A Comprehensive Text Book on Self-emulsifying Drug Delivery Systems

Different Methodologies for Improving Solubility and Bioavailability

Ravinder Verma¹, Deepak Kaushik¹, *, Ritu Kaushik¹, Vandana Singh¹

¹ Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak (Haryana), 124001, India

Abstract

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.

Keywords: Crystal engineering, Cryogenic method, High-pressure homoge-nization, Liposomes, Nanostructured lipid carriers, Oral bioavailability.

* Corresponding author Deepak Kaushik: Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak (Haryana), 124001, India; Tel: +91 9315809626; E-mail: [email protected]

INTRODUCTION

The oral route is the most favorable route for the administration of the drug owing to its multiple benefits such as ease of administration, strong patient compliance, possibility of different release options, cost-effectiveness, self-administration, convenience for prolonged repeated use, the most valuable non-invasive and the most common route for the treatment of various diseases.

Drug delivery through the oral route is perfect for both solid and liquid dosage forms. Liquid dosage forms are noticeable because of the simplicity of administration, the precision of measurements, self-administration, pain avoidance and especially patient compliance [1].

As our human body comprises around 70% water, a drug must be soluble in aqueous GIT fluid to have adequate bioavailability. The drug present in the dosage forms discharges in gastrointestinal (GI) fluid after its breaks down that results in a solution after gentle agitation. This process is solubility dependent. The passage of the solution form of a drug across the cell lining membrane in the GI tract is permeability constrained. Then, the drug assimilates into the blood. The oral bioavailability of a drug is measured by the rate of drug solubility and permeability.

Difficulties in the Oral Drug Delivery

Notwithstanding numerous favorable circumstances, the oral drug delivery is a big challenge due to complex physicochemical characteristics of lipophilic drug compounds and physiological conditions. Gastrointestinal contents, pre-systemic metabolism, aqueous solubility, drug permeability, drug extent of dissolution and efflux pumps are some of the complex factors which affect the efficiency of drug administration through the oral route. Oral intake of lipophilic drug in a dosage form is effortlessly taken by patients, goes in GIT via a tremendously versatile environment. When a drug transits from a highly acidic pH to the digestive system, the stomach digestive enzymes and microflora alter its pH. In this perspective, the main issues of oral delivery are the physicochemical characteristics of drugs and physiological conditions of human body [2].

Oral Bioavailability

The majority of the new chemical compounds being worked on nowadays are planned to be utilized as solid dosage forms so that a viable and reproducible in vivo plasma concentration can be acquired after oral administration. In any case, poor retention and poor bioavailability do not allow oral route for intake of numerous drugs. That is why in many cases, injections are preferred for administration of such therapeutic moieties, for example, proteins and peptides due to their poor oral bioavailability that prompts high fluctuation and poor control of plasma concentrations and therapeutic effects.

The process of drug dissolution is vital for the therapeutic efficacy of the orally administered drug and route of intake. Drug dissolution includes the transfer of a solid drug into the aqueous phase in the physiological fluid. The dissolution extent of a drug is influenced by factors incorporated in the Noyes-Whitney equation [3].

Reason for Poor Oral Bioavailability

Less bioavailability is frequently connected with the drugs related to BCS II, III and IV. Drugs such as acyclovir, aspirin, atorvastatin, simvastatin, ibuprofen etc. with less water solubility and less permeability or both as are shown in Fig. (1).

There are a few reasons which are credited for poor bioavailability of drug. These components include drug properties, dosage form, solubility, acid-base characteristics, partition coefficient, large molecular size and fundamental physiology of the gastrointestinal tract (GIT). The gastrointestinal variables incorporate physiological properties of GIT fluids, gastric motility, gastric resistance time, presence of processing enzymes causing potential enzymatic degradation of the drug (e.g., cytochrome P450) and interaction with efflux transporter systems like P-glycoprotein (P-gp), poor membrane permeability and intestinal efflux properties of GIT lumen [4].

