Self-nano Emulsifying Formulations: An Encouraging Approach for Bioavailability Enhancement and Future Perspective

Abstract

Currently lipid-based formulations are playing a vital and promising role in improving the oral bioavailability of poorly water-soluble drugs. Lipid based formulations mainly consist of a drug dissolved in lipids such as triglycerides, glycerides, oils and surface active agent. Self nanoemulsifying formulations (SNEF) are isotropic mixtures of lipids/oils, surfactants and co-surfactants. On mild agitation followed by dilution in aqueous media, such as GI fluids, SNEF can form fine oil-in-water (o/w) nanoemulsions. Present chapter summarizes different types of lipid formulations with special emphasis on SNEF, availability of dosage forms, different components with natural surfactants from medicinal plants, mechanism of SNEF, recent advancements in oral drug delivery, solid SNEDDS, patents on SNEF and future prospects. SNEF emerging as powerful technique to improve solubility and commercialization of solid SNEF is the future novel drug delivery to improve bioavailability of poorly water soluble drugs.

1. Introduction

In recent years, promising efforts have been made to use the potentials of lipid drug delivery systems for solubility and bioavailability enhancement potential. Poorly water-solubility and bioavailability are major challenge in front of formulation of scientists in development of new formulation. Lipid-based drug delivery systems (LBDDS) have great potential of versatility and biocompatibility. Lipid-based formulations modified in different routes to adapt a broad range of products as per the requirements of disease and route of administration. The key factor of LBDDS is their safety and efficacy during design and development of medicines [1]. Recently LBDDS gained much importance in reducing variable food effects and enhancement of bioavailability of poorly water-soluble active pharmaceutical ingredient (API). LBDDS offers great advantages like controlled and targeted drug delivery, stability of developed formulation which is capable of carrying both lipophilic and hydrophilic drugs within it [2]. Lipid formulations classified in to liquid lipid-based formulations, emulsions or microemulsion, Self-emulsifying drug delivery systems (SEDDS), solid-in-oil (S/O) suspension, solid lipid-based formulations, lipid as particulate drug carriers, liposome, solid lipid nanoparticles (SLNs), neosome. Present work gives an overview of Self nano-emulsifying formulations, its components, future perspectives and applications in commercialization. SNEF is the most promising approach which overcomes poor water solubility; bioavailability and formulation difficulties poorly water-soluble drugs [3]. SNEF designed to increase solubility and bioavailability of drugs belonging to the BCS Class II-IV. SNEF comprehensively enhance the solubility and bioavailability of poorly water soluble drugs (PWSDs) by micelle formation. In SNEF API introduced as nanosized oil droplets. Rapid drug release of SNEF in the stomach due to the generation of nanosized oil droplets leads to the quick onset of action in the GI tract. SNEF easily dispersible due to the partitioning of a drug between oil and water which generates a larger interfacial area. SNEF offers ample of advantages such as reproducible plasma drug conc., decrease in variability of rate and extent of absorption [4]. SNEF holds the drug in a solution that allows enough time for drug absorption through GIT [5].

2. Self nano emulsifying formulations (SNEF)

SNEF is an isotropic mixture of surfactants, lipids, and solubilizers having great ability to form fine O/W nano-emulsion by mild agitation. It has droplet size 2–200 nm dispersion in water which improves increase the rate of dissolution and bioavailability of PWSDs [6]. SNEF is the most stable emulsion due to the partitioning of the drug between the oil and aqueous phase gives larger interfacial area. It is technically proven that droplet size of nanoemulsions was not affected by the fed and fasted dissolution conditions. Optimized nanoemulsions reduce bioavailability ratio in fed and fasted state which maintain reproducible plasma profile. Optimized formulation improves oral absorption of PWSDs hence the onset of action is quick. Nanoemulsion improves conc. of the drug in systemic circulation (bioavailability) which leads to a reduction of does and higher does related adverse effects in case of potential anticancer drugs [7].

2.1 Advantages of self nanoemulsifying formulations (SNEF)

1. Nanoemulsion (SNEF) has a much large surface area and free energy.

2. SNEF improve the bioavailability [8].

3. SNEF protects the drug from enzymatic degradation and hydrolysis by dissolving large quantity in lipids and make them suitable carrier for parental transport.

