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Pharmaceutical Product Characterization and Manufacturability of Surfactant-Enriched Oil Marbles with Abiraterone Acetate
Abstract
The present study investigates the physicochemical properties and stability of a novel lipid-based formulation—surfactant-enriched oil marbles containing abiraterone acetate. While the biopharmaceutical performance of this formulation has been reported recently, this study aims to fill the gap between a promising in vivo performance and industrial applicability. A series of techniques were employed to assess the solid-state characteristics of oil marble cores along with their physicochemical properties upon stability testing. The chemical stability of abiraterone acetate in the formulation was also investigated. The core of the formulation was found to be stable both physically and chemically over 12 months of storage. The in vitro performance of stressed samples was evaluated using a dissolution experiment. The formulation has successfully self-emulsified upon incubation in bio-relevant media, resulting in a fast and complete API release. An important issue connected with the excipient used as a covering material of oil marbles has been identified. The seemingly insignificant water sorption caused agglomeration of the oil marbles and consequently compromised the dissolution rate in some of the stressed samples. Replacing HPMC with lactose as a covering material resulted in more favorable properties upon storage. Overall, it has been shown that oil marbles are an industrially applicable concept of the solidified lipid-based formulation.
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Poorly water-soluble drugs continue to be a problematic, yet important class of pharmaceutical compounds for treatment of a wide range of diseases. Their prevalence in discovery is still high, and their development is usually limited by our lack of a complete understanding of how the complex chemical, physiological and biochemical processes that occur between administration and absorption individually and together impact on bioavailability. This review defines the challenge presented by these drugs, outlines contemporary strategies to solve this challenge, and consequent in silico and in vitro evaluation of the delivery technologies for poorly water-soluble drugs. The next steps and unmet needs are proposed to present a roadmap for future studies for the field to consider enabling progress in delivery of poorly water-soluble compounds.
In this work, the influence of drug load and physical state of R3040 in self-nanoemulsifying drug delivery systems (SNEDDS) on R3040 absorption in rats was assessed. Furthermore, an in vitro lipolysis model simulating rat conditions (rat lipolysis model) was compared to a human lipolysis model in regard to the prediction of the in vivo data. The formulations were SNEDDS 80 %, containing R3040 at 80 % of its equilibrium solubility in SNEDDS (Seq); super-SNEDDS solution with R3040 supersaturated at 200 % Seq; super-SNEDDS suspension containing R3040 at 200 % Seq; Chasing principle (drug-free SNEDDS followed by R3040 aqueous suspension) and R3040 aqueous suspension. The pharmacokinetic profiles of R3040 in SNEDDS 80 % and super-SNEDDS solution 200 % were superimposed and higher than for super-SNEDDS suspension 200 %, Chasing principle and aqueous suspension. Therefore, dosing R3040 dissolved in SNEDDS increased R3040 absorption irrespective of the drug load. While the human lipolysis model could not predict the rank order of absorption of the formulations, the rat lipolysis model predicted the similar absorption of R3040 in SNEDDS 80 % and super-SNEDDS solution 200 %. Thus, the rat lipolysis model showed to be an important step towards predictive in vitro models for rat studies.
Lipid-based drug delivery systems (LBDDS) are one of the most studied bioavailability enhancement technologies and are utilized in a number of FDA approved drugs. While researchers have used several general rules of thumb to predict which compounds are likely to benefit from LBDDS, formulation of lipid systems is primarily an empiric endeavor. One of the challenges is that these rules of thumb focus in different areas and are used independently of each other. The Developability Classification System attempts to link physicochemical characteristics with possible formulation strategies. Although it provides a starting point, the formulator still has to empirically develop the formulation. This article provides a review and quantitative analysis of the molecular properties of these approved drugs formulated as lipid systems and starts to build an approach that provides more directed guidance on which type of lipid system is likely to be the best for a particular drug molecule.
Background and objective:
Abiraterone acetate is approved for the treatment of metastatic castration-resistant prostate cancer. The originator abiraterone acetate (OAA) formulation is poorly absorbed and exhibits large pharmacokinetic variability in abiraterone exposure. Abiraterone acetate fine particle (AAFP) is a proprietary formulation (using SoluMatrix Fine Particle Technology™) designed to increase the oral bioavailability of abiraterone acetate. Here, we report on two phase I studies in healthy male subjects aged 18-50 years.
