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Hypothesis Topical and systemic methods are not able to deliver ophthalmic drugs for treatment of retinal diseases. Consequently, invasive monthly intravitreal injections through the eyeball are required to deliver retinal drugs. A reduction in the frequency of the injection through extended release of the drugs could have significant clinical benefits. Experiments Oleogels containing ethyl cellulose as the gelator at 10% (wt%) in soybean oil were loaded with dexamethasone above the solubility limit and expunged from a syringe to create cylindrical rods for extended drug delivery. The devices were imaged to explore particle distribution and drug release was measured under sink conditions in buffer. A model was developed and fitted to data to determine effective drug diffusivity. Findings Dexamethasone is released slowly due to the presence of the drug particles that serve as drug depots. The release increases from 600 to 3000 h as the drug loading is increased from 3% to 28%. The release profiles can be modeled by considering drug dissolution and diffusion, as well as the tortuosity of the matrix due to the presence of the voids formed after the drug particles have dissolved. The proposed approach is promising as the release profiles of the drug are comparable to commercial devices.

High drug load inhalable particles were prepared by co-spray drying a hydrophobic, crystalline, small molecule drug with various lipid or phospholipid excipients at a 9:1 molar ratio to understand the primary drivers of aerosol performance. The effect of excipient structure on solid-state, surface characteristics, and aerodynamic performance of the co-spray dried particles was studied while keeping the spray drying parameters constant. Spray drying of the drug with lipids produced crystalline drug particles, whereas phospholipids produced partially amorphous drug particles. All of the co-spray dried particles were nearly spherical with a smooth surface, except for the spray dried drug particles without excipients – which showed the presence of rough crystals on the surface. All co-spray dried particles showed surface enrichment of the excipient. The surface enrichment of the phospholipids was higher compared to the lipids. Co-spray dried particles that showed higher surface enrichment of excipients showed improved aerosol performance. In comparing all the excipients studied, distearyolphosphatidylcholine (DSPC) showed maximum enrichment on the particle surface and thereby significantly improved aerosol performance. This study demonstrated that the addition of small amounts of lipid excipients during spray drying can change surface morphology, composition, and cohesion, impacting aerosol performance of drugs.

Almost 40% of the new chemical entities at present self find out poorly water soluble drugs. Badly water soluble drugs have solubility and dissolution related bioavailability problems. Solubility is one of the most important parameter to give desired concentration of drug in systemic circulation to get its pharmacological response. Orally administered drugs obtained completely absorb only when they show fair solubility in gastric medium and such drugs shows good bioavailability. The solubility and dissolution properties of drugs perform an valuable role in the process of formulation development. Enhancement of solubility of drug is the most challenging job in drug development process. Solubilization may be affected by co solvent water interaction, micellar solubilization, reduction in particle size, inclusion complexes, solid dispersion, and change in polymorph. This review highlight various techniques of solubility enhancement with special emphasis on Chemical modification methods like Salt formation, Co-crystallization, Co-solvency, Hydrotropy, use of novel solubilizer etc along with physical modification techniques. Keywords: Salt formation, Co-crystallization, Solubility, particle technologies, Milling solubility enhancement, Cosolvent, physical and chemical methods.

This study concluded that Metformin HCl was successfully prepared as a liposomal drug delivery system by using two different techniques such as physical dispersion method and ether injection method. In this liposomes preparations, cholesterol ratio was constant and soya lecithin concentrations were gradually increased (like 1:1, 1:2 and 1:3). The liposomes prepared by physical dispersion method showed better percentage drug entrapment when compared with ether injection method. The morphological characters of prepared liposomes were determined with the help of optical microscope. The particle size was analyzed by Malven particle size analyzer. The results of the particle size showed, when the concentration of soya lecithin was increased the size of the particle was reduced. The in vitro release showed that as the concentration of soya lecithin was increased the release rate of drug was retarded. Among the two methods ether injection method showed prolonged action when compared to physical dispersion method. The stability studies for all the formulations were performed by keeping the formulations at two different temperatures 4oC±2oC and 25oC±2oC for a period of 30 days. After the stability period the formulations were tested for morphological analysis, percentage drug entrapment and in vitro drug release and compared with before stability study. There was no change in morphological characters at 4oC±2oC, but there was a slight reduced in particles size at 25oC±2oC. The percentage drug entrapment was reduced in all the formulations at both the conditions. The in vitro drug release was reduced for all the formulations. Liposomes prepared by physical dispersion method showed better stability compared with ether injection method.

A dissolution apparatus that uses a small volume of stationary medium (25 μL) has been developed for in vitro dissolution testing of respirable drug particles and used to evaluate the dissolution of two anti-tubercular drugs, moxifloxacin and ethionamide. Solubilities of moxifloxacin and ethionamide in phosphate buffered saline (PBS, pH 7.4) were 17.68 ± 0.85 mg mL−1 and 0.46 ± 0.02 mg mL−1 whereas in the presence of lung surfactant (0.4% w/v Curosurf® in PBS) solubilities were 20.76 ± 0.35 mg mL−1 and 0.56 ± 0.03 mg mL−1, respectively. A fine particle dose (∼50 µg) of aerodynamically separated moxifloxacin or ethionamide particles (

