Release Of Active Pharmaceutical Ingredients Research Articles

Novel in situ gel-forming solid dosage form (gfSDF) prepared by the simple syringe-based moulding: A screening study

The aim of this study was to prepare and optimize a novel type of in situ gel-forming solid dosage form (gfSDF) to be used in the treatment of mucosal/skin ulcerations. For this purpose, a simple but reliable syringe-based hot melt/moulding method was employed. Chloramphenicol (antibiotic) and ibuprofen (anti-inflammatory) were chosen as model active pharmaceutical ingredients (APIs) to be loaded into the gfSDFs. To optimize the formulations, the gfSDFs of different compositions were studied in terms of APIs release from the matrix, solid-state characteristics, gellification properties and gfSDFs resistance to mechanical stress. Release studies showed that both APIs were released at a constant rate at different pH (pH5 and 7.4, respectively) and the changes in the formulation composition affected the release behaviour. Differential scanning calorimetry (DSC) results evidenced the complete solubilization of both API in the solid matrix. Texture analysis showed that the gfSDFs were capable of swelling once in a contact with aqueous environment and that the textural properties changed extemporaneously from the solid to gel form. The gel formed after hydration exhibited high cohesiveness and adhesiveness, an indication of good mucoadhesion properties. Friability testing confirmed satisfactory physical strength for a solid dosage form.

Solid State NMR Characterization of Ibuprofen:Nicotinamide Cocrystals and New Idea for Controlling Release of Drugs Embedded into Mesoporous Silica Particles.

Grinding and melting methods were employed for synthesis of pharmaceutical cocrystals formed by racemic (R/S) and entiomeric (S) ibuprofen (IBU) and nicotinamide (NA) as coformer. Obtained (R/S)-IBU:NA and (S)-IBU:NA cocrystals were fully characterized by means of advanced one- and two-dimensional solid state nuclear magnetic resonance (SS NMR) techniques with very fast magic angle spinning (MAS) at 60 kHz. The distinction in molecular packing and specific hydrogen bonding pattern was clearly recognized by analysis of 1H, 13C, and 15N spectra. It is concluded from these studies that both methods (grinding and melting) provide exactly the same, specific forms of cocrystals. Thermal solvent-free (TSF) approach was used for loading of (R/S)-IBU:NA and (S)-IBU:NA into the pores of MCM-41 mesoporous silica particle (MSP). The progress and efficiency of this process was analyzed by NMR spectroscopy. It has been confirmed that TSF method is an effective and safe technique of filling the MSP pores with active pharmaceutical ingredients (APIs). By analyzing the NMR results, it has been further proved that excess of IBU and NA components, which are not embedded into the pores during melting and cooling, crystallize on the MCM-41 walls preserving very specific arrangement, characteristic for crystalline samples. By investigating kinetic of release for (R/S)-IBU/MCM-41, (S)-IBU:NA/MCM-41, and (R/S)-IBU:NA/MCM-41 samples containing active components exclusively inside of the pores, it was revealed that release of IBU is much faster for the first of the samples compared to those containing IBU and NA inside the pores. The hypothesis that the rate of release of API can be controlled by specific composition of cocrystal embedded into the MSP pore was further supported by study of (R/S)-IBU:BA/MCM-41 sample with benzoic acid (BA) as coformer.

Stimuli-responsive liposomes for drug delivery.

The ultimate goal of drug delivery is to increase the bioavailability and reduce the toxic side effects of the active pharmaceutical ingredient (API) by releasing them at a specific site of action. In the case of antitumor therapy, association of the therapeutic agent with a carrier system can minimize damage to healthy, nontarget tissues, while limit systemic release and promoting long circulation to enhance uptake at the cancerous site due to the enhanced permeation and retention effect (EPR). Stimuli-responsive systems have become a promising way to deliver and release payloads in a site-selective manner. Potential carrier systems have been derived from a wide variety of materials, including inorganic nanoparticles, lipids, and polymers that have been imbued with stimuli-sensitive properties to accomplish triggered release based on an environmental cue. The unique features in the tumor microenvironment can serve as an endogenous stimulus (pH, redox potential, or unique enzymatic activity) or the locus of an applied external stimulus (heat or light) to trigger the controlled release of API. In liposomal carrier systems triggered release is generally based on the principle of membrane destabilization from local defects within bilayer membranes to effect release of liposome-entrapped drugs. This review focuses on the literature appearing between November 2008-February 2016 that reports new developments in stimuli-sensitive liposomal drug delivery strategies using pH change, enzyme transformation, redox reactions, and photochemical mechanisms of activation. WIREs Nanomed Nanobiotechnol 2017, 9:e1450. doi: 10.1002/wnan.1450 For further resources related to this article, please visit the WIREs website.

