A Design-Conversed Strategy Establishes the Performance Safe Space for Doxorubicin Nanosimilars.

Nanomedicines exhibit multifaceted performances, yet their biopharmaceutics remain poorly understood and present several challenges in the translation from preclinical to clinical research. To address this issue and promote the production of high-quality nanomedicines, a systematic screening of the design space and in vivo performance is necessary. Establishing formulation performance specifications early on enables an informed selection of candidates and promotes the development of nanosimilars. The deconvolution of the pharmacokinetics enables the identification of key characteristics that influence their performances and disposition. Using an in vitro-in vivo rank-order relationship for doxorubicin nanoformulations, we defined in vitro release specifications for Doxil/Caelyx-like follow-on products. Additionally, our model predictions were used to establish the bioequivalence of Lipodox, a nanosimilar of Doxil/Caelyx. Furthermore, a virtual safe space was established, providing crucial insights into expected disposition kinetics and informing formulation development. By addressing bottlenecks in biopharmaceutics and formulation screening, our research advances the translation of nanomedicine from bench to bedside.

Glucagon: Delivery advancements for hypoglycemia management.

As the 100th anniversary of glucagon's discovery approaches, we reflect on the remarkable journey of understanding its pivotal role in glucose regulation. Advancements in glucagon delivery systems for managing hypoglycemia are unfolding with promise, albeit accompanied by formulation and implementation challenges. Recent developments include non-injectable methods like BAQSIMI® (Nasal glucagon) offers a user-friendly option, but stability, bioavailability, and rapid onset remain formulation hurdles. Closed-loop systems, combining glucagon with insulin, aim to automate glucose control, demanding stable and precise formulations compatible with complex algorithms. However, achieving co-delivery harmony and effective dual-hormone responses poses substantial challenges. Ogluo® and Gvoke HypoPen® are auto-injector pens, a ready-to-use solution that can rapidly control hypoglycemia and eliminate the need for mixing powder and liquid. GlucaGen® Hypokit® and Glucagon Emergency Kits are traditional deliveries that possess complexity during administration and are still widely used in clinical practice. In addition to this advancement, we have covered the recent patents and clinical trials of glucagon delivery. The synergy of patent innovation and clinical validation offers a glimpse into the transformative potential of glucagon delivery yet underscores the intricate path toward widespread adoption and improved diabetes care. Finally, this review will help the formulation scientist, clinicians, healthcare providers, and patient to manage hypoglycemia using glucagon.

A Comparative Preclinical Evaluation of a Novel Difluprednate 0.04% BID Ophthalmic Solution and Marketed 0.05% QID Ophthalmic Emulsion.

Purpose: The purpose of this study was to compare the efficacy, and ocular pharmacokinetics of a new 0.04% w/v bis in die means twice a day (BID) ophthalmic solution and marketed 0.05% w/v quater in die means four times a day (QID) ophthalmic emulsion of difluprednate in New Zealand white (NZW) rabbits. Methods: The preclinical proof of concept was established in paracentesis-induced acute inflammation, endotoxin-induced acute uveitis, and bovine serum albumin-induced chronic uveitis in NZW rabbit animal models. A comparison of clinical score, total cell count, and total protein was performed to determine efficacy. An ocular pharmacokinetic study was conducted to study the influence of the vehicle on the ocular absorption of the drug. Results: In both uveitis models, the new solution formulation and marketed emulsion formulation inhibited total clinical score, total cell count, PGE2, and total protein significantly more than the placebo and lipopolysaccharide (disease control) groups and were comparable. In an ocular pharmacokinetic study, the Cmax and AUC0-t of difluoroprednisolone 17-butyrate in humor were ∼2-fold higher after 14 days' instillation of new solution formulation (0.04% w/v, BID) compared with 14 days' instillation of marketed emulsion (0.05% w/v, QID). Conclusions: The study demonstrated that the efficacy of the solution formulation at a lower dose and reduced dosing regimen were comparable to that of the emulsion formulation. The reduction in strength and regimen may result in improved patient adherence and outcomes.

