A Review on Novel vesicular systems for enhanced Oral bioavailability of Lipophilic drugs

 

Lakavath Sunil Kumar*

Department of Pharmaceutics, Jangaon Institute of Pharmaceutical Sciences,

Yeshwanthpur, Jangaon, Telangana State – 506167, India.

 

ABSTRACT:

The poor oral bioavailability of many drugs is mainly due to the poor aqueous solubility, chemical instability and pre-absorptive metabolism. Numerous approaches have been developed for enhancement of oral bioavailability and were currently in the clinical application. Even though, some drugs not meet the required clinical application due to the patient compliance and ineffective therapeutic levels. Vesicular delivery systems are considered as alternative delivery for the enhancement the bioavailability of this category of drugs. The enhanced bioavailability of the liphophilic drugs from the vesicular systems mainly due to the increased effective surface area of the drug in the presence of lipids, surfactants and co surfactants, enhanced lymphatic uptake, altered gastric motility and by virtue of their small particle size. Extensive literature is available for the properties, applications, and preparation and evaluation methods. This review mainly dealt with the reported drug loaded various vesicular systems such as liposomes, niosomes, lipid nanoparticles, self-emulsifying delivery system, nanosuspensions.

 

 

 

INTRODUCTION:

Oral route of administration of drugs is the preferred choice of drug delivery, principally due to better patient compliance, ease of administration, and cheaper in terms of cost of production. The oral bioavailability and thus the efficacy, is an indication of the solubility of drug in the gastrointestinal fluids and its intestinal membrane permeability^1,2.

 

Earlier, lower bioavailability of oral dosage forms was only considered to be the aspect of physicochemical properties of the drug. In later phase due to advancement in technologies of drug delivery systems, numerous biochemical, biological, and receptors level interactions came into light as causes for such experimental results^3,4.

 

The prevalent application of combinatorial chemistry and high-throughput screening in the process of drug discovery during the period of past two decades has made new molecular entities (NME) highly insoluble in aqueous media. Orally administered drugs are obliged to dissolve in gastrointestinal (GI) fluids preceding their absorption into the body^5,6 (In view of the fact that in many instances the drug dissolution step is proved to be the rate limiting step, suitable formulation design can be a functional approach to improve the dissolution and thus the oral bioavailability of such molecules^7-11.

 

The drug dissolution in the GI tract (GIT) will be influenced by the characteristics of the GI components like volume of GI fluids, pH, surfactant concentration, and also the physico-chemical properties like pKa and log P of the drug. Numerous factors like molecular size, lipophilicity of the drug, in addition to its affinity to influx or efflux transporter proteins. Modification physicochemical properties like particle size reduction, salt formation may always do not work due to the limitations^12-15. In case of salt forms problems like feasibility of salt formation of neutral compounds, form conversion from salt to original acid or base form may lead to aggregation in GIT. Particle size reduction is not advantageous in case of very fine powders with poor wetting properties. Various strategies like solid dispersions¹⁶, cyclodextrins¹⁷, buccal delivery^18,19, gastro retentive delivery^20-22, floating tablets^23,24 and nano particular delivery systems were employed to overcome these issues concerned to poor bioavailability^25-28.

 

In this review attempts were made to discuss about and list of the drugs reported to enhance the oral bioavailability of lipophilic drugs using various vesicular systems such as liposomes, niosomes, lipid nanoparticles (solid lipid nanoparticles and nanostructures lipid carriers), and nanosuspensions and self-emulsifying drug delivery systems. Previously, some reports are published for the development of various nanodelivery systems for independent drugs such as candesratan cilexetil²⁹, pramipexole dihydrochloride³⁰, zaleplon³¹ and duloxetine³².

 

Liposomes:                                                                                                                                                               

Liposomes are bilayered small artificial vesicles of spherical shape that can be prepared by using the combination of cholesterol and natural non-toxic phospholipids³³. Due to their size and hydrophobic and hydrophilic character (besides biocompatibility), liposomes are promising systems for drug delivery. The physical and stability properties of liposomes are differing considerably and are depends with lipid composition, surface charge, size, and the method of preparation used for making^34,35. Furthermore, the rigidity and the charge of the bilayered mainly influenced by the composition of the bilayer^36,37. For example, unsaturated phosphatidylcholine species from natural sources i.e., egg or soybean phosphatidylcholine give much more permeable and less stable bilayers, whereas the saturated phospholipids with long acyl chains (for example, dipalmitoylphos phatidylcholine) form a rigid, rather impermeable bilayer structure³⁸. Liposomes and prolipiosmes are used to improve the oral bioavailability (BA) by increasing the residence time in the gastro intestinal tract (GIT), surface modification promote uptake and avoiding first-pass metabolism. Various reported liposome and proliposome formulations are presented in Table 1.

