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• Personalized dose, formulations, and drug delivery systems based on individual needs in the future. • Pharmaceutical particle and formulation development by using digital design approaches. • Possibility of personalized pharmaceuticals by on-demand or additive manufacturing. • Importance of small-scale powder handling and precise prediction of powder properties. Particle/powder technology is used in the manufacture of many pharmaceutical products, and research on the physical properties of particles in the nano- to micro-particle range is important in the pharmaceutical field. The concept of precision medicine will require an increasing shift in pharmaceutical manufacturing toward the design of individualized products. This perspective article focuses on particle design and powder technology for advanced formulations that will be needed in the future for individualized drug formulations and on-demand production. Nanoparticles as drug carriers in drug delivery systems will require particle designs to meet the treatment requirements of individual patients with a particular disease. In pharmaceutical manufacturing, process intensification, such as continuous manufacturing and integrated drug production from drug synthesis to final formulation, has attracted increased attention. Digital design approaches, such as artificial intelligence based on computer-aided development, also will be increasingly used. Continuous production of pharmaceutical products enables downsizing of manufacturing equipment, and on-demand manufacturing equipment has been developed. In addition, additive manufacturing, such as 3D printing, is considered to be suitable for personalized formulations, and small-scale powder handling and predictive modeling of powder characterization will be important for individual preparations. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Permeation rate showed the affinity of porous carriers with various solvents. • Permeation rate was strongly affected by the viscosity of the solvent. • Liquid absorption experiment could predict the available intra-particle pore volume. • Efficiently drug loaded particles could be prepared based on the results. Abstract Porous materials are attractive substances for designing pharmaceutical particulates. However, understanding the behavior of liquid absorption into the intra-pores and interstices of porous carrier particles is important to effectively manufacture active pharmaceutical ingredients (APIs) using these carriers. In this study, we established a simple and practical method for evaluating the liquid absorption behavior of porous carriers using force tensiometry and a capillary rise technique. Different-sized tablets of porous materials were prepared and evaluated by this method using various solvents to estimate liquid absorption into the intra-particle pores and interstices of the particles. The amount of liquid trapped in the interstices of the particles decreased with decreasing tablet volume, after which the amount of liquid in the intra-particle pores could be estimated. Finally, API-loaded particles were prepared by absorbing the API solution into porous carriers based on the intra-capacity revealed above. No free API was found on the surface of the prepared particles, as it was well absorbed into the intra-particle pores. Collectively, this tensiometer method using different-sized tablets of porous materials appears to be a promising technique for evaluating the liquid absorption characteristics of porous pharmaceutical materials. [ABSTRACT FROM AUTHOR]

In this study, we demonstrated that cationic liposomes with incorporated stearylamine (SA) inhibit viral infectivity without preloaded active pharmaceutical ingredients. Specifically, we correlated physiochemical properties of liposomes, such as zeta potentials and particle sizes, with virus infectivity using the BacMam™ reagent, which is based on recombinant baculovirus (BV). Compared with neutral or negatively-charged liposomes, SA liposomes suppressed BV infectivity in several mammalian cell lines, including A549 cells. SA liposomes inhibited BV infection over 80% by optimizing the liposomal concentration and exposure time with cells. Moreover, these antiviral SA liposomes were not cytotoxic, and reducing the embedded cholesterol contents intensified the antiviral effects and simultaneously increased the binding of SA liposomes to the cell membranes. These data indicate that binding of SA liposomes to cell membranes may block virus entry. Finally, we also demonstrated the antiviral effects of SA liposomes on herpes simplex virus type 1 in A549 cells, and showed comparable efficacy to that of the antiviral drug acyclovir. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) is an anthracycline widely used for the treatment of solid and hematological tumors. The aim of this study was to assess the adverse event profiles of conventional DOX and liposomal DOX. This is the first study to evaluate the effect of a liposomal formulation of DOX using spontaneous reporting system (SRS) databases. The SRS used was the US Food and Drug Administration Adverse Event Reporting System (FAERS). This study relied on definitions of preferred terms provided by the Medical Dictionary for Regulatory Activities (MedDRA) and the standardized MedDRA Queries (SMQ) database. We also calculated the reporting odds ratios (RORs) of suspected drugs (conventional DOX; PEGylated-liposome DOX; non-PEGylated-liposome DOX). The FAERS database contained 7,561,254 reports from January 2004 to December 2015. The number of reported AE cases for conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX was 5039, 3780, and 349, respectively. Conventional DOX and liposomal DOX have potential risks of causing myelosuppression, cardiotoxicity, alopecia, nausea, and vomiting, among other effects. The RORs (95% CI) from SMQ for haematopoietic leucopenia associated with conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX were 12.75 (11.89–13.68), 6.43 (5.81–7.13), and 14.73 (11.42–18.99), respectively. Liposomal DOX formulations were associated with lower RORs with regard to myelosuppression, cardiotoxicity, and alopecia than the conventional DOX was. The RORs (95% CI) for palmar-plantar erythrodysesthesia (PPE) associated with conventional DOX, PEGylated-liposome DOX, and non-PEGylated-liposome DOX were 6.56 (4.74–9.07), 64.77 (56.84–73.80), and 28.76 (15.77–52.45), respectively. This study is the first to evaluate the relationship between DOX liposomal formulations and their adverse event profiles. The results indicate that careful observation for PPE is recommended with the use of liposomal DOX, especially PEGylated-liposome DOX formulations. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to enhance the dissolution and oral absorption of poorly water-soluble active pharmaceutical ingredients (APIs) using nanoparticle suspensions prepared with a PureNano™ continuous crystallizer (PCC). Method: Nanoparticle suspensions were prepared with a PCC, which is based on microfluidics reaction technology and solvent-antisolvent crystallization. Phenytoin, bezafibrate, flurbiprofen, and miconazole were used as model APIs. These APIs were dissolved in ethanol and precipitated by the addition of water and polyvinyl alcohol. Batch crystallization (BC) using a beaker was also performed to prepare the suspensions. Both PCC and BC formulations were freeze-dried before being characterized in vitro and in vivo. Results: The particle sizes of the nanoparticle suspensions prepared with the PCC were smaller than those prepared by BC. The dissolution rate of each API in vitro significantly increased after crystallization. Reducing the particle size of either the BC or PCC formulation led to increased API flux across Caco-2 cell monolayers. PCC preparations showed higher plasma concentrations after oral administration, demonstrating the advantages of a fast dissolution rate and increased interaction with the gastrointestinal tract owing to the smaller particle size. Conclusions: PCC can continuously produce nanoparticle APIs and is an efficient approach for improving their oral bioavailability. [ABSTRACT FROM AUTHOR]

