Effect of hydroxy propyl cellulose grade and foam quality on foam granulation of a high drug load formulation.

Foam granulation is a relatively newer wet granulation process whereby foamed binder solutions are added to the powders in the mixer to reduce localized over-wetting encountered during the wet granulation. This study is the first to investigate the effect of binder grade and foam quality on foam granulation process and granule properties of a high drug load formulation. Two different HPC grades, HPC LF (two times more viscous) and HPC EXF at an equivalent 7.4%w/w solution concentration, and foam quality of 50%, 90% and binder solution dripped were added to a high drug load (81%w/w) formulation for wet granulation. The granules were evaluated for compactibility and resultant compact strengths. The 50% foam quality of either HPC LF and HPC EXF resulted in lowest impeller power reading and water activity compared to 90% foam quality or dripped HPC solution. Granules prepared with 50% foam quality also exhibited smaller granule size, wider size distribution and higher specific surface area, resulting in higher compactibility. Whilst the granules prepared with different foamed HPC grades were not significantly different in compression behavior, they were higher in compact strengths, suggesting that foam mixing was more efficient in binder distribution compared to binder liquid penetration and distribution.

The Impact of Disintegrant Type, Surfactant, and API Properties on the Processability and Performance of Roller Compacted Formulations of Acetaminophen and Aspirin.

In formulation development, certain excipients, even though used in small quantities, can have a significant impact on the processability and performance of the dosage form. In this study, three common disintegrants, croscarmellose sodium (CCS), crospovidone (xPVP), and sodium starch glycolate (SSG) as well as the surfactant sodium lauryl sulfate (SLS) were evaluated for their impact on the processability and performance of a typical dry granulation formulation. Two model compounds, the mechanically brittle and chemically inert acetaminophen and the mechanically ductile carboxylic acid aspirin, were used for the evaluation. It was found that the disintegrants were generally identical in their impact on the processability and little difference was observed in the granulation and compression processes. The exception is that when xPVP was used in the formulation of the brittle acetaminophen, lower compression forces were needed to reach the same tablet hardness, suggesting a binding effect of xPVP for such systems. In general, CCS and xPVP tend to provide slightly better disintegration than SSG. However, in the case of aspirin, a strong hydrogen bonding interaction between the carboxylic acid group of aspirin and the carbonyl group of xPVP was observed, resulting in slower release of the drug after fast disintegration. SLS was found to have a significant impact on the processability due to its lubricating effect, resulting in higher compression forces needed to achieve the target tablet hardness. Due to the higher degree of compression, the disintegration and dissolution of both drugs became slower despite the wetting effect of SLS.

Mitigation of Adverse Clinical Events of a Narrow Target Therapeutic Index Compound through Modified Release Formulation Design: An in Vitro, in Vivo, in Silico, and Clinical Pharmacokinetic Analysis.

BMS-914392 is a tricyclic pyranoquinoline BCS class 2 weak base that demonstrates high solubility in low pH environments. Initial clinical studies indicated that rapid release of high dose BMS-914392 led to transient adverse events associated with peak plasma concentrations. A modified release (MR) formulation strategy was proposed to suppress the peak blood concentration and maintain total exposure to overcome the adverse effects. Three modified release prototype formulations were developed and tested via a USP 3 dissolution method to verify that each formulation can effectively slow the release of BMS-914392. A pharmacokinetic (PK) absorption model was employed to guide the formulation development and selection. Simulations showed good agreement with plasma levels measured after oral dosing in dogs. Identification of key formulation factors to achieve release rates suitable for blunting peak blood levels without diminishing exposure were achieved through combined preclinical data and use of GastroPlus simulations. PK absorption model refinements based on phase 1 data, dog pharmacokinetic results, and in vitro data provided reliable predictions of human absorption profiles and variability in patients. All three prototype formulations demonstrated lower maximum plasma concentrations of BMS-914392 and maintained satisfactory relative bioavailability. Both the PK absorption model and subsequent clinical data indicated that an acidified hydrophilic matrix MR formulation had the greatest potential to reduce the incidence of adverse events and showed the best exposure profile in fasted state healthy subjects with and without famotidine coadministration. The risk based development process achieved successful screening and selection of a suitable modified release formulation to enable clinical efficacy trials.

