Enhancing the Permeability of BCS Class III Drugs

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nLiterature Review

nIntroduction

nBSC Class III drugs are characterized by low permeability and high solubility. The properties of a drug such as gastrointestinal permeability, dissolution and solubility are crucial aspects that regulate the extent and rate of absorption and availability of drug. The solubility of a drug in water is an essential characteristic that plays a vital part in the drug absorption following oral administration. Moreover, it controls the use of parenteral drug administration (Agrawal, Gupta & Chaturvedi, 2012, p. 1). Drug bioavailability and solubility is beneficial in testing and controlling the properties of drugs in the process of drug development and design. The solubility of a drug is a measure of equilibrium and rate of dissolution where a solid drug turns into a solution. In this regard, the rate of dissolution is important, especially during restricted time.

nOral drug availability is based on first-pass metabolism, rate of dissolution, permeability of drug, aqueous solubility and efflux mechanism efflux (Khadka, Ro, Kim, Kim, Kim, Kim, & Lee, 2014, p. 2). Besides, drug permeability and aqueous solubility play a vital role in oral drug bioavailability. Research indicates nearly 70 percent of the drugs candidates have poor water solubility, especially during drug development. Therefore, drug candidates with poor solubility as well as poor dissolution in gastrointestinal fluids are an inhibiting factor to the bioavailability of in vivo following oral administration. In this respect, dissolution through in vitro experiments has been identified as crucial elements in the development of drugs consequently increasing the rate of dissolution of drugs that have poor solubility (Shaikh, Nikita, Derle & Bhamber, 2012, p. 3). In addition, it involves promoting their bioavailability because it is a big challenge in pharmacology.

nBiopharmaceutics classification system (BCS)

nBiopharmaceutics classification system uses intestinal permeability and aqueous solubility of drug substance. In the in vitro dissolution, BCS use two crucial factors: intestinal and solubility permeability that regulate the extent and rate of oral absorption from the solid state of a drug to its bioavailability (Date, Desai, Dixit, & Nagarsenker, 2010, p. 17). Therefore, BCS is an important agency in drug development particularly of oral drug products. A drug substance is regarded as highly soluble if it can dissolve in 250 ml. In addition, its pH should range between 1.0 and 7.5 in an aqueous media. On the contrary, permeability is the ability of a drug substance to pass through intestinal membranes. A drug with a higher permeability should have 90 percent intestinal absorption depending on mass balance (Khadka, Ro, Kim, Kim, Kim, Kim, & Lee, 2014, p. 2).

nPharmaceutical powders

nMost of the drugs are available in powder form hence the science of pharmaceutics dealing with powder technology is very crucial in the current pharmaceutics. Most notably, due to advanced technology, the industry is formulating powder drugs that have higher dissolution and solubility properties. In addition, it incorporates other primary processes such as grinding, formulating and mixing, additives to produce desired features or composites and particles performance. Particle property is an important concept in dosage performance and fabrication of form. Important particle features such as wettability, hygroscopicity, surface chemistry, adhesiveness, size, shape, brittleness and hardness are essential for proper dosage (Khadka, Ro, Kim, Kim, Kim, Kim, & Lee, 2014, p. 4). These strategies are used to develop a drug that is highly soluble in the gastro intestinal tract.

nBarriers of Intestinal Drug Permeability

nSeveral biological factors affect the permeability of the drugs through the intestinal walls. These factors include tight junctions, basal cell membrane, the mucous layers and unstirred layer of water (Shaikh, Nikita, Derle & Bhamber, 2012, p. 3). Others include lymph and capillaries walls and cell content such as mucosal peptidases, which reduces the bioavailability of class III drugs.

nMucous

nA layer of mucous involves nucleic acids, protein, electrolytes and mucins (water glycoproteins) that provide coverage of epithelial cells in the whole intestines. Glycocalyx binds the layer to the apical surface via a glycoprotein that is 500 nm thick. The layer of unstirred water contains partial a mucous layer and has a minimum thickness of 100 µm. In addition, a pH in the epithelial layer is about six, which provides an acidic environment. Apical cell membrane is made up of lipid molecules consisting both lipophilic and a hydrophobic parts (Shaikh, Nikita, Derle & Bhamber, 2012, p. 4). The layer also contains lipids, cholesterol, phosphatidic acid, phosphatidylinositol, ethanolamine and phosphatidylcholine.

