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Advanced Drug Delivery Reviews (v.60, #6)
Lipid-based systems for the enhanced delivery of poorly water soluble drugs
by Christopher J.H. Porter; Kishor M. Wasan; Panayiotis Constantinides (pp. 615-616).
Biopharmaceutical challenges associated with drugs with low aqueous solubility—The potential impact of lipid-based formulations by C.M. O'Driscoll; B.T. Griffin (pp. 617-624).
The percentage of new chemical entities synthesised with low aqueous solubility and high therapeutic efficacy is growing, this presents major challenges for the drug delivery scientists. The role of physicochemical properties in identification of suitable drug candidates for oral lipid-based delivery systems is discussed. A knowledge of the interplay of physicochemical and biopharmaceutical drug properties with the physiological environment of the gastro-intestinal tract (GIT), as a prerequisite to successful formulation design, is reviewed. The importance of excipient selection with an emphasis on bioactive excipients is stressed. The need for more examples of in vitro–in vivo correlations as a means of maximizing the development potential and commercial future for lipid-based formulations, and, promoting confidence within the industry for these delivery systems is highlighted.
Keywords: Lipid-based formulations; Bioactive excipients; Solubility; In vitro–in vivo correlations
Formulation of lipid-based delivery systems for oral administration: Materials, methods and strategies by Colin W. Pouton; Christopher J.H. Porter (pp. 625-637).
Oral lipid-based drug delivery systems may include a broad range of oils, surfactants, and cosolvents. This diversity makes comparison of lipid-based formulations difficult. Although the relationship between formulation and drug absorption is understood at a conceptual level, performance in vivo cannot be predicted with confidence at present. The Lipid Formulation Classification System (LFCS) identifies the factors which are likely to affect performance in vivo. There is now a need to establish performance criteria which will facilitate in vitro– in vivo correlation studies. In this review we discuss the properties of excipients, and identify criteria for selection of excipients for lipid-based formulations. Excipients are discussed in the context of the LFCS, our existing knowledge of the fate of these materials during dispersion and digestion, and the likely consequences of their use in formulations. We outline the formulation strategies that can be used for each type of lipid formulation, and suggest a framework for the in vitro testing of each type. Finally we address the choice of lipid formulations in relation to the physicochemical properties of the drug.
Keywords: Lipid-based formulations; Self-emulsifying drug delivery systems; Excipients; Lipid Formulation Classification System; Formulation strategies; Surfactants; Self-dispersion
What determines drug solubility in lipid vehicles: Is it predictable? by Sagar S. Rane; Bradley D. Anderson (pp. 638-656).
Lipid-based drug delivery systems are of increasing interest to the pharmaceutical scientist because of their potential to solubilize drug molecules that may be otherwise difficult to develop. The ability to predict lipid solubility is an important step in being able to identify the right excipients to solubilize and formulate drugs in lipid formulations. However, predicting lipid solubility is complicated by the fact that interfacial effects may play a dominant role in these mixtures and the solubility may be affected by the microstructure (microemulsions, emulsions, oily solutions, etc.), as well as by the physicochemical properties of the oil, surfactant, co-solvent, and the drug. This review illustrates the fundamental factors that govern solubility in lipid mixtures and discusses models built at varying levels of sophistication to estimate the solubility. Examples from the literature are presented that demonstrate the application of these models, how their choice is related to the drug/lipid employed, and the challenges involved in solubility prediction. New data on the role water plays in altering lipid solubility, not only through its interaction with the solute, but also by changing the structure of lipids by promoting lipid organization are highlighted. The available data demonstrate that a rational understanding of solubilization in lipids is a worthwhile pursuit and models to predict at least the relative solubility from chemical structure have potential. Prediction of absolute solubility is more difficult as it requires knowledge of the drug's escaping tendency from the crystalline state. In recent years, it has become amply clear that for polar solutes, specific interactions are a critical factor governing solubility. Methods that can better take into account the specific as well as non-specific interactions between the solute and solvent, and the lipid microstructure, hold considerable promise for the future.
Keywords: Lipid-based formulations; Drug solubility prediction; Microemulsions; Microstructure; SMEDDS; Effect of water
Advanced screening assays to rapidly identify solubility-enhancing formulations: High-throughput, miniaturization and automation by Wei-Guo Dai; Crystal Pollock-Dove; Liang C. Dong; Shu Li (pp. 657-672).
