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.     

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.     

Preparation of starch macrocellular foam for increasing the dissolution rate of poorly water-soluble drugs

Starch macrocellular foam (SMF), a novel natural bio-matrix material, was prepared by the hard template method in order to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. Nitrendipine (NDP) was chosen as a model drug and was loaded into SMF by the solvent evaporation method. SMF and the loaded SMF samples (NDP-SMF) were characterized by scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. In vitro drug release studies showed that SMF significantly increased the dissolution rate of NDP. In vivo studies showed that the NDP-SMF tablets clearly increased the oral bioavailability of NDP in comparison with the reference commercial tablets. All the results obtained demonstrated that SMF was a promising carrier for the oral delivery of poor water-soluble drugs.     

Solid dispersions, part I: recent evolutions and future opportunities in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs

INTRODUCTION: In recent years, the number of active pharmaceutical ingredients with high therapeutic impact, but very low water solubility, has increased significantly. Thus, a great challenge for pharmaceutical technology is to create new formulations and efficient drug-delivery systems to overcome these dissolution problems. AREAS COVERED: Drug formulation in solid dispersions (SDs) is one of the most commonly used techniques for the dissolution rate enhancement of poorly water-soluble drugs. Generally, SDs can be defined as a dispersion of active ingredients in molecular, amorphous and/or microcrystalline forms into an inert carrier. This review covers literature which states that the dissolution enhancement of SDs is based on the fact that drugs in the nanoscale range, or in amorphous phase, dissolve faster and to a greater extent than micronized drug particles. This is in accordance to the Noyes-Whitney equation, while the wetting properties of the used polymer may also play an important role. EXPERT OPINION: The main factors why SD-based pharmaceutical products on the market are steadily increasing over the last few years are: the recent progress in various methods used for the preparation of SDs, the effect of evolved interactions in physical state of the drug and formulation stability during storage, the characterization of the physical state of the drug and the mechanism of dissolution rate enhancement.     

Mesoporous silica formulation strategies for drug dissolution enhancement: a review

Introduction: Silica materials, in particular mesoporous silicas, have demonstrated excellent properties to enhance the oral bioavailability of poorly water-soluble drugs. Current research in this area is focused on investigating the kinetic profile of drug release from these carriers and manufacturing approaches to scale-up production for commercial manufacture.

Areas covered: This review provides an overview of different methods utilized to load drugs onto mesoporous silica carriers. The influence of silica properties and silica pore architecture on drug loading and release are discussed. The kinetics of drug release from mesoporous silica systems is examined and the manufacturability and stability of these formulations are reviewed. Finally, the future prospects of mesoporous silica drug delivery systems are considered.

Expert opinion: Substantial progress has been made in the characterization and development of mesoporous drug delivery systems for drug dissolution enhancement. However, more research is required to fully understand the drug release kinetic profile from mesoporous silica materials. Incomplete drug release from the carrier and the possibility of drug re-adsorption onto the silica surface need to be investigated. Issues to be addressed include the manufacturability and regulation status of formulation approaches employing mesoporous silica to enhance drug dissolution. While more research is needed to support the move of this technology from the bench to a commercial medicinal product, it is a realistic prospect for the near future.     

Improved dissolution behavior of lipophilic drugs by solid dispersions: the production process as starting point for formulation considerations

Introduction: Many new drug substances have low aqueous solubility which can cause poor bioavailability after oral administration. The application of solid dispersions is a useful method to increase the dissolution rate of these drugs and thereby improve their bioavailability. So far, several methods have been developed to prepare solid dispersions. To obtain a product with the desired attributes, both the formulation and production processes should be considered.

Areas covered: The most currently used methods to produce solid dispersions, such as the fusion method, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation, are reviewed in this paper. In addition, the physicochemical characteristics of the obtained solid dispersions are discussed.

Expert opinion: Solid dispersions can be successfully prepared by simple fusion, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation. Hot melt extrusion, spray drying and freeze drying are processes that can be applied for large scale production. The simple fusion method is not very suitable for large scale production, but is particularly suitable for screening formulations. The most recent method to produce sold dispersions is supercritical fluid precipitation. The process conditions of this method need extensive investigation, in particular in relationship with the selection of the type of carrier and/or solvent. Both processes and formulation aspects strongly affect the characteristics of solid dispersion products. Furthermore, application of crystalline solid dispersions is gaining increasing interest because they are thermodynamically more stable than amorphous solid dispersions.     

应用纳米技术增加难溶性药物吸收的研究进展

随着高通量筛选等新技术的出现,涌现出许多难溶性的候选药物。利用纳米技术能减小难溶性药物的粒径,增加其溶解度、溶出度和口服生物利用度,减少食物效应的影响。本文介绍了纳米粒的制备方法,商用的专利纳米技术以及应用纳米技术成功上市的药品。纳米技术对改善生物药剂学分类体系（BCS）Ⅱ类药物的吸收具有广阔的前景。     

The role of the carrier in the formulation of pharmaceutical solid dispersions. Part II: amorphous carriers

ABSTRACT

Introduction: Amorphous solid dispersions are considered as one of the most powerful strategies to formulate poorly soluble drugs. They are made up of an active pharmaceutical ingredient (API) dispersed at the molecular level in an amorphous polymeric carrier. As the latter component constitutes the largest part of the formulation, its characteristics will contribute to a large extent to the properties and behavior of the solid dispersion.