Also, the irreversible expulsion of drugs by first-pass organs, including the digestive system, liver and lungs, are other impediments of drug retention. Likewise, despite their high permeability a large portion of the new chemical entities are commonly assimilated in the upper part of the small intestinal system, retention being significantly decreased after ileum. Therefore, if these drugs are not discharged in GIT, they will have less bioavailability. In this manner, the real difficulties of the pharmaceutical industries are the identification of the methodologies that reduce the oral retention of the drugs. Drug discharge is an essential and restricting parameter for the oral bioavailability of drugs, especially for drugs with less GIT solubility and high permeability. Enhancing the drug discharge profile of these drugs is conceivable to upgrade their bioavailability and diminish side effects [5, 6].

Fig. (1))

Biopharmaceutical classification system.

Lipinski's rule of five has been broadly proposed as a qualitative prognostic model for assessment of the retention of ineffectively assimilated candidates. The rule of 5 forecasts that poor retention or permeation occurs when more than 5H- bond donors are present, 10H-bond acceptors, molecular weight is higher than 500 and log P more than 5. Thus, in vivo estimation of new drug applicants in the creature is carried out to demonstrate the retention of drugs. Inadequately assimilated drugs represent a test to the formulation of researchers to create appropriate dosage form which can improve their bioavailability [7].

Drug Solubility

Drug solubility is defined as the quantity of drug that passes it into solution when the equilibrium is achieved between the solute of drug in solution and any surplus, un-dissolved drug to create a saturated state solution at a predefined temperature.

The oral bioavailability relies upon different aspects like aqueous solubility, drug permeability, drug extent of dissolution, first-pass metabolism, pre-systemic metabolism and so forth. The majority of continuous reasons for less oral bioavailability are identified with less solubility and less permeability. The solubility and disintegration rate of the drugs are directly related with each other. In this way, the bioavailability of a drug is subordinate to its dissolution and solubility parameters, as well as its membrane permeability and associated with degradation of the drug. There are various factors influencing solubilization such as the size of particle, temperature, pressure, molecular size, polarity, polymorphs and nature of solute & solvent.

Requirement for Solubility Improvement

Drug retention through GIT can be restricted by a variety of variables. The major contributors among these are less water solubility and less permeability of the drug candidate through a membrane. When administered orally, it should first break down in gastric and additional intestinal fluids before it can penetrate the layers of GIT to arrive in blood circulation. Henceforth, two territories of pharmaceutical investigations need attention: one enhancing the bioavailability of orally administered drug candidates, and second is improving its solubility and extent of dissolution in water-soluble drugs. The BCS is a logical structure for arranging a drug compound based on its aqueous solubility and intestinal permeability [8].

APPROACHES TO ENHANCE ORAL BIOAVAILABILITY

The bioavailability of a drug is defined as the rate and extent to which a dissolved drug is assimilated and becomes available at its site of action. Various innovations can be utilized to improve solubility and among them, solid dispersion approach can be effectively helpful for the improvement of items from lab scale to commercial scale with a wide variety of powder qualities. Different pharmaceutical particle strategies are utilized to solve the issues related to the low water solubility of drug substances. The molecule approaches can be classified into two categories: traditional techniques and advanced particle strategies. Various approaches to enhance oral bioavailability are shown in Fig. (2).

The chemical modifications and formulation modifications are the few ways involved in enhancing the oral bioavailability. Chemical modification includes soluble pro-drug, salt formation and 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 (SEDDS), liposomes, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers. The formulation approach is a superior option to a chemical modification approach, which may prompt the change in chemical structure and this may impact the pharmacological action. The achievement of the formulation modification approach is additionally restricted as they require the drugs to have particular properties, for instance, there should be an occurrence of β-cyclodextrin complexation, suitable molecular size and shape [9, 10].

Fig. (2))

Approaches to enhance oral bioavailability.

Current advanced particle technology can conquer the constraints of conventional strategies and more proficient techniques can be adopted for developing inadequately soluble drugs. The new techniques are created from traditional strategies where the fundamental guideline is the reduction of particle size for improving its solubility.

