Drug delivery strategies for poorly water-soluble drugs: the industrial perspective

Introduction: For poorly soluble compounds, a good bioavailability is typically needed to assess the therapeutic index and the suitability of the compound for technical development. In industry, the selection of the delivery technology is not only driven by technical targets, but also by constraints, such as production costs, time required for development and the intellectual property situation.

Areas covered: This review covers current developments in parenteral and oral delivery technologies and products for poorly water-soluble compounds, such as nano-suspensions, solid dispersions and liposomes. In addition, the use of biorelevant dissolution media to assess dissolution and solubility properties is described. Suggestions are also included to systematically address development hurdles typical of poorly water-soluble compounds intended for parenteral or oral administration.

Expert opinion: A holistic assessment is recommended to select the appropriate delivery technology by taking into account technical as well as intellectual property considerations. Therefore, first and foremost, a comprehensive physico-chemical characterization of poorly water-soluble compounds can provide the key for a successful selection and development outcome. In this context, the identified physical form of the compound in the formulation is used as a guide for a risk–benefit assessment of the selected oral delivery technology. The potential of nano-suspensions for intravenous administration is unclear. In the case of oral administration, nano-suspensions are mainly used to improve the oral absorption characteristics of micronized formulations. The development of an in situ instantaneous solubilization method, based on stable, standardized liposomes with low toxicity, opens new avenues to solubilize poorly water-soluble compounds.     

Drug delivery strategies for poorly water-soluble drugs

The drug candidates coming from combinatorial chemistry research and/or the drugs selected from biologically based high-throughput screening are quite often very lipophilic, as these drug candidates exert their pharmacological action at or in biological membranes or membrane-associated proteins. This challenges drug delivery institutions in industry or academia to develop carrier systems for the optimal oral and parenteral administration of these drugs. To mention only a few of the challenges for this class of drugs: their oral bioavailability is poor and highly variable, and carrier development for parenteral administration is faced with problems, including the massive use of surface-active excipients for solubilisation. Formulation specialists are confronted with an even higher level of difficulties when these drugs have to be delivered site specifically. This article addresses the emerging formulation designs for delivering of poorly water-soluble drugs.     

难溶性药物给药策略的研究

很多新活性药物在生物体内溶解度很小,如何增加药物溶解度,提高其生物利用度是药物制剂工作中的一大难题.本文就近年来国外针对难溶性药物给药策略的研究进行综述.     

Oral formulation strategies to improve solubility of poorly water-soluble drugs

Introduction: In the past two decades, there has been a spiraling increase in the complexity and specificity of drug–receptor targets. It is possible to design drugs for these diverse targets with advances in combinatorial chemistry and high throughput screening. Unfortunately, but not entirely unexpectedly, these advances have been accompanied by an increase in the structural complexity and a decrease in the solubility of the active pharmaceutical ingredient. Therefore, the importance of formulation strategies to improve the solubility of poorly water-soluble drugs is inevitable, thus making it crucial to understand and explore the recent trends.

Areas covered: Drug delivery systems (DDS), such as solid dispersions, soluble complexes, self-emulsifying drug delivery systems (SEDDS), nanocrystals and mesoporous inorganic carriers, are discussed briefly in this review, along with examples of marketed products. This article provides the reader with a concise overview of currently relevant formulation strategies and proposes anticipated future trends.

Expert opinion: Today, the pharmaceutical industry has at its disposal a series of reliable and scalable formulation strategies for poorly soluble drugs. However, due to a lack of understanding of the basic physical chemistry behind these strategies, formulation development is still driven by trial and error.     

Asymmetric membrane capsules for delivery of poorly water-soluble drugs by osmotic effects

A non-disintegrating polymeric capsule system, in which asymmetric membrane offers an improved osmotic effect, was used to deliver poorly water-soluble drugs in a control manner. The capsule wall membrane was made by a phase inversion process, in which asymmetric membrane was formed on stainless-steel mold pins by dipping the mold pins into a coating solution containing a polymeric material followed by dipping into a quench solution. This study evaluates the influence of coating formulation that was cellulose acetate (CA), ethylcellulose (EC), and plasticizer (glycerin and triethyl citrate). Results show capsule that made by CA with glycerin (formulation A), which appear in asymmetric structure and are able to release chlorpheniramine maleate (CM) in significant percentage. Two poorly water-soluble drugs of felodipine (FL) and nifedipine (NF) were selected as the model drug to demonstrate how the controlled release characteristics can be manipulated by the design of polymeric capsules with an asymmetric membrane and core formulations. Results show that sodium lauryl sulfate (SLS) is able to promote the release of FL from polymeric capsules prepared with CA with asymmetrical membrane. The addition of solubilizer, including RH40, PVP K-17, and PEG 4000 could enhance the release of FL but with an extent not being related to its solubility. Based on these results, influence of core formulation variables, including the viscosity and added amount of hydroxypropyl methylcellulose (HPMC), the added amount of SLS, and drug loading were examined on the release of NF. It was found that HPMC of 50 cps was suitable to be a thickening agent and both added amount of HPMC and SLS showed a comparable and profoundly positive effect, whereas NF loading had no influence on the drug release percent and rate. There existed a synergistic interaction between HPMC and SLS on the release percent and rate.     