Methods:
In Study 101, 20 subjects were randomized in a crossover design to single doses of AAFP 100, 200, or 400 mg or OAA 1000 mg taken orally under fasting conditions. Results suggested that AAFP 500 mg would be bioequivalent to OAA 1000 mg in the fasted state. To confirm the bioequivalence hypothesis and to further expand the AAFP dose range, in Study 102, 36 subjects were randomized in a crossover design to single doses of AAFP 125, 500, or 625 mg or OAA 1000 mg. Both studies included a 7-day washout period between administrations.
Results:
Dose-dependent increases in the area under the plasma concentration-time curve and maximum plasma concentration with AAFP were observed in both studies. The AAFP 500-mg bioavailability relative to OAA 1000 mg measured by the geometric mean ratio for area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration was 93.4% (90% confidence interval 85.3-102.4), area under the plasma concentration-time curve from time zero to infinity was 91.0% (90% confidence interval 83.3-99.4), and maximum plasma concentration was 99.8% (90% confidence interval 86.3-115.5). Dose proportionality was seen across all AAFP dose levels (100-625 mg). Abiraterone acetate fine particle was found to be safe and well tolerated in this study.
Conclusion:
Abiraterone acetate fine particle 500 mg was demonstrated to be bioequivalent to OAA 1000 mg in healthy volunteers under fasted conditions.
A liquid marble is a liquid droplet coated with hydrophobic powder which enables the marble to be manipulated like a soft solid. Recently, liquid marbles have been used in applications such as microbioreactors for three-dimensional cell cultures and could be a new platform for digital microfluidics. Despite its potential significance, there is a lack of a systematic, thorough review and discussion on the manipulation schemes for liquid marbles. This paper presents past and recent manipulation schemes for liquid marbles. This paper discusses the major working principles, their advantages and drawbacks. Finally, the paper concludes with recent applications and the challenges of this research area.
The principle objective of formulation of lipid-based drugs is to enhance their bioavailability. The use of lipids in drug delivery is no more a new trend now but is still the promising concept. Lipid-based drug delivery systems (LBDDS) are one of the emerging technologies designed to address challenges like the solubility and bioavailability of poorly water-soluble drugs. Lipid-based formulations can be tailored to meet a wide range of product requirements dictated by disease indication, route of administration, cost consideration, product stability, toxicity, and efficacy. These formulations are also a commercially viable strategy to formulate pharmaceuticals, for topical, oral, pulmonary, or parenteral delivery. In addition, lipid-based formulations have been shown to reduce the toxicity of various drugs by changing the biodistribution of the drug away from sensitive organs. However, the number of applications for lipid-based formulations has expanded as the nature and type of active drugs under investigation have become more varied. This paper mainly focuses on novel lipid-based formulations, namely, emulsions, vesicular systems, and lipid particulate systems and their subcategories as well as on their prominent applications in pharmaceutical drug delivery.
Lipid excipients are applied for numerous purposes such as taste masking, controlled release, improvement of swallowability and moisture protection. Several melting techniques have evolved in the last decades. Common examples are melt coating, melt granulation and melt extrusion. The required equipment ranges from ordinary glass beakers for lab scale up to large machines such as fluid bed coaters, spray dryers or extruders. This allows for upscaling to pilot or production scale. Solvent free melt processing provides a cost-effective, time-saving and eco-friendly method for the food and pharmaceutical industries. This review intends to give a critical overview of the published literature on experiences, formulations and challenges and to show possibilities for future developments in this promising field. Moreover, it should serve as a guide for selecting the best excipients and manufacturing techniques for the development of a product with specific properties using solvent free melt processing.