Drug inhalation provides localized drug therapy for respiratory diseases. However, the therapeutic efficacy of inhaled drugs is limited by rapid clearance from the lungs. Small hydrophilic compounds have short half-lives to systemic absorption. We developed a liposomal formulation as a sustained-release strategy for pulmonary delivery of procaterol hydrochloride (PRO), a short-acting pulmonary β2-agonist for asthma treatment. After PRO-loaded liposomes were prepared using a pH gradient (remote loading) method, 100-nm liposomes improved residence times of PRO in the lungs. PRO encapsulation efficiency and release profiles were examined by screening several liposomal formulations of lipid, cholesterol, and inner phase. Although PRO loading was not achieved using the conventional hydration method, PRO encapsulation efficiency was >60% using the pH gradient method. PRO release from liposomes was sustained for several hours depending on liposomal composition. The liposomal formulation effects on the PRO behavior in rat lungs were evaluated following pulmonary administration in vivo . Sustained PRO release was achieved using simplified egg phosphatidylcholine (EPC)/cholesterol (8/1) liposome in vitro , and greater PRO remnants were observed in rat lungs following pulmonary administration. Extended pharmacological PRO effects were observed for 120 min in a histamine-induced bronchoconstriction guinea pig model. We indicated the simplified EPC/cholesterol liposome potential as a controlled-release PRO carrier for pulmonary administration. [ABSTRACT FROM AUTHOR]

This study investigated the preparation of orally disintegrating tablets (ODTs), which were prepared from spray-dried composite particles (CPs) of erythritol and porous silica (Sylysia 350) by direct tableting. Powder X-ray diffraction and differential scanning calorimetry indicated that erythritol was embedded in silica pores and remained in the crystalline state. CPs containing erythritol/porous silica ratios of 1:1, 2:1, and 3:1 showed excellent compactability resulting from strong binding properties. Although erythritol powder has poor compactability and caused problems during tableting, adding a small amount of CPs to erythritol improved tablet hardness. CPs containing an erythritol:porous silica ratio of 2:1 most effectively improved erythritol compactability. Erythritol powder containing CPs showed higher deformability than that of physical mixtures, and CPs inhibited elastic recovery after compression because of strong interparticulate bonding. Furthermore, CPs retained function as dry binders when stored under humid conditions. Placebo ODTs prepared with CPs (erythritol:porous silica ratios of 1:1, 2:1, and 3:1) and crospovidone (Kollidon® CL) as a disintegrant showed both excellent tablet hardness and rapid disintegration. We confirmed that the use of CPs improved manufacturing of ODTs containing active pharmaceutical ingredients using an appropriate compression pressure. [ABSTRACT FROM AUTHOR]

Abstract: Our previous study demonstrated that surface modification of liposomes using polyvinyl alcohol with a hydrophobic anchor (PVA-R) achieved sustained absorption from the lung after pulmonary administration and prolonged the pharmacological effects of the model peptide drug. In the present study, the behavior of PVA-R-modified liposomes in the lung and whole body was monitored using a real-time in vivo imaging system. Subsequently, the influence of surface modification with PVA-R on liposomal behavior in lung tissue was examined. Indocyanine green (ICG) was used as a near-infrared label of PVA-R-modified liposomes and was used to observe their dynamic behavior using non-invasive in vivo imaging (IVIS® imaging system) after pulmonary administration to rats. PVA-R-modified submicron-sized liposomes (ssLips) induced long-term retention in the lung compared with unmodified liposomes. Moreover, liposome association with alveolar macrophages (NR8383) was decreased by PVA-R modification in vitro. Therefore, PVA-R modification may prevent rapid elimination of ssLips by macrophages, thereby increasing retention in the lung. [Copyright &y& Elsevier]

Abstract: This work explored submicron-sized lipid emulsion as potential carriers for intraocular drug delivery to the posterior segment via eye drops. The effects of physicochemical properties of lipid emulsion on drug delivery were evaluated in vivo using mice. Different formulations of submicron-sized lipid emulsions were prepared using a high pressure homogenization system. Using coumairn-6 as a model drug and fluorescent marker, fluorescence could be observed in the retina after administration of the lipid emulsion. The fluorescence intensity observed after administration of medium chain triglycerides containing the same amount of coumarin-6 was much lower than that observed after administration of lipid emulsions. The inner oil property and phospholipid emulsifier did not affect the drug delivery efficiency to the retina. However, compared with unmodified emulsions, the fluorescence intensity in the retina increased by surface modification using a positive charge inducer and the functional polymers chitosan (CS) and poloxamer 407 (P407). CS-modified lipid emulsions could be electrostatically interacted with the eye surface. By its adhesive property, poloxamer 407, a surface modifier, possibly increased the lipid emulsion retention time on the eye surface. In conclusion, we suggested that surface-modified lipid emulsions could be promising vehicles of hydrophobic drug delivery to the ocular posterior segment. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to prepare orally disintegrating tablets (ODTs) by directly compressing a mixture of sugar alcohol (mannitol) and micronized crospovidone (M-CPVP). When the mixture of mannitol and M-CPVP was co-processed by ball milling, the physicochemical properties of the resultant tablets were considerably improved, particularly their stability during storage. Several types of coground mixtures using a different ratio of M-CPVP/mannitol and processing time were tested to determine the appropriate aggregates for designing the ODTs. Without this co-processing, the powder mixture had poor compactibility, and the stability of the tablet was inferior, probably due to the high hygroscopicity of M-CPVP. The ODTs containing coground M-CPVP/mannitol showed good stability for six months under humid conditions with rapid disintegration (<30s) and increased hardness of the tablets (tensile strength>1.0MPa). Tablet stability could not be achieved using a physical mixture of M-CPVP/mannitol without including the coground process. We also demonstrated that ODTs containing an active ingredient, acetaminophen, could be prepared using this cogrinding method. [Copyright &y& Elsevier]

Nanomedical applications of biodegradable poly( DL-lactide-co-glycolide) (PLGA) nanoparticles (NPs) developed are discussed in this review. A surface-functionalized PLGA NP platform for drug delivery was established to encapsulate a number of macromolecular drugs such as peptides and nucleic acids as well as low-molecular-weight drugs by the emulsion solvent diffusion method. The interaction of PLGA NPs with cells and tissues could be controlled by changing the surface properties of NPs, suggesting their potential utility for the intracellular drug delivery of nucleic acid-based drugs. Furthermore, orally administered NF-κκB decoy oligonucleotide-loaded CS-PLGA NPs are also useful in treating experimental colitis. These approaches using surface-modified PLGA NPs could be able to open new possibilities for nucleic acid-based drug delivery via noninvasive administration method. [ABSTRACT FROM AUTHOR]

Abstract: The objective of this study is to evaluate the effect of polymeric nanoparticles (NPs) on the allergic response of mast cells that release inflammatory mediators such as histamine through exocytosis. Submicron-sized biodegradable poly(dl-lactide-co-glycolide) (PLGA) NPs were prepared by the emulsion solvent diffusion method. Here, we examined the interactions of the mast cells with two types of PLGA NPs, unmodified NPs and NPs modified with chitosan (CS), a biodegradable cationic polymer. The cellular uptake of NPs increased by CS modification due to electrostatic interactions with the plasma membrane. NPs were taken up by mast cells through an endocytic pathway (endocytic phase) and then the cellular uptake was saturated and maintained plateau level by the exclusion of NPs through exocytosis (exocytic phase). Antigen-induced histamine release from mast cells was inhibited during the exocytic phase. The extent of histamine release inhibition was related to the amount of excluded NPs. Exocytic exclusion of NPs competitively antagonize the antigen-induced exocytotic release of histamine by highjacking exocytosis machinery such as SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, since histamine release was recovered in mast cells that overexpress SNAP-23. The inhibitory effect of the allergic response by PLGA NPs was also evaluated in vivo using the mouse model for systemic anaphylaxis. The administration of NPs suppressed the antigen-induced systemic allergic response in vivo. In conclusion, PLGA NP itself has actions to inhibit the allergic responses mediated by mast cells. [Copyright &y& Elsevier]