Nanomedicines for inflammatory diseases.

Inflammation is the body's natural defense mechanism in response to many diseases including infection, cancer, and autoimmune disease. Since the birth of nanotechnology at the end of the twentieth century, scientists have been utilizing the pathophysiologic features of inflammation, mainly leaky vasculature and the overexpression of biomarkers, to design nanomedicines that can deliver drugs with passive and active targeting mechanisms to inflamed tissue sites and achieve effective therapy. Recent advances in nanomedicine research have provided scientists with nanocarriers of many unique and tunable properties to match the specific requirements for the treatment of different inflammatory disease conditions. In this chapter, we describe some of the materials and methods used in the preparation and characterization of these nanomedicines, approaches used for the evaluation of their efficacy on a cellular and organ level, as well as available animal models. We also show how safety and biodistribution studies using anti-inflammatory nanomedicines are conducted in our laboratory for the treatment of rheumatoid arthritis animal models.

Effect of powder substrate on foaml drainage and collapse: implications to foam granulation.

Foam granulation is a relatively newer wet granulation process whereby foamed binder solutions are added to powders in a mixer. It is essential to understand the effect of powder substrate on foam drainage and half-life, which are relevant to nucleation and agglomeration during foam granulation. Hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) foams were characterized. Anhydrous lactose and stearic acid were selected as model soluble and insoluble substrates, respectively. The effect of these substrates on foam stability was measured by foam drainage and collapse time and microscopic observations. Both HPMC and HPC foams were similar in foam quality and foam density. Lactose destabilized both HPMC and HPC foams and foam drainage and collapse times were reduced two to four times in the presence of lactose. On the contrary, stearic acid did not significantly change foam drainage and collapse times. Microscopically, lactose exhibited rapid wetting within 15 s upon contacting the HPMC and HPC foam beds, whereas stearic acid remained unwetted even after 8 min and collapse of the foam beds. Substrate solubility can influence foam-substrate interaction. On the basis of this, we suggest potential mechanisms of nucleation and agglomeration of soluble and insoluble substrates during foam granulation.

Investigation into stability of poly(vinyl alcohol)-based Opadry® II films.

Poly(vinyl alcohol) (PVA)-based formulations are used for pharmaceutical tablet coating with numerous advantages. Our objective is to study the stability of PVA-based coating films in the presence of acidic additives, alkaline additives, and various common impurities typically found in tablet formulations. Opadry® II 85F was used as the model PVA-based coating formulation. The additives and impurities were incorporated into the polymer suspension prior to film casting. Control and test films were analyzed before and after exposure to 40°C/75% relative humidity. Tests included film disintegration, size-exclusion chromatography, thermal analysis, and microscopy. Under stressed conditions, acidic additives (hydrochloric acid (HCl) and ammonium bisulfate (NH(4)HSO(4))) negatively impacted Opadry® II 85F film disintegration while NaOH, formaldehyde, and peroxide did not. Absence of PVA species from the disintegration media corresponded to an increase in crystallinity of PVA for reacted films containing HCl. Films with NH(4)HSO(4) exhibited slower rate of reactivity and less elevation in melting temperature with no clear change in melting enthalpy. Acidic additives posed greater risk of compromise in disintegration of PVA-based coatings than alkaline or common impurities. The mechanism of acid-induced reactivity due to the presence of acidic salts (HCl vs. NH(4)HSO(4)) may be different.

Case studies with new excipients: development, implementation and regulatory approval.

The purpose of this article is to describe the process whereby new excipients become accepted and to describe three case studies to illustrate the process. New excipients are defined according to the 2005 FDA Guidance on Nonclinical Safety Evaluation of New Excipients. The requirements for safety data submission for new excipients used in different classes of products for different durations are outlined in the guidance. Currently, the development of new excipients is linked to the development and approval of new drug products that contain them. New excipients that are used in US-approved drug products become listed in the FDA Inactive Ingredients Guide (IIG) database. Thereafter, US Pharmacopeia monographs for the new excipients are proposed. New excipients are reviewed and become accepted in the same way in Europe and Japan, except that there is no equivalent IIG database. Therefore, the focus of this article will be on the FDA review process. Three case studies, polyoxyl 15 hydroxystearate, sulfobutyl ether cyclodextrin and silicified microcrystalline cellulose, are used to illustrate how new excipients are accepted and implemented.