Poorly water-soluble drug candidates are becoming more prevalent. It has been estimated that approximately 60-70% of the drug molecules are insufficiently soluble in aqueous media and/or have very low permeability to allow for their adequate and reproducible absorption from the gastrointestinal tract (GIT) following oral administration. Formulation scientists have to adopt various strategies to enhance their absorption. Lipidic formulations are found to be a promising approach to combat the challenges. In this review article, potential advantages and drawbacks of various conventional techniques and the newer approaches specifically the self-emulsifying systems are discussed. Various components of the self-emulsifying systems and their selection criteria are critically reviewed. The attempts of various scientists to transform the liquid self-emulsifying drug delivery systems (SEDDS) to solid-SEDDS by adsorption, spray drying, lyophilization, melt granulation, extrusion, and so forth to formulate various dosage forms like self emulsifying capsules, tablets, controlled release pellets, beads, microspheres, nanoparticles, suppositories, implants, and so forth have also been included. Formulation of SEDDS is a potential strategy to deliver new drug molecules with enhanced bioavailability mostly exhibiting poor aqueous solubility. The self-emulsifying system offers various advantages over other drug delivery systems having potential to solve various problems associated with drugs of all the classes of biopharmaceutical classification system (BCS).
Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.
To evaluate pharmacokinetics, safety, and tolerability of abiraterone acetate (AA) in healthy men.
Two phase I studies (dose-escalation study and dose-proportionality study) were conducted in healthy men aged 18-55 years. All subjects received 4 consecutive single doses of AA (250, 500, 750 and 1,000 mg). The dose-escalation study subjects (N = 33) received AA doses in a sequential manner, starting with the lowest dose. The dose-proportionality study subjects (N = 32) were randomly allocated (1:1:1:1) to receive each of the 4 doses in a four-way crossover design.
A dose-related increase in abiraterone exposure was observed in both studies. Over the evaluated dose range, the mean abiraterone maximum plasma concentrations increased from 26 to 112 ng/mL in dose-escalation study and from 40 to 125 ng/mL in dose-proportionality study; the mean area under the plasma concentration-time curve from 0 to the last measurable plasma concentration increased from 155 to 610 ng.h/mL in dose-escalation study, and from 195 to 607 ng.h/mL in dose-proportionality study. In the dose-proportionality study, abiraterone exposure was dose proportional between 1,000 and 750 mg doses; however, the exposure was slightly greater than dose proportional when exposures at 500 and 250 mg doses were compared with the exposure at 1,000 mg. Single doses of AA were well tolerated in healthy men, and safety profile was consistent with its known toxicities in CRPC patients.
Systemic exposure to abiraterone increased with increasing doses of AA (250-1,000 mg) in healthy men; AA was well tolerated in this population.
To develop solid self-emulsifying drug delivery systems (SEDDS) for lipids using poloxamer 188 as both solidifying and emulsifying agents.
Mixtures of various lipids with poloxamer 188 and PEG 8000 were prepared at ~75°C. The molten mixtures, with and without dissolved drugs (fenofibrate and probucol), were then cooled to room temperature. When solids formed, they were characterized by powder XRD, DSC, microscopy using cross-polarization and confocal fluorescence techniques, dispersion test in water and particle size analysis of dispersions.
When mixed with poloxamer 188 or PEG 8000, lipids consisting of monoesters of fatty acids with glycerol or propylene glycol formed solid systems, but not di- and tri-esters, which showed phase separation. Added to water, the solid systems containing poloxamer 188 started to disperse in water forming oil globules of 200-600 nm. No emulsification of lipids was observed from solids containing PEG 8000, indicating that the surfactant property of poloxamer 188 was responsible for emulsification. Powder XRD, DSC and microscopic examination revealed that poloxamer 188 and PEG 8000 maintained their crystallinity in solid systems, while the lipids were interspersed in between crystalline regions. The drug remained solubilized in the lipid phase.
A novel solid SEDDS is developed where the drug can be solubilized in liquid lipids and then the lipidic solution can be converted to solid mass by dispersing into the microstructure of poloxamer 188.