4. SNEF provide large O/W interfacial area and ultra-low interfacial tension

5. SNEF improves low aqueous solubility, low permeability, gastric irritation, enzymatic degradation, and stability.

6. Site specificity and targeted drug delivery can be achieved with SNEF [9].

2.2 Disadvantages of self nanoemulsifying formulations (SNEF)

1. Formulation of SNEF is expensive in recent years due to technological development in a high-pressure homogenizer and ultrasonic equipment of high coast [10].

2. Storage conditions temperature and Ph affects stability [11].

3. Composition of SNEF

3.1 Lipid/oil phase

Choice of specific lipid phase has critical importance in the formulation of optimized SNEF. Maximum capacity of lipid to solubilize selected drug and high drug loading capacity are the major criteria for selections of lipid for the development of nanoemulsion. Oil phase has a great ability to increase drug loading capacity for transport of drug in systemic circulation by an increase in absorption of PWSDs [12]. Omega oil is essential fatty acids that the human body needs for metabolic functioning. Human body needs Essential Fatty acids (EFAs) to remove toxic harmful waste products, cell membrane repair and to get optimum nutrition. Main objective of EFAs to generate prostaglandins which controls functions such as blood pressure, heart rate, regulating inflammation, blood clotting etc. Omega oil also helps in treatment of breast, colon and prostate cancer [13]. Some are mentioned in Table 1.

General class	Examples	Commercial name
Lipids	Soya lipid,Polyoxy- 35 castor oil	Accutane soft gelatin capsule, Cremophor EL
MCTs	Triglycerides of capric acids; Triace tin	Miglyol,Labrafac crodamol, Captex,; Captex
Medium-chain mono and diglycerides	Capric acids -Mono- and diglycerides	Capmul, Akoline
Mono-glycerides (Long-chain)	GMO-Glyceryl monooleate	Maisine,Peceol, GMO-Capmul
Polyethylene Glycol (Fatty acids esters)	Polyethylene Glycol monolaurate/dilaurate; Polyethylene Glycol dicaprylate/caprate	Capryol, capmul, Sefsol; Lauroglycol, capmule, lauroglycol; Migylol, captex
Esters fatty acid	Isopropyl myristate	Crodamol EO
Fatty acids	Caprylic acid	Crossential
Vitamins	Vitamin E D-alpha TocopherylPoly ethylene Glycol1000 Succinate; (Vit.E-TPGS)	Tocofersolan

Table 1.

Commonly used oils in SNEF.

3.2 Surfactants

For design and development of optimized SNEF large no. of compounds have properties of surfactants but few orally acceptable such as nonionic surfactants having low HLB. A large number of surfactant is associated with toxicity. Hence the safety is a major concern while a selection of Surfactant molecule (Table 2) [12].

General class	Examples	Commercial name
Polysorbates	Sorbitan monolaurate	Tween 80, crillet 4
Sorbitan esters	Sorbitan monolaurate	Span 20,68,80,; Crill 1,3,4
Copolymers	Poloxamer 188 and 407	Pluronic F-68 and F 127
Castor oil	Castor oil	Cremphor, Etocas
Polyglycolyzed glycerides	Linoleoyl macrogol glycerides; Oleoyl macrogol glycerides; Caprylocapryol macrogol glycerides; Polyglyceryl oleate; Lauroyl macrogol glycerides; Stearoyl macrogyl glycerides	Labrafil, Labrasol, Plurol oleique, Gelucire, Gelucire
Phospholipids	Soybean / sunflower lecithin	ALCOLEC®

Table 2.

Commonly used surfactants in SNEF [14].

4. Solubilizers

Solubilizers are incorporated in nanoemulsions to increase drug loading capacity to modulate droplet size and self emulsification time of optimized formulation (Table 3) [15].

General class	Examples
Alcohols (Short-chain)	C2H5OH
Alkame (Diols and Triols)	PEG
Polyethylene glycols	PEG 400
Glycol ethers	Diethylene glycol monoethyl ether(transcutol)

Table 3.

Commonly used solubilisers in SNEF [16].