Novel Discoveries and Clinical Advancements for Treating Onychomycosis: A Mechanistic Insight.

Onychomycosis continues to be the most challenging disease condition for pharmaceutical scientists to develop an effective drug delivery system. Treatment challenges lie in incomplete cure and high relapse rate. Present compilation provides cumulative information on pathophysiology, diagnostic techniques, and conventional treatment strategies to manage onychomycosis. Novel technologies developed for successful delivery of antifungal molecules are also discussed in brief. Multidirectional information offered by this article also unlocks the panoramic view of leading patented technologies and clinical trials. The obtained clinical landscape recommends the use of advanced technology driven approaches, as a promising way-out for treatment of onychomycosis. Collectively, present review warrants the application of novel technologies for the successful management of onychomycosis. This review will assist readers to envision a better understanding about the technologies available for combating onychomycosis. We also trust that these contributions address and certainly will encourage the design and development of nanocarriers-based delivery vehicles for effective management of onychomycosis.

Preclinical Evaluation of a Novel Once-a-Day Brimonidine Ophthalmic Nanosuspension.

Purpose: This article aims to describe a preclinical proof of concept for a novel once-a-day (OD) brimonidine ophthalmic nanosuspension. Methods: The preclinical proof of concept was established using New Zealand white rabbits as animal models. Dose-finding, multiple-dose efficacy, ocular pharmacokinetic, and hemodynamic studies were performed in normotensive rabbits. Steroid-induced ocular hypertension model in rabbits was used to study efficacy in glaucomatous pathophysiology. The test (0.35% OD suspension) and reference (0.15% three times a day [TID] solution) were compared. Results: The intraocular pressure (IOP) reduction was sustained for 0.35% and 0.5% strengths but not for other lower strengths tested or reference strengths. A 0.35% OD suspension reduced IOP >2 mmHg after 24 h of dosing, which was not seen with the reference. After multiple dosing, 0.35% OD suspension reduced IOP by 4-6 mmHg after 24 h, which was comparable to the 0.15% TID reference solution. An ocular pharmacokinetic study showed that the brimonidine was rapidly absorbed and distributed throughout the eye after topical administration. Concentration was higher in tissues with high α2 receptors, such as cornea-conjunctiva, iris/ciliary body, and choroid/retina. The steady-state concentrations in these organs were also significant after 24 h of the last dose. There was an indication of increased plasma levels, so a hemodynamic study was performed to assess any adverse effects. All hemodynamic parameters were normal and no new unusual safety findings were observed. Conclusions: The study demonstrated that the novel brimonidine 0.35% ophthalmic nanosuspension is both safe and effective when administered OD and is comparable to the marketed reference formulation administered TID.

Revisiting the in-vitro and in-vivo considerations for in-silico modelling of complex injectable drug products.

Complex injectable drug products (CIDPs) have often been developed to modulate the pharmacokinetics along with efficacy for therapeutic agents used for remediation of chronic disorders. The effective development of CIDPs has exhibited complex kinetics associated with multiphasic drug release from the prepared formulations. Consequently, predictability of pharmacokinetic modelling for such CIDPs has been difficult and there is need for advanced complex computational models for the establishment of accurate prediction models for in-vitro-in-vivo correlation (IVIVC). The computational modelling aims at supplementing the existing knowledge with mathematical equations to develop formulation strategies for generation of predictable and discriminatory IVIVC. Such an approach would help in reduction of the burden of effect of hidden factors on preclinical to clinical translations. Computational tools like physiologically based pharmacokinetics (PBPK) modelling have combined physicochemical and physiological properties along with IVIVC characteristics of clinically used formulations. Such techniques have helped in prediction and understanding of variability in pharmacodynamic parameters of potential generic products to clinically used formulations like Doxil®, Ambisome®, Abraxane® in healthy and diseased population using mathematical equations. The current review highlights the important formulation characteristics, in-vitro, preclinical in-vivo aspects which need to be considered while developing a stimulatory predictive PBPK model in establishment of an IVIVC and in-vitro-in-vivo relationship (IVIVR).