nThe protection of the structure of the membrane, there is Calcium ions and phospholipids, which reduces the permeability and lipophilicity of the membrane. In addition, cholesterol is used to control mechanism of the membrane that can enhance gel-state membrane fluidity or reduce the liquid crystalline membrane fluidity. Natural fatty acids affect the order of membrane by affecting the phospholipid organization (Agrawal, Gupta & Chaturvedi, 2012, p. 7). Permeability of the cell membrane can increase through decreasing the molar ratio cholesterol-phospholipid. The movement of hydrophilic material across the cell membrane is limited by lipid bilayer. In this respect, transport of polar solute, ions and water across the membrane needs another mechanism (Shaikh, Nikita, Derle & Bhamber, 2012, p. 4). For instance, diffusion via carriers and pores can transport polar materials.

nBasal cell membrane

nThe basal cell membrane consists of a phospholipid bilayer that is nine nm thick. The bilayer contains protein molecules. Due to lower concentration of glycoshingo lipids, basolateral membrane fluidity surpasses apical membrane (Shaikh, Nikita, Derle & Bhamber, 2012, p. 4). Therefore, the basal membrane provides a barrier of lower level as compared to apical membrane.

nTight Junctions

nZonula occludentes (tight junctions) are areas that offer communication in the epithelial cells particularly between apical ends and are formed by a number of strands. Their permeability increases as the number of strands decreases, which leads to leakiness of the epithelial cells (Shaikh, Nikita, Derle & Bhamber, 2012, p. 9). In addition, the small intestines have leaky epithelial cells, thus increasing permeability. However, the permeability decreases in the distal direct ions opposite apical cell membrane. For solutes that have medium sizes, there is passive penetration of ions. Furthermore, tight junctions are selective of the type of cations that pass through them. Therefore, cations that have a molecular weight of 350 nm and a diameter more than 0.8 nm cannot pass through the tight junctions (Ashiru, Patel, & Basit, 2008, p. 10). The tight junctions have few number of large pores and large numbers of large pores.

nCapillary walls

nThe capillary wall is situated nearly 500 nm beneath the basal membrane. Due to the presence of large pores, the intestinal lymph and blood capillaries do not provide any significant barrier to absorption of drugs. Nonetheless, most of the hydrophilic drugs are slowly transported through the capillary wall relative to hydrophilic compounds because of limitation of absorption site (Shaikh, Nikita, Derle & Bhamber, 2012, p. 5).

nStrategies to enhance permeability of BSC Class III drugs

nSelf-double emulsifying drug delivery systems (SDEDDS)

nOral bioavailability of class II drugs can be enhanced through self-double emulsifying drug delivery systems. However, the industrial application of this strategy is limited because of minimum stability. A novel formation can be established which is stable via optimization formulation. Self-double emulsifying drug delivery system (SDEDDS) can impromptu emulsify to water-in-oil-in-water binary emulsion in the expanded aqueous environment of gastrointestinal tract. Water-in-oil-in-water binary emulsions are advanced systems involving aqueous droplets spread within huge oil droplets (Khadka, Ro, Kim, Kim, Kim, Kim, & Lee, 2014, p. 15). The aqueous droplets encapsulated internally via the oil membrane acts as a storage reservoir for hydrophilic drugs. The structure has produced great results as they enhance oral bioavailability of drugs. Water-in-oil-in-water double emulsions are developed through two main methods of emulsification. Self-double emulsifying drug delivery system is emulsified in aqueous gastrointestinal environment (Shaikh, Nikita, Derle & Bhamber, 2012, p. 13). The process also produces hard or soft gelatin capsules that are easily stored and administered. There are also steady formulation systems.