СУЧАСНИЙ СТАН СТВОРЕННЯ, ВИРОБНИЦТВА ТА ДОСЛІДЖЕННЯ ТАБЛЕТОВАНИХ ЛІКАРСЬКИХ ПРЕПАРАТІВ. Повідомлення 26. Таблетки для розжовування: характеристика, класифікація, методи одержання, допоміжні речовини при виробництві таблеток для розжовування

У статті наведено результати літературного огляду щодо особливостей виробництва таблеток для розжовування.

The evaluation of physical properties of injection molded systems based on poly(ethylene oxide) (PEO)

The effect of product design parameters on the formation and properties of an injection molded solid dosage form consisting of poly(ethylene oxide)s (PEO) and two different active pharmaceutical ingredients (APIs) was studied. The product design parameters explored were melting temperature and the duration of melting, API loading degree and the molecular weight (Mw) of PEO. The solid form composition of the model APIs, theophylline and carbamazepine, was of specific interest, and its possible impact on the in vitro drug release behavior.Mw of PEO had the greatest impact on the release rate of both APIs. High Mw resulted in slower API release rate. Process temperature had two-fold effect with PEO 300,000g/mol. Firstly, higher process temperature transformed the crystalline part of the polymer into metastable folded form (more folded crystalline regions) and less into the more stable extended form (more extended crystalline regions), which lead to enhanced theophylline release rate. Secondly, the higher process temperature seemed to induce carbamazepine polymorphic transformation from p-monoclinic form III (carbamazepine (M)) into trigonal form II (carbamazepine (T)). The results indicated that the actual content of carbamazepine (T) affected drug release behavior more than the magnitude of transformation.

Regenerated cellulose capsules for controlled drug delivery: Part IV. In-vitro evaluation of novel self-pore forming regenerated cellulose capsules

In the present work, the release mechanisms of active pharmaceutical ingredients (APIs) enclosed in self-pore forming regenerated cellulose (RC) two-piece hard shell capsules are described. The RC capsules were fabricated using a modified dip-coating approach, which yielded an assembled dosage form that was equivalent in size and shape to a conventional gelatin two-piece hard shell capsule. Drug release characteristics from RC capsules were evaluated using potassium chloride, diphenhydramine hydrochloride, tramadol hydrochloride, niacinamide, acetaminophen and ketoprofen as model APIs. The RC capsules act as a barrier coated reservoir device that releases the enclosed API at a zero order release rate. When comparing all the API's release behavior from RC capsules, a power-law relationship was observed between their zero-order release rates and their respective aqueous solubilities. Osmotic as well as diffusive mechanisms are involved in the release of the enclosed API. The osmotic mechanism's contribution to zero order release rate increases as the aqueous solubility of the tested APIs inside the capsule increases. The osmotic mediated flux and the apparent diffusivity of the APIs through the capsule wall is a competitive process and the osmotic mediated flux of the enclosed API begins to override its diffusivity through the capsule wall as the API solubility increases. This behavior is attributed to the wide range of pore sizes observed in RC membranes, from our prior analysis. The fluid permeability analysis shows that the RC capsules presented in this work may be better suited for osmotic drug delivery applications than conventional encapsulated systems described in the literature.

СУЧАСНИЙ СТАН СТВОРЕННЯ, ВИРОБНИЦТВА ТА ДОСЛІДЖЕННЯ ТАБЛЕТОВАНИХ ЛІКАРСЬКИХ ПРЕПАРАТІВ. Повідомлення 24. Осмотичні системи вивільнення та доставки лікарських речовин: розробка, характеристика та їх класифікація

Проведено огляд літературних джерел щодо розробки та дослідження осмотичних систем вивільнення та доставки лікарських речовин

Practices of pharmaceutical waste generation and discarding in households across Portugal.