 

Table 1: List of reported liposomes for improved oral bioavailability

Drug	Type of formulation	Components	Type of study	Animals	Inference	Reference
vincristine	Liposome	Dihydrosphingomyelin	In vivo	Rats	Increase in half-life and residence time	39
Dehydrosilymarin	Proliposome	soybean phospholipids, cholesterol	In vivo	Rabbits	2.28-folds	40
Zaleplone	Proliposome	soyphosphatidylcholine (HSPC) and cholesterol	In vivo	Rats	2 to 5 fold enhancement in BA	37
Heparin	Liposome	soyphosphatidylcholine and cholesterol	In vivo	Rats	3-times	41
Valsartan	Proliposomes	dimyristoyl phosphatidylglycerol sodium (DMPG) and cholesterol	In vivo	Rats	2.02-folds	42

 

 

Niosomes:

Niosomes are multilameller vesicular structure of nonionic surfactants, similar to liposomes and are composed of non-ionic surfactant instead of phospholipids which are the components of liposomes^43-45. So, niosome or non-ionic surfactant vesicles are now widely studied as an alternative tool to liposome. Various types of surfactants have been reported to form vesicles, and have the capacity to entrap and retain the hydrophilic and hydrophobic solute particles. Niosomes mainly contain two types of components i.e., nonionic surfactant and the additives. The non-ionic surfactants form the vesicular layer and the additives used in niosome preparation are cholesterol and the charged molecules⁴⁶. The presence of the steroidal system (cholesterol) improves the rigidity of the bilayer and is important component of the cell membrane and their presence in membrane affects bilayer fluidity and permeability. This carrier system protects the drug molecules from the premature degradation and inactivation due to unwanted immunological and pharmacological effects⁴⁷. In recent years, niosomes have been extensively studied for their potential to serve as a carrier for the delivery of drugs, antigens, hormones and other bioactive agents. Besides this, niosome has been used to solve the problem of insolubility, instability and rapid degradation of drugs. Table 2 describes the various reported niosomal formulations.

 

Table 2: List of reported niosomes for improved oral bioavailability

Drug	Components	Type of study	Animals	Inference	Reference
Aciclovir	Cholesterol, span 60, Dicetylphosphare	In vivo	Rabbits	2-fold increase in BA	48
Griseofulvin	Span 20, 40, 60, cholesterol, DCP	In vivo	Rats	Increase in MRT	49
Clarithromycin	Span 20, 40, 60, and 80 and cholesterol	In vivo	Rats	1.5-fold enhancement in BA	50
Diltiazem	Span 60 or Brij-52 wif cholesterol	In vivo	Rats	Increased AUC	51
Gliclazide	Span 60 and cholesterol	In vivo	Rats	Reduction in blood glucose level	52

 

 

Lipid nanoparticles:

Solid lipid nanoparticles and nanostructured lipid carriers are the extensively used lipid-based nanoparticles. Solid lipid nanoparticles (SLNs) are sub-micron colloidal carrier nanoparticles with particle size range from 50-1000 nm^53,54. SLNs are mainly composed of solid lipids, which are stable as solid at room temperature. Stability and aggregation of particles were reducing by the incorporation of surfactant and co-surfactant respectively. The commonly used solid lipids include triglycerides (Dynasan-112, Dynasan-114, Dynasan-116 and Dyanasan-118) mixed glycerides (Compritol ATO 888, glyceryl monobehenate) and monoglycerides (stearic acid, glyceryl monostearate)⁵⁵. SLNs have the advantages of biocompatibility, reduced toxicity, used for incorporation of both hydrophilic and liphophilic drugs and enhanced oral bioavailability and also pharmacodynamic activity^56,57. The enhanced oral bioavailability of drugs might be due to enhanced surface area by the addition of surfactants, by virtue of small particle size, presence of lipids promotes the gastric motility and also promote the lymphatic transport by reducing the first-pass metabolism and also tumor targeting⁵⁸ and ocular delivery⁵⁹. Drug loaded SLNs for enhancement of oral BA are showed in Table 3.