Development of solubility-enhancing formulations for poorly water-soluble compounds always poses a challenge. Conventional formulation screening assays are potentially time-consuming and labor-intensive and, moreover, require a large amount of a compound; they are not ideal when compound availability and testing time are limited. In recent years, in-vitro screening assays that are rapid, inexpensive, minimally labor-intensive, and require only small quantities of a compound have become available. These advanced assays allow high-throughput automation, miniaturization, and parallel processing, thereby enabling scientists to rapidly identify solubility-enhancing formulations with milligram or sub-milligram quantities of an active pharmaceutical ingredient (API). This article reviews these assays for rapidly screening the aqueous solubility of lead compounds and the solubility-enhancing formulations with limited quantities of API.
Keywords: Screening assay; Formulation; High-throughput; Miniaturization; Automation; Solubility
Enhancing intestinal drug solubilisation using lipid-based delivery systems by Christopher J.H. Porter; Colin W. Pouton; Jean F. Cuine; William N. Charman (pp. 673-691).
Lipid-based delivery systems are finding increasing application in the oral delivery of poorly water-soluble, lipophilic drugs. Whilst lipidic dose forms may improve oral bioavailability via several mechanisms, enhancement of gastrointestinal solubilisation remains argueably the most important method of absorption enhancement. This review firstly describes the mechanistic rationale which underpins the use of lipid-based delivery systems to enhance drug solubilisation and briefly reviews the available literature describing increases in oral bioavailability after the administration of lipid solution, suspension and self-emulsifying formulations. The use of in vitro methods including dispersion tests and more complex models of in vitro lipolysis as indicators of potential in vivo performace are subsequently described, with particular focus on recent data which suggests that the digestion of surfactants present in lipid-based formulations may impact on formulation performance. Finally, a series of seven guiding principles for formulation design of lipid-based delivery systems are suggested based on an analysis of recent data generated in our laboratories and elsewhere.
Keywords: Drug absorption; Lipid-based delivery systems; Self-emulsifying drug delivery systems; In vitro; lipolysis; Solubilisation
Enhancing drug absorption using lipids: A case study presenting the development and pharmacological evaluation of a novel lipid-based oral amphotericin B formulation for the treatment of systemic fungal infections by Kristina Sachs-Barrable; Stephen D. Lee; Ellen K. Wasan; Sheila J. Thornton; Kishor M. Wasan (pp. 692-701).
The development of a safe and efficacious drug involves a balance between bioavailability, toxicity and disposition within the body. If the drug is hydrophobic or acid labile, oral administration may lead to poor systemic exposure, necessitating a parenteral treatment regime. Amphotericin B (AmpB) is one example of a well established, highly efficacious drug that has a 50 year history of intravenous therapy. AmpB formulated as a micellar dispersion (Fungizone®; FZ) for IV use, remains one of the most effective agents in the treatment of systemic fungal infections, yet no oral formulations are currently commercially available. Recently, our laboratory has developed new oral lipid-based AmpB formulations with enhanced gastrointestinal (GI) tract absorption and antifungal activity with minimum renal toxicity. This review article will discuss these findings and present data to support two potential mechanisms for the enhanced GI tract absorption of AmpB when formulated in this oral lipid-based delivery system, namely an increase in lymphatic drug transport and a decrease in pre-systemic transporter-mediated drug efflux.
Keywords: Abbreviations; AmpB; amphotericin B; CSA; cyclosporine A; FZ; Fungizone®; GI; gastrointestinal; PgP; P; -glycoprotein; HIV; human immunodeficiency virus; AIDS; autoimmune deficiency syndrome; RBC; red blood cells; SNEDDS; self-nanoemulsification drug delivery system; PEG; poly(ethylene glycol); HPLC; high-pressure liquid chromatography; UV; ultraviolet; MW; molecular weight; ABLC; amphotericin B lipid complex; DOC; deoxycholate; T; max; time to maximum concentration; Cl; systemic clearance; AUC; area under the concentration–time curve; C; max; maximum peak concentration; TG; triglycerides; CFU; colony forming units; SEDDS; self-emulsifying drug delivery systems; ABC; ATP-binding cassette; TMD; transmembrane domains; NBD; nucleotide binding domain; BCRP; breast cancer related protein; MDR; multidrug resistance; MRP; multidrug resistance related protein; Rh123; rhodamine 123.Amphotericin B; P; -glycoprotein; Lymphatic drug transport; Peceol®; Oral formulation; Gastrointestinal absorption; Antifungal activity; Renal toxicity; Pharmacokinetics
Lipid-based delivery systems and intestinal lymphatic drug transport: A mechanistic update by Natalie L. Trevaskis; William N. Charman; Christopher J.H. Porter (pp. 702-716).