This work is the first nationwide study in Portugal on pharmaceutical waste generated at households, exploring people's attitudes and risk perception. The waste audit was carried out from September to November 2014, targeting pharmaceutical products kept by a sample of families (n = 244). This campaign was an assignment of VALORMED, the non-profit association that manages waste and packaging from expired and unused pharmaceutical products collected by the pharmacies. On average, each household kept at home 1097 g of pharmaceutical products, of which 20% were in use, 72% were not in use, and 8% were mostly expired products ready to discard. Face-to-face interviews with householders showed that 69% of the respondents claimed returning pharmaceutical waste to the local pharmacy. However, this figure is overrated, probably owing to a possible 'good answer' effect. The barriers identified to proper disposal were mainly established routines and lack of close disposal points. This study also provides an insight into the Portuguese awareness and daily practices concerning pharmaceutical waste, which is the cornerstone of any future strategy to reduce the release of active pharmaceutical ingredients into ecosystems.

Tracking immune-related cell responses to drug delivery microparticles in 3D dense collagen matrix

Beyond the therapeutic purpose, the impact of drug delivery microparticles on the local tissue and inflammatory responses remains to be further elucidated specifically for reactions mediated by the host immune cells. Such immediate and prolonged reactions may adversely influence the release efficacy and intended therapeutic pathway. The lack of suitable in vitro platforms limits our ability to gain insight into the nature of immune responses at a single cell level. In order to establish an in vitro 3D system mimicking the connective host tissue counterpart, we utilized reproducible, compressed, rat-tail collagen polymerized matrices. THP1 cells (human acute monocytic leukaemia cells) differentiated into macrophage-like cells were chosen as cell model and their functionality was retained in the dense rat-tail collagen matrix. Placebo microparticles were later combined in the immune cell seeded system during collagen polymerization and secreted pro-inflammatory factors: TNFα and IL-8 were used as immune response readout (ELISA). Our data showed an elevated TNFα and IL-8 secretion by macrophage THP1 cells indicating that Placebo microparticles trigger certain immune cell responses under 3D in vivo like conditions. Furthermore, we have shown that the system is sensitive to measure the differences in THP1 macrophage pro-inflammatory responses to Active Pharmaceutical Ingredient (API) microparticles with different API release kinetics. We have successfully developed a tissue-like, advanced, in vitro system enabling selective “readouts” of specific responses of immune-related cells. Such system may provide the basis of an advanced toolbox enabling systemic evaluation and prediction of in vivo microparticle reactions on human immune-related cells.

A novel in situ hydrophobic ion pairing (HIP) formulation strategy for clinical product selection of a nanoparticle drug delivery system

The present studies were aimed at formulating AZD2811-loaded polylactic acid–polyethylene glycol (PLA–PEG) nanoparticles with adjustable release rates without altering the chemical structures of the polymer or active pharmaceutical ingredient (API). This was accomplished through the use of a hydrophobic ion pairing approach. A series of AZD2811-containing nanoparticles with a variety of hydrophobic counterions including oleic acid, 1-hydroxy-2-naphthoic acid, cholic acid, deoxycholic acid, dioctylsulfosuccinic acid, and pamoic acid is described. The hydrophobicity of AZD2811 was increased through formation of ion pairs with these hydrophobic counterions, producing nanoparticles with exceptionally high drug loading—up to five fold higher encapsulation efficiency and drug loading compared to nanoparticles made without hydrophobic ion pairs. Furthermore, the rate at which the drug was released from the nanoparticles could be controlled by employing counterions with various hydrophobicities and structures, resulting in release half-lives ranging from about 2 to 120h using the same polymer, nanoparticle size, and nanoemulsion process. Process recipe variables affecting drug load and release rate were identified, including pH and molarity of quench buffer.Ion pair formation between AZD2811 and pamoic acid as a model counterion was investigated using solubility enhancement as well as nuclear magnetic resonance spectroscopy to demonstrate solution-state interactions. Further evidence for an ion pairing mechanism of controlled release was provided through the measurement of API and counterion release profiles using high-performance liquid chromatography, which had stoichiometric relationships. Finally, Raman spectra of an AZD2811-pamoate salt compared well with those of the formulated nanoparticles, while single components (AZD2811, pamoic acid) alone did not.A library of AZD2811 batches was created for analytical and preclinical characterization. Dramatically improved preclinical efficacy and tolerability data were generated for the pamoic acid lead formulation, which has been selected for evaluation in a Phase 1 clinical trial (ClinicalTrials.gov Identifier NCT 02579226). This work clearly demonstrates the importance of assessing a wide range of drug release rates during formulation screening as a critical step for new drug product development, and how utilizing hydrophobic ion pairing enabled this promising nanoparticle formulation to proceed into clinical development.