Triple negative breast cancer and non-small cell lung cancer: Clinical challenges and nano-formulation approaches.

Triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) are amongst the most aggressive forms of solid tumors. TNBC is highlighted by absence of genetic components of progesterone receptor, HER2/neu and estrogen receptor in breast cancer. NSCLC is characterized by integration of malignant carcinoma into respiratory system. Both cancers are associated with poor median and overall survival rates with low progression free survival with high incidences of relapse. These cancers are characterized by tumor heterogeneity, genetic mutations, generation of cancer-stem cells, immune-resistance and chemoresistance. Further, these neoplasms have been reported for tumor cross-talk into second primary cancers for each other. Current chemotherapeutic regimens include usage of multiple agents in tandem to affect tumor cells through multiple mechanisms with various such combinations being clinically tested. However, lack of controlled delivery and effective temporospatial presence of chemotherapeutics has resulted in suboptimal therapeutic response. Consequently, passive targeted albumin bound paclitaxel and PEGylated liposomal doxorubicin have been clinically used and tested with newer drugs for improved therapeutic efficacy in these cancers. Active targeting of nanocarriers against surface overexpressed proteins in both neoplasms have been explored. However, use of single agent nanoparticulate formulations against both cancers have failed to elicit desired outcomes. This review aims to identify clinical unmet need in these cancers while establishing a correlation with tested nano-formulation approaches and issues with preclinical to clinical translation. Lipid and polymer-based drug-drug and drug-gene combinatorial nanocarriers delivering multiple chemotherapeutics simultaneously to desired site of action have been detailed. Finally, emerging opportunities such as pharmacological targets (immune check point and epigentic modulators) as well as gene-based modulation (siRNA/CRISPR/Cas9) and the nano-formulation challenges for effective treatment of both cancers have been explored.

Pharmacokinetics and Pharmacology of Latanoprost 0.005% without Benzalkonium Chloride Vs Latanoprost 0.005% with Benzalkonium Chloride in New Zealand White Rabbits and Beagles.

Purpose: Many intraocular pressure (IOP)-lowering medications contain benzalkonium chloride (BAK), a preservative associated with unfavorable outcomes.A formulation of latanoprost 0.005% ophthalmic without BAK is approved by the FDA and indicated for reduction of IOP in patients with open-angle glaucoma or ocular hypertension. We present two preclinical studies of latanoprost 0.005% BAK-free vs latanoprost with BAK; one examining plasma and ocular tissue pharmacokinetics (PK) in New Zealand white rabbits, and one comparing in vivo IOP-lowering efficacy in healthy beagles.Methods: In the PK study, one drop of treatment (latanoprost BAK-free or latanoprost with BAK) was instilled into both eyes of rabbits in each treatment group (n = 18). At 0.25, 0.5, 1, 4, 6, and 24 hours postdose, three rabbits per study group underwent terminal blood and tissue collection.In the IOP study, in the first dosing period, both eyes of each beagle received either 1 drop latanoprost BAK-free or latanoprost with BAK, once daily for 10 days. After a 10-day washout period, a second 10-day dosing period was conducted and latanoprost BAK-free or latanoprost with BAK were dosed in the opposite eyes, respectively. IOP measurements were taken at 1, 6, and 12 hours postdose.Results: The maximum plasma concentration for latanoprost BAK-free and latanoprost with BAK occurred 0.25 hours after administration (174.1 vs 217.2 pg/mL, respectively). Area under the concentration time curve from zero to infinity was highest in aqueous humor for latanoprost BAK-free and latanoprost with BAK (133.1 vs 119.6 hr·ng/mL, respectively) and was not estimable in vitreous humor. In beagles, once-daily administration of latanoprost BAK-free or latanoprost with BAK led to a significant reduction in IOP vs baseline (P < .001); there was no difference between groups (P > .05).Conclusions: Latanoprost BAK-free showed comparable activity in reducing IOP, and comparable plasma and ocular PK parameters to latanoprost with BAK.