Particle size is a key parameter when dealing with drug particle formation, delivery or dissolution. The correct measurement of particle size depends on various factors, such as sample preparation or dilution, but also on the choice of method for its characterization. In this work, we study the process of precipitation of poorly water-soluble drug Valsartan from supersaturated solution in the presence of nonionic surfactant Tween 20. Several techniques including dynamic light scattering (DLS) operated in several measuring modes, optical microscope (OM) and static light scattering (SLS) were used to analyze the kinetics of particle formation. As concluded by the results, the increase in turbidity of the solution seriously limits the application of classical DLS to properly measure the particle size and polydispersity. One way to get around this restriction is by dilution, which however results in a decrease in the size of Valsartan particles in the studied population. In contrast, here we present for a first time technique based on modulated 3D cross correlation DLS equipped with the sample goniometer to determine size of submicron particles of the drug in highly turbid solutions. Additionally, a modified OM was used to measure micron-sized particles for samples without any dilution in a continuous mode. Measured particle sizes combined with measured Valsartan concentration allowed us to identify mechanism responsible for the particle formation from supersaturated solutions. The main mechanism, as it is shown in this work, is covering surface of precipitate particles by the amount of used Tween 20.
Abiraterone acetate has limited bioavailability in the fasted state and exhibits a strong positive food effect. We present a novel formulation concept based on the so-called oil marbles (OMs) and show by in vitro and in vivo experiments that the food effect can be suppressed. OMs are spherical particles with a core-shell structure, formed by coating oil-based droplets that contain the dissolved drug by a layer of powder that prevents the cores from sticking and coalescence. OMs prepared in this work contained abiraterone acetate in the amorphous form and showed enhanced dissolution properties during in vitro experiments when compared with originally marketed formulation of abiraterone acetate (Zytiga®). Based on in vitro comparison of OMs containing different oil/surfactant combinations, the most promising formulation was chosen for in vivo studies. To ensure relevance, it was verified that the food effect previously reported for Zytiga® in humans was translated into the rat animal model. The bioavailability of abiraterone acetate formulated in OMs in the fasted state was then found to be enhanced by a factor of 2.7 in terms of AUC and by a factor of 4.0 in terms of Cmax. Crucially, the food effect reported in the literature for other abiraterone acetate formulations was successfully eliminated and OMs showed comparable extent of bioavailability in a fed-fasted study. Oil marbles therefore seem to be a promising formulation concept not only for abiraterone acetate but potentially also for other poorly soluble drugs that reveal a positive food effect.
Abiraterone acetate is a potent drug used for the treatment of metastatic castration resistant prostate cancer. However, currently marketed product containing crystalline abiraterone acetate exhibits strong positive food effect which results in strict dosing regimen. In the present work, a rational approach towards design of novel abiraterone acetate formulations that would allow increased bioavailability on a fasting stomach and thus decreased food effect is presented. Precipitation experiments in biorelevant media were designed to assess pH induced precipitation of the drug and a pool of polymeric excipients was then screened for their potential to inhibit precipitation. The best performing polymeric excipients were subsequently used as carriers for the preparation of amorphous solid dispersions. Two main approaches were followed in order to formulate the drug. The first approach relies on the suppression of precipitation from a supersaturated solution whereas the second one is based on the hypothesis that when the release of the drug is tuned, optimal uptake of the drug can be reached. Optimized formulation prototypes were tested in a rat animal model in an incomplete block, randomized bioequivalence study to assess their relative bioavailability under fasting conditions. We show that both formulation approaches lead to increased bioavailability of abiraterone acetate on a fasting stomach with bioavailability in rats being enhanced up to 250 % compared to the original drug product containing crystalline drug.
Abiraterone acetate, marketed as Zytiga®, is an antiandrogen medication used in the treatment of prostate cancer. Abiraterone acetate is a BCS Class IV compound associated with several oral delivery challenges. Its low solubility and high lipophilicity lead to poor oral bioavailability (<10%) and a dramatic positive food effect (5 to 10-fold). Hence, a large dose of abiraterone acetate (1000 mg per day) is prescribed to patients who must fast for at least 1 hour before and 2 hours after administration. The recent expiry of Zytiga®s' patent has led to the emergence of publications describing improved oral formulation strategies for abiraterone acetate. This review aims to discuss the characteristics of abiraterone acetate that lead to its unfavorable oral delivery, examine the oral formulation strategies that have been applied, and to describe potential alternative oral formulation strategies that have been used for other BCS Class IV drugs, to determine the most valuable strategies to develop novel and improved alternatives to the current commercial product. Specific emphasis of this review is placed on enabling oral formulation strategies that can improve solubilization and bioavailability, reduce the clinical dose and remove the pharmaceutical food effect to ultimately provide prostate cancer patients with a more efficient formulation with greater patient compliance.