In response: Government perspective.

In response: Government perspective.

РОЗРОБКА СКЛАДУ НОВОГО ЛІКАРСЬКОГО ЗАСОБУ ДЛЯ МІСЦЕВОГО ЛІКУВАННЯ МІКОЗУ СТОП У ФОРМІ РІДКОГО ПЛАСТИРУ

<p>DEVELOPMENT OF COMPOSITION OF NEW DRUG PRODUCT FOR TOPICAL TREATMENT OF FOOT MYCOSIS IN THE FORM OF LIQUID PLASTER<br />O.O. Vashchenko<br />Danylo Halytsky Lviv National Medical University, Lviv<br />Summary: The article represents a brief description of liquid plasters as a dosage form and their advantages compared to other dosage forms for cutaneous application. The results of investigations on the pharmaceutical development of the liquid plaster for topical treatment of foot mycosis are shown. Terbinafine hydrochloride was selected as an active pharmaceutical ingredient. Cellulose acetate butyrate, propylene glycol and ethyl acetate were used to prepare the plaster base. <br />Key words: foot mycosis, liquid plaster, terbinafine hydrochloride.<br />Introduction. Fungal infections occupy a dominant position in the structure of skin diseases. Foot mycoses are among the most common types of skin mycoses. Despite the wide arsenal of antifungal drugs, the incidence of mycoses has not reduced. However, the opposite effect is observed: there is a tendency for the formation of the resistant forms of fungal infections, the increasing of their invasiveness, and the decreasing of macroorganism’s resistance. Therefore, the search for new antifungal agents and the development of new highly efficient preparations is a well justified task.<br />Promising direction in the treatment of foot mycosis is the introduction of drug products in the new dosage forms, i.e. in the form of liquid plasters (LP), into the pharmaceutical and medical practice.<br />Methods: informative (search, analysis and systematization of the information); physical and physical-chemical (appearance of LP and film, solubility, film thickness); pharmacotechnological (drying time and adhesion of film); mathematical (statistical data processing).<br />Results and discussion. Application of drug products in the form of LP for topical treatment of foot mycosis is a far-reaching therapeutic approach. LP compared to other dosage forms for cutaneous application has the following advantages: it is applied directly into the affected area; it provides a prolonged release of active pharmaceutical ingredient (API); increasing of API concentration in the film after the solvent evaporation gives rise to a concentration gradient and enhances the drug penetration into the skin; a formed film acts as a barrier to reinfection and restricts the spread of fungal cells. <br />Terbinafine hydrochloride in the concentration of 1 % was chosen as an API for the pharmaceutical development of LP for treatment of foot mycosis. It is a broad spectrum antifungal agent that also exhibits antibacterial activity. Terbinafine hydrochloride is a highly lipophilic and keratophilic drug and distributes in high concentrations into the skin and nails. <br />The quality and efficacy of drug product depends not only on the API, but also the performance of excipients. Excipients used in the formulation of LP should provide the homogeneity of solution and the formation of a uniform elastic film with good adhesive properties after the solvent evaporation. <br />Based on the results of investigations, the following excipients in the quantities needed to achieve the desired quality parameters of drug product were selected for the development of antifungal LP: cellulose acetate butyrate (film-forming agent), propylene glycol (plasticizer with penetrating properties), ethyl acetate (solvent). <br />Conclusions. Treatment of foot mycosis is a significant problem of the current healthcare system. The introduction of new drug products in various dosage forms, particularly in the form of LP, is a promising solution to the problem. To that end, composition of antifungal LP with terbinafine hydrochloride was theoretically and experimentally substantiated.</p>