nBile salts

nBile that consists of taurine and glycine conjugates of chenideoxycholic acid and colic acid increases the process of lipolysis and lipid product transportation via the layer of unstirred water by micellar solubilization. The bacterial flora metabolizes the bile salts that escape in the ileum from active reabsorption to lithocholic acid and deoxycholic acid. The decreasing hydrophilicity order includes taurine conjugates followed by glycine conjugates and finally the free bile salts. Increase in the number of hydroxyl groups causes an increase in polarity (Shaikh, Nikita, Derle & Bhamber, 2012, p. 14). Bile salts have the capacity to bind calcium and their binding capacities reduce with growing hydrophilicity. The bile salts affects the structure of glycocalyx in the intestine that reduce intestinal and gastric mucous. Low concentrations of bile salts influence the structure of tight junction. However, research has indicated that the use of bile salts to promote bioavailability of drugs in man faces many challenges as it lead to destruction of mucosa membrane.

nNano emulsions

nThe nano emulsions is a beneficial mechanism for delivery of oral drugs having poor permeability or drugs with higher lipophilic. They also have the ability to improve the permeation and solubilizing of the cell membrane (Date, Desai, Dixit, & Nagarsenker, 2010, p. 7). Furthermore, oral nano emulsions enable increases gastrointestinal absorption and minimize intra & inter-individual unevenness of drug variety. Besides, since they have huge interfacial area, they are characterized by promising drug release abilities. They also provide a specific magnitude of protection against destruction. In some case, nano emulsions can self-emulsify, especially in aqueous substances. Therefore, there are important in production of oral formulations. For instance, pluronics are utilized as wetting agents and solubilizes because of their low toxicity. Pluronics is also useful in transport of drugs via carriers based on the structural compositions. Nano emulsions is used accelerate the lipophilic drugs stabilization (Shaikh, Nikita, Derle & Bhamber, 2012, p. 15). Research has indicated that the nano emulsions affect permeation through the intestine of both paracellularly and transcelllularly transported drugs.

nPhytolipid delivery systems

nThe permeability of class III drugs can be improved using phytosomes. The new technology produces cell-like substances that protect the plant extract from secretions of the gastrointestinal tract. The majority of water-soluble phyto-compounds have poor permeability when administered through oral or topical means (Agrawal, Gupta & Chaturvedi, 2012, p. 5). However, phyto-constituents, which are water-soluble, are converted into phytosomes since the latter are lipid-compatible molecules. The phytosomes delivery system is a beneficial system because it has enhances bioavailability and do not compromise the safety of nutrients. A phytosomes is a product produced through combination of plant compounds and natural phospholipids (Ashiru, Patel, & Basit, 2008, p. 2). Therefore, if forms complex lipophilic substance that is soluble in non-polar solvents. Phytosomes is an herbal product that is easily absorbed hence increases the bioavailability of drugs such as BSC class III.

nPhytosomes has many advantages because it promotes the insoluble polar phyto-constituents absorption via oral and topical administrations, which leads to substantial therapeutic advantages. Since the absorptions of these drugs increases, their dose requirements also reduce. Phosphatidylcholine is also beneficial in phytosomes preparation and it acts as a carrier and hepatoprotective thus providing synergistic benefits when combined with hepatoprotective substances (Agrawal, Gupta & Chaturvedi, 2012, p. 9). In addition, it leads to formation of chemical bonds between phyto-constituent and phosphatidylcholine molecule leading to advanced stability. Furthermore, the use of phyto-constituents in phytosomes form enhances the absorption of percutaneous.

nVarious studies have demonstrated that phytosomes can be used to deliver insoluble drugs after oral administrations through the cell membrane. For instance, phospholipid complex has been used in improve the permeability of silybin in rats. Moreover, phytosomes from grape seeds produced higher bioavailability of hydrogenated phosphatidylcholine (Shaikh, Nikita, Derle & Bhamber, 2012, p. 12). The green tea extracts contains relatively higher polyphenolic fractions and it contains beneficial elements such as anticariogenic, antiatherosclerotic, antimutagenic, antioxidant and anticarcinogenic (Agrawal, Gupta & Chaturvedi, 2012, p. 7-9). Therefore, herbal products that have medicinal properties can be delivered via phytosomes because they provide higher permeability of hydrophilic compounds through gastrointestinal tract and skin.