Self-emulsifying drug delivery systems (SEDDS) offer potential for overcoming the inherent slow dissolution and poor oral absorption of hydrophobic drugs by retaining them in a solubilised state during gastrointestinal transit. However, the promising biopharmaceutical benefits of liquid lipid formulations has not translated into widespread commercial success, due to their susceptibility to long term storage and in vivo precipitation issues. One strategy that has emerged to overcome such limitations, is to combine the solubilisation and dissolution enhancing properties of lipids with the stabilising effects of solid carrier materials. The development of intelligent hybrid drug formulations has presented new opportunities to harness the potential of emulsified lipids in optimising oral bioavailability for lipophilic therapeutics. Specific emphasis of this review is placed on the impact of solidification approaches and excipients on the biopharmaceutical performance of self-emulsifying lipids, with findings highlighting the key design considerations that should be implemented when developing hybrid lipid-based formulations.
Self-emulsifying drug delivery systems (SEDDS) are considered as a potential platform for mucosal drug delivery. The in vitro-in vivo correlation, however, is in particular for this type of delivery systems considerably poor resulting quite often in a simple trial and error approach in order to optimize formulations. One reason for this situation is certainly the lack of appropriate methods to determine the drug release from SEDDS in vitro, as the process is particularly troublesome. For quantification of the drug in the release medium the oily droplets need to be separated. In most studies this is achieved by utilizing a separating membrane such as dialysis membranes or filters having a huge impact on the obtained release profile. Moreover, sink conditions are very often not provided. As drug release from SEDDS is based on a simple diffusion process from a lipophilic liquid phase into an aqueous liquid phase, a likely more meaningful way to characterize the release behaviour might be just the determination of the distribution coefficient (log DSEDDS/RM) of the drug between the SEDDS pre-concentrate and the release medium (RM). As log D is simply the measure of the difference in solubility of a compound in two phases, it can be determined by measuring solubility of drug or drug complex in the SEDDS pre-concentrate and in the release medium in a separate manner. The impact of log DSEDDS/RM on the in vivo drug release behaviour is discussed including various case studies.
The use of capsules goes back to the early days of pharmacy, and since these early days capsules have evolved significantly to meet the current needs of the patient and pharmaceutical industry. Some of the early developments in capsule technology occurred as pharmacy evolved from dispensing compounded medication to the dispensing of manufactured products; during this change there were numerous advances in gelatin, capsule shell design and high speed manufacturing equipment. Currently the pharmaceutical industry is undergoing a sea change as the blockbuster drugs become harder and harder to find, more of the value of a drug product comes from a dosage form with advanced delivery capabilities that can improve therapeutic outcomes. For example, capsule filling technologies have been developed for the manufacture of multiparticulate delivery systems, multiple dosage form systems such as a tablet in a capsule, combination products and delivery systems with multiphasic release rates. In addition, capsules have always played an important role in the drug development process because hand filling or semiautomatic filling capsule formulations have minimal requirements and can be quickly developed. Given this context, the chapter will discuss the capsule dosage form in the drug development process starting with a discussion of gelatin, the different types of capsules shells, formulation and manufacturing. Also, we will discuss specialty capsules and capsule fills.