ВПЛИВ РОЗЧИННИХ НАПОВНЮВАЧІВ ІЗ РІЗНИМ РОЗМІРОМ ЧАСТОК НА КІНЕТИКУ ВИВІЛЬНЕННЯ ТРИМЕТАЗИДИНУ ДИГІДРОХЛОРИДУ IN VITRO З МАТРИЧНИХ ТАБЛЕТОК

<p><strong>EFFECT OF SOLUBLE DILUENTS WITH DIFFERENT PARTICLE SIZE ON DISSOLUTION PROFILE OF TRIMETAZIDINE DIHYDROCHLORIDE FROM MATRIX TABLETS</strong></p><p><strong>V. V. Mohylyuk, L. L. Davtian </strong></p><p>ShupykNationalMedicalAcademyof Postgraduate Education, Kyiv</p><p><strong>Summary: </strong>The effect of soluble diluent lactose monohydrate and sorbitol with average particle size 11, 17, 251 and 110, 299, 531 µm, respectively, on dissolution profile of trimetazidine dihydrochloride model substance from matrix tablets with insoluble and unswellable Ethocel 10, insoluble and swellable Kollidon SR, soluble and swellable Methocel K4M as matrix formers was investigated. The effect of soluble diluents particle size on drug release from matrix tablets with different matrix formers was established and explained.<strong></strong></p><p><strong>Key words: </strong>matrix tablet, Ethocel, Kollidon SR, Methocel K, sorbitol, lactose.</p><p><strong>Introduction. </strong>Oral matrix tablets are the modern dosage forms using which could be achieved desirable in vitro release kinetics of active pharmaceutical ingredient (API) and correspondent in vivo concentration level. That’s why the study of factors that affect in vitro dissolution release of API is an actual task and the effect of diluents particle size is one of these factors. There are two main types of matrix systems with different mechanism of soluble components release: with soluble matrix former that is forming the gel layer on the surface of matrix and with insoluble matrix former. The aim of this study is to investigate the effect of diluent’s particle size on dissolution profile of trimetazidine dihydrochloride from matrix tablets with insoluble and unswellable Ethocel 10, insoluble and swellable Kollidon SR, soluble and swellable Methocel K4M as matrix formers.</p><p><strong>Methods.</strong> Particle size distribution measurement by the laser scattering method, tablet manufacturing using direct compression method for more predictable tablet structure, dissolution test and matrix tablets structure evaluation by optical microscopy were used for experiment.</p><p><strong>Results and discussion.</strong> On a more detailed level tablet components form clusters. These clusters have a specific structure that is depending on the number, size, shape, volume ratio of the components and the method of tablets manufacture. Soluble sorbitol and less soluble lactose monohydrate were used for experiment. The drug release from Ethocel 10 matrix was decreased with diluents particle size increasing. The drug release from Kollidon SR matrix was decreased with soluble diluents particle size increasing from 17 to 110 µm and follow particle size increasing from 110 to 513 µm almost hadn’t affect. Diluents particle size almost hadn’t effect on drag release from Methocel K4M matrix tablets too. The effect of diluents particle size increasing on release from insoluble unswellable Ethocel 10 and insoluble swellable Kollidon SR matrices could be explained from position of percolation theory by more isolated clusters formation and porosity decreasing. The almost absence of diluents particle size effect on drug release from soluble swellable Methocel K4M matrix could be explained by diffusion mechanism predominance. The release of trimetazidine dihydrochloride (340 g/ml) from Ethocel 10, Kollidon SR and Methocel K4M matrix tablets was faster when used sorbitol (>4000 g/ml) than lactose monohydrate (210 g/ml). This result is consistent with the higher solubility of sorbitol in comparison with lactose monohydrate.</p><p><strong>Conclusions.</strong> Decreasing of trimetazidine dihydrochloride dissolution kinetics from Ethocel 10 matrix tablets with lactose and sorbitol particle size increasing was established. The dissolution kinetics from Kollidon SR matrix tablets was decreased with soluble diluent particle size increasing from 17 to 110 µm, but sorbitol particle size increasing from 110 to 513 µm had no effect on dissolution profile. Particle size of soluble diluents had no significant effect on dissolution kinetics from Methocel K4M matrix tablets. The dissolution kinetics from tablets with Ethocel 10, Kollidon SR and Methocel K4 as matrix formers was decreased with diluent solubility decreasing.</p>