A phase I pharmacokinetic and safety study of Paclitaxel Injection Concentrate for Nano-dispersion (PICN) alone and in combination with carboplatin in patients with advanced solid malignancies and biliary tract cancers.

PURPOSE: Paclitaxel injection concentrate for nano-dispersion (PICN) is a Cremophor-free, nanotechnology-driven paclitaxel formulation. This phase I study examined the safety, tolerability, pharmacokinetics and maximum tolerated dose (MTD) of PICN alone and in combination with carboplatin. Its early efficacy in unresectable biliary tract cancers (BTCs) was also evaluated. METHODS: This multi-center study comprised two parts. Part A contained a dose-escalation cohort following "3 + 3" design using PICN monotherapy in advanced solid tumors (Part A1); Part A2 dose-expansion cohort was then conducted in advanced BTCs due to observed efficacy in Part A1. Part B1 and B2 evaluated escalating dose of PICN with carboplatin in advanced solid tumors. PICN was administered as a 30 min-infusion every 3 weeks without pre-medications for hypersensitivity reactions. RESULTS: Thirty-six patients received PICN monotherapy in Part A and 21 received PICN plus carboplatin in Part B. The MTD of PICN was determined to be 295 mg/m2 both as a monotherapy and in combination with carboplatin at AUC 5. Dose-proportional exposure in paclitaxel Cmax and AUC was observed overdose range from 175 to 325 mg/m2 for PICN monotherapy and its combination with carboplatin. Carboplatin did not alter PICN exposure. Clinically significant toxicities mainly include neutropenia and peripheral neuropathy. PICN monotherapy yielded a response rate of 20% in unresectable BTCs. CONCLUSION: This study demonstrated the safety and stable pharmacokinetics of PICN as a monotherapy and in combination with carboplatin. Single-agent PICN showed promising antitumor activity in advanced BTCs, warranting further studies to investigate its role in gastrointestinal cancers.

Physiochemical Properties and Cytotoxicity of a Benzalkonium Chloride-Free, Micellar Emulsion Ophthalmic Formulation of Latanoprost.

PURPOSE: Prostaglandin derivatives are used widely to reduce intraocular pressure associated with open-angle glaucoma. The most widely used prostaglandin derivative, latanoprost, is available in an ophthalmic solution that is solubilized and preserved with 0.02% benzalkonium chloride (BAK), which has been shown to be cytotoxic to corneal cells. Latanoprost ophthalmic solution with BAK requires specific storage temperatures, which can impact the supply cycle. Here, we describe the production, physicochemical characteristics, and cytotoxicity profile of a micelle formulation that solubilizes latanoprost without the need for BAK. METHODS: The optimum concentration of castor oil with the surfactant polyethylene glycol (15) hydroxystearate was determined, and the mixture stirred. Various surfactants were tested to determine the ideal mixture to form a micelle formulation. Viscosity, zeta potential, surface tension, droplet size, and osmolality of the batches were tested. The cytotoxicity of the micelle formulation was determined in a corneal cell viability assay that compared positive and negative controls, latanoprost without BAK, latanoprost with BAK, and placebo. RESULTS: A castor oil concentration of 0.15% produced a micelle formulation with a diameter of <100 nm. This micelle formulation had unique characteristics that were not mimicked when either the surfactant or the oil was changed. The physicochemical characteristics in multiple batches of the micelle formulation did not vary significantly between batches. Long-term and accelerated stability studies showed latanoprost potency remained constant for 24 months at 25°C/75% relative humidity (RH) and at 40°C/25% RH for 6 months. CONCLUSION: The micelle formulation technology system is capable of solubilizing latanoprost in an ophthalmic formulation without the need for BAK. The system is stable at room temperature.

Curcumin loaded poly (amidoamine) dendrimer-plamitic acid core-shell nanoparticles as anti-stress therapeutics.