We investigated doxorubicin (DOX)-loaded nanospheres (NS) formulated using a biodegradable polymer, poly( D, L-lactide-co-glycolide) (PLGA), for targeted chemotherapy of brain tumours. A nonionic surfactant, polysorbate 80 (P80), was used to modify the surfaces of PLGA NS to improve cellular drug delivery. DOX-loaded PLGA NS were formulated by emulsion solvent diffusion and characterised for DOX encapsulation and in vitro release. The effectiveness of DOX-loaded P80-PLGA NS was investigated in A172 human glioblastoma cells. The drug release pattern was dependent on the pH of the medium. Quantitatively, the cellular uptake of NS was significantly increased by P80 surface modification compared with unmodified NS. Confocal laser scanning microscopy studies revealed that DOX was released from NS following accumulation in the cell nuclei. DOX-loaded P80-PLGA NS could significantly inhibit both DOX efflux from the cells and cell proliferation compared with a DOX solution. [ABSTRACT FROM AUTHOR]

Abstract: Chitosan (CS)-modified poly(d,l-lactide-co-glycolide) (PLGA) nanospheres (NS) were developed and evaluated for use with a nuclear factor kappa B (NF-κB) decoy oligonucleotide (ODN) oral delivery system in an experimental model of ulcerative colitis (UC). Decoy ODN-loaded PLGA NS were prepared by an emulsion solvent diffusion method, and the physicochemical properties of NS were investigated. CS-modified PLGA NS (CS-PLGA NS) showed positive zeta potential, while unmodified PLGA NS (plain-PLGA NS) were negatively charged. Decoy ODN uptake studies with Caco-2 cells using confocal laser scanning microscopy (CLSM) indicated that CS-PLGA NS were more effectively taken up by the cells than plain-PLGA NS. Decoy ODN-loaded CS-PLGA NS were able to improve the stability of ODN against DNase I or an acidic medium, such as gastric juice. Daily oral administration of CS-PLGA NS in a rat model significantly improved dextran sulfate sodium-induced diarrhea, bloody feces, shortening of colon length, and myeloperoxidase activity. Furthermore, decoy ODN-loaded CS-PLGA NS were specifically deposited and adsorbed on the inflamed mucosal tissue of the UC model rat. These results suggested that CS-PLGA NS provide an effective means of colon-specific oral decoy ODN delivery in UC. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we investigated surface-modified nanoparticles (NP) formulated using a biodegradable polymer, poly(d,l-lactide-co-glycolide) (PLGA), for targeting central nervous system (CNS) diseases. Polysorbate 80 (P80), poloxamer 188 (P188), and chitosan (CS) were used to modify the surfaces of PLGA NP to improve the brain delivery of NP. Surface-modified PLGA NP were formulated using an emulsion solvent diffusion method. 6-Coumarin was used as a fluorescent label for NP. The different formulations of 6-coumarin-loaded PLGA NP were injected into rats via carotid arteries. NP remaining in the brain were evaluated quantitatively, and brain slices were observed using confocal laser scanning microscopy (CLSM). Carotid artery administration was more effective for delivering NP into the brain compared to intravenous administration. After administration, NP concentrations in the brain were increased by NP surface modification, especially CS- and P80-PLGA NP. CLSM observations indicated that P80-PLGA NP could cross the blood–brain barrier and thus serve as a drug delivery system for the CNS. These results indicate that surface-modified PLGA NP have a high potential for use in CNS delivery systems. [ABSTRACT FROM AUTHOR]

Abstract: We previously developed chitosan (CS)-modified poly (d,l-lactide-co-glycolide) (PLGA) nanospheres (NS) by an emulsion solvent diffusion method as a gene delivery system. In this study, PLGA NS were modified using polysorbate 80 (P80) to improve their cellular uptake. We investigated the cellular uptake, intracellular distribution, and transfection efficiency of P80-modified PLGA NS (P80-PLGA NS) for a plasmid DNA delivery system in A549 cells. The cellular uptake and transfection efficiency of P80-PLGA NS were greater than CS-modified PLGA NS (CS-PLGA NS). The uptake of unmodified NS and CS-PLGA NS was mediated, predominantly, by clathrin-mediated endocytosis. In contrast, a specific endocytic pathway could not be determined for the cellular uptake of P80-PLGA NS. The intracellular distributions of PLGA NS depended on their surface properties. P80-PLGA NS were not cytotoxic for A549 cells. Thus, P80-PLGA NS could be used as an effective gene delivery system; the surface properties of PLGA NS are key parameters for optimal intracellular uptake and distribution. [Copyright &y& Elsevier]

Abstract: Chitosan (CS) surface-modified poly(d,l-lactide-co-glycolide) (PLGA) nanospheres (NS) for a siRNA delivery system were evaluated in vitro. siRNA-loaded PLGA NS were prepared by an emulsion solvent diffusion (ESD) method, and the physicochemical properties of NS were investigated. The level of targeted protein expression and siRNA uptake were examined in A549 cells. CS-modified PLGA NS exhibited much higher encapsulation efficiency than unmodified PLGA NS (plain-PLGA NS). CS-modified PLGA NS showed a positive zeta potential, while plain-PLGA NS were negatively charged. siRNA uptake studies by observation with confocal leaser scanning microscopy (CLSM) indicated that siRNA-loaded CS-modified PLGA NS were more effectively taken up by the cells than plain-PLGA NS. The efficiencies of different siRNA preparations were compared at the level of targeted protein expression. The gene-silencing efficiency of CS-modified PLGA NS was higher and more prolonged than those of plain-PLGA NS and naked siRNA. This result correlated with the CLSM studies, which may have been due to higher cellular uptake of CS-modified PLGA NS due to electrostatic interactions. It was concluded that CS-modified PLGA NS containing siRNA could provide an effective siRNA delivery system. [Copyright &y& Elsevier]

Abstract: The authors have previously developed poly(dl-lactic-co-glycolic acid) (PLGA) nanospheres (NSs) as a nanoparticulate drug carrier for pulmonary administration. The present study demonstrates that chitosan (CS)-modified PLGA NSs (CS-PLGA NSs) are preferentially taken up by human lung adenocarcinoma cells (A549). PLGA NSs prepared using a water–oil–water emulsion solvent evaporation method were surface-modified by adsorption of CS. The physicochemical parameters of PLGA NS, including average size and surface charge, were measured to identify which parameter influenced cellular uptake of PLGA NS. Uptake was confirmed using fluorescence spectrophotometry and was visualized in A549 cells with confocal laser scanning microscopy (CLSM). The cytotoxicities of non- and CS-PLGA NS systems were compared in vitro by MTS assay. Cellular uptake of PLGA NS increased with decreasing diameter to the submicron level and with CS-mediated surface modification. Cellular uptake of PLGA NS was energy dependent, as shown by a reduction in uptake at lower incubation temperatures and in hypertonic growth medium used as an inhibitor of clathrin-coated pit endocytosis. CS-PLGA NSs were taken up by A549 cells in an energy-dependent manner, suggesting a clathrin-mediated endocytic process. CS-PLGA NS demonstrated low cytotoxicity, similar to non-PLGA NS. [Copyright &y& Elsevier]