Direct compression offers a simple route to generate pharmaceutical dosage units and is core to the growing arena of continuous manufacturing. However, direct compression can be untenable for some active materials. This paper will outline three specific challenges API's can present to direct (active pharmaceutical ingredients) compression. The first involves API's having exceedingly high aspect ratio ("needles") or small particle size resulting in low bulk density and poor flow properties. Two additional cases are relatively newer challenges to direct compression driven by the growing need for solubility enhancing formulations, and involve nano-crystalline materials and spray dried amorphous dispersions. Multiple approaches for managing high aspect ratio or micronized API's have been implemented during the crystallization process or via particle coating downstream from API isolation. Fewer options have been reported for the successful conversion of nano-crystalline materials or spray dried amorphous dispersions into materials amenable to direct compression as these materials offer another specific set of challenges. One route that has not been explored that stands to allow continuous drug product processing across a broader product portfolio involves evaluating opportunities at the drug substance/drug product interface. Here, the options achieved through targeted introduction of excipients to the drug substance processing steps during product precipitation and/or isolation from a product slurry are discussed. This approach introduces new opportunities for designing multicomponent particles through productive and inherently continuous processes. This also offers a longer-term potential route to integrate across continuous drug substance processing to continuous drug product processing.

For drug delivery to the lungs, the aerodynamic size of drug particles plays a predominant role in determining the sites of deposition in the airway, and the particles with the size less than 2μm are highly expected as they will be preferably delivered to the ideal site of alveolar regions. In this paper, a novel platform technology has been developed, where the water (containing pharmaceutically active agents)-in-oil (w/o) microemulsions were spray-dried to generate nanosized drug particles that were able to be homogeneously dispersed in the propellant to form an exceptionally stable suspensions with no precipitates or flocculates during a long time storage. High fine particle (

Analgesics is a multibillion dollar worldwide industry. Oxycodone, an opioid, is currently administered using controlled release tablets; although this has resulted in considerable control over pain management, the controlledrelease tablets have been abused by drug users. Measures to curb illicit use of the drug have not been successful, to date. This study proposes that by incorporating the medicine into a micro- to nano-structurally optimized delivery material, release concentrations that cannot exceed therapeutic target levels will be achieved and therefore, curbing its misuse, even when the carrier material is crushed. Using Dextromethorphan (Dextro) as a model drug, silica xerogels (sol-gels) were synthesized by mixing tetramethoxysilane, Deionized water and HCl, in addition to Dextro-methanol solution. Different drug loads and water-to-alkoxide ratios were observed to alter the micro- and nanostructurural properties. Different particle sizes were produced by crushing the xerogel discs, after which they were sieved and immersed in 5mg/ml PBS solution. Concentration of released Dextro was measured spectrophotometrically at 280 nm. The effect of particle size on in vitro release of Dextro from xerogels, as a function of immersion time, demonstrated that both micro- to nano-sized particles exhibited timedependent release of Dextro. Although the release from nano-sized particles was noticeably faster than from the micro-sized ones, they did not show any burst release. Data obtained demonstrate that synthesizing a delivery system capable of achieving the controlled-release of therapeutically relevant doses and misuse resistance are attainable.

The aim of this study was to design agomelatine loaded long acting injectable microspheres, with an eventual goal of reducing the frequency of administration and improving patient compliance in treatment of depression. AGM-loaded microspheres were prepared by an O/W emulsion solvent evaporation method. The physicochemical properties and in vitro performance of the microspheres were characterized. The pharmacokinetics of different formulations with various particle sizes and drug loadings were evaluated. AGM-loaded microspheres with drug loading of 23.7% and particle size of 60.2 μm were obtained. The in vitro release profiles showed a small initial burst release (7.36%) followed by a fast release, a period of lag time and a second accelerated release. Pore formation and pore closure were observed in vitro, indicating that the release of drug from microspheres is dominated by water-filled pores. Pharmacokinetic studies showed that AGM microspheres could release up to 30 days in vivo at a steady plasma concentration. As well, particle size and drug loading could significantly influence the in vivo release of AGM microspheres. AGM-loaded microspheres are a promising carrier for the treatment of major depressant disorder.

Pulmonary dissolution of poorly soluble drug substances (DSs) may limit the drug absorption rate and consequently influence clinical performance. Dissolution rate is thus an important quality attribute, and its influence on in vivo drug release must be characterized, understood, and controlled early in the development process. The aim of this study is to establish an in vitro dissolution method with the capability to capture therapeutically relevant differences in the dissolution rate between drug batches and drug compounds. A method was developed by which a biorelevant aerosol fraction was captured on a filter using a sedimentation technique in a modified Andersen cascade impactor to avoid particle agglomeration. Subsequently, the filters were transferred to a commercial Transwell system where dissolution in 3 mL of phosphate buffer at pH 6.8 with 0.5% sodium dodecyl sulfate (SDS) occurred at sink conditions. Dissolved DS was quantified over time using UPLC-UV. Dissolution data was obtained on a series of micronized and aerosolized lipophilic DSs, budesonide, fluticasone furoate (FF), fluticasone propionate (FP), and AZD5423. The latter is a lipophilic AstraZeneca development compound available in two different mass median diameters (MMD), 1.3 (AZD5423