nPolyethylene glycol 400

nPolyethylene glycol 400 (PEG 400) is a product that improves solubility and enhances transport of drug through the intestines. The drugs have the ability to stagnate fluids in the intestines because it is osmotically active. Consequently, it enhances the volume of bulk fluid that promotes peristalsis and transit. For instance, ranitidine – a class III drug is normally absorbed via the small intestines (Ashiru, Patel, & Basit, 2008, p. 1). The polyethylene glycol 400, sorbitol and sodium acid pyrophosphate increases the permeability of the ranitidine. The PEG 400 increases the permeability of the intestines that helps ranitidine drugs to pass through the intestines. Ranitidine is usually conveyed through tight junctions that involves the paracellular route (Ashiru, Patel, & Basit, 2008, p. 3). Various studies suggest that this form of transport is responsible of 60 percent of the movement while transcellular processes is responsible of 40 percent.

nA dose of 10g of PEG 400 enhanced approximately 30 percent of the ranitidine bioavailability and permeability in the intestines by nearly 37 percent in male subjects. Researches indicate that PEG 400 affects the drug absorption as well as transit period. Most notably, the study identified that PEG 400 reduces the transit period across the small intestines by 23 percent, 20 percent and 9 percent when used in concentrations of 5g, 2g and 1g respectively (Ashiru, Patel, & Basit, 2008, p. 5). For oral absorption of ranitidine increased by 41 percent in presence of 1 g of polyethylene glycol 400 although the transit time was reduced. Therefore, the PEG 400 has the ability to regulate the permeability of the intestines and enhances the rate of absorption (Ashiru, Patel, & Basit, 2008, p. 5). In control groups showed that, male volunteers had a bioavailability of ranitidine of 23 percent in PEG 400 absence. However, male volunteers that used 1g of the drug increased ranitidine bioavailability to 49 percent. Furthermore, the study showed that lower concentration of PEG 400 e.g., 0.75 produced better bioavailability of ranitidine (63 percent) as compared to control groups in males. Nonetheless, in females, the bioavailability of ranitidine was reduced in presence of PEG 400 and no association could be developed between the menstrual cycle stage and the ranitidine bioavailability (Ashiru, Patel, & Basit, 2008, p. 7). Therefore, gender factors play a crucial role in the PEG 400 effects in enhancement of class III bioavailability in human beings.

nSelf-Nano emulsifying Drug Delivery Systems (SNEDDS)

nSelf-Nano emulsifying drug delivery system uses liquid mixtures involving solubilizers, coemulsifiers, surfactants and oil. It unexpectedly establishes oil-in-water nanoemulsion of nearly 200 nm or less after water dilution. The choice of components of SNNEDS depends of the physiological fate, ability of drug solubilization and physicochemical features (Date, Desai, Dixit, & Nagarsenker, 2010, p. 1). SNEDDS is beneficial to human beings because it improves the bioavailability of BSC Class III drugs through oral dosage. Over the past decades, nanotechnology has played a crucial role in delivery of drugs. In this respect, SNEDDS enhances hydrophobic drugs solubility and enhances permeability of BCS class III (Date, Desai, Dixit, & Nagarsenker, 2010, p. 3). Moreover, it regulates the drug disposition and biodistribution of drugs. In physiological milieu, nanotechnology protects against drug degradation as they facilitate delivery of certain drugs to specific site of action.

nSNEDDS helps to improve intestinal permeability of BSC class III drugs such as metformin and atenolol thus improving bioavailability and therapeutic efficacy. In this respect, this form of drug delivery system applies anhydrous type of nanoemulsion. The cosurfactants and coemulsifiers enable nanoemulsfication of the drugs in the intestines. SNEDDS provides beneficial effects in drug delivery systems since it enhances chemical and physical stability thus enabling long-term storage (Shaikh, Nikita, Derle & Bhamber, 2012, p. 19). In addition, it is possible to use drugs in hard or soft gelatin capsules or hydroxypropylmethylcellulose capsules. The latter facilitates patient acceptability and commercial viability. Furthermore, drugs developed via nanotechnology are palatable and it can be used in capsules.