Abstract: The purpose of this paper was to establish the surface modified poly(d,l-lactide-co-glycolide) (PLGA) nanosphere platform with chitosan (CS) for gene delivery by using the emulsion solvent diffusion (ESD) method. The advantages of this method are a simple process under mild conditions without sonication. This method requires essentially dissolving both polymer and drug in the organic solvent. Therefore a hydrophilic drug such as nucleic acid is hardly applied to the ESD method. Nucleic acid can easily form an ion-complex with cationic compound, which can be dissolved in the organic solvent. Thereafter, nucleic acid solubility for organic solution can increase by complexation with cationic compound. We used DOTAP as a cationic compound to increase the loading efficiency of nucleic acid. By coating the PLGA nanospheres with CS, the loading efficiency of nucleic acid in the modified nanospheres increased significantly. The release profile of nucleic acid from PLGA nanospheres exhibited sustained release after initial burst. The PLGA nanospheres coated with chitosan reduced the initial burst of nucleic acid release and prolonged the drugs releasing at later stage. Chitosan coated PLGA nanosphere platform was established to encapsulate satisfactorily wide variety of nucleic acid for an acceptable gene delivery system. [Copyright &y& Elsevier]

To enable the efficient delivery of drugs to the lungs, the drug particle design for most dry powder inhalers (DPIs) involves reducing the aerodynamic particle size to a few microns using methods such as spray-drying or jet-milling. Stresses, including heat and the shear forces generated by the preparation processes, may result in the degradation and denaturation of drugs such as those based on peptides and proteins. Here, we showed that cryo-milled polyvinyl alcohol nanofiber mats loaded with α-chymotrypsin by electrospinning exhibited suitable inhalation properties for use in DPIs, while maintaining enzymatic activity. The cryo-milled nanofiber mats were porous to fine particles, and the particle size and drug stability depended on the freezing and milling times. The median diameter of the milled fiber mats was 12.6 μm, whereas the mass median aerodynamic diameter was 5.9 μm. The milled nanofiber mats were successfully prepared, while retaining the enzymatic activity of α-chymotrypsin; furthermore, the activity of milled fiber mats that had been stored for 6 months was comparable to the activity of those that were freshly prepared. This novel method may be suitable for the DPI preparation of various drugs because it avoids the heating step during the DPI preparation process. [ABSTRACT FROM AUTHOR]

Abstract: We prepared surface-modified poly(d,l-lactide-co-glycolide) (PLGA) nanospheres (NS) for use as cellular drug and gene delivery systems using an emulsion solvent diffusion method. In this study, we screened for an appropriate surface modifier to improve NS cellular uptake. Poly-l-lysine (PLL)-modified PLGA NS were taken up by A549 cells in significantly higher amounts (17-fold) than unmodified NS. In order to provide a novel function, PLGA NS were hybrid-modified using both; a cationic polymer, PLL, and a nonionic surfactant, polysorbate 80, to improve cellular uptake in serum-containing medium (SCM). Hybrid modification abrogated the decreased PLGA NS cellular uptake in SCM as a result of better dispersion in serum compared to PLL-PLGA NS, which aggregated in SCM. Luciferase activity of Hybrid-NS/pCMV-Luc complexes in A549 cells in SCM was 122-fold higher than PLL-NS. Hybrid-PLGA NS were not cytotoxic for A549 cells. In conclusion, Hybrid-PLGA NS have great potential as effective cellular drug delivery carriers. [Copyright &y& Elsevier]

[Display omitted] • Constant-volume shear test for the texture of cosmetic oil-wet powders. • Effect of dimethicone and squalane on the powder rheology of sericite. • Stress relaxation ratios indicate the sericite with dimethicone feels soft. • Shear cohesions indicate the sericite with squalane feels moist. • Reports variations in the shape of PYL resulting from different oil contents. Although sensory evaluation is often used to evaluate cosmetic powder textures, such evaluations are problematic because they are subjective and depend on human senses. Consequently, an objective evaluation is highly desired. We therefore report herein the use of a constant-volume shear tester to objectively evaluate the physical properties of a cosmetic powder. The goal of the study is to detect the differences in the physical properties of powders, which is done by applying a constant-volume shear test to oil-wet powders of differing textures mixed with dimethicone or squalane. Differences between dimethicone and squalane mixtures appear in the stress relaxation ratio (softness), the shear cohesion (moist feeling), the internal friction coefficient for friction (for normal stress of <10 kPa) between powder beds (smoothness), and the dynamic friction coefficient for friction between powder beds. Although the oils presented a similar degree of the powder yield locus, the shape of the powder yield locus indicates the state of the powder beds. The results of the study show that constant-volume shear testing can be used to objectively evaluate oil-wet powder textures. [ABSTRACT FROM AUTHOR]

This study aimed to develop polyvinyl alcohol (PVA) nanofibers encapsulating 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)/siRNA complexes via electrospinning for the delivery of nucleic acid-based drugs. It also focused on the influence of the intrinsic properties of PVA on the efficacy of the system. PVA nanofibers, with diameters of 300–400 nm, were obtained, within which the siRNA remained intact and the DOTAP/siRNA complexes were uniformly dispersed. By incorporating DOTAP/siRNA complexes into the PVA nanofibers and assessing the impact of their RNA interference (RNAi) activity in A549-Luc cells, a stable inhibition of luciferase expression was observed. An examination of the nanofiber preparation process revealed that even when DOTAP or siRNA were added separately to the PVA solution without forming complexes, the RNAi effect was retained. The DOTAP/siRNA complexes released from the PVA nanofibers were internalized by the cells, with some PVA residues remaining on their surfaces. The significance of the degree of hydrolysis and polymerization of PVA on the performance of nanofibers was highlighted. Notably, PVA with a low degree of hydrolysis substantially enhanced RNAi effects, with luciferase expression inhibition reaching 91.5 ± 0.7%. Nanofibers made of PVA grades with anionic or cationic modifications were also evaluated, suggesting that they affect the efficacy of siRNA delivery. The insights obtained suggest avenues for future research to optimize drug delivery systems further. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract In the design of the orally disintegrating films (ODFs), it is important to determine the disintegration time (DT) precisely and properly. These films' DTs are usually assessed by a disintegration test defined in the pharmacopoeias, but under the conditions of such tests, a much larger volume of water is used and a stronger up-down movement is applied compared to the conditions of the human oral cavity. Here we developed and tested our new disintegration test system for ODFs. We chose a disintegration test device (the Tricorptester®, Okada Seiko, Tokyo) for orally disintegrating tablets. This device enabled the mechanical dropping of the test medium. We designed an exclusive fixture for ODFs, made an opening in the center of the fixture, and optimized the size of the opening (i.e., the cell). We also investigated that test conditions including the types of test media, the dropping height, flow rate, dropping methods, and medium holding methods. With a passage sensor attached to the Tricorptester, the device was able to automatically detect the DTs of ODFs. We thus successfully developed a new disintegration test system and optimized the operating conditions. Using this system, model ODFs and the commercial ODFs can be properly evaluated. [ABSTRACT FROM AUTHOR]