Over the past 20 years, solution-based spray dried powders have transformed inhaled product development, enabling aerosol delivery of a wider variety of molecules as dry powders. These include inhaled proteins for systemic action (e.g., Exubera®) and high-dose inhaled antibiotics (e.g., TOBI® Podhaler™). Although engineered particles provide several key advantages over traditional powder processing technologies (e.g., spheronized particles and lactose blends), the physicochemical stability of the amorphous drug present in these formulations brings along its own unique set of constraints. To this end, a number of approaches have been developed to maintain the crystallinity of drugs throughout the spray drying process. One approach is to spray dry suspensions of micronized drug(s) from a liquid feed. In this method, minimization of drug particle dissolution in the liquid feed is critical, as dissolved drug is converted into amorphous domains in the spray-dried drug product. The review explores multiple formulation and engineering strategies for decreasing drug dissolution independent of the physicochemical properties of the drug(s). Strategies to minimize particle dissolution include spray blending of particles of different compositions, formation of respirable agglomerates of micronized drug with small porous carrier particles, and use of common ions. The formulations extend the range of doses that can be delivered with a portable inhaler from about 100 ng to 100 mg. The spray-dried particles exhibit significant advantages in terms of lung targeting and dose consistency relative to conventional lactose blends, while still maintaining the crystallinity of drug(s) in the formulated drug product.

Co-milling of a drug with a co-former is an efficient technique to improve the solubility of drugs. Besides the particle size reduction, the co-milling process induces a structural disorder and the creation of amorphous regions. The extent of drug solubility enhancement is dependent on the proper choice of co-milling co-former. The aim of this work was to compare the effects of different co-formers (meglumine and polyvinylpyrrolidone) on the dissolution rates of glass forming (indomethacin) and non-glass forming (mefenamic acid) model drugs. A positive impact of the co-milling on the dissolution behavior was observed in all co-milled mixtures, even if no substantial amorphization was observed. While meglumine exhibited pronounced effects on the dissolution rate of both drugs, the slightest enhancement was observed in mixtures with polyvinylpyrrolidone. The evaluation of specific release rate revealed the surface activation of drug particle is responsible for improving the dissolution rate of both drug types, but for the glass former, this surface activation could be persistent while maintaining a high dissolution rate even until a high fraction of drug is released. Our results, therefore, indicate that adequate co-former choice and consideration of drug glass forming ability are important for a successful co-milling approach to poorly water-soluble drugs.

Over the past two decades nanosizing technology has become one of the most successful formulation approaches for improving the bioavailability of poorly soluble drugs, which show a low oral absorption due to low dissolution velocity. Nanocrystals are nanoparticles of pure drug, without any matrix material, with an average diameter below 1 µm (typically in the range of 200-500 nm), which can be prepared in both water and non-water media as colloidal nanosuspensions stabilized using surfactants or polymers. The reduction of the drug particle diameter below 1 µm increases the dissolution velocity by increasing the particle surface and decreasing the diffusion layer thickness. Nanosuspension production processes involve two different approaches such as bottom-up (drug nanocrystal precipitation) and top-down (drug particle disintegration) technologies or a combination of two. Within these main approaches, a variety of possible techniques to achieve particle size reduction have been proposed by different research groups from both industry and academia. Even though nanosuspensions formulations have been especially studied for oral and parenteral administration, nanocrystals have showed a great potential also for topical delivery through alternative routes such as dermal, pulmonary and ocular route. The purpose of this review is to describe the main technologies used to produce nanosuspensions as well as to explore the most significant results and progresses obtained by application of drug nanocrystal formulations through topical routes.

The potential for inadvertent inhalation of over-the-counter (OTC) aerosol/powder drug products for topical application requires understanding of the characteristic size distributions of the airborne particles or droplets generated when these products are used as per the directions on the product label. Particle/droplet size is an important factor in determining the depth of particle penetration into the respiratory system after inhalation. Because particles penetrating beyond the larynx into the lung may lead to adverse respiratory effects, OTC aerosol or powder drug product particle size distribution is important to characterize. In this study, laser diffraction was used to analyze the particle size distribution of 32 currently marketed OTC drug products as emitted after actuation or air dispersion from their final package. Among the products surveyed were sunscreens, antiperspirants, topical analgesics, skin protectants, and acne products. The results may be useful to the U.S. Food and Drug Administration in its mission to protect as well as promote public health.

Drug delivery methods can impact efficacy as much as the nature of the drug itself. Microparticles made of biodegradable polymers such as poly(D, l -lactide-co-glycolide) and poly(lactic acid) (PLA) have been studied extensively for controlled release of diverse drugs. By using a modified solvent extraction/evaporation method called precision particle fabrication (PPF), uniform microparticles such as single-wall microspheres, double-wall microspheres and liquid-core microcapsules have been fabricated with precise control of their geometric structures. By producing particles of uniform size, which has crucial impact on drug release behaviors, PPF-fabricated microparticles provide unique insights about drug release mechanism. Using small-molecule and macromolecule model drugs, our group demonstrated that physicochemical properties of the polymers and drugs and structural properties of the matrix can greatly impact drug distribution within microparticles, particle erosion and drug release rates. By careful selection of particle size and shell thickness, uniform microparticles can achieve “zero-order”, pulsatile or tandem release of drugs.