Despite poor bioavailability of the drug and in vivo stability, curcumin has been reported for many pharmacological activities. Considering the potential of dendrimers as a drug delivery system, current research work is focused on the formulation and characterization of G4 PAMAM dendrimer-Palmitic acid core-shell nanoparticle-containing curcumin as antistress therapeutics to maximize the bioavailability of curcumin. Various formulations were prepared using different concentrations of palmitic acid and an optimized ratio of dendrimer and curcumin. All formulations were investigated for evaluation of physicochemical parameters, encapsulation efficiency, and in vitro release. Particle size, PDI, zeta-potential, and encapsulation efficiency of final formulation was found to be 257.9 ± 0.365 nm, 0.10 ± 0.004, 3.59 ± 0.167 mV, and 80.87%, respectively. In vitro release studies have shown that 53.62 ± 2.431% of the drug was released after 24 h. In vivo studies pharmacokinetic parameters, drug distribution, pharmacological, and toxicological were also estimated using swiss albino mice. The findings have shown the selected formulation is better than plain curcumin formulation.

Paclitaxel injection concentrate for nanodispersion versus nab-paclitaxel in women with metastatic breast cancer: a multicenter, randomized, comparative phase II/III study.

Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab-paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m(2) [n = 64] and 295 mg/m(2) [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m(2) every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m(2) every 3 weeks was effective and well tolerated and showed similar tolerability compared with nab-paclitaxel 260 mg/m(2) every 3 weeks. Statistically, significant differences were not observed in the PICN and nab-paclitaxel treatment arms for radiologist-assessed ORR or median PFS. The novel paclitaxel formulation, PICN, offers apart from efficacy, potential safety advantage of decreased use of corticosteroid pretreatment and the absence of the risk of transmission of blood product-borne disease.

Sorbitan ester organogels for transdermal delivery of sumatriptan.

The partial phase behavior, rheological, and drug release characteristics of an organogel (OG) composed of water, isooctane and sorbitan esters, sorbitan monopalmitate (Span-40) and poly(oxyethylene)sorbitan monostearate (Polysorbate-60) were studied. Phase diagrams showed decreasing areas of optically isotropic organogel region depending on the surfactant ratio, Kw and drug incorporation. The nonbirefringent, clear isotropic solution suggested the reverse micellar/microemulsion nature of the organogel without any molecular ordering. The increase in drug concentration in OGs leads to increase in the viscosity and sol-gel transition temperature (Tg). Fractal dimension (df) values calculated for different compositions suggested that the density of the tubular network increases with increasing drug concentration in OGs. The release rate of the drug from OGs was found to be non-Fickian through the dialysis membrane. The permeation rate of sumatriptan from pig skin was 0.231 mg/h/cm2 (781.9 nmol/h/cm2). The study indicates potential of OG as a reservoir system for transdermal drug delivery.

From ultrathin capsules to biaqueous vesicles.

The layer-by-layer (LbL) adsorption of anionic polyelectrolytes (PE) and tobramycin sulfate (TbS) multilayers on zinc oxide core particles followed by the controlled core-removal process leads to the formation of ultrathin capsules, which gradually convert to biaqueous vesicles and emulsionlike systems depending on the hydrophilicity/hydrophobicity of the PE backbone, PE/TbS ratio, and Zn2+ concentration. The unique characteristics of the PE/TbS multilayer capsules result because of the formation of PE/TbS/H2O biphasic liquid systems unlike the other LbL capsular systems that form stiff PE coacervates when mixed together in water. This paper investigates the PE/TbS ultrathin capsule to biaqueous vesicle transition and its physicochemical properties.

Ultrathin antibiotic walled microcapsules.