After oral administration, the majority of drug molecules are absorbed across the small intestine and enter the systemic circulation via the portal vein and the liver. For some highly lipophilic drugs (typically log P>5, lipid solubility>50 mg/g), however, association with lymph lipoproteins in the enterocyte leads to transport to the systemic circulation via the intestinal lymph. The attendant delivery benefits associated with lymphatic drug transport include a reduction in first-pass metabolism and lymphatic exposure to drug concentrations orders of magnitude higher than that attained in systemic blood. In the current review we briefly describe the mechanisms by which drug molecules access the lymph and the formulation strategies that may be utilised to enhance lymphatic drug transport. Specific focus is directed toward recent advances in understanding regarding the impact of lipid source (both endogenous and exogenous) and intracellular lipid trafficking pathways on lymphatic drug transport and enterocyte-based first-pass metabolism.
Keywords: Drug; Lymph; Absorption; Intestine; Formulation; Lipid; Delivery; Oral
Predicting drug disposition, absorption/elimination/transporter interplay and the role of food on drug absorption by Joseph M. Custodio; Chi-Yuan Wu; Leslie Z. Benet (pp. 717-733).
The ability to predict drug disposition involves concurrent consideration of many chemical and physiological variables and the effect of food on the rate and extent of availability adds further complexity due to postprandial changes in the gastrointestinal (GI) tract. A system that allows for the assessment of the multivariate interplay occurring following administration of an oral dose, in the presence or absence of meal, would greatly benefit the early stages of drug development. This is particularly true in an era when the majority of new molecular entities are highly permeable, poorly soluble, extensively metabolized compounds (BDDCS Class 2), which present the most complicated relationship in defining the impact of transporters due to the marked effects of transporter–enzyme interplay. This review evaluates the GI luminal environment by taking into account the absorption/transport/elimination interplay and evaluates the physiochemical property issues by taking into account the importance of solubility, permeability and metabolism. We concentrate on the BDDCS and its utility in predicting drug disposition. Furthermore, we focus on the effect of food on the extent of drug availability (F), which appears to follow closely what might be expected if a significant effect of high fat meals is inhibition of transporters. That is, high fat meals and lipidic excipients would be expected to have little effect on F for Class 1 drugs; they would increase F of Class 2 drugs, while decreasing F for Class 3 drugs.
Keywords: Absorption; BCS; BDDCS; Disposition; Elimination; Food effects; Interplay; Transporter
Approaches for the development of solid and semi-solid lipid-based formulations by V. Jannin; J. Musakhanian; D. Marchaud (pp. 734-746).
Interest in Lipid Based Drug Delivery (LBDD) has developed over the past decade fuelled by a better understanding of the multiple roles lipids may play in enhancing oral bioavailability. Moreover, the emergence of novel excipients with acceptable regulatory and safety profiles coupled with advances in formulation technologies have greatly improved the potential for successful lipid based formulations.With the growing interest in this field, there is an increasing need for guidelines in excipient selection and characterization; material handling, formulation design, and processing techniques to obtain effective and patient-compliant dosage forms. The aim of this review is to present the recent approaches in selecting the most appropriate lipid system(s); methods for characterization of their behavior in vitro and in vivo; and the current formulation and processing techniques to obtain various solid dosage forms.
Keywords: Bioavailability enhancement; Excipient; Formulation; Lipid-based drug delivery systems; Process; Technology
Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into capsules for oral administration by Ewart T. Cole; Dominique Cadé; Hassan Benameur (pp. 747-756).
The encapsulation of liquids and semi-solids provides solutions for convenient delivery through improved oral absorption of poorly water-soluble drugs. In addition, low dose (content uniformity), highly potent (containment), low melting point drugs, those with a critical stability profile and those for which a delayed release is required are candidates for liquid or semi-solid formulations. Both hard and soft capsules can be considered and in each case the capsule wall may comprise gelatin or some other suitable polymer such as hypromellose. The choice of a hard or soft capsule will depend primarily on the components of the formulation which provides the best absorption characteristics as well as on the physical characteristics, such as the viscosity of the formulation and the temperature at which the product needs to be filled. Numerous excipients are available for formulation of lipid-based systems and their compatibilities with hard gelatin capsules have been tested. The availability of new enhanced manufacturing equipment has brought new opportunities for liquid-filled hard capsules. Filling and sealing technologies for hard capsules, provides the formulator with the flexibility of developing formulations in-house from small scale, as required for Phase I studies, up to production.