Lipid nanoemulsions and -suspensions are being intensively investigated as carriers for poorly water soluble drugs. The question on where model compounds or probes are localized within the dispersions has been the subject of several studies. However, only little data exists for pharmaceutically relevant molecules in dispersions composed of pharmaceutically relevant excipients. In this work, the localization of drugs and drug-like substances was studied in lipid nanoemulsions and -suspensions. Conclusions about the drug localization were drawn from the relations between lipid mass, specific particle surface area and drug load in the dispersions. Additionally, the achievable drug loads of the liquid and the solid lipid particles were compared. Nanoemulsions and -suspensions comprised trimyristin as lipid matrix and poloxamer 188 as emulsifier and were prepared with different well-defined particle sizes. These pre-formed dispersions were passively loaded with either amphotericin B, curcumin, dibucaine, fenofibrate, mefenamic acid, propofol, or a porphyrin derivative. The physico-chemical properties of the particles were characterized; drug load and lipid content were quantified by UV spectroscopy and high performance liquid chromatography, respectively. For all drugs the passive loading procedure was successful in both emulsions and suspensions. Solid particles accommodate drug molecules preferably at the particle surface. Liquid particles can accommodate drugs at the particle surface as well as in the core; the distribution between the two sites is drug specific. It is also drug specific whether solid or liquid particles yield higher drug loads. As a general rule, smaller particles led to higher drug loads than larger ones. Propofol and the porphyrin derivative displayed eutectic interaction with the lipid and crystal growth after loading, respectively.

The enhancement in bioavailability of the drugs is one of the most important concerning aspects of the pharmaceutical industries. Preparation of nanoparticles or microparticles of these drugs is the newest formulation strategies. The size and morphology of a drug are affecting several essential pharmaceutical properties. In general, the drug delivery system needs narrow particle size distribution with regular particle shape, particularly, an engineered drug particles to meet biopharmaceutical and processing needs. An antisolvent crystallization technique is being used to prepare nanoparticles or microparticles for poorly water soluble drugs at research scale. This method has an ability to change the solid-state properties of pharmaceutical substances including the modification of crystal formation and particle size distributions. Therefore, various operating variables and their effect on the particle size of poorly water soluble drugs in an anti-solvent crystallization have been reviewed.

Dry powder inhalation has good potential to be an alternative route of drug administration, especially for the treatment of lung and systemic diseases. However, typically only a small fraction of the dose can be delivered to the lower airways. Continuous effort on the drug formulation is undergoing to improve the deep lung deposition. Key properties of the drug and carrier particles and their relationships with the particle dispersibility and deposition properties in the lung are discussed individually. Some recent drug formulation techniques for dry powder inhalation are also reviewed.

Pulmonary cell cultures are increasingly used to predict in vivo drug absorption after inhalation, similar to intestinal cell culture models that have already been well established to predict oral drug absorption. In contrast to the intestinal barrier, however, the so-called air-blood barrier of the lung is covered only with a thin film of liquid, on which the aerosol particles are deposited. The aim of this study was to investigate the relevance of this apical liquid film on the drug absorption rate when deposited as a dry powder formulation on pulmonary epithelial cells in vitro.Budesonide and salbutamol sulfate were chosen as model drugs, and for each drug three generic aerosol powder formulations were used. Filter-grown monolayers of the human bronchial epithelial cell line Calu-3 were used as a model, using various volumes of apical liquid.Although proven to be bioequivalent in vivo for each of the two drugs, the generic dry powder fomulations showed strikingly different epithelial transport rates in vitro, depending on the amount of apical liquid and the deposition technique, and suggesting that the dissolution of the aerosol particles in the apical liquid volume was rate limiting for the overall absorption rate. However, we found that the absorption rates of the formulations were similar after aerosolization and deposition in a multistage liquid impinger, which simulates more realistically the detachment of the drug crystals from the carrier lactose and their aerodynamic particle size-dependent deposition in the respiratory tract following inhalation from a dry powder inhaler. These data demonstrate the need for improved in vitro test systems to allow deposition of aerosol particles on the air-liquid interface cultivated cell monolayers by simultaneously taking into account aerodynamic properties.

Drug particle physical properties are critical for the efficiency of a drug delivered to the lung. The purpose of this study was to produce ultrafine sumatriptan succinate particles for inhalation.Sumatriptan succinate particles were produced via reactive precipitation without any surfactants. Several low toxic organic solvents such as acetone, isopropanol, and tetrahydrofuran were investigated as the reaction medium. And the dry powder was obtained via spray drying. FT-IR, HPLC, SEM and XRD were exploited to characterize the physicochemical properties of the ultrafine sumatriptan succinate dry powder. The aerosol performance of the powder was evaluated using an Aeroliser connected to a multi stage liquid impinger operating at 60 l/min.The mean particle size of the ultrafine sumatriptan succinate particles obtained under optimum conditions was in the range of 630-679 nm and consequently they were in the respirable range. The spray-dried powder whose fine particle fraction was increased up to 50.6 +/- 8.2% showed good aerosol performance whereas the vacuum-dried powder was approximate 18.2 +/- 3.0%.Good aerosol performance ultrafine sumatriptan succinate particles could be produced by reactive precipitation without any additives followed by spray drying at the optimum parameters.