Ultrathin microcapsules comprised of anionic polyelectrolytes (PE) and a polycationic aminoglycoside (AmG) antibiotic drug were prepared by depositing PE/AmG multilayers on zinc oxide (ZnO) colloid particles using the layer-by-layer self-assembly technique and subsequently dissolving the ZnO templated cores. The polyelectrolytes, dextran sulfate sodium (DxS) and poly(styrenesulfonate) (PSS), were selected owing to their different backbone structure. An aminoglycoside, tobramycin sulfate (TbS), was used for studying DxS/TbS or PSS/TbS multilayer films. The multilayer growth on ZnO cores was characterized by alternating zeta potential values that were different for the DxS/TbS and PSS/TbS multilayers due to the PE chemistry and its interaction with Zn(2+) ions. Transmission and scanning electron microscopy provide evidence of PE/TbS multilayer coating on ZnO core particles. The slow acid-decomposition of the ZnO cores using weak organic acids and the presence of sufficient quantity of Zn(2+) in the dispersion were required to produce antibiotic multilayer capsules. There was no difference in the morphological characteristics of the two types of capsules; although, the yield for [PSS/TbS](5) capsules was significantly higher than for [DxS/TbS](5) capsules which was related to the physicochemical properties of DxS/TbS/Zn(2+) and PSS/TbS/Zn(2+) complexes forming the capsule wall. The TbS quantity in the multilayer films was determined using a quartz crystal microbalance and high performance liquid chromatography techniques which showed less TbS loading in both, capsules and multilayers on planar gold substrate, than the theoretical DxS:TbS or PSS:TbS stoichiometric ratio. The decomposition of the [PE/TbS](6) multilayers was fastest in physiological buffer followed by mannitol and water. The decomposition rate of the [PSS/TbS](6) multilayers was slower than [DxS/TbS](6) monolayers. The incomplete decomposition of DxS/TbS under saline conditions suggests the major role of hydrogen bonding for stability of DxS/TbS multilayers. A combination of hydrogen bonding and hydrophobic interaction between phenyl rings in PSS was responsible for PSS/TbS multilayer stability. In vivo studies in rabbits highlight the safety and sustained drug delivery potential of the PE/AmG microcapsules. The antibiotic walled ultrathin capsules presented here are suitable for sustained ophthalmic antibiotic delivery.

Solubility enhancement of indomethacin with poly(amidoamine) dendrimers and targeting to inflammatory regions of arthritic rats.

This work includes investigation on solubility enhancement of indomethacin (IND) in the presence of poly(amidoamine) (PAMAM) dendrimers and passive targeting of the PAMAM/IND complex so formed to the inflamed regions in an animal model. The complex formation was confirmed by infrared and (1)H nuclear magnetic resonance spectroscopy methods. Solubility of IND in aqueous G4-PAMAM followed Higuchi's A(N) curve depending on pH of the solubilizing medium. The solubility was decreased upon addition of dendrimer to the IND saturated solution at various pH, indicating aggregation behavior of the PAMAM/IND complex and conforming to the Higuchi's A(N) solubility profile. The in vitro release of IND from the PAMAM/IND complex through a cellophane membrane, from a Franz diffusion cell, showed 79 +/- 3.2% drug release in 24 h. The drug release was further retarded in the presence of human serum albumin (HSA) suggesting the significance of complex HSA binding in altering in vivo behavior of the complex. Intravenous administration of the PAMAM/IND complex formulation in rats showed a two-compartment pharmacokinetic profile. Enhanced effective IND concentrations in the inflamed regions were obtained for the prolonged time period with the PAMAM/IND complex compared to the free drug in arthritic rats indicating preferred accumulation of IND to the inflamed region. The targeting efficiency of PAMAM/IND complex was 2.29 times higher compared to free drug. In contrast to the previous investigations, two interesting findings reported here are: (a) solubility behavior of IND in G4-PAMAM dendrimer deviates from linearity with increasing concentrations of dendrimer at acidic to neutral pH values and (b) inspite of lymphatic drainage, retention of PAMAM/IND complexes occurs at the inflammatory site.

Phase structures of a hydrated anionic phospholipid composition containing cationic dendrimers and pegylated lipids.