Keywords: Gelatin capsules; Hypromellose; Liquid filling; Formulation characteristics; Licaps™; Drug Delivery System
Advances in lipid nanodispersions for parenteral drug delivery and targeting by Panayiotis P. Constantinides; Mahesh V. Chaubal; Robert Shorr (pp. 757-767).
Parenteral formulations, particularly intravascular ones, offer a unique opportunity for direct access to the bloodstream and rapid onset of drug action as well as targeting to specific organ and tissue sites. Triglyceride emulsions, liposomes and micellar solutions have been traditionally used to accomplish these tasks and there are several products on the market using these lipid formulations. The broader application of these lipid systems in parenteral drug delivery, however, particularly with new chemical entities, has been limited due primarily to the following reasons: a) only a small number of parenteral lipid excipients are approved, b) there is increasing number of drugs that are partially or not soluble in conventional oils and other lipid solvents, and c) the ongoing requirement for site-specific targeting and controlled drug release. Thus, there is growing need to expand the array of targetable lipid-based systems to deliver a wide variety of drugs and produce stable formulations which can be easily manufactured in a sterile form, are cost-effective and at least as safe and efficacious as the earlier developed systems. These advanced parenteral lipid-based systems are at various stages of preclinical and clinical development which include nanoemulsions, nanosuspensions and polymeric phospholipid micelles. This review article will showcase these parenteral lipid nanosystems and discuss advances in relation to formulation development, processing and manufacturing, and stability assessment. Factors controlling drug encapsulation and release and in vivo biodistribution will be emphasized along with in vitro/in vivo toxicity and efficacy case studies. Emerging lipid excipients and increasing applications of injectable lipid nanocarriers in cancer chemotherapy and other disease indications will be highlighted and in vitro/in vivo case studies will be presented. As these new parenteral lipid systems advance through the clinic and product launch, their therapeutic utility and value will certainly expand.
Keywords: Abbreviations; PEG; polyethylene glycol; CMC; critical micelle concentration; PIT; phase-inversion temperature; PE; phosphatidylethanolamine; MTD; maximum tolerated dose; C; max; maximum plasma concentration; AUC; area under the plasma concentration–time curve; EPR; enhanced permeability retention; LCM; lipid-coated microbubbles; LDL; low-density lipoprotein; DSPE; 1,2-Distearoyl-; sn; -Glycero-3-Phosphoethanolamine or distearoylphosphatidylethanolamine.Parenteral delivery; Lipid-based systems; Nanoemulsions; Nanosuspensions; Polymeric phospholipid micelles; Manufacturing; Product stability; Cell and tissue targeting; Biodistribution; Pharmacokinetics
Lipid excipients and delivery systems for pharmaceutical development: A regulatory perspective by Mei-Ling Chen (pp. 768-777).
The use of lipid-based dosage forms for enhancement of drug absorption or delivery has drawn considerable interest from pharmaceutical scientists. The unique characteristics of these dosage forms, however, present significant challenges to pharmaceutical industry and regulatory agencies in many ways. For example, safety assessment is necessary when the use of a new lipid excipient is considered. An important question for lipid formulation is whether the drug remains in solubilised form along the gastrointestinal (GI) tract after it is administered. Certain lipid excipients and surfactants have been reported to change intestinal permeability or interfere with enzyme/transporter activity, thereby affecting drug bioavailability. The potential influence of biopharmaceutical and/or pathophysiological factors on the drug or lipid excipient(s) needs to be explored. For a complex lipid-based dosage form, the conventional in vitro dissolution methods may not be appropriate for predicting in vivo performance in view of the convoluted GI processing of the lipid vehicle and formulationOf paramount importance is to identify any gaps in the scientific understanding of lipid-based dosage forms so that regulatory issues can be addressed. More mechanistic studies should be encouraged to facilitate a better understanding of the pharmaceutical characteristics of lipid formulations and complex interactions between lipid excipient, drug and physiological environment. This review discusses some regulatory considerations in the use of lipid excipients and delivery systems for pharmaceutical development. Implications in the regulatory determination of pharmaceutical equivalence, bioequivalence and therapeutic equivalence are also illustrated.
Keywords: Lipid-based dosage form; Lipid-based formulation; Modified release; Liposome; In vitro; release; Therapeutic equivalence; Bioequivalence; Pharmaceutical equivalence; Food and Drug Administration