The therapeutic index (TI) of locally acting inhaled drug products depends on a number of parameters and processes: the particle size distribution of the inhaled aerosol, the dose-efficacy response curves at the deposition sites, the amount of drug absorbed into the systemic circulation from the lung as well as the gastrointestinal (GI) tract, and the dose-effect curves for the different adverse drug reactions. In this review, we present qualitative scenarios, combining these effects and showing the possible influence of an envisaged change in the particle size distribution in the inhaled dose of a locally acting drug product on the TI. These scenarios are a valuable tool in the development of inhalation drug products. As a surrogate for the inhaled dose in vivo, we use the fine particle mass (FPM), measured by in vitro measurements. Using these scenarios, we reviewed the literature on bronchodilators and corticosteroids for reported associations between a change in the FPM and/or particle size distribution within the FPM, and the TI. We conclude that decreasing the particle size of an inhalation product may alter the TI both in a positive as well as a negative sense. So, smaller particle are not always better. © 2008 Bentham Science Publishers Ltd.

The top-down approach is frequently used for drug nanocrystal production. A large number of review papers have referred to the top-down approach in terms of process parameters such as stabilizer selection. However, a very important factor, that is, the influence of drug properties, has been not addressed so far.This review will first discuss different nanocrystal technologies in brief. The focus will be on reviewing the different drug properties such as solid state and particle morphology on the efficiency of particle size reduction during top-down processes. Furthermore, the drug properties in the final nanosuspensions are critical for drug dissolution velocity. Therefore, another focus is the characterization of drugs in obtained nanosuspension.Drug physical properties play an important role in the production efficiency. The combinative technologies using modified drugs could significantly improve the performances of top-down processes. However, further understanding of the drug millability and homogenization will still be needed. In addition, a carefully established characterization system for nansuspension is essential.

The aim of this study was to better understand the mass transport mechanisms controlling drug release from PLGA microparticles. New insight was gained based on the experimental monitoring of single microparticle swelling. An oil-in-water (O/W) solvent extraction/evaporation method was used to prepare ketoprofen-loaded microparticles, varying the initial drug loading from 0.6 to 45.2%. Importantly, the microparticle size was kept about constant. At low ketoprofen loadings, the release patterns were clearly tri-phasic: an initial burst release was followed by a period with an about constant release rate and a final (again rapid) drug release phase. With increasing initial drug content the onset of the third release period was shifted to earlier time points. At even higher drug loadings, the release patterns became more or less bi- or mono-phasic. Interestingly, all types of microparticles showed substantial swelling after a lag-time, which coincided with the onset of the third (and again rapid) drug release phase at low loadings and proceeded it by 1 or 2d at higher drug loadings. The substantial microparticle swelling set on as soon as a critical PLGA molecular weight was reached (around 20 kDa). Thus, the onset of the third drug release phase from the PLGA microparticles might be explained as follows: once the macromolecules are sufficiently short, substantial amounts of water penetrate into the system, significantly increasing the mobility of the drug within the microparticles and resulting in increased drug release rates.

Itraconazole (ITZ), a triazole antifungal agent, is a poorly water-soluble drug that is orally administered for treatment of fungal infections such as allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis (IA). ABPA is relatively well controlled but IA can be fatal, especially in immunosuppressed patients. Aerosolized ITZ delivered to the lung may provide a local treatment and prophylaxis against IA at the primary site of infection in the lungs. Variations of the percent fine particle fraction (FPF), the percent emitted dose, and the physical properties of the aerosol (e.g., crystallinity) can confound consistent delivery.ITZ NanoClusters were formulated via milling (top-down process) or precipitation (bottom-up process) without using any excipients. Itraconazole formulations (ITZ) were prepared by milling 1 gram of micronized itraconazole in 300 mL of fluid. The suspension was collected at 0.5, 1, and 2 hours milling time. Milled ITZ was compared to ITZ prepared by anti-solvent precipitation and to the stock micronized itraconazole. The aerosolization performance of ITZ formulations was determined using an Andersen Cascade Impactor (ACI).The physicochemical properties and aerosol performance of different ITZ NanoClusters suggested an optimized wet milling was the preferred process compared to precipitation. ITZ NanoClusters prepared by wet milling showed better aerosol performance compared to micronized ITZ as received and ITZ NanoClusters prepared by precipitation. ITZ NanoClusters prepared by precipitation methods also showed an amorphous state, while ITZ milled in 10% EtOH maintained the crystalline character of ITZ throughout a 2 hour milling time.The aerosol performance of milled ITZ NanoClusters was dramatically improved compared to micronized ITZ as received due to the difference of drug particle structures. ITZ NanoCluster formulations represent a potential engineered drug particle approach for inhalation therapy, providing effective aerosol properties and stability due to the crystalline state of the drug powders.

Particle uptake by Peyer's patches offers the possibility of tailoring vaccines that can be delivered orally. However, particle uptake by the follicle-associated epithelium in the gastrointestinal tract depends on several different factors that are the physicochemical properties of the particles, the physiopathological state of the animal, the analytical method used to evaluate the uptake and finally the experimental model. These parameters do not allow a clear idea about the optimal conditions to target the Peyer's patches. The goal of this review is to clarify the role of each factor in this uptake.