 

Nanostructured lipid carriers:

Nanostructured lipid carriers (NLCs) are considered as modified form of solid lipid nanoparticles. The difference between the SLNs and NLCs is replace one part of the solid lipid with liquid lipid and observed for improved properties⁷². In general, the NLCs made of 1:3 to 1:4 ratio of liquid lipid to solid lipid and along with surfactants and cosurfactants. NLCs minimize drug expulsion, increase the drug encapsulation and stability of loaded drug compared with SLNs⁷³ (Radtke et al., 2005). Preparation of NLCs mainly involves in the section of liquid lipid and solid lipid and their respective ratio, selection of surfactants and cosurfactants, in some instances miscellaneous agents such as viscosity modifiers, antioxidants and preservatives⁷⁴. NLCs like SLNs also prolonged the drug release, controlled and sustained delivery^75,76, increased gastric residence time⁷⁷. Various drugs loaded NLCs are depicted in Table 4.

 

Table 3: Various drug loaded solid lipid nanoparticles

Drug	Lipid	Inference	Reference
Baicalin	Stearic acid	Enhanced bioavailability	60
Carvedilol	Poloxamer	Improved BA	61
Nisoldipine	Tripalmitate	Improved BA	62
Rosuvastatin calcium	Dynasan 114, Dynasan116, Dynasan 118	Improved BA	63
Felodipine	Dynasan 114, 116 and 118	Improved BA	64
Lacidipine	Dynasan 114, 116 and 118	Improved oral BA	65
Candesartan cilexetil	Dynasan 114, Dynasan116, Dynasan 118	Improved BA	66
Rosuvastatin calcium	Dynasan 112	Improved BA	67
Zaleplon	Dyansan 114	Improved bA	68
Olmesartan medoxomil	GMS and SA	Improved BA	69
Zotepine	Dynasan	Improved BA	70
Ketoconazole	Dynasan	Improved BA	71

Table 4: Various drug loaded Nanostructured lipid carriers

Drug	Lipid	Method used	Inference	Reference
Chlorambucil	Stearic acid and oleic acid	Ultrasonication	Improved drug action	78
Curcumin	Soylecithin and Poloxamer 188	Solvent evaporation	11.93-fold	79
Carvedilol	Stearic acid and Oleic acid	Sonication	3.95-fold	80
Raloxifene hydrochloride	Glyceryl monostearate and Capmul MCM C8	solvent emulsification/evaporation	3.57-f0ld bioavailability enhancement	81
Vincristine sulfate	Hyaluronic acid	Emulsion solvent evaporation	1.8-fold	82
Atorvastatin	Capryol, lecithin	High pressure homogenization	3.6-fold	83
Nisoldipine	Dynasan 114	Ultrasonication	Improved drug action	84
Zotepine	Dynasan	Ultrasonication	Improved BA	85
Ketoconazole	Dynasan 116	Ultrasonication	Improved BA	86
Ropinirole	Dynasan	Ultrasonication	Improved BA	87

 

 

Nanosuspension:

Nanosuspensions are submicron colloidal dispersions of nano-sized drug particles stabilized by the surfactants⁸⁸. Nanosuspensions consist of the poorly water-soluble drug without any matrix material suspended in dispersion^89-91. These can be used to enhance the solubility of drugs that are poorly soluble in water as well as lipid media. As a result of increased solubility, the rate of flooding of the active compound increases and the maximum plasma level is reached faster. This approach is useful for molecules with poor solubility, poor permeability, or both, which poses a significant challenge for formulators. The reduced particle size renders the possibility of intravenous administration of poorly soluble drugs without any blockade of the blood capillaries. The suspensions can also be lyophilized and into a solid matrix⁹². Apart from these advantages, it also has the advantages of liquid formulations over others^93,94. Enhance the solubility and bioavailability of drugs, suitable for hydrophilic drugs, higher drug loading can be achieved, dose reduction is possible, enhance the physical and chemical stability of drugs^95,96 (and provides a passive drug targeting^97-99. List of drugs developed as nanosuspensions are reported in Table 5.