[Display omitted] A powder formulation for mucosal administration of mRNA-encapsulated lipid nanoparticles (mRNA-LNPs) is expected to be useful for respiratory diseases. Although freeze-drying is widely used to obtain solid formulations of mRNA-LNPs, highly hydrosoluble cryoprotectants, such as sucrose are necessary. However, sucrose is not a suitable excipient for inhalation powders because of its hygroscopic and deliquescence properties. Spray freeze-drying (SFD) is a method to produce inhalable powder formulation. In this study, we prepared inhalable powder formulations of mRNA-LNPs without deliquescence excipients using pH-modified SFD, which strengthens the interaction between mRNA and ionizable lipids of LNPs by acidic pH modifier, leading to retention of the encapsulated structure of mRNA-LNPs even after SFD. Powdered mRNA-LNPs were suitable for inhalation, and mRNA was encapsulated in LNPs after SFD. The mRNA encapsulation efficiency and mRNA transfection efficiency of pH-modified SFD-mediated powdered mRNA-LNPs were higher than those of conventional SFD, although they were significantly lower than those of liquid intact mRNA-LNPs. However, after long-term storage, the powdered formulation of the mRNA-LNPs exhibited higher mRNA transfection efficiency than liquid mRNA-LNP. Powdered mRNA-LNPs also exerted their function in air–liquid interface cultivation and in vivo intratracheal administration. Collectively, the powder formulation of mRNA-LNPs especially prepared by SFD is expected to be applied for dry powder inhalers. [ABSTRACT FROM AUTHOR]

[Display omitted] • The influence of excipients on selective-laser-sintered printlets was investigated. • Various thermoplastic polymers and different grades of mannitol were used as excipients. • Excipient selection based on powder flowability and printability was emphasized. • Printlets have higher porosity and dissolution rates than conventional tablets. In this study, the impact of excipients on the quality of printlets manufactured using selective laser sintering (SLS) 3D printing was investigated. Various thermoplastic polymers, commonly used as pharmaceutical additives, and mannitol of different particle property grades, were used as excipients. SLS can produce complex structures and customize drug release rates; therefore, it can be used for personalized medicine. The significance of selecting suitable excipients, focusing on their powder flowability and printability, and their influence on the printlet properties was evaluated. An optimal amount of yellow iron oxide, a necessary laser-absorbing agent for printlet formation, was determined. Results revealed that excipients with optimal flow and shape characteristics considerably enhanced the printlet quality. The relation between the powder properties of excipients (internal friction angle, shear adhesion force, and flow function coefficient) and the SLS printing outcomes was evaluated using the powder shear cell test. The powder properties considerably affected the application of the powder layer using a spreader from the powder reservoir to the building platform. Moreover, the electron laser density impacted the printlet hardness. The as-fabricated printlets exhibited higher porosity and faster dissolution rates than traditional tablets, suggesting the potential advantages of using SLS in drug manufacturing. [ABSTRACT FROM AUTHOR]

We evaluated the drug-encapsulation state of insulin (INS)-loaded liposome using a novel column-switching HPLC system that can automatically separate unloaded drug from encapsulated drug by hydrophobic interaction. When the INS-loaded liposome was dispersed in water (pH 7.4), the encapsulation efficiency (EE) obtained by the column-switching HPLC system was consistent with that obtained by a conventional ultracentrifugation method. However, the INS-loaded liposome dispersed in 0.1% acetic acid (pH 3.3) showed disagreement between the EEs obtained by both methods. Considering the results of particle size, zeta potential, and transmission electron microscope (TEM) observations, we hypothesized that the column-switching HPLC method was able to distinguish INS adsorbed onto the liposome surface from the encapsulated INS, although an ultracentrifugation method precipitated the adsorbed INS onto the liposome surface along with the encapsulated INS. Therefore, the novel column-switching HPLC system may be a more accurate and useful technique for characterization and optimization of the INS-loaded liposome formulation. [ABSTRACT FROM AUTHOR]

[Display omitted] • We prepared enzyme inhalation powders by cryomilling electrospun nanofiber mats. • Mannitol increased the friability of nanofiber mats composed of polyvinyl alcohol. • Mannitol conferred excellent aerosol performance to nanofiber mats. • The ratio of mannitol composition and milling time determined enzymatic integrity. • Inhalation of milled nanofiber mats did not induce significant damage to mouse lung. Dry powder inhalers (DPIs) are the first choice for inhalation drug development. However, some conventional DPI formulation processes require heating, which may damage high molecular weight drugs such as proteins and nucleic acids. In this study, we propose a novel DPI preparation process that avoids the use of heat. Dry powders were prepared by cryomilling nanofiber mats composed of polyvinyl alcohol, D(−)-mannitol (Man), and α-chymotrypsin (α-Chy) as the model drug using the electrospinning method. The addition of Man conferred high dispersibility and excellent in vitro aerosol performance to the nanofiber mat powder in a very short milling time (less than 0.5 min) as assessed using the Andersen cascade impactor. Powders were classified according to the degree of friability, and among these, nanofiber mats containing 15 % Man and milled for 0.25 min exhibited the highest aerosol performance. Nanofiber mats containing Man milled for less than 0.5 min also exhibited greater α-Chy enzymatic activity than a nebulized α-Chy solution. Furthermore, single inhalation induced no significant lung tissue damage as evidenced by lactate dehydrogenase activity assays of mouse bronchoalveolar lavage fluid. This novel DPI formulation process may facilitate the safe and efficient inhalational delivery of therapeutic proteins. [ABSTRACT FROM AUTHOR]

[Display omitted] • Working team in JPMA made a consideration for implementing MCS for oral solid dosage forms. • It was prepared based on surveys of pharmaceutical companies in Japan, EU and the US. • It helps systemic approach for selecting manufacturing method based on API properties. The Manufacturing Classification System (MCS) classifies oral solid dosage forms according to the properties of the active pharmaceutical ingredient (API) to improve the selection of appropriate manufacturing methods. The concept of MCS was proposed by a group of European and American pharmaceutical scientists as part of the MCS Working Group. This topic has also generated interest in Japan, and the Japan Pharmaceutical Manufacturers Association (JPMA) considers it useful to investigate the actual status of manufacturing method selection in Japan with application of MCS framework. Since the manufacturing method and its selection are not in the public domain in Japan, the JPMA MCS project team conducted a survey in collaboration with the member companies. This paper summarizes the results of this survey and provides a proposal for the industrial environment in Japan while taking into account the results of the previous EU/US surveys. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to investigate the feasibility of surface-modified liposomes for pulmonary delivery of a peptide. Chitosan oligosaccharide (oligoCS) and polyvinyl alcohol with a hydrophobic anchor (PVA-R) were used as surface modifiers. The effect of liposomal surface modification on the behavior of the liposomes on pulmonary administration and potential toxicity were evaluated in vitro and in vivo. In an association study with A549 cells, PVA-R modification reduced interaction with A549 cells, whereas oligoCS modification electrostatically enhanced cellular interaction. The therapeutic efficacy of elcatonin (eCT) after pulmonary administration to rats was significantly enhanced and prolonged for 48h after separate administration with oligoCS- or PVA-R-modified liposomes. oligoCS-modified liposomes adhered to lung tissues and caused opening of tight junctions, which enhanced eCT absorption. On the other hand, PVA-R-modified liposomes induced long-term retention of eCT in the lung fluid, leading to sustained absorption. Consequently, surface modification of liposomes with oligoCS or PVA-R has potential for effective peptide drug delivery through pulmonary administration. [Copyright &y& Elsevier]