Purpose. To set up a theoretical basis for identifying biowaivers among Class II drugs and apply the methodology developed to nonsteroidal anti-inflammatory drugs (NSAIDs). Methods. The dynamics of the two consecutive drug processes dissolution and wall permeation are considered in the time domain of the physiologic transit time using a tube model of the intestinal lumen. The model considers constant permeability along the intestines, a plug flow fluid with the suspended particles moving with the fluid, and dissolution in the small particle limit. The fundamental differential equation of drug dissolution-uptake in the intestines is expressed in terms of the fraction of dose dissolved. Results. The fundamental parameters, which define oral drug absorption in humans resulting from this analysis, are i) the formulation-related factors, dose, particle radius size, and ii) the drug-related properties, dimensionless solubility/dose ratio (1/q), and effective permeability. Plots of dose as a function of (1/q) for various particle sizes unveil the specific values of these meaningful parameters, which ensure complete absorption for Class II drugs [(1/q) < 1]. A set of NSAIDs were used to illustrate the application of the approach in identifying biowaivers among the NSAIDs. Conclusions. The underlying reason for a region of fully absorbed drugs in Class II originates from the dynamic character of the dissolution-uptake processes. The dynamic character of the approach developed allows identification of biowaivers among Class II drugs. Several biowaivers among the NSAIDs were identified using solubility data at pH 5.0 and in fed-state-simulated intestinal fluid at pH 5.0. The relationships of formulation parameters, dose, particle radius, and the drug properties, dimensionless solubility/dose ratio (1/q), and permeability with the fraction of dose absorbed for drugs with low 1/q values [(1/q) < 1] can be used as guidance for the formulation scientist in the development phase.

Drug powders containing micron-size drug particles are used in several pharmaceutical dosage forms. Many drugs, especially newly developed substances, are poorly water soluble, which limits their oral bioavailability. The dissolution rate can be enhanced by using micronized drugs. Small drug particles are also required in administration forms, which require the drug in micron-size size due to geometric reasons in the organ to be targeted (e.g., drugs for pulmonary use). The common technique for the preparation of micron-size drugs is the mechanical comminution (e.g., by crushing, grinding, and milling) of previously formed larger particles. In spite of the widespread use of this technique, the milling process does not represent the ideal way for the production of small particles because drug substance properties and surface properties are altered in a mainly uncontrolled manner. Thus, techniques that prepare the drug directly in the required particle size are of interest. Because physicochemical drug powder properties are decisive for the manufacturing of a dosage form and for therapeutic success, the characterization of the particle surface and powder properties plays an important role. This article summarizes common and novel techniques for the production of a drug in small particle size. The properties of the resulting products that are obtained by different techniques are characterized and compared.

▪ Abstract The new field of therapeutic aerosol bioengineering (TAB), driven primarily by the medical need for inhaled insulin, is now expanding to address medical needs ranging from respiratory to systemic diseases, including asthma, growth deficiency, and pain. Bioengineering of therapeutic aerosols involves a level of aerosol particle design absent in traditional therapeutic aerosols, which are created by conventionally spraying a liquid solution or suspension of drug or milling and mixing a dry drug form into respirable particles. Bioengineered particles may be created in liquid form from devices specially designed to create an unusually fine size distribution, possibly with special purity properties, or solid particles that possess a mixture of drug and excipient, with designed shape, size, porosity, and drug release characteristics. Such aerosols have enabled several high-visibility clinical programs of inhaled insulin, as well as earlier-stage programs involving inhaled morphine, growth hormone, beta-interferon, alpha-1-antitrypsin, and several asthma drugs. The design of these aerosols, limited by partial knowledge of the lungs' physiological environment, and driven largely at this stage by market forces, relies on a mixture of new and old science, pharmaceutical science intuition, and a degree of biological-impact empiricism that speaks to the importance of an increased level of academic involvement.

Purpose. To provide guidance in setting particle size specifications for poorly soluble drugs to minimize variability in absorption. Methods. A previously reported computer method was used to simulate the percent of dose absorbed as a function of solubility, absorption rate constant, dose, and particle size. Results. The simulated percent of dose absorbed was tabulated over a realistic range of solubilities, absorption rate constants, and doses using drug particle sizes that might be typically found in a dosage form. Conclusions. The greatest effect of particle size on absorption was simulated for low dose- low solubility drugs. In general, the sensitivity of absorption to particle size decreased with increasing dose or solubility. At a solubility of 1 mg/mL, particle size had practically no effect on the percent of dose absorbed over the range of doses simulated (1–250 mg).

Particulate drug delivery via hair follicles represents a promising concept, although requirements are high. This process must be realized at the desired depth and at the appropriate time, due to the fact that the particles themselves are not able to overcome the follicular skin barrier. In the present study, a novel triggering concept for the release of a model drug from the delivering particles is presented based on the application of two different particle types of the same size, where one particle type is the drug carrier, and the second one is loaded with a protease. The latter particle type is supposed to interact with the drug-carrying particles to trigger the drug release. A mixture of both particles was applied onto porcine skin samples, followed by follicular analysis. As a control, the particles were applied unaided without protease, whereas one skin area remained untreated. The investigations revealed that the protease was able to release the model drug from the delivering particles in significant depths within the hair follicle (866 ± 62 nm). Additionally, an uptake of the model drug in the sebaceous gland was observed after release providing a promising novel approach for the development of treatment strategies for different skin diseases.

The entrapment of Netilmicin sulphate (NTS) in polyalkylcyanoacrylate nanoparticles could be of therapeutic interest particularly in the treatment of infection that localise in the macrophages. In fact, aminoglycosides are excluded from macrophages and therefore represent an ineffective therapy for the treatment of typhoid fever, despite the excellent in vitro activity. In this case the colloidal delivery system ensures the NTS targeting to the macrophages. In this paper it is shown that the various formulation conditions are capable of influencing: trapping capacity, particle size, molecular weight distribution. The nanoparticle preparation was carried out using three different methods in the presence of Tween 80 and Pluronic F68, as non-ionic surfactant. The incorporation method consisting in adding the drug to the polymerisation medium led to very low values of NTS entrapment, in addition, formation of instable suspension was obtained increasing the NTS concentration over 5 mg/ml. The other two...