5. Mechanism of SNEF

In nanoemulsions, entropy change favors dispersion as compared to the energy required to increase the surface area of dispersion. SNEF mainly involves surface free energy which is used by nanoemulsion to produce new surface area in oil and water system can be represented in following equation

$$\Delta G=\sum N\pi r^2\sigma$$E1

Where ∆G is the surface free energy associated, N is the number of droplets of radius r and ó represents the interfacial energy [17]. Emulsifying agent stabilizes the emulsion when two phases immiscible concerning time to decrease interfacial area. In nanoemulsions, coalescence is avoided due to droplets of monolayer which reduce interfacial energy required for the formulation of nanoemulsion. Free energy required for formulations is low, positive or negative [18].

6. SNEF and recent advancements in oral drug delivery

SNEF is a recent advancement in lipid-based nanoemulsions and it is a promising strategy to solubilize drug molecule in the lipid phase which is biocompatible. SNEF play dual function it protects entrapped drug molecule against degradation in GI fluids also absorption of the drug in lymphatic transport increased. It mainly focused on the impact on the size and surface nature of nanocarriers on targeted uptake by entrecote [19, 20]. Figure 1 shows an overview of encapsulated SNEF developed for oral administration. SNEF expressed as to potential nanoemulsion which is thermodynamically and kinetically more stable hence it has great ability to enhance oral bioavailability of PWSDs [21]. In 1995 for first-time saquinavir was introduced in the market in salt form having only 4% bioavailability in a hard gelatin capsule. After 02 years bioavailability increased 03 folds in human by formulating in SNEF with medium-chain mono- and diglycerides [22, 23].

Figure 1.

Enhancement of oral bioavailability through SNEF.

7. Phase diagram of lipid formulations

The phase diagram in SNEF is constructed to choose a right potential candidate of oil, surfactant, and co-surfactant which is selected by varying concentration of surfactant, oil, and solubilizers depending on physiochemical properties of API such as surface activity and polarity. Orange colored area of self good self emulsification are established by diluting the mixture of oil and surfactant sequentially phase studies are performed by an increase in the amount of water (Figure 2). Once equilibrium is achieved types of phases recognized by using an optical microscope or cross-polarized viewer [24, 25].

Figure 2.

Schematic ternary phase diagram of SNDDS system.

8. Methods of preparation of nanoemulsion

(Figure 3)

Figure 3.

Methods of Preparation of Nanoemulsions.

9. In vitro-in vivo correlation (IVIVC) for self nanoemulsion

New drug synthesis and design, optimization of new drug and its formulations are very costly and time consuming processes and IVIVC play prime importance in it. Optimization demands in vivo bioequivalence data in human to ascertain similarity of the new formulation. Due to this load importance of performing bioequivalence studies significantly increase hence coast of formulation and optimization process increases. To solve this problem it is necessary to perform in vitro tests that can interpret bioavailability data. IVIVC concept was established in scientific research studies which give a prediction of in-vitro parameter with in vivo activity [26, 27]. The IVIVC predominantly used in the product development to decrease the human trials during the formulation development and to support biowaivers. IVIVC acts as vital tool for correlating in vitro and in vivo data. Core balance of IVIVC study in development and optimization of new formulation with minimum human trials [28]. IVIVC is a mathematical model which predicts the relation between rate and extent of drug release and plasma drug concentration. For drugs that are administered orally, dissolution and intestinal permeation are considered as the rate-limiting steps for the absorption. Bioavailability is calculated by controlling dissolution profile, therefore, if an excellent correlation exists between in vitro dissolution test and a bioavailability parameter, then controlling the dissolution profile will permit the evaluation of bioavailability [29]. The in vitro drug release studies of the formulations can be performed using dissolution, disintegration tests on t other hand in vivo pharmacokinetic study performed on animal models. Apart from this, there is a limited number of IVIVC studies conducted using lipid formulations. To get strong IVIVC relationship a large no. of nanoemulsions of PWSDs administered orally. Clinical data of more human volunteers along with in detail evaluation of in-vitro and in vivo solubility of poorly water soluble drugs entrapped in lipid vehicles [30].