Areas covered: Amorphous polymers are most often used in modern solid dispersion formulations. This review discusses carrier properties like molecular weight, conformation, hygroscopicity, their stabilization effects, issues related to solid dispersion manufacturing technology, response to downstream processing, and potential to generate supersaturation, next to criteria to select a carrier to formulate stable amorphous solid dispersions.

Expert opinion: Different amorphous carriers lead to solid dispersions with various properties in terms of physical stability, phase behavior and drug release rate and extent. Despite more than 50 years of intensive research in this field it remains difficult to predict what carrier is best suited for a given API, pointing to the complex nature of this formulation strategy. Sustained efforts to understand the link and complex interplay between material properties, processing parameters, physical stability and dissolution behavior are required from pharmaceutical scientists with a strong physicochemical background to shift the development from trial and error to science driven.     

The role of the carrier in the formulation of pharmaceutical solid dispersions. Part I: crystalline and semi-crystalline carriers

ABSTRACT

Introduction: As a consequence of the target and drug candidate identification process, drugs with higher hydrophobicity and/or lipophilicity are being selected for further development, leading to solubility and dissolution rate limited oral bioavailability, and hence potential failure of the intended therapeutic goal. Solid dispersions were introduced as a formulation strategy in the early 1960s to tackle this issue and are still an area of intensive research activity.

Areas covered: There has been a shift in the type of carriers that were used in the formulation of solid dispersions as nowadays, amorphous carriers are most often used, whereas in early stages of solid dispersions development, crystalline and semi-crystalline carriers were most commonly applied. In this review, we will discuss several aspects related to the use of crystalline and semi-crystalline carriers such as their molecular and related physical structure, and their physical chemical properties related to formulation of poorly soluble drugs.

Expert opinion: The inherent crystallinity of this type of carrier hinders the formation of high-load solid solutions as mainly the amorphous domains of a carrier are able to accommodate drug molecules. Hence these carriers are not currently first choice excipients to formulate solid dispersions.     

Supersaturation,nucleation, and crystal growth during single- and biphasic dissolution of amorphous solid dispersions: Polymer effects and implications for oral bioavailability enhancement of poorly water soluble drugs

The influence of polymers on the dissolution, supersaturation, crystallization, and partitioning of poorly water soluble compounds in biphasic media was evaluated. Amorphous solid dispersions (ASDs) containing felodipine (FLD) and itraconazole (ITZ) were prepared by hot melt mixing (HMM) using various polymers. The ASDs were analyzed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and HPLC. Amorphous drug conversion was confirmed using DSC and PXRD, and drug stability by HPLC. Single- and biphasic dissolution studies of the ASDs with concurrent dynamic light scattering (DLS) and polarized light microscopic (PLM) analysis of precipitated drugs were performed. HPLC revealed no HMM-induced drug degradation. Maximum partitioning into the organic phase was dependent upon the degree of supersaturation. Although the highest supersaturation of FLD was attained using Eudragit® EPO and AQOAT® AS-LF with better nucleation and crystal growth inhibition using the latter, higher partitioning of the drug into the organic phase was achieved using Pharmacoat® 603 and Kollidon® VA-64 by maintaining supersaturation below critical nucleation. Critical supersaturation for ITZ was surpassed using all of the polymers, and partitioning was dependent upon nucleation and crystal growth inhibition in the order of Pharmacoat® 603 > Eudragit® L-100-55 > AQOAT® AS-LF. HMM drug-polymer systems that prevent drug nucleation by staying below critical supersaturation are more effective for partitioning than those that achieve the highest supersaturation.     

Carbamazepine solubility enhancement in tandem with swellable polymer osmotic pump tablet: A promising approach for extended delivery of poorly water-soluble drugs

Elementary osmotic pump (EOP) is a unique extended release (ER) drug delivery system based on the principle of osmosis. It has the ability to minimize the amount of the drug, accumulation and fluctuation in drug level during chronic uses. Carbamazepine (CBZ), a poorly water-soluble antiepileptic drug, has serious side effects on overdoses and chronic uses. The aim of the present study was to design a new EOP tablet of CBZ containing a solubility enhancers and swellable polymer to reduce its side effects and enhance the patient compliance. Firstly, a combination of solubilizing carriers was selected to improve the dissolution of the slightly soluble drug. Then, designing the new EOP tablet and investigating the effect of different variables of core and coat formulations on drug release behavior by single parameter optimization and by Taguchi orthogonal design with analysis of variance (ANOVA), respectively. The results showed that CBZ solubility was successfully enhanced by a minimum amount of combined polyvinyl pyrrolidone (PVP K30) and sodium lauryl sulfate (SLS). The plasticizer amount and molecular weight (MW) together with the osmotic agent amount directly affect the release rate whereas the swellable polymer amount and viscosity together with the semi-permeable membrane (SPM) thickness inversely influence the release rate. In addition, the tendency of following zero order kinetics was mainly affected by the coat components rather than those of the core. Further, orifice size does not have any significant effect on the release behavior within the range of 0.1 mm to 0.8 mm. In this study we report the successful formulation of CBZ-EOP tablets, which were similar to the marketed product Tegretol CR 200 and able to satisfy the USP criterion limits and to deliver about 80% of CBZ at a rate of approximately zero order for up to 12 h.