A new model has been developed for predicting size distributions delivered from pressurized metered dose inhalers (pMDIs) that contain suspended drug particles. This model enables the residual particle size distribution to be predicted for a broad range of formulations. It expands on previous models by allowing for polydisperse micronized input drug, multiple suspended drugs, dissolved drug, and dissolved or suspended excipient to be included in the formulation. The model indicates that for most pMDI configurations, the majority of droplets contain no drug or a single drug particle and the residual particle size distribution delivered from the pMDI is essentially equivalent to the size distribution of the micronized drug used in the formulation. However, for pMDIs with a high drug concentration or that use small micronized drug particles, there can be a substantial fraction of the droplets that contain multiple drug particles. The residual particle size distribution obtained from these pMDIs can be substantially larger than the size distribution of the micronized drug. Excellent agreement was observed between size distributions predicted using this model and those obtained from experimental cascade impactor measurements (r(2)=0.97), thus demonstrating the ability of the model to accurately predict the size distributions obtained from suspension pMDIs.

In this study, the drug delivery performance of pollen-shape hydroxyapatite (HA) carriers is assessed and compared with conventional lactose (LA) carriers. Budesonide (Bd) is used as the model drug. Three drug mixing ratios of 2:1, 10:1 and 45:1 (carrier:drug, w/w) are used. The attachment of the drug with the carrier is characterized by sieving test. It is found that the drug content in the blends with HA particles is higher than the blends with LA. In vitro inhalation experiments are also conducted in an Andersen cascade impactor (ACI) equipped with a Rotahaler at gas flow rates of 30 and 60 L/min. The HA blends show high emitted dose (ED) of 82-90% at 30 L/min while the LA blends are observed to have ED of 69-82% at the same conditions. The high emission of the HA blends also allows high fine particle fraction (FPF) of 10-18% while the FPF of the LA blends are 3-15%. At a gas flow rate of 60 L/min, all the HA and LA blends show compatible ED (83-95% for HA blends and 82-84% for LA blends) and FPF (19-41% for HA blends and 21-34% for LA blends).

The objective was to investigate the nature and extent of short-term dynamic changes to dissolution within specific interactive mixtures following blending. Two micronized drugs, nitrazepam and flunitrazepam, were formulated into lactose-based interactive mixtures containing a micronized surfactant. The dissolution rate of the drugs decreased significantly over a period of days after preparation. The dissolution was modelled using a multi-exponential equation, allowing estimation of agglomeration and dissolution rate. From this model, decreasing dissolution rates were consistent with increasing agglomeration. Particle-sizing studies provided evidence of an increase in drug agglomerates over the same timescale. This is the first study to report short-term dissolution changes immediately following secondary processing. Several hypotheses are proposed for increases in agglomeration, which potentially relate to changes in surface charge, particle rearrangements, recrystallisation at surfaces and the role of moisture, although the role of mechanical processing on agglomerate behaviour remains poorly understood. The observations from this study may have wider implications, for dissolution and for other powder-based drug delivery systems which include interactive mixtures with fine powders. This study emphasizes the need for improved understanding if we are to implement a "Quality by Design" ethos to improve control and risk management over the performance and stability of these systems.

To investigate the cellular internalization pathways of shape- and size-specific particles as a function of zeta potential in different cell types.A top-down particle fabrication technique called PRINT was utilized to fabricate monodisperse 1 microm cylindrical particles. Cellular internalization of these PRINT particles was monitored using confocal microscopy, flow cytometry, and transmission electron microscopy. The endocytic pathway used by 1 microm cationic PRINT particles was evaluated using different inhibitory strategies. Cytotoxicity assays were used to determine the toxicity of both cationic and anionic PRINT particles in multiple cell types.Particle internalization was confirmed using confocal microscopy, flow cytometry and transmission electron microscopy. The mechanism of internalization of positively charged PRINT particles was found to be predominantly clathrin-mediated endocytosis and macropinocytosis with very few particles utilizing a caveolae-mediated endocytic pathway. The exposed charge on the surface of the particles had a significant effect on the rate of endocytosis in all cell types tested, except for the macrophage cells. No significant cytotoxicity was observed for all PRINT particles used in the present study.Cylindrical 1 microm PRINT particles were readily internalized into HeLa, NIH 3T3, OVCAR-3, MCF-7, and RAW 264.7 cells. Particles with a positive zeta potential exhibited an enhanced rate of endocytosis compared to negatively charged particles with identical sizes and shapes. It was found that PRINT particles with a positive zeta potential were endocytosed into HeLa cells using predominantely clathrin-mediated and macropinocytotic pathways.

The aim of the present work is to examine the viability of using large hollow nanoparticulate aggregates as the therapeutic carrier particles in dry powder inhaler delivery of nanoparticulate drugs. The large hollow carrier particles are manufactured by spray drying of nanoparticulate suspensions of biocompatible acrylic polymer with loaded drugs. The size and concentration of the nanoparticles, as well as the phospholipids inclusion, have been known to influence the resulting morphology (i.e. size and degree of hollowness) of the spray-dried carrier particles. The effects of the resulting morphology of the carrier particles on the drug release rate are therefore investigated by varying the above three variables. The results of the drug release study are presented using aspirin and salbutamol sulfate as the model drugs with a varying degree of water solubility. The results indicate that the drug release rate is governed by the degree of hollowness of the carrier particles, and to a lesser extent by the nanoparticles size, as a result of the variation in the drug loading capacity of nanoparticles of different sizes.