Actively targeted low-dose camptothecin as a safe, long-acting, disease-modifying nanomedicine for rheumatoid arthritis.

PURPOSE: Camptothecin (CPT), a potent topoisomerase I inhibitor, was originally discovered as an anticancer agent to induce programmed cell death of cancer cells. Recent evidence suggests that, similar to cancer, alterations in apoptosis and over-proliferation of key effector cells in the arthritic joint result in rheumatoid arthritis (RA) pathogenesis. Initial in vitro studies have suggested that camptothecin inhibits synoviocyte proliferation, matrix metalloproteinases expression in chrondrocytes and angiogenesis. This study is one of the first to test, in vivo, RA as a new indication for CPT. METHODS: To circumvent insolubility, instability and toxicity of CPT, we used biocompatible, biodegradable and targeted sterically stabilized micelles (SSM) as nanocarriers for CPT (CPT-SSM). We also surface-modified CPT-SSM with vasoactive intestinal peptide (VIP) for active targeting. We then determined whether this nanomedicine abrogated collagen-induced arthritis (CIA) in mice. RESULTS: Based on our findings, this is the first study to report that CPT was found to be efficacious against CIA at concentrations significantly lower than usual anti-cancer dose. Furthermore, a single subcutaneous injection of CPT-SSM-VIP (0.1 mg/kg) administered to CIA mice mitigated joint inflammation for at least 32 days thereafter without systemic toxicity. CPT alone needed at least 10-fold higher dose to achieve the same effect, albeit with some vacuolization in liver histology. CONCLUSION: We propose that CPT-SSM-VIP is a promising targeted nanomedicine and should be further developed as a safe, long-acting, disease-modifying pharmaceutical product for RA.

Use of cyclodextrins as a cosmetic delivery system for fragrance materials: linalool and benzyl acetate.

The aim of this study was to increase the stability and water solubility of fragrance materials, to provide controlled release of these compounds, and to convert these substances from liquid to powder form by preparing their inclusion complexes with cyclodextrins (CDs). For this purpose, linalool and benzyl acetate were chosen as the fragrance materials. The use of beta-cyclodextrin (beta CD) and 2-hydroxypropyl-beta-cyclodextrin (2-HP beta CD) for increasing the solubility of these 2 fragrance materials was studied. Linalool and benzyl acetate gave a B-type diagram with beta CD, whereas they gave an A(L)-type diagram with 2-HP beta CD. Therefore, complexes of fragrance materials with 2-HP beta CD at 1:1 and 1:2 molar ratios (guest:host) were prepared. The formation of inclusion complexes was confirmed using proton nuclear magnetic resonance ((1)H-NMR) spectroscopy and circular dichroism spectroscopy. The results of the solubility studies showed that preparing the inclusion complex with 2-HP beta CD at a 1:1 molar ratio increased the solubility of linalool 5.9-fold and that of benzyl acetate 4.2-fold, whereas the complexes at a 1:2 molar ratio increased the solubility 6.4- and 4.5-fold for linalool and benzyl acetate, respectively. The stability and in vitro release studies were performed on the gel formulations prepared using uncomplexed fragrance materials or inclusion complexes of fragrance materials at a 1:1 molar ratio. It was observed that the volatility of both fragrance materials was decreased by preparing the inclusion complexes with 2-HP beta CD. Also, in vitro release data indicated that controlled release of fragrances could be possible if inclusion complexes were prepared.

Camptothecin in sterically stabilized phospholipid nano-micelles: a novel solvent pH change solubilization method.

