Improving drug-like properties of insulin and GLP-1 via molecule design and formulation and improving diabetes management with device & drug delivery.

There is an increased incidence of diabetes worldwide. The discovery of insulin revolutionized the management of diabetes, the revelation of glucagon-like peptide-1 (GLP-1) and introduction of GLP-1 receptor agonists to clinical practice was another breakthrough. Continued translational research resulted in better understanding of diabetes, which, in combination with cutting-edge biology, chemistry, and pharmaceutical tools, have allowed for the development of safer, more effective and convenient insulins and GLP-1. Advances in self-administration of insulin and GLP-1 receptor agonist therapies with use of drug-device combination products have further improved the outcomes of diabetes management and quality of life for diabetic patients. The synergies of insulin and GLP-1 receptor agonist actions have led to development of devices that can deliver both molecules simultaneously. New chimeric GLP-1-incretins and insulin-GLP-1-incretin molecules are also being developed. The objective of this review is to summarize molecular designs to improve the drug-like properties of insulin and GLP-1 and to highlight the continued advancement of drug-device combination products to improve diabetes management.

Potency and Stability of Intradermal Capsaicin: Implications for Use as a Human Model of Pain in Multicenter Clinical Trials.

Intradermally injected capsaicin has been used extensively both as a human pain model and to assess analgesic efficacy. Factors such as dose, formulation, route, and site are known to affect its sensitivity. We determined whether potency and stability of capsaicin solutions were further sources of variability when following strict manufacturing guidelines. Capsaicin solution (1.0 mg/mL) was prepared according to Current Good Manufacturing Practice (cGMP) guidelines and aseptically filled into sterile amber borosilicate vials and stored at 5°C, 25°C, and 30°C. All samples were analyzed at one, three, six, and twelve months. Chemical stability was determined using HPLC and physical stability was evaluated by visual inspection of color changes, clarity, particulate matter, and product/ container closure abnormalities during each sampling time. Capsaicin intradermal injection was found to be sterile and retained 95% of the initial concentration for at least one year, regardless of studied storage temperatures (P<0.0001). Visual inspection indicated no changes in color, clarity, particulate matter, and product/ container closure abnormalities in all samples. These data show that capsaicin solutions (1.0 mg/mL) maintain their potency and stability over one year when manufactured according to cGMP guidelines. These results suggest that in clinical trials manufacturing of capsaicin solutions is recommended over extemporaneous compounding.

Targeted liposomal drug delivery systems for the treatment of B cell malignancies.

Nanoparticulate systems have demonstrated significant potential for overcoming the limitations of non-specific adverse effects related to chemotherapy. The treatment of blood malignancies employing targeted particulate drug delivery systems presents unique challenges and considerable research has been focused towards the development of targeted liposomal formulations for B cell malignancies. These formulations are aimed at achieving selectivity towards the malignant cells by targeting several cell surface markers which are over-expressed in that specific malignancy. CD19, CD20, CD22 and CD74 are few of such markers of which CD19, CD22 and CD74 are internalizing and CD20 is non-internalizing. Systems which have been developed to target both types of these cell surface markers are discussed. Specifically, the efficacy and development of targeted liposomes is considered. A number of studies have demonstrated the advantages of targeted liposomal systems encapsulating doxorubicin or vincristine. However, liposomal encapsulation of newer anti-neoplastic agents such as AD 198 which are superior to doxorubicin should be considered.

Core-shell-type lipid-polymer hybrid nanoparticles as a drug delivery platform.

The focus of nanoparticle design over the years has evolved toward more complex nanoscopic core-shell architecture using a single delivery system to combine multiple functionalities within nanoparticles. Core-shell-type lipid-polymer hybrid nanoparticles (CSLPHNs), which combine the mechanical advantages of biodegradable polymeric nanoparticles and biomimetic advantages of liposomes, have emerged as a robust and promising delivery platform. In CSLPHNs, a biodegradable polymeric core is surrounded by a shell composed of layer(s) of phospholipids. The hybrid architecture can provide advantages such as controllable particle size, surface functionality, high drug loading, entrapment of multiple therapeutic agents, tunable drug release profile, and good serum stability. This review focuses on current research trends on CSLPHNs including classification, advantages, methods of preparation, physicochemical characteristics, surface modifications, and immunocompatibility. Additionally, the review deals with applications for cancer chemotherapy, vaccines, and gene therapeutics. FROM THE CLINICAL EDITOR: This comprehensive review covers the current applications of core-shell-type lipid-polymer hybrid nanoparticles, which combine the mechanical advantages of biodegradable polymeric nanoparticles and biomimetic advantages of liposomes to enable an efficient drug delivery system.

Development and validation of a spectrofluorimetric method for the determination of erlotinib in spiked human plasma.

A rapid and sensitive spectrofluorimetric method was developed and validated for the determination of erlotinib (ETB), a potent anticancer drug, in spiked human plasma without any derivatization. The described method was validated and the analytical parameters of linearity, accuracy, precision (intra- and inter-day), limit of detection (LOD), and limit of quantification (LOQ) were evaluated. The relation between the fluorescence intensity and concentration was found to be linear (r(2) 0.9998) over the range 125 to 1000 ng/mL with the detection limit of 15 ng/mL. A simple liquid-liquid extraction method was followed in order to extract the drug from spiked plasma. The mean absolute recoveries of ETB were 85.59 % (±0.57), 86.91 % (±1.77) and 89.31 % (±3.01) at spiked plasma ETB concentration of 5000, 3750 and 2500 ng/mL, respectively. The spectrofluorimetric method presented here is a rapid, simple, specific, and reproducible method and can be used to characterize the plasma pharmacokinetics of ETB.