We investigated the feasibility of densely polyethylene glycol (PEG2000)-modified liposomes as mucus-penetrating particles (MPPs) for oral delivery of systemically absorbed peptides. The oral absorption of MPPs and mucoadhesive liposomes modified with glycol chitosan (GCS) was compared. In an in vitro artificial mucus model, the densely PEGylated liposomes showed mucus permeability. Intracellular uptake of liposomes was evaluated in a Caco-2 and mucus-secreting Caco-2/HT29 co-culture. Intracellular uptake of MPPs was unaffected by mucus in the co-culture system, whereas the cellular uptake of GCS-liposomes was lower with a mucus layer than in Caco-2 alone. Rat in vivo oral absorption of liposomes was evaluated by using fluorescein isothiocyanate dextran (FD) as a model peptide drug. Oral absorption was higher for densely PEGylated than for unmodified liposomes and was PEG-concentration dependent, but excessive PEGylation decreased FD blood concentration. PEGylated liposomes incorporating spermine (SPM) as an absorption enhancer were then designed and showed the highest in vivo absorption of FD of all tested formulations. The pharmacological effects of the oral liposomes were evaluated by using elcatonin and did not correlate with FD oral absorption. The non-PEGylated SPM liposomes showed the highest pharmacological effect, suggesting the need for drug-specific optimization of liposomal components and surface modifiers. [ABSTRACT FROM AUTHOR]

The tensile test is the most widely used method for testing the mechanical characteristics of orally disintegrating films (ODFs). The other available test is the folding endurance (FE) test, which is more suitable for clarifying the actual strength during the manufacturing and dosing. However, the FE test is performed manually, and the FE number it generates has not been adequately analyzed as an index. The aim of this studies were to establish an automatic method for determining the FE number, and to compare the resulting FE numbers with the tensile properties. For this purpose, a desktop-model endurance test machine was used. First, the operating conditions—i.e., the folding angle, the folding speed and the weight requirement were optimized using ODF models. Secondly, the FE of ODFs prepared from three film formers (HPMC, HPC, and PVA) and with insoluble particles (calcium carbonate), plasticizers (glycerin) and APIs (acetaminophen), was evaluated and compared with the tensile properties. Lastly, the commercial ODFs were investigated. The results showed that our automatic system could be successfully used to determine the FE characteristics of ODFs. FE was suggested to relate to not only the strength but also the elongation during the tensile test. [ABSTRACT FROM AUTHOR]

Abstract 8‑Methoxypsoralen (8-MOP) in combination with ultraviolet A (PUVA) is a photochemotherapy for management of psoriasis. 8-MOP is a natural compound from Psoralea corylifolia. The present work was undertaken to evaluate the percutaneous absorption of five compounds derived from P. corylifolia , and to further explore the inhibitory effect on psoriasis-like lesions generated by imiquimod stimulation in a mouse model. 8-MOP, psoralen, isopsoralen, psoralidin, and bakuchiol were comparatively tested for in vitro skin permeation, keratinocyte apoptosis, and in vivo antipsoriatic potency. The pig ear skin deposition of 8-MOP, isopsoralen, and bakuchiol at an equimolar dose was 0.47, 0.58, and 0.50 nmol/mg, respectively, which was comparable and higher than that of psoralen (0.25 nmol/mg) and psoralidin (0.14 nmol/mg). Psoralidin and bakuchiol were absorbed into the skin without further penetration across the skin. Besides experimental data of physicochemical properties, the hydrogen bond number, total polarity surface, and stratum corneum lipid docking calculated could explain the correlation of the penetrant structure with the skin permeability. The antiproliferative activity against keratinocytes was stronger for 8-MOP and isopsoralen than the others. Topical application of PUVA by using 8-MOP and isopsoralen on imiquimod-induced plaque significantly reduced transepidermal water loss from 55 to 33 and 38 g/m2/h, respectively. The epidermal thickening elicited by imiquimod (117 μm) was decreased to 62 and 26 μm by 8-MOP and isopsoralen application. IL-6 expression in psoriasiform skin was downregulated by isopsoralen but not 8-MOP. Isopsoralen may be a potential candidate for PUVA therapy. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

In the manufacture of tablets, especially in direct tableting processes, the flowability of excipient powders and formulated powders is one of the most important characteristics. In the past two decades, orally disintegrating tablets (ODTs) have been prepared as popular solid dosage forms for elderly patients. Many types of mannitol granules have been developed and marketed as new pharmaceutical excipients for ODTs, owing to the solubility and palatability of mannitol. Characterizing the flow behaviors of these mannitol granules is essential to their use. The flowability of mannitol excipients was the focus of the present study. A fine crystalline mannitol powder, eight commercial types of mannitol granules and four types of mannitol mixture granules were evaluated. Two flowability testers were used for comparing and analyzing the samples’ flowabilities. A variety of methodologies were used: an assessment using Carr’s index, a shear test and a dynamic flow test. Mannitol powder showed the lowest Carr’s index, meaning the lowest flowability. Spherical mannitol granules showed the lowest angle of internal friction in the shear test and extremely low basic flow energy in the dynamic flow test. Larger granules showed relatively high values for Carr’s index, but also a relatively high total flow energy. [ABSTRACT FROM AUTHOR]

Abstract: As a demonstration of an alternative to the challenges faced with batch pharmaceutical manufacturing including the large production footprint and lengthy time‐scale, we previously reported a refrigerator‐sized continuous flow system for the on‐demand production of essential medicines. Building on this technology, herein we report a second‐generation, reconfigurable and 25 % smaller (by volume) continuous flow pharmaceutical manufacturing platform featuring advances in reaction and purification equipment. Consisting of two compact [0.7 (L)×0.5 (D)×1.3 m (H)] stand‐alone units for synthesis and purification/formulation processes, the capabilities of this automated system are demonstrated with the synthesis of nicardipine hydrochloride and the production of concentrated liquid doses of ciprofloxacin hydrochloride, neostigmine methylsulfate and rufinamide that meet US Pharmacopeia standards. [ABSTRACT FROM AUTHOR]