The manufacture of fine particles of two steroid drugs - progesterone and medroxyprogesterone acetate- has been investigated through the rapid expansion of supercritical solutions (RESS). The motivation was the production of particles with improved characteristics for use in the pharmaceutical industry. Solubility data for each drug in supercritical CO2 were measured prior to performing the RESS experiments as these data are essential for accurate experimental design. The solubility data were measured using a dynamic apparatus at pressures between 100 and 240 bar and at 313.1 K and 333.1 K. Particles were manufactured by expanding a solution of supercritical CO2 saturated with drug through a micro-nozzle to pressures of 50 bar or less. Sufficient amount of particles was manufactured to allow particle characterization tests to be completed. Particle size, particle size distribution and specific surface area were used as assessment measures to compare the product samples obtained in different experimental conditions. The RESS technique produced particles that were significantly smaller than existing samples manufactured using jet-milling.

The release of the model polypeptide drug bovine serum albumin (BSA) from macroporous ethylene-vinyl acetate copolymer matrices has been investigated over a wide range of drug loadings and particle sizes. At low drug loadings a fraction of the drug is released relatively quickly from the matrix surface, but the remainder of the drug is virtually trapped within the matrix and is released at an extremely slaw rate. At high drug loadings all drug is released. A simple model of drug trapping, based on a modification to percolation theory, is proposed. The model predictions are qualitatively in agreement with the data, but are unable to predict certain quantitative features. It is suggested that the discrepancies are due to a nonuniform distribution of drug in the matrices, which is shown to exist by scanning electron microscopy.

The influence of pH of the dissolution fluid on the in-vitro release of acetylsalicylic acid from hard gelatin capsules has been studied for a series of particle size fractions of the drug. Generally, the time required for 50% of the drug content of the capsule to appear in solution during a dissolution test, T50, increased as the pH increased from 1·2 to 2·0; thereafter the value of T50 decreased as the pH increased from 3 to 7. These changes were found to be related to the apparent solubility of the drug. The extent of the changes was found to be further dependent on the particle size of the drug. For capsules filled with particle size fractions of 2·5 and 5·5 μm median diameter, the changes were small. Larger changes were observed with particles of median diameters of 45,100, 220 and 330 μm while the largest changes (greater than two-fold) were obtained with particles of median diameter 130 and 430 μm. The type of kinetics that could be used to express the release rates was found to be particle size-dependent. For particles of 45 μm and larger, the release rate followed an apparent zero order process while an apparent first order process represented the release for the two smallest particle size fractions.

Three particle sizes (450, 120, and 5 µm) of theophylline were encapsulated in low molecular weight cellulose acetate propionate (intrinsic viscosity, 1.08 dl/g) by the solvent evaporation method. The theoretical drug content for all the batches of microspheres was 50% (w/w). Particle size analysis revealed that about 50% of the microspheres containing the large theophylline crystals (average length of 450 µm) were greater than 500 µm in diameter, whereas only about 35% of the microspheres containing the medium drug crystals (average length of 120 µm) were greater than 500 µm in diameter. The drug content of the larger microspheres prepared from the large drug crystals and the medium drug crystals was much greater than the theoretical drug content (50%, w/w); however, the drug content of all the batches of microspheres containing micronized drug was close to 50% (w/w). Release of the drug in simulated intestinal fluid was very rapid from microspheres containing large and medium drug crystals, while release was slower and more predictable from microspheres made from micronized drug.

Phenobarbital suspensions containing drug particles of different size ranges were separately administered, intramuscularly, to beagle dogs. The particle size of the dose affected the blood drug level curves. A comparison of the areas under the curves with the respective particle sizes indicated that particle size influenced the biological availability of phenobarbital. Data obtained suggest that by controlling the drug particle size, one may be able to regulate the duration of action of phenobarbital.

Many approaches have been developed over time to overcome the bioavailability limitations of poorly soluble drugs. With the advances in nanotechnology in recent decades, science and industry have been approaching this issue through the formulation of drugs as nanocrystals, which consist of “pure drugs and a minimum of surface active agents required for stabilization”. They are defined as “carrier-free submicron colloidal drug delivery systems with a mean particle size in the nanometer range, typically between 10–800 nm”. The primary importance of these nanoparticles was the reduction of particle size to nanoscale dimensions, with an increase in the particle surface area in contact with the dissolution medium, and thus in bioavailability. This approach has been proven successful, as demonstrated by the number of such drug products on the market. Nonetheless, despite the definition that indicates nanocrystals as a “carrier-free” system, surface active agents are necessary to prevent colloidal particles aggregation and thus improve stability. In addition, in more recent years, nanocrystal properties and technologies have attracted the interest of researchers as a means to obtain colloidal particles with modified biological properties, and thus their interest is now also addressed to modify the drug delivery and targeting. The present work provides an overview of the achievements in improving the bioavailability of poorly soluble drugs according to their administration route, describes the methods developed to overcome physicochemical and stability-related problems, and in particular reviews different stabilizers and surface agents that are able to modify the drug delivery and targeting.