10. Solid SNEF

As Nanoemulsions facing problems related to stability, handling, formulation and development scientist decided to overcome these hurdles related to stability and converted nanoemulsions into solid-state and concept of solid SNEF coined. Solid dosage forms are most convenient and stable for handling and they are dry solid powder overcomes hurdles of stability. Adsorption on a solid carrier is the best technique involved to convert liquid nanoemulsion to solid SNEF apart from other techniques available such as spray drying and freeze-drying. The choice right process for the formulation of solid SNEF Mainly depends on the properties of API, such as solubility, stability, and compatibility with other ingredients and nature of the oil phase of the formulation. Adsorption on the surface of adsorbent act as a binder and it is coast effective, accurate, optimizable, uncomplicated and large scale manufacturing is possible with ease. Adsorption on solid carrier adsorbs heat and moisture sensitive drugs can be formulated into SNEF also it has an advantage over other methods. Commonly used adsorbents in SNEF are Neusilin-US2, Fujicalin, Aerosil etc. [31].

10.1 Ideal characteristics of an adsorbent

1. Adsorb viscous, sticky and oily nanoemulsions

2. Compatible, safe, freely flow able, high bulk density,

3. Should not alter dissolution profile once converted to solid form.

Researchers developed and characterized solid nanoemulsion granules (SNGs) of ezetimibe and ezetimibe-simvastatin in combination by using aerosol 200 as adsorbent. Results of X-ray diffraction shows improvement in the solubility of drugs in SNGs. Scanning electron microscopy indicates no precipitation of drug on the surface carrier. Drastic enhancement in dissolution profile of the drug in SNGs when compared to pure drug. Plasma level data in rats show a significant decrease in total cholesterol level compared to pure drug (Figure 4).

Figure 4.

SEM of SNEF adsorbed on neusilin-US2 adsorbant.

10.2 Evaluation of SNEF

• Thermodynamic stability studies

• Robustness to dilution

• Assessment of Efficiency of self-emulsification

• % Transmittance

• Viscosity

• Dye solubilization test

• Cloud point measurement

10.3 SNEF: Potential explored

Self nanoemulsions have a unique capability to improve therapeutic effectiveness oral bioavailability of PWSDs which is proved by various in-vitro-in-vivo methodologies. Pharmacodynamic efficacy of drugs improved by formulating PWSDs in nanoemulsions. The solubility of PWSDs in different lipids, surfactants, and solubilizers along with their compatibility is key factors while the successful formulation of SNEF [32]. The key investigations that describe the potential of SNEF in oral drug delivery are listed in Tables 4 and 5.

Drug	Therapeutic use	Components	In vitro/in vivo observation
Β-lactamase	A model protein	Hydrogenated lecithin, Cremophor EL, Transcutol, lauroglycol FCC	2–3-fold BA increment compared with the solution
Biphenyl dimethyl dicarboxylate	Hepa to protection	Tween 80, transcutol, Miglyol 812	1.7–6-fold improvement in BA
Cyclosporine A	Immunosuppressant	Cremophor EL, Capmul, MCM C8, Orange oil	Improvement in dissolution rate
Anethole trithione	Chemopreventive	Tween 80, PG, cremophor RH 40 MCT	Improved stability and in vitro dissolution profile

Table 4.

Potential of SNEF in oral drug delivery.

Patent No.	Agency	Year	API	Lipid/Oil	Surfactant
US2013/0303495A1	United State Patent	2013	Testosterone	Castor Oil	Cremophor RH40, Imwotor 742
US8728518B2	United State Patent	2014	Butylpthalide	Castor Oil, Almond Oil, Oleic acid	Cremophor EL,Labrafac CM10,Labrasol M1944,Mabrafil M2125CS
W02014/205226A1	World Intellectual Property Organization	2014	Progesterone,; Fenofibrate	Castor Oil,; Polysorbate-20,40,60	Propylene Glycol, Monocaprylate Glyceryl Mono caprylate
W02014/009434A1	World Intellectual Property Organization	2014	Abiraterone	Corn Oil, Olive Oil, Sunflower Oil	Labrafac,; Captex, PEG
W02015/142307A1	World Intellectual Property Organization	2015	Rosuvastatin	Oleic Acid	Labrasol, Labrafil M1944, Transcutol.
W02016/141098A1	World Intellectual Property Organization	2016	Ophthalmic Drugs	Castor Oil, Olive Oil, Sunflower Oil	Labrafac,; Captex,; PEG
WO2017/017649A1	World Intellectual Property Organization	2017	Astaxanthin	Akoline CM C	Labrasol, Tween 80
US9918965B2	United State Patent	2018	Diindolylmethane	Peppermint Oil	Gelucire, Capryol, Polysorbate 80
W02018/011808A1	World Intellectual Property Organization	2018	Cannabinoids	Castor Oil	Polysorbate 80, PEG 1000

Table 5.

