatic duct. Rat is mainly used as an animal model, but other large animals such as dogs, pigs, and sheep have also been reported. Most SMEDDS formulations have not been capable to come into the sale due to lack of effective in vitro tests that are representative of authentic in vivo behavior. Impact of lipidic excipients, the influence of self-emulsifying lipidbased formulations on food effect, and reduction of food effect are discussed thoroughly; these affect limited lymphatic assimilation. This chapter highlights the various lymphatic mechanisms that help in attaining improved bioavailability, various factors, and various models used for the assessment of drug assimilation via the lymphatic system.

Various applications of SMEDDS are discussed in detail in this chapter, which include: upgrading the solubility and bioavailability, protection against biodegradation, effortless production and scale-up, diminishment in inter-subject and intra-subject inconstancy and food impacts, the capability to convey peptides that are liable to enzymatic hydrolysis in GIT, no impact on the lipid digestion and improvement in drug loading capability. Different variables affecting the performance of SMEDDS formulation are the nature, amount of the drug, polarity of the lipophilic phase, and a charge on a droplet of emulsion. Globule size, percent transmission, robust dilution, zeta potential measurement, cloud point estimation, stability studies, in vitro lipolysis, in vitro drug release assessment, permeability study, etc., are various evaluation parameters for SMEDDS/LBDDS that are discussed briefly. This chapter highlights various advantages, evaluation parameters, and marketed products related to SMEDDS.

From the point of view of dosage forms, S-SEDDS represents the solid dose formulation with self-emulsification features. The S-SEDDS becomes the focal point when adding liquid or semisolid SE components into powders or nanoparticles through various solidification strategies, such as adsorption to solid carriers, spray drying, spray cooling, supercritical liquid-based technique, melt extrusion, nanoparticle technology, etc. S-SMEDDS offers various benefits, such as diminishing the threat of interaction of the SMEDDS ingredients with the shell of the capsule. Immediate or controlled-release formulations can be formulated, relying upon the decision of the powder ingredient to be incorporated in the formulation; SE granules or pellets diminish the rate of the gastric emptying time and smooth entry in the gut, which generally leads to less threat of dosage fluctuations. Various types of S-SMEDDS include SE solid dispersions, SE tablets, SE enteric-coated dry emulsion, SE beads, SE sustained-release microspheres, SE nanoparticles, SE mouth dissolving film, SE floating dosage form, positively charged SMEDDS, self-double-emulsifying drug delivery system, supersaturatable SMEDDS, and so on. While lecithin-linker SEFs, sponges carrying SMEDDS, herbal SMEDDS and SE phospholipid suspension are novel S-SMEDDS. Different issues are related to the solidification strategies, such as the quantity of solidifying ingredients, the release rate of the drug, degradation of drug amid solidifying procedure, difficulty in content uniformity, decrease in drug loading limit and the probability of remaining solvents amid granulation and so on. In this chapter, an attempt has been made to highlight the various methods for solidifying SMEDDS, their issues and types of Solid- SMEDDS.

Herbal drugs have been utilized for a large number of years in the east and ongoing popularity among customers on the planet. These days, 80% of the total populace use pharmaceuticals, which are obtained from plants. Around the world, such drugs make up a 25% of the pharmaceutical armory. SEDDS has a potential for enhancing the bioavailability of inadequately ingested plant parts/actives. Both the crude herb and the extract consist of confounded blends of natural synthetics, which may incorporate unsaturated fats, sterols, alkaloids, flavonoids, glycosides, saponins, tannins and terpenes. Be that as it may, a large portion of herbal constituents are poorly water-soluble and have lipophilic features and reduce distribution, prompting diminished bioavailability and subsequently diminished treatment efficiency, thus requiring repetitive administration or enlarged dose. A variety of herbal drugs and conventional pharmaceuticals being exploited for the formulation of SMEDDS are either extracts or consist of volatile and fixed oils such as zedoary turmeric oil, quercetin, kaempferia parviflora, silymarin, baicalein, hesperidin, curcumin, vinpocetine, nobiletin, oridonin, apigenin, berberine, puerarin and so on which have been discussed here in brief. The nanosized NDDS of herbal drugs has a potential future for upgrading the action and defeating issues related to herbal drugs. This chapter highlights the preformulation study and various phytoconstituents used for the development of SEFs.

In vitro models evaluate lipid-based drug delivery systems for enhancing solubilization and discharge of the drug. After ingestion, the food particles experience different physical and chemical changes that prompt their fragmentation into little pieces and change into less complex atomic groups that can be effortlessly absorbed into the blood. The dynamic mono and multi-compartmental models have become more advanced with in vivo information input. The Dynamic Gastric Model (DGM) has two sections: One is the body and the other is the antrum of the gastric. Up until now, TNO gastro-Intestinal Model-1(TIM-1) is considered to mimic the closest reproduction of the energy and flow of human retention. Pancreatic lipase, bile salts, phospholipids and calcium ions are involved in the intestinal lipolysis. The intestinal lipolysis is typically assessed by the rate and degree of free unsaturated fats discharged due to the activity of P-LIP. These can be estimated utilizing diverse strategies such as colorimetric enzymatic test, gas chromatography and pH-stat titration. The various in vivo pharmacokinetic aspects of LBFs are formulation and solubilization, dispersibility, dilution and effect on pharmacokinetics that have been described in this chapter. Other pharmacokinetic parameters including assimilation and bioavailability improvement, the impact of excipient choice on bioavailability, lymphatic transport and food effect reduction have been summarized. This chapter highlights the various in vitro digestion models and pharmacokinetic aspects of LBFs.