Self-assembled sorbitol-derived supramolecular hydrogels for the controlled encapsulation and release of active pharmaceutical ingredients.

A simple supramolecular hydrogel based on 1,3:2,4-di(4-acylhydrazide)benzylidene sorbitol (DBS-CONHNH2), is able to extract acid-functionalised anti-inflammatory drugs via directed interactions with the self-assembled gel nanofibres. Two-component hydrogel-drug hybrid materials can be easily formed by mixing and exhibit pH-controlled drug release.

In vivo evaluation of different formulation strategies for sustained release injectables of a poorly soluble HIV protease inhibitor

At present no scientific rationale exists for selecting a particular enabling strategy to formulate a poorly water-soluble drug, although this is crucial as it will influence the in vivo performance of the resulting formulation. This study provides an insight into this complicated decision making process for a poorly soluble human immunodeficiency virus (HIV) protease inhibitor based upon in vivo test results. A formulation strategy based on the molecular dispersion of this active pharmaceutical ingredient (API) into a biphasic matrix consisting of water-insoluble poly(lactic-co-glycolic acid) (PLGA) and water-soluble polyvinylpyrrolidone (PVP) was evaluated. The long-term in vivo performance of this strategy was compared to that of other solubility enhancing approaches by evaluating exposure of the API in male Beagle dogs. Solid dispersions, based on a PLGA/PVP matrix, were compared to solid dispersions in a pure PLGA matrix. Additionally these solid dispersion strategies were compared to the strategy of particle size reduction by means of an API microsuspension. The in vivo performance of the various formulations over a period of 28days after intramuscular injection was evaluated by the observed initial burst release, plasma concentration-time profiles, time at which maximum plasma levels were reached and the estimated bioavailability. Compared to the other formulation strategies assessed, it was concluded that the addition of PVP in a PLGA matrix resulted in vivo in a more sustained release as well as a higher amount of drug released from the polymeric matrix. This was explained based on the structure of these binary PLGA/PVP matrices where the pore network originating from rapidly dissolving PVP plays a key role. Moreover, the results suggest that the API release from this type of formulation could be delayed by increasing the amount of PLGA in the formulation.

Comparison of film-coated retarded release pellets manufactured by layering technique or by bed rotor pelletization

In order to investigate the influence of coatings for controlled active pharmaceutical ingredient (API) release, two types of pellets were used. Microcrystalline pellets were coated with a model API using the Wurster fluidized bed technique in laboratory scale (layered Cellets). Another type of pellets consisting of microcrystalline cellulose and model API was manufactured by fluidized bed rotor pelletization (matrix pellets (MP)). Both kinds of pellets were coated in a Wurster fluidized bed process with a polymer mixture of ethylcellulose to achieve retarded API release. With layered Cellets and an increased thickness of the ethylcellulose layer, the lag-time was increased and the release rate was decreased. In the case of MP, retardation was less pronounced probable due to inhomogeneous polymer film formation as a result of the porous particle surface. To reduce the surface roughness, the MP were coated with polyvinylpyrrolidone (PVP) as an intermediate smoothing layer, in a first trial step by step. In a second trial, pelletization and the coating steps were performed in an uninterrupted process. Intermediate PVP coating improved the ethylcellulose film formation and led to a more pronounced retardation of API release. The uninterrupted process of matrix pellet manufacturing and coating results in a product with only low retarded release.

Cubic and hexagonal liquid crystals as drug delivery systems.