Lipid based formulations (LBF) provide well proven opportunities to enhance the oral absorption of drugs and drug candidates that sit close to, or beyond, the boundaries of Lipinski's 'rule-of-five' chemical space. Advantages in permeability, efflux and pre-systemic metabolism are evident; however, the primary benefit is in increases in dissolution and apparent intestinal solubility for lipophilic, poorly water soluble drugs. This review firstly details the inherent advantages of LBF, their general properties and classification and provides a brief retrospective assessment of the development of LBF over the past fifty years. More detailed analysis of the ability of LBF to promote intestinal solubilisation, supersaturation and absorption is then provided alongside review of the methods employed to assess formulation performance. Critical review of the ability of simple dispersion and more complex in vitro digestion methods to predict formulation performance subsequently reveals marked differences in the correlative ability of in vitro tests, depending on the properties of the drug involved. Notably, for highly permeable low melting drugs e.g. fenofibrate, LBF appear to provide significant benefit in all cases, and sustained on-going solubilisation may not be required. In other cases, and particularly for higher melting point drugs such as danazol, where re-dissolution of crystalline precipitate drug is likely to be slow, correlations with on-going solubilisation and supersaturation are more evident. In spite of their potential benefits, one limitation to broader use of LBF is low drug solubility in the excipients employed to generate formulations. Techniques to increase drug lipophilicity and lipid solubility are therefore explored, and in particular those methods that provide for temporary enhancement including lipophilic ionic liquid and prodrug technologies. The transient nature of these lipophilicity increases enhances lipid solubility and LBF viability, but precludes enduring effects on receptor promiscuity and off target toxicity. Finally, recent efforts to generate solid LBF are briefly described as a means to circumvent the need to encapsulate in soft or hard gelatin capsules, although the latter remain popular with consumers and a proven means of LBF delivery.
We introduce a new estimator of particle size polydispersity for dynamic light scattering data, which quantifies the relative width of the intensity-weighted distribution of diffusion coefficients. Simulated dynamic light scattering data are analyzed in order to: i) compare the accuracy and precision of the new polydispersity indicator to polydispersity measurements from standard cumulant and moment analysis (MA) fits; ii) establish for each method the optimum data range for fitting. While MA is preferable at low polydispersity, the new estimator is the most accurate and precise one at intermediate and large polydispersity. Finally, we successfully apply the method proposed here to real data from colloidal particles, microgels and polymer solutions.
Oil-in-water emulsions are common vehicles for lipids as nutrients and for the delivery of poorly water-soluble drugs. Enhancing oral bioavailability of these drugs using lipid-based formulations (LBF) or self-emulsifying drug delivery systems is one of the current challenges in pharmaceutical industry. Many of the compounds found in LBF (acylglycerols, surfactants with esterified fatty acids,…) are however potential substrates for digestive enzymes. Their digestion (or lipolysis) in the gastrointestinal (GI) tract is critical for drug dissolution and absorption: it can be beneficial (drug solubilisation/dispersion) or deleterous (drug precipitation) depending on the drug-LBF association. A better understanding of the fate of LBF in the GI tract is therefore required to engineer efficient lipid-based drug delivery systems. In vitro models for testing simultaneously LBF digestion and drug dispersion are in development to predict drug solubilization and bioavailability, select the best drug-LBF association and obtain better in vitro-in vivo correlations. So far, research in this area has focused on LBF lipolysis under intestinal conditions because the small intestine is the main target for drug delivery and absorption, as well as the main site of digestion by pancreatic enzymes. Lipolysis however starts within the stomach through the action of gastric lipase, the first enzyme involved in fat digestion in humans. In vitro digestion experiments show that most LBFs are submitted to gastric lipolysis, and therefore, both intragastric and intestinal digestions are critical for the fate of LBF and drug solubility.
Internal normalization (IN) serves as a quantitative tool in gas chromatography. Nevertheless, its utilization in liquid chromatography is not widely employed, as several requirements need to be taken into account. However, IN can be used in case of relative amounts estimation when the absolute concentration is not the crucial factor. This suits very well in pharmaceutical analysis when the relative amount of active pharmaceutical ingredient (API) impurities is to be estimated with a limited knowledge of statistics, such as t-test and linear regression.
The determination of three prasugrel impurities in the real sample by means of IN and the comparison of these results with external standard calibration was presented. The IN method was validated by test of population means and variances agreement and the agreement of external calibration and IN was performed by Student t-test. The influence of impurities concentration above and below is also discussed as well as the validation parameters, LOD and LOQ. It was found that the results achieved by external calibration and IN are statistically the same and, therefore, IN is a proper method for relative amount estimation of API impurities.