nSome of the SNEDDS having permeability enhancing capacities include cosurfactants e.g. alcohol and Transcutol, Surfactants e.g. polysorbate 80 and Labrasol as well as oily phases e.g. propylene glycol ester of caprylic acid and oleic acid. Most notably, research indicates that nanoemulsion has the ability to improve permeability of Caco-2 and does not cause any destruction to the respective cells (Date, Desai, Dixit, & Nagarsenker, 2010, p. 7). Drugs such as ezetimibe and cyclosporine have higher cases of patient noncompliance because of intra- and inter-subject changes causing lower drug performance.

nThe SNEDDS formulation requires comprehensive understanding of the process of nanoemulsfication as well as biological and physiological properties of its components. Some of the factors that affect formulation process include components ration particularly oil-to-surfactant ratio, the pH and temperature during aqueous process and physicochemical drug properties including polarity, pKa, and lipophilicity (Date, Desai, Dixit, & Nagarsenker, 2010, p. 9). In the process of SNEDDS formulation, an acceptable route of administration should be developed to promote acceptability. However, when administered as SNEDDS, these drugs have higher rate of bioavailability (Shaikh, Nikita, Derle & Bhamber, 2012, p. 13). In addition, when administered through SNEDDS, fed and fasted states do not affect their bioavailability. SNEDDS also ensures that there is faster onset of action of BSC class III drugs, which ultimately manages conditions such as angina, hypertension and inflammation. Due SNEDDS use, many hydrophobic drugs such as antidiabetic and antihypertensive have lower dosage because of higher bioavailability (Date, Desai, Dixit, & Nagarsenker, 2010, p. 10). There is a huge challenge of protein drug delivery through the intestines because of poor stability, poor permeability and higher hydrophilicity. However, SNEDDS has solved the permeability of oral delivery of protein drugs such as beta-lactamase.

nIt uses hydrogenated phospholipids integrated into SNEDDS since it enhances permeability of Caco-2 cells. It also helps to enhance the permeability of natural phytochemicals. Since natural phytochemicals have a great potential in treatment and prevention of illnesses such as hepatitis, diabetes, arthritis and cancer, their bioavailability are highly valued (Date, Desai, Dixit, & Nagarsenker, 2010, p. 11). However, these drugs are not used in clinics because of poor stability and solubility. Therefore, SNEDDS solves the problem by improving the bioavailability of these drugs. Therefore, SNEDDS is a crucial factor in the delivery of drugs orally.

nCyclodextrin inclusion complex

nCyclodextrins (CDs) are oligosaccharides, which are cyclic in nature encompassing d (+) glucopyranose units connected via 1, 4 glucosidic bonds. They have a special ability of establishing inclusion complexes with different molecules because of their unique. The CDs have great ability to interact with the drugs to improve their permeability and ultimately enhancing their bioavailability (Khadka, Ro, Kim, Kim, Kim, Kim, & Lee, 2014, p. 13). In addition, these drugs are orally non-toxic hence; they are useful in oral administration of drugs. Inclusion of CD improves the solubility and permeability of complex tablet formulations.

nChitosan derivatives

nChitosan is a polymer that is used in delivery of drugs since it is biocompatible and non-toxic substance. It enhances paracellular permeability, especially when protonated across mucosalepithelia. At neutral pH, the drug has enabled bioavailability of peptide drugs in the gastrointestinal tract. Using Trimethyl chitosam chloride (TMC) enhances cationic peptide permeation across the intestinal epithelial cells (Khadka, Ro, Kim, Kim, Kim, Kim, & Lee, 2014, p. 9). It has the ability to interact with tight junctions components cause higher penetration of paracellular routes. Monocarboxy methylated chitosan can (MCC) produce visco-elastic gels because it is a poly ampholytic polymer at neutral pH. The MCC is able to enhance the absorption and permeability of low molecular weight heparin across the intestinal walls (Shaikh, Nikita, Derle & Bhamber, 2012, p. 17). Nonetheless, most of the chitosan derivatives cause huge damage of cell membrane hence they change the intestinal variability.