VARIOUS TECHNIQUES FOR IMPROVING BIOAVAILABILITY

Salt Formation

Salt formation is the most common approach for ionizable drugs to enhance solubility and dissolution of the drug. Salts are framed by proton exchange from acid to base. As indicated by the Henderson-Hassel Balch equation, the adjustment in pH profoundly impacts the aqueous solubility of an ionizable drug [8, 11].

Theoretically, the solubility of the weakly basic drug increases with diminishing pH at the pH range between its pKa and pH max. The expanded saturable solubility depends upon the dissolving area that participates in the greater disintegration rate by salt development. For example, the solubility of different diclofenac salts varies by a factor of 100 [10].

The dissolution rate of specific salt is generally unique with its parent candidate. Sodium and potassium salt of weak acids dissolve more hastily than an unadulterated salt. Limitation of the salt form is epigastric pain because of elevated alkalinity that leads to precipitation of atmospheric water and carbon dioxide, their reactivity, patient conformity and commercialization [12]. Salt development of neutral candidates isn't possible and weak acid and weak base salts may not always be practically possible to synthesize [13].

Cyclodextrins Based Complexes

Cyclodextrins are oligosaccharides consisting of a hydrophobic core cavity and hydrophilic external shell. There are various kinds of cyclodextrins based on the number of attached α-D-glucopyranose units. These are widely used in several pharmaceutical and nutraceutical compositions. They form an inclusion complex with poorly water-soluble drugs by entrapping them into their hydrophilic cavity as shown in Fig. (3). This leads to an increase in their solubility and results in improved bioavailability [14].

In pharmaceutical formulation methods, cyclodextrins are valuable solubilizers. The critical procedure related to the solubilization capability of cyclodextrins (CDs) is the incorporation of the developed complex, while the solubilization process may also be contributed by a non-inclusion complexation and supersaturation. There are a few strategies for the formation of a drug-cyclodextrin complex.

Fig. (3))

Inclusion complexes of cyclodextrins.

Particle size, amount of complex development and the level of amorphous nature of the finished product result in the selection of planning technique which is vital when outlining drug cyclodextrin edifices. As far as toxicology and kinetics of solubility are concerned, CDs are well-thought-out in having advantage over organic solvents, drug entrapment efficacy and high drug loading capacity. After studying these investigations, it is concluded that CDs, particularly β-CD, can be an appropriate ingredient in pharmaceutical molecule innovation for enhancing the solubility of drugs with poor solubility [15, 16].

Jakab et al., introduced baicalin and its CD complexes with enhanced bioavailability that have a bioactive phytopharmacon [17]. Complexation with cyclodextrin molecules isn't suitable for medicated molecules with no solubility in aqueous and organic solvents.

Gao et al., formulated diuron loaded inclusion complex. They altered physicochemical properties by using β-CD that resulted in the enhancement of its herbicidal performance [18].

Saeid et al., formulated melphalan loaded complex using β-CD macrocycle. They found that the 18:1 βCDg-Mel complex enhanced biological performance 2–3-times and lessen its concentration by approximately half for maximal inhibitory concentration [19].

Kontogiannidou et al., formulated mucoadhesive tablets of piroxicam using co-evaporation method. They concluded that the drug discharge pattern was Me-CD > HP-β-CD > β-CD, whereas the ex vivo investigation demonstrated that chitosan-based tablets appreciably enhanced the transportation of drugs [20].

Techniques of Complexation

Various techniques of complexation include:

Kneading Technique

The drug with the appropriate polymer in various proportions is placed in the mortar and triturated with a little amount of ethanol to prepare slurry. Gradually the drug is fused into slurry with consistent trituration. The slurry is then exposed to air drying at 250°C for 24hrs to obtain complex. The resulting complexes are pulverized, sift through 80 mesh and placed in a desiccator over fused CaCl2.

Co-precipitation Technique

The drug is broken up in ethanol at moderate temperature and the reasonable carrier is disintegrated in filtered water. Distinctive molar proportions of drug and appropriate carriers are blended. The blend is mixed at a controlled temperature for 60 minutes and evaporation of the solvent is done. Pulverize resultant material, sift through 80 mesh and placed in desiccators.