Abstract Self-microemulsifying drug delivery system (SMEDDS) has emerged as a vital strategy to formulate poor water soluble compounds for bioavailability enhancement. However, certain limitations are associated with SMEDDS formulations which include in vivo drug precipitation, formulation handling issues, limited lymphatic uptake, lack of predictive in vitro tests and oxidation of unsaturated fatty acids. These limitations restrict their potential usage. Inclusion of polymers or precipitation inhibitors within lipid based formulations helps to maintain drug supersaturation after dispersion. This, thereby, improves the bioavailability and reduces the variability on exposure. Also, formulating solid SMEDDS helps to overcome liquid handling and stability problems. Usage of medium chain triglycerides (MCT) and suitable antioxidants to minimize oxidation of unsaturated fatty acids are few of the steps to overcome the limitations associated with SMEDDS. The review discussed here, in detail, the limitations of SMEDDS and suitable measures that can be taken to overcome them.
To critique the stability complications seen in formulating poorly water-soluble, problematic drugs in lipids, modified lipids, and polyethylene oxide solvents and surfactants in hard and soft gelatin capsules as well as some parenterals, a literature search was performed and personal experiences, and those of colleagues, collated. The literature is replete with examples of molecules undergoing rapid oxidative degradation in the presence of polyethylene oxide based solvents and surfactants as well as in the presence of unsaturated lipids. More recently appreciated is instability caused by the reaction of amine and amide drugs, with formaldehyde, formic acid found in many of these solvents as impurities and other degradation byproducts of the solvents themselves. One would expect acylation and transacylation reactions to be more common than reported but the literature has some good examples. An added complexity is occasionally seen with the use of hard and soft gelatin capsules with these solvents. The chemical stability of drugs in liquid and semi-solid formulations in the presence of lipids, modified lipids, and polyoxyethylene oxide-based solvents and surfactants can be complex, further exacerbated by the use of gelatin capsules, and can lead to a plethora of degradation pathways often not seen when the same drugs are formulated in solid dosage forms.
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.
The first order electric field correlation function of laser light scattered by polydisperse solutions of macromolecules can be written as a sum or distribution of exponentials, with decay rates proportional to the diffusion coefficients of the solute molecules. It is shown that the logarithm of this correlation function is formally equivalent to a cumulant generating function. A method is described by which the distribution function of the decay rates (and thus the extent of polydispersity) can be characterized, in a light scattering experiment, by calculation of the moments or cumulants. The systematic and random statistical errors in the calculated cumulants are discussed.
The paper summarizes 10-years of experience gained by various groups in the study of liquid marbles. Liquid marbles are non-stick droplets wrapped by micro- or nanometrically scaled particles. Marbles are separated from solid or liquid support by air pockets. This fact determines the unusual non-Amontonian friction inherent for liquid marbles. Scaling laws governing the marbles' shape and dynamics are presented. Liquids and powders used for fabrication of liquid marbles are surveyed. The effective surface tension of liquid marbles is discussed. The paper reviews properties and applications of liquid particles. Liquid marbles demonstrate a potential as micro-reactors, micro-pumps, pH, gas and water pollution sensors. Cosmetics applications and water storage with the use of liquid marbles are of considerable industrial interest. Challenges and trends of future investigations in the field are envisaged.Graphical AbstractThe paper summarizes the experience gained by researchers in the study of marbles. Liquid marbles are non-stick droplets wrapped by micro- or nanometrically scaled particles. The paper reviews properties and applications of liquid particles.View high quality image (282K)Research Highlights► The paper summarizes 10-years of experience gained by various groups in the study of liquid marbles. ► Liquid marbles are non-stick droplets wrapped by micro- or nanometrically scaled particles. ► Liquids and powders used for fabrication of liquid marbles are surveyed. The effective surface tension of liquid marbles is discussed. ► The unusual non-Amontonian friction inherent for liquid marbles is treated. ► Applications of liquid marbles are reviewed.