 

Self-emulsifying drug delivery systems:

Self-emulsifying drug delivery systems (SEDDS) are one of the approaches to improve the oral bioavailability of poorly soluble drugs by presenting the drug in the form of small droplets of oil and maintaining it in a dissolved state throughout its transit time in GIT^109-110. SEDDS are the systems with of a mixture of oil and surfactant and they are capable of forming O/W emulsions upon gentle agitation provided by the gastrointestinal movements. In such a system, the lipophilic drug is incorporated in solution, in small droplets of oil in solution from. The large interfacial area generated by these smaller sizes of droplets, facilitates drug diffusion into intestinal fluids¹¹¹. Additionally, increased fraction of absorption by lymphatic transport, avoids hepatic first-pass metabolism of drugs which are prone to extensive metabolism¹¹². The SEDDS are the delivery systems which were engineered through a specific combination of selected lipids and emulsifiers in a specific ratio. In addition, for a specific drug a particular SEDDS should be developed using different excipients with different physicochemical properties to improve overall hydrophilicity of the drug^113,114. On digestion in GIT lipid excipients form different colloidal species (vesicles, micelles and liquid crystalline phases) in the intestinal lumen which further had an impact on dissolution and absorption of drug co-administered¹¹⁵ (Porter et al., 2008). Many of the excipients were reported to aid in lymphatic bypass and also considerably reducing the access to pre-systemic transporter mediated drug efflux like P-glycoprotein (P-gp)¹¹⁶. Table 6 presents the list of different drug loaded SEDDS formulations.

 

 

Table 5: Nanosuspensions of reported drugs as oral delivery vehicle

Drug	Components	Type of study	Animals	Inference	Reference
Curcumin	SLS and PVP	In vivo	Rats	6.8-fold	100
Efaverinz	Sodium lauryl sulfate and PVP K30	In vivo	Rats	2.19-fold increase in BA	101
Furosemide	PVP		Rats	1.38-folds	102
Felodipine	PVA and HPMC	In vivo	Rats	Enhanced AUC	103
Cefdinir	SLS and PVP	In vivo	Rats	1.75-folds	104
Cefdinir	Zirconium oxide	In vivo	Rats	3-fold	105
Curcumin	SLS and PVP	In vivo	Rtas	4.2-fold	106
Olmesartn medoxomil	SLS	In vivo	Rats	2.45-fold	107

Table 6: List of reported SEDDS formulations

Drug	Components	Size (nm)	Remarks	Reference
Cinnarizine SNEDDS	Sesame oil/ Cremophor RH 40 Oleic acid Brij 97 (Co-surfactant) Ethanol	28.1 ± 0.96	Approximately increased by 25% compared to conventional tablets	117
Silymarin SMEDDS	Ethyl linoleate/Tween 80/ethyl alcohol	10-20	48.82-fold compared to drug suspension	118
Rosuvastatin calcium SNEDDS	Cinnamon oil/labrasol; CapmulMCMC8	120-170	2.45-fold compared to drug suspension	119
Curcumin SMEDDS	Ethyl oleate/ emulsifier OP + Cremorphor EL (1:1), co-surfactant (PEG 400)	21.4 ± 1.5	3.86-fold compared to drug suspension	120
Amiodarone and talinolol SNEDDS	Triglyceride (trilaurin for amiodarone and tricaprin (for talinolol) / polyoxyl 40-hydroxy castor oil, Tween 20, and Span 80 and lecithin	10±0.03 (for Amiodarone) 45±0.07 (for tricaprin)	2 and 3 fold increase for Amiodarone and Talinolol respectively	121

 

 

CONCLUSION:

The enhancement of oral bioavailability of drugs was mainly depends on aqueous solubility and permeability properties. Various oral deliveries such as buccal delivery, floating delivery approaches have been developed for the enhancement of bioavailability was reported and commercialized for the human health care. Alternatively, vesicular delivery of poorly soluble drugs promotes and extended the drug release by improving the gastric residence time, by altering the gastric mobility, presence of small particle size and also promotes the lymphatic uptake. Therefore, increase the oral absorption of the poorly soluble drugs. Some of the nano delivered drug molecules are presently under clinical trials. The development of nano carriers from bench-to-bed side is a very crucial process but, it provides beneficial advantages to the population.

 

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Received on 18.11.2020          Modified on 12.12.2020

Accepted on 30.12.2020       ©A&V Publications All right reserved