Camptothecin (CPT) is a topoisomerase I inhibitor that acts against a broad spectrum of cancers. Unfortunately clinical application of CPT is limited by insolubility, instability, and toxicity problems. To circumvent these delivery problems of CPT, we propose biocompatible, targeted sterically stabilized micelles (SSM) as nanocarriers for CPT (CPT-SSM). SSM composed of polyethylene glycol (PEGylated) phospholipids are attractive nanocarriers for CPT delivery because they are sufficiently small to extravasate through the leaky microvasculature of tumor and inflamed tissues for passive targeting. The purpose of this study was to develop a novel method of preparing CPT-SSM based on its pH dependent, reversible carboxylate-lactone conversion chemistry. CPT carboxylate was added to SSM at pH 5 that favored the formation of active but hydrophobic CPT lactone for spontaneous association with SSM. The kinetics of CPT conversion and CPT-SSM formation, and the effect of varying CPT-PEGylated phospholipid molar ratio on CPT-SSM properties and CPT solubilization were evaluated. CPT converted gradually from the carboxylate form to lactone, and CPT-SSM were formed after 12 h incubation. The mean size of CPT-SSM was approximately 14 nm. CPT solubilization (approximately 12 microg/ml) and other CPT-SSM micelle properties did not change significantly with increasing CPT to PEGylated hospholipid molar ratios using this novel method, unlike the coprecipitation/reconstitution technique previously reported. This reproducible CPT solubilization in SSM was attributed to avoidance of drug aggregate formation by this method. The advantages of our solvent pH change method to prepare CPT-SSM support further investigations of this approach to other hydrophobic drugs similar to CPT in chemistry and also CPT molecular solubilization in other nanocarriers.

Camptothecin in sterically stabilized phospholipid micelles: a novel nanomedicine.

BACKGROUND: Camptothecin (CPT) is a well-established topoisomerase I inhibitor against a broad spectrum of cancers. However, poor aqueous solubility, instability, and toxic effects to normal tissues have limited CPT clinical development. Recently, sterically stabilized micelles (SSM) composed of polyethylene glycol (PEGylated) phospholipids have been introduced as safe, biocompatible nanocarriers for the delivery of poorly water-soluble drugs. It was the aim of this study to develop and evaluate in vitro camptothecin-containing SSM (CPT-SSM) as a novel nanomedicine for parenteral administration. METHODS: The solubilization potential, stability, and in vitro cytotoxicity of CPT in SSM were studied. Lyophilization of CPT-SSM under controlled conditions was also studied. RESULTS: The mean size of CPT-SSM was found to be approximately 14 nm with a narrow size distribution. CPT-SSM were prepared by coprecipitation reconstitution. At a concentration of 15 mmol/L of PEGylated phospholipids where no micelle-micelle interaction was observed, CPT solubilization in SSM was 25-fold higher than CPT in buffer. We determined that CPT can be solubilized in SSM up to molar ratios of CPT/lipid = 0.0063:1. Above this critical molar ratio, heterogeneous systems of CPT-SSM and CPT self-aggregated particles were formed. CPT in SSM was at least 3 times more stable and 3-fold more cytotoxic to MCF-7 cells than CPT alone. Furthermore, CPT-SSM alone was lyophilized without additional lyoprotectants and cryoprotectants and reconstituted without any significant change in properties. CONCLUSION: We have shown that CPT in SSM is a promising nanomedicine with improved drug solubility, stability, freeze-drying properties, and anticancer activity. It is anticipated that, because of the nanosize and steric stability of the micelles, CPT-SSM will be passively targeted to solid cancers in vivo, resulting in high drug concentration in tumors and reduced drug toxicity to the normal tissues.

Role of nanotechnology in targeted drug delivery and imaging: a concise review.

The use of nanotechnology in drug delivery and imaging in vivo is a rapidly expanding field. The emphases of this review are on biophysical attributes of the drug delivery and imaging platforms as well as the biological aspects that enable targeting of these platforms to injured and diseased tissues and cells. The principles of passive and active targeting of nanosized carriers to inflamed and cancerous tissues with increased vascular leakiness, overexpression of specific epitopes, and cellular uptake of these nanoscale systems are discussed. Preparation methods-properties of nanoscale systems including liposomes, micelles, emulsions, nanoparticulates, and dendrimer nanocomposites, and clinical indications are outlined separately for drug delivery and imaging in vivo. Taken together, these relatively new and exciting data indicate that the future of nanomedicine is very promising, and that additional preclinical and clinical studies in relevant animal models and disease states, as well as long-term toxicity studies, should be conducted beyond the "proof-of-concept" stage. Large-scale manufacturing and costs of nanomedicines are also important issues to be addressed during development for clinical indications.