Introduction:
Lipid-based formulations have emerged as potential dosage forms to harvest effectively the therapeutic benefits of existing lipophilic molecules and new chemical entities. Compared with existing excipients, lipids by virtue of their unique physicochemical properties and resemblance to in vivo components demonstrate the extra advantage of improving the bioavailability of lipophilic and highly metabolizable drugs. Moreover, if used as the major excipient, lipids can reduce the required dose and even the toxicity of drugs with poor aqueous solubility.
Areas covered:
This review deals with the importance of multiparticulate systems in drug delivery, the therapeutic and manufacturing advantages of lipids as excipients, and the technological advances made so far in utilizing lipids for multiparticulate dosage forms, with emphasis on their application and success on an industrial scale. Lipids are being widely formulated into different multiparticulate dosage forms using innovative modifications of conventional equipment with relative ease, using methods such as melt-granulation, adsorption on solid support, spray-cooling, melt-extrusion/spheronization, freeze-pelletization, pastillation, and so on.
Expert opinion:
There is still a need to design new simple dosage forms and to upgrade existing manufacturing technology, in order to open up new avenues in drug delivery, for preparing patent non-infringing formulations of existing drug products, and to help patients receive treatment at an affordable cost.
Accurate characterization using static light scattering (SLS) and dynamic light scattering (DLS) methods mandates the measurement and analysis of singly scattered light. In turbid samples, the suppression of multiple scattering is therefore required to obtain meaningful results. One powerful technique for achieving this, known as 3D cross-correlation, uses two simultaneous light scattering experiments performed at the same scattering vector on the same sample volume in order to extract only the single scattering information common to both. Here we present a significant improvement to this method in which the two scattering experiments are temporally separated by modulating the incident laser beams and gating the detector outputs at frequencies exceeding the timescale of the system dynamics. This robust modulation scheme eliminates cross-talk between the two beam-detector pairs and leads to a fourfold improvement in the cross-correlation intercept. We measure the dynamic and angular-dependent scattering intensity of turbid colloidal suspensions and exploit the improved signal quality of the modulated 3D cross-correlation DLS and SLS techniques.
Contemporary pharmaceutical pipelines are often highly populated with poorly water-soluble drug candidates necessitating novel formulation technologies to provide dosage forms with appropriate biopharmaceutical properties. The configuration of supersaturating drug delivery systems (SDDS) is a promising concept to obtain adequate oral bioavailability. SDDS contain the drug in a high energy or otherwise rapidly dissolving form such that intraluminal concentrations above the saturation solubility of the drug are generated. For the strategy to be useful, the formed supersaturated solution must then be stabilized to allow for significant absorption and eventually sufficient bioavailability. The stabilization of a supersaturated solution can be accomplished by adding precipitation inhibitors which may act through a variety of mechanisms. The goal of this review is to assess methods and excipients associated with the development of SDDS and provide some context for their use. In addition, the future directions and factors likely to contribute to or detract from optimal dosage form selection are assessed. This includes a discussion on the potential effect of the gastrointestinal physiology on the ability to attain and maintain supersaturation as this information is essential in designing useful formulations based on the supersaturating concept.
The characterization of the mechanical properties of single uncoated pellets was performed in order to verify if these parameters could be used to predict the pellets aptitude to be compressed or utilized differently. Different ratios of microcrystalline cellulose and lactose monohydrate were used for the preparation of four batches of pellets by an extrusion/spheronization process. The 0.6-0.71 mm pellet fraction was used for the tests. Crushing strength and stress relaxation tests were carried out on the single pellets. The first test provided information of both the mechanical strength and the fragmentation aptitude. The second test provided information about their deformation ability (viscous flow) and residual elasticity (stress relaxation modulus). The results obtained from these tests were then compared with those obtained from the Heckel analysis. An excellent consistency was discovered between the parameters obtained from both the stress relaxation and crushing strength tests on one side and the Heckel parameters on the other side. Tests performed on single pellets are very useful tools to predict their deformation and fragmentation aptitude under compression and can be used for early insight of the pellet aptitude to be compressed.
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.
Understanding material properties in pharmaceutical product development and manufacturing: powder flow and mechanical properties
- D Zhou
- Y Qiu
Developing Solid Oral Dosage Forms
- S W Hoag