Lipids have been widely used as main constituents in various drug delivery systems, such as liposomes, solid lipid nanoparticles, nanostructured lipid carriers, and lipid-based lyotropic liquid crystals. Among them, lipid-based lyotropic liquid crystals have highly ordered, thermodynamically stable internal nanostructure, thereby offering the potential as a sustained drug release matrix. The intricate nanostructures of the cubic phase and hexagonal phase have been shown to provide diffusion controlled release of active pharmaceutical ingredients with a wide range of molecular weights and polarities. In addition, the biodegradable and biocompatible nature of lipids demonstrates the minimum toxicity and thus they are used for various routes of administration. Therefore, the research on lipid-based lyotropic liquid crystalline phases has attracted a lot of attention in recent years. This review will provide an overview of the lipids used to prepare cubic phase and hexagonal phase at physiological temperature, as well as the influencing factors on the phase transition of liquid crystals. In particular, the most current research progresses on cubic and hexagonal phases as drug delivery systems will be discussed.

Optimization and control of crystal shape and size in protein crystallization process

Large molecule protein crystals have shown significant benefits in the delivery of biopharmaceuticals to achieve high stability, high concentration of active pharmaceutical ingredients (API), and controlled release of API. However, among the about 150 biopharmaceuticals on the market by 2004, only insulin has been marketed in crystalline form. A major technological challenge is that protein crystallization has a very complicated environment and is affected by many factors. There is currently a lack of knowledge on large scale production of protein crystals. In contrast to the majority of previous work on protein crystallization that was centered on single crystal scale, the current research is focused on computational study of protein crystallization at process scale, investigating the growth behavior of a population of crystals in a crystallizer. Using a newly developed morphological population balance model that can simulate the multidimensional size distributions of a population of crystals, known as shape distribution, an optimization technique is applied to optimize the growth of individual faces with the aim of obtaining desired crystal shape and size distributions. Using a target shape as the objective function, optimal temperature and supersaturation profiles leading to the desired crystal shape were derived. Genetic algorithm was investigated and found to be an effective optimization technique for the current application. Since tracking an optimum temperature or supersaturation trajectory can be easily implemented by manipulating the coolant flowrate in the reactor jacket, the methodology provides a feasible closed-loop mechanism for protein crystal shape tailoring and control.

Recent Advances in Pulsatile Oral Drug Delivery Systems

It is well established that several diseases exhibit circadian behavior, following the relevant rhythm of the physiological functions of the human body. Their study falls in the fields of chronobiology and chronotherapeutics, the latter being essentially the effort of timely matching the treatment with the disease expression, in order to maximize the therapeutic benefits and minimize side effects. Pulsatile drug delivery is one of the pillars of chronopharmaceutics, achieved through dosage form design that allows programmable release of active pharmaceutical ingredients (APIs) to follow the disease's time profile. Its major characteristic is the presence of lag phases, followed by drug release in a variety of rates, immediate, repeated or controlled. The scope of this review is to summarize the recent literature on pulsatile oral drug delivery systems and provide an overview of the ready to use solutions and early stage technologies, focusing on the awarded and pending patents in this technical field during the last few years.

One-Step Preparation of Poly-Lactic-Co-Glycolic-Acid Microparticles to Prevent the Initial Burst Release of Encapsulated Water-Soluble Proteins

An initial burst is often observed during the release of active pharmaceutical ingredients (APIs) from poly-lactic-coglycolic-acid (PLGA) microparticles (MPs) which have been prepared by the emulsion-solvent evaporation method. Herein, we describe the development of a simple one-step coating method that suppresses the initial burst release process. This new method involves coating the PLGA-MPs with PLGA, with the coating process being performed through the phase separation of PLGA on the surface of PLGA-MPs using the emulsion-solvent evaporation method. Bovine serum albumin (BSA) was encapsulated in the PLGA-MPs as a model API. The coated MPs were spherical in shape with no pores on their smooth surface, whereas the non-coated PLGA-MPs had porous surfaces. An in vitro release study showed that the residual levels of BSA in the coated and non-coated PLGA-MPs after 1 h were about 99% and 16% of the original loads, respectively. The one-step coating method therefore represents a useful method for preparing PLGA-MPs that do not give an initial burst release of proteinaceous APIs.