The effect of 4th generation poly(amidoamine) dendrimer (4G PAMAM) present in an anionic phospholipid composition, consisting of hydrogenated soyphosphatidylcholine (HSPC), cholesterol (CH), dicetyl phosphate (DCP), and poly(ethylene glycol) (Mw approximately 2000) derivatized phosphatidylethanolamine (PEG2000-PE), on the hydration and liquid crystalline structure formation was investigated. The optical and polarized light microscopies of the liposomal dispersion obtained from the hydrated lipid composition show two types of birefringent structures (mesophases): plastic, wormlike microstructures and conventional, over-elongated lamellae. Differential scanning calorimetry (DSC) shows an increase in the liquid crystalline phase transition (Tg) of the lipid composition from 60 to 94 degrees C with increasing 4G PAMAM concentrations from 0 to 0.011 mM, respectively. The Tg values of the two microstructures were 68 and 84 degrees C, respectively, indicating that the plastic microstructures were 4G PAMAM/DCP-complexes-rich (alpha mesophases) and the conventional and elongated lamellae were dendrimer-doped HSPC/CH-rich microstructures (beta mesophases). Optical microscopy shows that the alpha mesophases convert into various other types of vesicular structures such as giant unilamellar vesicles and biliquid foams, upon heating above the phase transition temperature of the lipid composition (approximately 60-65 degrees C). The microstructure transformation is a result of an osmotic influx of water and the detergent action of PEG2000-PE present in the lipid composition. The transmission electron microscopy (TEM) images of the liposomal dispersion show particles embedding circular transparent domains that exactly correlate to the theoretical 4G PAMAM/DCP complex sizes, thus, providing evidence of 4G PAMAM interspersed within the two mesophases. Small-angle X-ray scattering (SAXS) measurements indicate that the alpha mesophases are a dendrimer-interlinked, symmetrically undulated lamellar phase and the beta mesophases are dendrimer-doped, occasionally kinked lamellae. An increase in dendrimer concentration in the lipid composition was found to decrease interlamellar spacing. On the basis of optical microscopy, DSC, TEM, and SAXS data, a model of dendrimer-doped mesophase structure and lamellae fusion is proposed. This investigation provides new self-assembled materials for drug/gene delivery and supplements the understanding of mechanisms involved in various biological processes such as membrane fusion, transmembrane permeation, and endocytosis.

Stepwise self-assembled poly(amidoamine) dendrimer and poly(styrenesulfonate) microcapsules as sustained delivery vehicles.

Hollow microcapsules comprised of poly(styrenesulfonate) (PSS) and a fourth generation poly(amidoamine) dendrimer (4G PAMAM) were prepared by depositing PSS/4G PAMAM multilayers on melamine formaldehyde (MF) colloid particles by the layer-by-layer self-assembly technique and subsequently dissolving the templated cores. The PSS/4G PAMAM layers were unstable toward the core removal procedure (pH approximately 1), resulting in a low yield of intact hollow capsules (<10% for 3.5 microm diameter MF templates). Stretching of the multilayer film due to core swelling during MF core dissolution leads to partial or complete destruction of capsules, giving discrete PSS-4G PAMAM complexes. Yields were increased by increasing inter- and intramolecular attractive forces between the PSS chains in the capsules through electrostatic, hydrophobic, and a combination of these interactions. The yields, however, were practically unaffected by enhancing such effects between dendrimer molecules. Transmission electron microscopy and scanning force microscopy measurements show no deformation for 3.5 microm capsules stabilized through the various interactions stated above. Further, capsules were filled with low molecular weight dextran sulfate and subsequently loaded with a model, therapeutically active molecule, doxorubicin hydrochloride (DOX). Release of DOX from the capsules was also studied to highlight the drug delivery potential of the dendrimer-based microcapsules.

Effect of dendrimer on entrapment and release of bioactive from liposomes.

An active encapsulation method to obtain high entrapment in liposomes is described. The method harnesses the ability of dendrimer to interact with oppositely charged phospholipid and solubilize acidic drugs in their interior. The high drug entrapment in liposomes is due to the enhanced entrapment of dendrimer, which creates sink in the liposomal aqueous compartment where the methotrexate (MTX) molecules are fluxed in. The encapsulation increases with dendrimer generation. The release of bioactive was also decreased by this method. The method may be useful to entrap drugs with relatively high therapeutic dose.