nDiscussion

nBSC class III drugs have poor permeability through biomembrane in the small intestines. Consequently, poor drug permeability leads to low bioavailability in the body. Bioavailability is the degree or rate of absorption of drugs in its dosage form. It is very crucial in drug administration as it determines the amount of drugs in the systemic circulation. Low drug permeability is a huge problem that should be considered during the formulation process of new BSC Class III drugs. In addition, enhancement of permeability of Class III drugs helps to promote oral ingestion because this is the most convenient route of drug delivery among human beings (Shaikh, Nikita, Derle, & Bhamber, 2012). Therefore, enhancing the permeability of BSC Class III drugs not only helps to improve drug bioavailability but also leads to higher patients compliance, reduces sterility challenges and it is cost-effective. Many studies have investigated different techniques of enhancing solubility of these drugs. Due to emergence of advanced technologies in pharmaceutical sciences such as nanotechnology, effective techniques have emerged to improve the permeability (Khadka, Ro, Kim, Kim, Kim, Kim, & Lee, 2014). Most of these techniques enhances drug solubility and permeability, protects the drug from destruction in gastrointestinal tract and enables delivery of class III drugs to targeted places.

nConclusion

nClass III drugs are highly soluble but have poor permeability. Therefore, these drugs have poor bioavailability in the body, particularly through oral administration. The body has many barriers that prevent drug permeability which include tight junctions, basal cell membrane, the mucous layers and unstirred layer of water. Others include lymph and capillaries cell walls (Shaikh, Nikita, Derle, & Bhamber, 2012). However, there is a variety of strategies to enhance permeability of BSC class III drugs, which includes Self-double emulsifying drug delivery systems (SDEDDS), Nano emulsions, Phytolipid delivery systems, Polyethylene glycol 400, and Self-Nano emulsifying Drug Delivery Systems (SNEDDS). Self-double emulsifying drug delivery systems improves the permeability through novel formation and water-in-oil-in-water emulsions in the gastrointestinal tract. Through nanoemulsion techniques the drugs is protected in the intestines that increases time to transit via the membrane. Phytolipid delivery systems uses phytosomes that increases permeability of plant extracts because it forms complex lipophilic substance (Agrawal, Gupta, & Chaturvedi, 2012, p. 7-9). Polyethylene glycol 400 stagnate fluids in the small intestines, which increases peristalsis and transit. Self-Nano emulsifying drug delivery systems use different liquid mixtures such as surfactants, coemulsifiers and solubilizers. It improves intestinal permeability of BSC class III drugs such as metformin and atenolol thus improving bioavailability and therapeutic efficacy.

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nReferences

nAgrawal, V. K., Gupta, A., & Chaturvedi, S. (2012). Improvement in Bioavailability of Class-III Drug: Phytolipid Delivery System. A Review. International Journal of Pharmacy and Pharmaceutical Sciences. 4(1).

nAshiru, D. A., Patel, R., & Basit, A. W. (2008). Polyethylene glycol 400 enhances the bioavailability of a BCS class III drug (ranitidine) in male subjects but not females. Pharmaceutical research, 25(10), 2327-2333.

nDate, A. A., Desai, N., Dixit, R., & Nagarsenker, M. (2010). Self-nanoemulsifying drug delivery systems: formulation insights, applications and advances. Nanomedicine, 5(10), 1595-1616.

nKhadka, P., Ro, J., Kim, H., Kim, I., Kim, J. T., Kim, H., … & Lee, J. (2014). Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability. asian journal of pharmaceutical sciences, 9(6), 304-316.

nShaikh, M. S., Nikita, D., Derle, D., & Bhamber, R. (2012). Permeability enhancement techniques for poorly permeable drugs: A review. J. Appl. Pharm. Sci, 2(06), 34-9.