[Display omitted] • We prepared ibuprofen-isonicotinamide co-crystal granules. • The granules were produced directly and continuously by a continuous-spray granulator. • The granulation conditions affected the particle size and the yield of the granules. • Compared to ibuprofen bulk, the granules improved the circularity and the flowability. • The co-crystallization did not change the solubility of ibuprofen. The importance of granulation is paramount for tablet manufacturing, and is based on the fact that granulated powders are characterized by improved flowability, compressibility, segregation, and dust reduction. The aim of this study was to prepare and characterize continuous granules of high drug content by using a continuous-spray granulator (CTS-SGR). Ibuprofen (IBU), a drug of low-flowability, was selected as the model drug. As IBU has a low melting point and cannot easily granulate on its own, we employed isonicotinamide (INA) as a coformer that would allow us to prepare co-crystal granules containing 60 % IBU. The results of the undertaken differential scanning calorimetry and powder X-ray diffraction revealed that the IBU and the INA in the granules formed co-crystals. The granulation conditions affected the particle size and the yield of the granules; in fact, a low air supply temperature, a low atomizing air rate, and a high solution flow rate ensured a high granulation efficiency. Moreover, continuous granulation increased the yields of the formulations compared to those obtained through a short-run granulation, and high yields were obtained after applying a low atomizing air rate. The circularity of the granules exceeded 90 %, and their flowability improved when compared to that of the IBU bulk. The undertaking of dissolution studies revealed no change in the elution amount of IBU as a result of the co-crystallization. Our study shows that it is possible to produce high-content IBU granules in a direct and continuous manner through the co-crystallization of IBU and the use of a CTS-SGR. [ABSTRACT FROM AUTHOR]

Taste detection systems using electronic sensors are needed in the field of pharmaceutical design. The aim of this study was to propose an advanced technique using a taste-sensing system to evaluate the bitterness of an orally disintegrating film (ODF) samples. In this system, a solid film sample is kept in the test medium with stirring, and the sensor output is recorded. Model films were prepared using a solution-casting method with a water-soluble polymer such as pullulan, HPMC, HPC or PVP as film formers, and donepezil hydrochloride and quinine hydrochloride as model bitter-tasting active pharmaceutical ingredients (APIs). The results showed that this advanced techniques could detect the emergence of bitterness along the time course. Increasing the amount of donepezil hydrochloride increased the sensor output. The sensor output was suppressed at the very early stage of the test, and then increased. Both the film thickness and the use of additives markedly affected the delay of the sensor output. The profile of the sensor output was accurately related to the release of APIs. It was concluded that this advanced technique could detect the onset of bitterness during the initial stage of ODF administration. [ABSTRACT FROM AUTHOR]

Before designing tablet formulations, it is important to understand the “Tableting Properties” of excipients and API (active pharmaceutical ingredient) powders. Those properties refer to “Compressibility”, “Compactability” and “Manufacturability”, which are difficult to evaluate quantitatively. In this study, we aimed to evaluate the “Tableting Properties” by using a benchtop single-punch tablet press, developed recently to measure these parameters using a single device. In order to facilitate understanding of the results visually, we proposed a new plot, where the X-axis showed the tensile fracture stress and the Y-axis showed the ejection stress. This plot, which is composed of four regions, shows the combination of “Compactability” and “Manufacturability”. We confirmed the ability of this device to evaluate the characteristics of typical pharmaceutical additives as a value of “Tableting Properties”. Losartan potassium was used as an API, and Dilactose R and MCC as an excipient with good “Tableting Properties”. The ejection stresses of losartan potassium and Dilactose R were very high. An increase in magnesium stearate shifted the point along the Y-axis in this plot, and it meant an improvement in “Manufacturability”. It was confirmed that the device and plot are useful in designing formulations efficiently using a small amount of sample powders. [ABSTRACT FROM AUTHOR]

Poly(lactic-co-glycolic acid) (PLGA) nanospheres loaded with papain were prepared by the emulsion solvent diffusion in water (ESD) and the w/o/w emulsion solvent evaporation (ESE) methods. The nanosphere loaded with papain from the ESE method gave smaller particle sizes (220–232 nm) and higher encapsulation efficiency of about two-folds than those from the ESD method. The morphology of the nanospheres loaded with papain prepared by the ESE method exhibited spherical shape and smooth surface investigated by SEM and TEM. The release profile of papain from the PLGA nanospheres of the ESD and ESE method indicated two phases with an initial rapid phase of 6 h and followed by the slow release phase of 48 h. The unloaded PLGA nanospheres from the two methods did not show any cytotoxicity in human skin fibroblasts, while the unloaded papain gave toxicity more than the loaded papain of 1.5 times. Papain loaded in PLGA nanospheres prepared by the ESE method was more chemical stable than the unloaded papain of eight and three times when kept at 4°C and 25°C for 6 weeks, respectively. The developed stable and low cytotoxic nanosphere loaded with papain can be further developed as topical products. [ABSTRACT FROM AUTHOR]

Abstract: Investigation into the use of near-infrared (NIR) as a Process Analytical Technology has been conducted for in-process monitoring of coating amounts for oral pharmaceutical products. However, the low specificity of NIR spectra has made it time consuming and costly to establish quantitative calibration models for commercial production. Here we revealed that long-chain hydrocarbyl group compounds containing saturated hydrocarbon chains, such as cetyl and stearyl, exhibit specific and strong absorption in the short wavelength (SW)-NIR region (800–1100nm) with limited interference from peaks corresponding to other components. To simplify the quantitative model, we used cetanol as a model tracer of coating amount to enhance detection sensitivity and analytical precision. The coating amount on crystalline cellulose granules was determined only from the intensity of NIR absorption at a single wavelength, which was attributed to the tracer. The results showed close agreement with quantitative analyses from gas chromatography and measurement of weight gain. In conclusion, we determined coating amount with considerable accuracy from NIR absorption at a single wavelength in the SW-NIR region using the long-chain hydrocarbyl containing compound as a tracer, thereby eliminating the need for complicated statistics. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to prepare a functional dry powder capable of effectively improving the bioavailability of hydrophobic bioactive ingredients in crude drugs. A dry powder formulation from an ethanol extract of Brazilian green propolis was achieved in the presence of α-glycosyltransferase-treated stevia (Stevia-G). The resulting powder dispersed easily into an aqueous medium, and the average particle size of the suspension was about 350nm. Propolis is known as a mixture of more than 200 ingredients; therefore, the suspension contains particles of hydrophobic compounds as well as dissolved molecules of several other compounds. In the suspension, the dissolved amounts of artepillin C and drupanin, representative hydrophobic bioactive compounds in propolis, in water were dramatically improved compared to their normal solubility. When the resulting propolis/Stevia-G powder was administrated into rats, pronounced absorption enhancement of artepillin C and drupanin could be detected. Stevia-G may have the potential to yield simultaneous absorption enhancement to multiple hydrophobic ingredients in crude drugs. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to develop surface-modified liposomes that enhance the efficiency of eye drop drug delivery to the retina. Various molecular weights and concentrations of the water-soluble cationic polymer poly-l-lysine (PLL) were used to modify the surface of submicronized (100nm) liposomes. Physicochemical properties of surface-modified liposomes were determined in vitro, and the efficiency of drug delivery to the retina was investigated in vivo. Using coumarin-6 as a model drug and fluorescent marker, we show that liposome surface modification by PLL dramatically increased delivery to mouse retina segments after eye drop administration. However, when PLL of high molecular weight (>30,000) was used at higher concentrations (>0.05%), aggregation of surface-modified liposomes increased particle size and hampered distribution to inner ocular tissues. As a result, the efficiency of drug delivery of these aggregated surface-modified liposomes was the same as unmodified liposomes. The optimal molecular weight and concentration of PLL in drug-delivering liposomes were 15,000–30,000 and 0.005%, respectively. Under these conditions, PLL-modified liposomes were not cytotoxic in corneal or conjunctival cells. In conclusion, surface-modified liposomes have great potential as effective retinal drug delivery carriers in eye drop formulations. [Copyright &y& Elsevier]