Patents of SNEF.

11. Applications of SNEF

11.1 Bioavailability and solubility improvement

Drug of Class-П drug (Low solubility/high permeability) and formulated in SNEF, then it increases the solubility. Ketoprofen is a non-steroidal anti-inflammatory drug (NSAIDs), mainly it is used for sustained release formulation. In chronic therapy ketoprofen cause gastric irritation due to its low solubility its release from sustained formulations is incomplete. As ketoprofen developed in nanoemulsion complete drug release form sustained formulation of ketoprofen achieved successfully. Ketoprofen developed in SNEF producing oil in water O/W emulsion, droplets of nanoemulsion make drug available for absorption in dissolved form in GIT.Many different approaches available to achieve sustained release which causes decrease in irritation and increase in bioavailability such as matrix pallets, nanocrystals, micro particles, floating oral system apart from these SNEF found upper hand over these [33].

11.2 Protection against biodegradation

SNEF enhance absorption due to larger surface area, reduction in surface area; reduce degradation of PWSDs having both low oral bioavailability and poor water solubility due to degradation of drug by enzymatic degradation and acidic Ph in stomach.

11.3 Solid SNEF

Self emulsifying formulations adsorbed on solid carrier and converted in to free flowing power which may filled in to capsule or compressed in to tablet with suitable excipients. To overcome stability related problems of nanoemulsions these are adsorbed on adsorbents to convert them in solid dosage forms tablet or capsule [34].

11.4 SNEF for TCM

Silybin protects liver cells from damage of drinking, smoking and liver-damaging drugs. Due to low solubility of silybin in water it has very low bioavailability when given orally. Hence when silybin formulated in SNEF with ethyl linoleate as lipid, Tween and dimethyl isosorbide as surfactant and co-surfactant respectively bioavailability of silybin increased 04 folds.

12. Future perspectives

In recent years modernization in SNEF research drastically enhance solubility and oral bioavailability of poorly water soluble moieties. The conversion of liquid to a solid SNEF drastically reduces the drug degradation rate. Therefore, it has vital importance to study novel tools and techniques to enhance bioavailability drugs. With help of sophisticated equipment’s and modern techniques liquid SNEF converted to a solid form including tablets and pellets. Modern adsorbents like neusilin-US2 should be used for converting liquid SNEF into a solid powder without change in physiochemical properties of drug along with increase in volume and density [35].

13. Conclusions

Approximately 40% newly synthesized drug moieties are associated with poor water solubility, low bioavailability, high intra- and inter-subject variability, and a lack of dose proportionality. SNEF is now becoming a promising approach to enhance solubility, dissolution and hence bioavailability of poorly water-soluble drugs. An additional advantage of SNEF over simple oily solutions is that they provide a large interfacial area for the partitioning of the drug between oil and water. Incorporation of a liquid SNEF into a solid dosage form may combine the advantages of SNEF with those of a solid dosage form and overcome the disadvantages of liquid formulations. Conclusively, SNEF would be a promising approach for poorly water soluble drugs to improve its therapeutic interventions.

Acknowledgments

The authors are thankful to Department of Pharmaceutics Sant Gajanan Maharaj College of Pharmacy Mahagaon and Trustees of Sant Gajanan Maharaj College of Pharmacy Mahagaon for providing required guidance and support for completion of this work.

Conflict of interest

The authors declare no conflict of interest.

Notes/thanks/other declarations

Special thanks to Shivtej S. Galatage for his countionous support throughout the work.

List of abbreviations

SNEF

Self nano-emulsifying Formulations

O/W

Oil-in-water

LBDDS

Lipid-based drug delivery systems

API

Active pharmaceutical ingredient

PWSDs

Poorly water soluble drugs

SLNs

Solid Lipid Nanoparticles

EFAs

Essential Fatty acids

IVIVC

In vitro in vivo correlation

SNGs

Solid nanoemulsion granules

NSAIDs

Non-steroidal anti-inflammatory drug