纳米给药系统在难溶性药物制剂研究中的应用

近年来,难溶性药物给药系统一直是制剂学研究的重点和难点之一。纳米载体由于其良好的生物相容性及可装载大量难溶性药物等特点而被广泛应用于难溶性药物给药系统的研究,该类载体主要包括纳米粒、脂质体、纳米乳、聚合物胶束、纳米混悬剂等。本文结合近几年国内外文献报道,对纳米给药系统在难溶性药物制剂研究中的最新进展进行概述。     

Oral formulation strategies to improve solubility of poorly water-soluble drugs

INTRODUCTION: In the past two decades, there has been a spiraling increase in the complexity and specificity of drug-receptor targets. It is possible to design drugs for these diverse targets with advances in combinatorial chemistry and high throughput screening. Unfortunately, but not entirely unexpectedly, these advances have been accompanied by an increase in the structural complexity and a decrease in the solubility of the active pharmaceutical ingredient. Therefore, the importance of formulation strategies to improve the solubility of poorly water-soluble drugs is inevitable, thus making it crucial to understand and explore the recent trends. AREAS COVERED: Drug delivery systems (DDS), such as solid dispersions, soluble complexes, self-emulsifying drug delivery systems (SEDDS), nanocrystals and mesoporous inorganic carriers, are discussed briefly in this review, along with examples of marketed products. This article provides the reader with a concise overview of currently relevant formulation strategies and proposes anticipated future trends. EXPERT OPINION: Today, the pharmaceutical industry has at its disposal a series of reliable and scalable formulation strategies for poorly soluble drugs. However, due to a lack of understanding of the basic physical chemistry behind these strategies, formulation development is still driven by trial and error.     

Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs

Polymeric micelles have a whole set of unique characteristics, which make them very promising drug carriers, in particular, for poorly soluble drugs. Our review article focuses on micelles prepared from conjugates of water-soluble polymers, such as polyethylene glycol (PEG) or polyvinyl pyrrolidone (PVP), with phospholipids or long-chain fatty acids. The preparation of micelles from certain polymer-lipid conjugates and the loading of these micelles with various poorly soluble anticancer agents are discussed. The data on the characterization of micellar preparations in terms of their morphology, stability, longevity in circulation, and ability to spontaneously accumulate in experimental tumors via the enhanced permeability and retention (EPR) effect are presented. The review also considers the preparation of targeted immunomicelles with specific antibodies attached to their surface. Available in vivo results on the efficiency of anticancer drugs incorporated into plain micelles and immunomicelles in animal models are also discussed.     

Polymeric micelles for delivery of poorly water-soluble compounds

Amphiphilic polymers assemble into nanoscopic supramolecular core-shell structures, termed polymeric micelles, which are under extensive study for drug delivery. There are several reasons for this growing interest. Polymeric micelles maybe safe for parenteral administration relative to existing solubilizing agents (for instance, Cremophor EL), permitting an increase in the dose of potent yet toxic and poorly water soluble compounds. Polymeric micelles solubilize important poorly water-soluble compounds, such as amphotericin B (AmB), propofol, paclitaxel, and photosensitizers. A major factor in drug solubilization is the compatibility of a drug and a core of a polymeric micelle. In this context, we may consider Pluronics, poly(ethylene glycol) (PEG)-phospholipid conjugates, PEG-b-poly(ester)s, and PEG-b-poly(L-amino acid)s for drug delivery. Polymeric micelles may circulate for prolonged periods in blood, evade host defenses, and gradually release drug. Thus, they may show a preferential accumulation at sites of disease such as solid tumors. Polymeric micelles inhibit p-glycoprotein at drug-resistant tumors, gastrointestinal tract, and blood/brain barrier, perhaps providing a way to overcome drug resistance in cancer and increase drug absorption from the gut and drug absorption into the brain. Lastly, polymeric micelles may reduce the self-aggregation of polyene antibiotics, key membrane-acting drugs used to combat life-threatening systemic fungal diseases. In this way, they may reduce its dose-limiting toxicity without a loss of antifungal activity.     