In this study, we investigated the feasibility of a system based on liposomal surface modification with a novel mucoadhesive polymer-lectin conjugate for the pulmonary delivery of therapeutic peptides and proteins. We covalently attached wheat germ agglutinin (WGA), a ligand that specifically interacts with alveolar epithelial cells, to carbopol (CP), a mucoadhesive polymer, using the carbodiimide method and then evaluated the efficacy and potential toxicity of CP-WGA surface-modified liposomes in vivo and in vitro. In association studies, CP-WGA modification enhanced the interaction with A549 lung epithelial cells compared with unmodified or CP-modified liposomes. This increased association was dependent on temperature and the surface concentration of free WGA. These results suggested synergy of WGA and CP, and retention of the biological cell binding activity of WGA, leading to improved liposome-cell interactions. Moreover, improvement of liposomal bioadhesion to lung epithelia significantly enhanced and prolonged the therapeutic efficacy of calcitonin, a model peptide drug, without any evidence of toxicity, following administration of calcitonin-loaded CP-WGA-modified liposomes. Hence, surface modification of liposomes with CP-WGA has potential for effective pulmonary administration of peptides. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1281-1289, 2013 [ABSTRACT FROM AUTHOR]

Abstract: The feasibility of a rapid automated method for determination of the encapsulation efficiency (EE) of a liposome formulation using a column-switching HPLC system was confirmed by employing several types of liposome formulations containing doxorubicin (DXR). A suspension of DXR liposome was injected directly into an online solid-phase extraction (SPE) system comprising a Diol SPE column and an ODS SPE column connected in series. Free (not encapsulated) DXR was trapped on the Diol SPE column, whereas encapsulated DXR was eluted without interaction. The eluted encapsulated DXR was trapped on the ODS SPE column after being extracted from the inner phase of the liposome by mixing with an organic solvent. Trapped free and encapsulated DXR were eluted sequentially and analyzed separately by gradient HPLC. The time taken by this automated method was only 25min, whereas conventional methods such as ultracentrifugation are time consuming and labor intensive. Validation results and comparison with ultracentrifugation suggested that our method was sufficiently accurate and sensitive to be used to evaluate EE of a liposome formulation without complicated pretreatment. [Copyright &y& Elsevier]

Abstract: An efficient liposomal formulation for targeting the retina was produced as an optimal means of distributing therapeutic agents to the retina. Diclofenac was used as a model compound for liposome encapsulation, and the release rate and distribution to the retina were investigated. The calcium acetate gradient method was found to be the optimal method for encapsulating diclofenac into liposomes. Entrapment efficiency using this method was greater than 97%, whereas conventional hydration method achieved 51.3%. The resultant formulation obtained with the gradient method caused aggregation and/or fusion of liposomes. To avoid inhibition of retinal delivery due to the aggregation of the carrier, surface modification was performed simultaneously with the gradient method. The increase in particle size of the liposomal formulation clearly was inhibited for a long time in the presence of polyvinyl alcohol or its derivative. This observation may be explained by surface modification of the liposomes by physisorption or anchoring effect of polymers on the surface of the lipid bilayer. Furthermore, the sustained release profile of the diclofenac formulation was retained after modification. An in vivo animal study revealed that concentration of the accumulated diclofenac in the retina–choroid was enhanced 1.8-fold by surface-modified liposome entrapment compared to that of the unaltered diclofenac solution. [Copyright &y& Elsevier]

The oral bioavailability of drugs is limited by factors such as poor membrane permeability, low solubility, and low dissolution rate. Silymarin (SLM) is a health-food active ingredient that is good for immunosuppression and tumor suppression. However, obtaining a good oral bioavailability is difficult owing to its poor solubility and low dissolution ability. To overcome these concerns, we previously prepared SLM nanoparticles (NPs) using the high-pressure crystallization method (PureNanoTM) and freeze-dried them with erythritol (Ery) or hydroxypropyl-β-CyD (HP-β-CyD) as a water-soluble dispersion stabilizer. In the present study, we investigated the mechanism underlying the improved absorption of SLM/hypromellose (HPMC)/HP-β-CyD NPs after oral administration. The SLM/HPMC nano-suspension prepared using PureNanoTM exhibited a narrow size distribution. The size of the SLM/HPMC/HP-β-CyD NPs was approximately 250 nm after hydration. The SLM/HPMC/HP-β-CyD NPs were rapidly dissolved, and demonstrated a high solubility under supersaturated conditions. Additionally, they exhibited good wettability and their membrane permeability was improved compared with that of SLM original powder. These results suggest that the formulation of SLM NPs using PureNanoTM and freeze-drying with HP-β-CyD improves the absorption of SLM after oral administration by enhancing solubility, wettability, and membrane permeability. [ABSTRACT FROM AUTHOR]

Pulmonary drug administration for the treatment of lung cancer is useful because the drug is directly delivered to the lung tissues with minimal invasiveness and higher efficiency compared to other conventional methods. However, it is critical to enhance drug accumulation in the lung cancer tissues to achieve sufficient therapeutic efficacy. The submicron-sized liposome (ssLip) preparation is one of the most promising approaches to enhance drug accumulation in the lungs; however, ssLips prepared for conventional inhalation do not have tumour selectivity. Therefore, in this study, we prepared folate (FA)-modified ssLip (FA-ssLip) to enhance drug accumulation in folate receptor (FR)-expressing lung cancer cells, and evaluated its physicochemical properties and potential as a drug carrier in pulmonary administration. In addition, we prepared rapamycin (RM-an autophagy-inducing anticancer drug)-loaded FA-ssLip (RM/FA-ssLip) and investigated its anti-tumour effect. FA-ssLip showed excellent nanoparticle properties with submicron size (approximately 120 nm) and high lung accumulation in lung cancer mouse model-bearing LL2 cells—a mouse Lewis lung carcinoma cell line. RM/FA-ssLip showed significant cytotoxic activity in FR-expressing cancer cells. In addition, pulmonary administration of RM/FA-ssLip extended the survival of LL2 cell tumour-bearing mice. Taken together, our results suggest the potential of FA-ssLip as a pulmonary drug carrier for the efficient treatment of lung cancer. [Display omitted] [ABSTRACT FROM AUTHOR]