Spray Drying

A spray dryer is utilized for the evaporation of drug and carrier solution in various proportions. The solutions are prepared by dissolving a drug in methanol and carrier in Milli Q water and the two solutions are then blended to obtain a clear solution. Then, the solution is introduced into the spray dryer for evaporation of the solvent and spray-dried blend of drug with carrier for 20-30 min, as shown in Fig. (4) [21, 22].

Fig. (4))

Overview of spray drying process.

Zhang et al., developed chitosan-based microspheres of Panax notoginseng extract, Codonopsis extract and Atractylodes extract with this technique. In vitro investigation showed a sustained release effect of the formulation. The particle diameter was 10.27±1.05 μm with an encapsulation efficiency of 91.28±1.04% [24].

Pohlen et al., developed simvastatin loaded dry emulsion with this technique employing a mixture of caprylic, capric TG and 1-oleoyl-rac-glycerol, mannitol, HPMC, tween 20. This formulation resulted in suitable particle size distribution, good reconstitution ability and enhanced dissolution profile [25].

Wijiani et al., developed curcumin-spray dried powder with self-assembled casein and sucrose, as a protectant. It showed a significant increase of drug solubility in presence of sucrose [26].

Novel Formulation Approaches for Bioavailability Enhancement

There are some novel formulations for the bioavailability enhancement which are discussed below:

Polymeric Micelles

Polymeric micelles have risen as possible transporters for inadequately soluble drugs by making their inner core sluble and contributing appealing features such as a lesser size and an affinity to sidestep hunting by the mononuclear phagocyte system. In these systems, the lipophilic parts frame the center of the micelle, while the hydrophilic part forms the micelle's outer layer. The non-polar particles are solubilized inside the lipophilic part while polar compounds will be adsorbed on the surface of the micelles and molecules with moderate polarity will be dispersed with surfactants at an intermediate location as shown in Fig. (5) [27].

Drug loading is done by two different methods. The primary technique is the direct dissolution technique and the second technique is the solvent removal technique. The direct dissolution technique is a basic technique in which moderately hydrophobic block co-polymers are used along the drug in an aqueous solvent. Another technique is related to amphiphilic copolymers, which do not solubilize promptly in an aqueous phase and need an organic solvent for dissolving together. Micelle arrangement relies on the solvent removal process that can be performed by one of the few strategies like dialysis, solution casting, o/w emulsion and freeze-drying [28].

Fig. (5))

Polymeric micelles with entrapped anti-cancer drugs.

These are advanced systems that not only improve the aqueous solubility of the numerous lipophilic drugs, but are also applicable in drug targeting, preparing unstable drugs and lessening their adverse effects. Because of their extensive materialness to an enormous group of therapeutic candidates, drug-loading into polymeric micelles is a gifted particle technique for developing other inadequately soluble drugs in the future [29, 30].

Liposomes

These are vesicles of phospholipid (PL), involving a PL bilayer encompassing water partition and can break up lipophilic drugs in their lipid sphere. In the light of their biphasic attributes and assorted variety in formulation and administration, they propose a dynamic and versatile innovation for the improvement of drug solubility. Entrapment or encapsulation of drugs into liposomes changes pharmacokinetics and pharmacodynamics features of water-insoluble drugs and thus facilitates enormous improvement in the bioavailability and therapeutic value of drugs. During storage, poor stability is one of the genuine confinements with liposomes as drug delivery systems [31]. Thus, the freeze-drying method is utilized to obtain dry powders with upgraded stability while keeping the potency of added drugs in the liposomal formulations. This is a promising methodology for developing drugs with poor aqueous solubility and additionally upgrading the stability of liposomal formulations [32].

Abud et al., evaluated a new formulation of sirolimus loaded liposome that resulted in negligible in vitro and in vivo toxicity in rabbit eyes [33].

Nkanga et al., encapsulated an isoniazid-hydrazone-phthalocyanine conjugate (Pc-INH) complex system in γ-CD that was further transformed into liposomes using crude soybean lecithin by simple organic solvent-free and heating techniques [34].

Solid Lipid Nanoparticles (SLNs)

SLNs are colloidal drug transporter systems that resemble with nanoemulsions, however they consist of solid lipid such as glycerides or