A novel excipient, 1-perfluorohexyloctane shows limited utility for the oral delivery of poorly water-soluble drugs

The applicability of the semi-fluorinated alkane 1-perfluorohexyloctane (F6H8) as a novel excipient in lipid based drug delivery systems was studied. Solubility studies of 11 poorly water soluble drugs (cinnarizine, danazol, estradiol, fenofibrate, griseofulvin, halofantrine, lidocaine, prednisolone, probucol, rolipram and siramesine) showed significantly lower equilibrium solubility in F6H8 compared to soy bean oil (long chain triglyceride). F6H8 was miscible with medium chain triglycerides (MCT) but not miscible with long chain triglycerides, neither was pure F6H8 nor the mixture F6H8:MCT (1:1) miscible with 7 commonly used surfactants (Cremophor EL, Span 20, Span 80, Labrasol, Softigen 767 and Gelucire 44/14, polysorbate 80). In vitro lipolysis studies confirmed that F6H8 was non-digestible. F6H8:MCT (1:1) showed initially faster lipolysis compared to pure MCT. Thus, final phase lipolysis was lower indicating that F6H8 may affect the lipolysis of MCT. However, in vivo bioavailability studies in rats showed the same plasma concentration-time profiles when dosing 10 mg/kg halofantrine at two dose levels of F6H8, MCT or F6H8:MCT (1:1) (AUC ranged from 3058 to 3447 h ng/ml, T_max ～ 6.0 h, C_max ranged from 168 to 265 mg/ml). Generally, the addition of polysorbate 80 shortened the time to reach C_max (T_max ranged 1.3–4.5 h), but had limited effect on the bioavailability from F6H8 or MCT in combination with polysorbate 80 (4:1) (AUC ranged from 3807 to 4403 (h ng/ml)). Although a synergistic effect was obtained with halofantrine in F6H8:MCT:polysorbate 80 (2:2:1) (AUC 5574 ± 675 h ng/ml; mean ± SEM), it was not superior to dosing halofantrine in pure polysorbarte 80 (AUC 7370 ± 579 h ng/ml; mean ± SEM). The applicability of F6H8 as an excipient for future use in lipid based formulations for poorly water soluble drugs is therefore considered to be very limited.     

Microcrystals for dissolution rate enhancement of poorly water-soluble drugs

Slight dissolution rates related to poor water-solubility are one of the well-known difficulties to be covered during the development of new drug substances. The poorly water-soluble drug ECU-01, a low molecular enzyme-inhibitor with anti-inflammatory properties for oral administration, shows a poor dissolution rate. This study is intended to enhance the drug dissolution rate by using microcrystals. The common way for micronization is the milling of previously formed larger crystals. However, milling shows several disadvantages as the newly created surfaces are thermodynamically activated due to the high energy input and not naturally grown. In this study microcrystals were not produced using any cutting up techniques, but only by association. Naturally grown microcrystals were prepared by a precipitation method in the presence of stabilizing agents (e.g. gelatin, chitosan, different types of cellulose ethers) followed by spray-drying of the formed dispersion. First the drug was dissolved in acetone and then precipitated by rapid pouring an aqueous solution of the stabilizer into the drug solution. Particularly, cellulose ethers were able to form stable and homogeneous dispersions of microcrystals (mean particle size = 1 microm) showing a tight particle size distribution. By spray-drying, the drug powder was obtained. The dissolution rate is significantly enhanced (common drug: 4% after 20 min/microcrystals 93% after 20 min) due to the large surface, which is hydrophilized by adsorbed stabilizers as shown by the decreased contact angle (65 and 30 degrees, respectively).     

Lipid-based formulations for oral administration of poorly water-soluble drugs

Lipid-based drug delivery systems have shown great potentials in oral delivery of poorly water-soluble drugs, primarily for lipophilic drugs, with several successfully marketed products. Pre-dissolving drugs in lipids, surfactants, or mixtures of lipids and surfactants omits the dissolving/dissolution step, which is a potential rate limiting factor for oral absorption of poorly water-soluble drugs. Lipids not only vary in structures and physiochemical properties, but also in their digestibility and absorption pathway; therefore selection of lipid excipients and dosage form has a pronounced effect on the biopharmaceutical aspects of drug absorption and distribution both in vitro and in vivo. The aim of this review is to provide an overview of the different lipid-based dosage forms from a biopharmaceutical point of view and to describe effects of lipid dosage forms and lipid excipients on drug solubility, absorption and distribution.     

Swellable elementary osmotic pump (SEOP): an effective device for delivery of poorly water-soluble drugs.

