EFFECT OF PHYSICOCHEMICAL PROPERTIES OF EMULSIONS FORMED BY SELF-EMULSIFYING DRUG DELIVERY SYSTEMS (SEDDS) ON THE SOLUBILIZATION STATE OF DRUG: IN VITRO STUDY


Naser M. Y. Hasan

Abstract


Objective: Parameters in the oil pre-concentrate which can affect the solvent capacity of the resultant dispersion such as, oil-cosurfactant ratio, type of surfactant used in the system, the inclusion of water soluble co-solvents and the solubilization capacity of native surfactants such as, bile salts and lecithin were studied in an attempt to circumvent crystallization of drug during its passage in the gut.  

Methods: Different types of self-emulsifying systems representing type II, IIIA and IIIB were used to probe the influence of the various physicochemical properties of the resultant dispersions on the fate of dissolved model lipophilic drug. This was achieved by studying emulsification behavior of lipid systems in fed and fasted biological fluids, analyzing solubilization/drug crystallization kinetics and oil droplet diameter measurement.   

Results: Self-micro-emulsifying lipid systems lost solvent capacity on dispersion and were not able to keep the drug in solution at equilibrium. Miglyol 812/Imwitor ratio in the pre-concentrate mixture appeared to influence the kinetics of drug crystallization. Pre-microemulsion systems containing Tagat TO dispersions were found to hold more drugs in solution at equilibrium than in the case of systems containing Cremophor RH40. The inclusion of as little as 10-20% PEG in the lipid mixture accelerated drug precipitation. Bile salt-lecithin mixed micelles appears to some extent enhance the solubilization capacity of these systems after dispersion

Conclusions: Solvency of emulsions formed by self-emulsifying drug delivery in various emulsification media is a crucial parameter influencing the fate of dissolved drug after dispersion of the formulations.


Keywords


SEDDS, SMEDDS, Lipid formulations, Medium chain mono- and glycerides, Poorly water-soluble compounds

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- Review – An update on the use of oral phospholipid excipients

Peter van Hoogevest

Phospholipid Research Center, Im Neuenheimer Feld 515, D-69120 Heidelberg, Germany

ARTICLE INFO

Keywords:

Phospholipids

Oral

Solid dispersions

Mixed micelles

Emulsions

Absorption

Conversion to solids

ABSTRACT

The knowledge and experiences obtained with oral phospholipid excipients is increasing continuously.

Nevertheless the present number of oral products using these excipients as essential excipient is very limited.

This is remarkable to note, since phospholipids play a significant role in the food uptake mechanisms of the GI

tract and these mechanisms could be translated into suitable dosage forms and corresponding drug delivery

strategies. In addition, phospholipid excipients are multifunctional biodegradable, non-toxic excipients, which

can be used in oral dosage forms as wetting agents, emulsifier, solubilizer and matrix forming excipients.

Especially natural phospholipid excipients, made from renewable sources, may be considered as environmentally

friendly excipients and as a viable alternative to synthetic phospholipid and non-phospholipid analogues. This

review describes 1) essential physico-chemical properties of oral phospholipid excipients 2) the fate of orally

administered phospholipids with respect to absorption and metabolism in the GI tract 3) the main dosage forms

used for oral administration containing phospholipids. These elements are critically assessed and areas of future

research of interest for the use of oral phospholipid excipients are summarized.

Introduction

This Special Issue of the European Journal of Pharmaceutical

Sciences gives an update on the present and future oral use of phos-

pholipid excipients. It was decided to make such an issue to compensate

for the relatively low number of publications and pharmaceutical pro-

ducts related to oral phospholipid excipients.

This situation is remarkable to note, since it is well known that

phospholipids are multifunctional excipients which can be technologi-

cally used as solubilizer, wetting agent, emulsifier and as building

component of colloidal particles like liposomes, mixed micelles etc. In

addition, phospholipids play an important physiological role in the

digestion and food (and drug) absorption process in the gastro intestinal

tract as essential component of bile. Also their general role as mem-

brane component of any cell membrane points to an absence of local

and systemic toxicity after oral administration. Indeed lecithin as the

main representative of oral phospholipid excipients has the GRAS status

at the US FDA (U.S. Food and Drug Administration, 2013). The same is

true for hydrogenated lecithin (U.S. Food and Drug Administration,

and for enzyme modified lecithin (U.S. Food and Drug

Administration, 2016), which is also called monoacyl-lecithin.

The above mentioned technical use in oral dosage forms requires an

understanding of the molecular structure and knowledge of the physi-

cochemical properties of phospholipids and the several classes of

phospholipids being used or being considered for oral dosage forms.

This review briefly reviews the pharmaceutically relevant properties

of phospholipids and comments the present knowledge of the oral use

of phospholipids and their prospects in conjunction with the publica-

tions presented in this Special Issue.

In this review, the following nomenclature, in accordance to inter-

national pharmacopeias, describing the several commercially available

natural lecithins/phospholipid excipient products, differing in phos-

phatidylcholine content, is being used and recommended. Lecithin is a

complex mixture of acetone insoluble phosphatides (i.e. phospholipids),

which consist chiefly of phosphatidylcholine, phosphatidylethanola-

mine, phosphatidylinositol and phosphatidic acid, present in conjunc-

tion with various amounts of other substances such as triglycerides,

fatty acids, and carbohydrates, as separated from the crude vegetable

oil source (United States Pharmacopeial Convention, 2014). The term

“lecithin” is used when the product contains less than 80% by weight

http://dx.doi.org/10.1016/j.ejps.2017.07.008

Received 17 March 2017; Received in revised form 30 June 2017; Accepted 7 July 2017

www.phospholipid-institute.com

E-mail address: pvanhoogevest@phospholipid-institute.com.

Abbreviations: AUC, Area under the curve; BCS, Biopharmaceutical classification system; BSE, Bovine spongiform encephalopathy; CCK, Cholecystokinin; CFR, Code of Federal

Regulations; CVD, Cardiovascular disease; DMSO, Dimethylsulfoxide; DOPE, 1, 2-dioleoyl-sn-glycero-3-phosphoethanolamine; GI, Gastrointestinal; GPC, Glycerophosphocholine; GRAS,

Generally recognized as safe; HLB, Hydrophilic-lipophilic-balance; m.t., more than; NDA, New drug application; n.l.t, not less than; NSAID, Non-steroidal anti-inflammatory drug; OTC,

Over the counter; PA, Phosphatidic acid; PC, Phosphatidylcholine; PE, Phosphatidylethanolamine; PG, Phosphatidylglycerol; P-gp, P-glycoprotein; PI, Phosphatidylinositol; POPC, 1-

palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; POV, Peroxide value; SEDDS, Self-emulsifying drug delivery systems; TMA, Trimethylamine; TMAO, Trimethylamine-N-oxide; TSE,

Transmissible spongiform encephalopathies

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