A new type of elementary osmotic pump (EOP) tablet for efficient delivery of poorly water-soluble/practically insoluble drugs has been designed. Drug release from the system, called swellable elementary osmotic pump (SEOP), is through a delivery orifice in the form of a very fine dispersion ready for dissolution and absorption. SEOP tablets were prepared by compressing the mixture of micronized drug and excipients into convex tablets. Factors affecting the release of drug from the SEOP tablets containing a poorly water-soluble drug, indomethacin, have been explored. The release behaviour of indomethacin from different formulations of this dosage form was studied at pH 6.8 for a period of 24h. The formulations were compared based on four comparative parameters, namely, D(24h) (total release after 24h), t(L) (lag time), RSQ(zero) (R square of zero order equation) and D%(zero) (percentage deviation from zero order kinetics). The drug release profile from osmotic devices showed that the type of polymer in the core formulation can markedly affect the drug release. The results showed that concentration of wetting agent in the core formulation was a very important parameter in D(24h) and release pattern of indomethacin from SEOP system. Increasing the amount of wetting agent to an optimum level (60mg) significantly increased D(24h) and improved zero order release pattern of indomethacin. Increasing concentration of caster oil (hydrophobic) in the semipermeable membrane of the device or hydrophilic plasticizer (glycerin) in coating formulation markedly increased t(L) and decreased D(24h). The results also demonstrated that aperture size is a critical parameter and should be optimized for each SEOP system. Optimum aperture diameter for the formulations studied here was determined to be 650microm for zero order release pattern. t(L) and D%(zero) were dramatically decreased whereas D(24h) and RSQ(zero) increased with increasing the aperture size to optimum level. This study also revealed that optimization of semipermeable membrane thickness is very important for approaching zero order kinetics.     

Microemulsions as drug delivery systems to improve the solubility and the bioavailability of poorly water-soluble drugs

Importance of the field: Microemulsions have been studied extensively as potential drug delivery vehicles for poorly water-soluble drugs. An understanding of the physicochemical and biopharmaceutical characteristics of the microemulsions according to administration routes will provide guidance for designing the formulations of microemulsions.

Areas covered in this review: In this paper, the use and the characteristics of microemulsions as drug delivery vehicles are reviewed. As the formulations of the microemulsion always include a great amount of surfactant and co-surfactant, which may cause hemolysis or histopathological alterations of the tissue, the potential toxicity or the irritancy of microemulsions is also discussed in this paper.

What the reader will gain: Developments of microemulsions for poorly water-soluble drugs in recent years are included in this review. Several factors limiting the commercial or clinical use of microemulsions are also discussed.

Take home message: Considering the potential in enhanced drug uptake/permeation and facing the limitations, their unique properties make microemulsions a promising vehicle for poorly water-soluble drugs.     

Solid dispersions,Part II: new strategies in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs

Introduction: The absorption of poorly water-soluble drugs, when presented in the crystalline state to the gastrointestinal tract, is typically dissolution rate-limited, and according to BCS these drugs belong mainly to class II. Both dissolution kinetics and solubility are particle size dependent. Nowadays, various techniques are available to the pharmaceutical industry for dissolution rate enhancement of such drugs. Among such techniques, nanosuspensions and drug formulation in solid dispersions are those with the highest interest.

Areas covered: This review discusses strategies undertaken over the last 10 years, which have been applied for the dissolution enhancement of poorly water-soluble drugs; such processes include melt mixing, electrospinning, microwave irradiation and the use of inorganic nanoparticles.

Expert opinion: Many problems in this field still need to be solved, mainly the use of toxic solvents, and for this reason the use of innovative new procedures and materials will increase over the coming years. Melt mixing remains extremely promising for the preparation of SDs and will probably become the most used method in the future for the preparation of solid drug dispersions.     

Solid dispersions, part II: new strategies in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs

INTRODUCTION: The absorption of poorly water-soluble drugs, when presented in the crystalline state to the gastrointestinal tract, is typically dissolution rate-limited, and according to BCS these drugs belong mainly to class II. Both dissolution kinetics and solubility are particle size dependent. Nowadays, various techniques are available to the pharmaceutical industry for dissolution rate enhancement of such drugs. Among such techniques, nanosuspensions and drug formulation in solid dispersions are those with the highest interest. AREAS COVERED: This review discusses strategies undertaken over the last 10 years, which have been applied for the dissolution enhancement of poorly water-soluble drugs; such processes include melt mixing, electrospinning, microwave irradiation and the use of inorganic nanoparticles. EXPERT OPINION: Many problems in this field still need to be solved, mainly the use of toxic solvents, and for this reason the use of innovative new procedures and materials will increase over the coming years. Melt mixing remains extremely promising for the preparation of SDs and will probably become the most used method in the future for the preparation of solid drug dispersions.