Application of acid-catalyzed hydrolysis of dispersed organic solvent in developing new microencapsulation process technology.

The aim of this study was to evaluate a new microencapsulation technology employing an acid-catalyzed solvent extraction method in conjunction to an emulsion-based microencapsulation process. Its process consisted of emulsifying a dispersed phase of poly(D,L-lactide-co-glycolide) and isopropyl formate in an aqueous phase. This step was followed by adding hydrochloric acid to the resulting oil-in-water emulsion, in order to initiate the hydrolysis of isopropyl formate dissolved in the aqueous phase. Its hydrolysis caused the liberation of water-soluble species, that is, isopropanol and formic acid. This event triggered continual solvent leaching out of emulsion droplets, thereby initiating microsphere solidification. This new processing worked well for encapsulation of progesterone and ketoprofen that were chosen as a nonionizable model drug and a weakly acidic one, respectively. Furthermore, the structural integrity of poly(D,L-lactide-co-glycolide) was retained during microencapsulation. The new microencapsulation technology, being conceptually different from previous approaches, might be useful in preparing various polymeric particles.

Low-volume binary drug therapy for the treatment of hypovolemia.

The selective regulation of total peripheral circulation in hypovolemic crisis offers a unique approach for treating and preventing hemorrhagic shock. Ideally, such a therapeutic intervention would require targeting of the striated muscle vascular beds without altering the vascular resistance in vital organ vascular beds. We discovered that a combination of cannabinoid receptor agonist, THC (Δ-tetrahydrocannabinol), and cyclooxygenase 2 inhibitor, NS-398, caused selective microvascular constriction in the mouse cremaster muscle manifested by a pronounced and significant 27.4% ± 7.9% decrease in vessel diameter relative to control (P < 0.01). This observation, and the reported lack of microvascular response in the mesentery and brain, led us to hypothesize that the drug combination could favorably redistribute blood volume in hypovolemia and prolong survival. To test the hypothesis, male Sprague-Dawley rats were subjected to a pressure-controlled hemorrhage (mean arterial pressure reduced to 30 ± 13.73 mmHg) then randomly assigned to one of six treatment groups (n = 6 per group). The untreated, NS-398-treated, and THC-treated groups manifested an insignificant difference in survival between groups after shock. The group treated with a combination of THC and NS-398 manifested a significant increase in mean survival from 53 ± 12 to 227 ± 23 min after shock (P < 0.001). The drug combination significantly reduced IL-1α, IL-1ß, IFN-γ, and IL-10 production compared with the group resuscitated with normal saline. In addition, histological evaluation indicated that the therapy protects the lungs and liver against hemorrhagic shock-induced damage. The combination of cannabinoid receptor agonist and cyclooxygenase 2 inhibitor represents a potentially new approach to low-volume therapeutic intervention for hypovolemia.

Evaluation of zeta-potential and particle size of technetium 99mTc-sulfur colloid subsequent to the addition of lidocaine and sodium bicarbonate.

UNLABELLED: The use of (99m)Tc-sulfur colloid lymphoscintigraphy for the determination of lymph flow patterns from a tumor site and localization of the sentinel node has been widely adopted. However, the effects of multiple injections of the radiopharmaceutical can range from mild discomfort to pain. pH-adjusted lidocaine HCl coadministered with (99m)Tc-sulfur colloid presents a risk of introducing instability of the radiopharmaceutical, which could lead to aggregation, possibly impeding the kinetics of lymphatic drainage from the tumor site. METHODS: In the present study, lidocaine pH-adjusted with 4.2%, 6.3%, or 8.4% sodium bicarbonate was added to the (99m)Tc-sulfur colloid radiopharmaceutical to monitor effects on radiochemical purity, zeta-potential, particle size, and pH. These parameters were then used to evaluate the short-term stability of the preparation. RESULTS: The study revealed that the formulation of lidocaine pH-adjusted with 8.4% sodium bicarbonate added to (99m)Tc-sulfur colloid demonstrated a similar change in zeta-potential (-4.09 +/- 2.90 mV) and particle size (10-330 nm) to that of control filtered (99m)Tc-sulfur colloid (-5.09 +/- 1.68 mV and 11-343 nm, respectively). However, the 4.2% preparation showed a zeta-potential of -3.01 +/- 2.24 mV and a particle size range of 10-351 nm. The pH of the 8.4% buffered preparation, at 7.1, was closer to physiologic pH than was the control, at 6.0. The 6.3% pH-adjusted lidocaine-(99m)Tc-sulfur colloid preparation failed radiochemical purity; thus, it was not included in the analysis. CONCLUSION: Compared with other (99m)Tc-sulfur colloid test formulations of 4.2% and 6.3% pH-adjusted lidocaine, the 8.4% sodium bicarbonate pH-adjusted lidocaine-(99m)Tc-sulfur colloid preparation, taken as a whole, yielded superior quality-control parameters. This formulation would be an acceptable alternative to the control.

Targeted nanoparticulate drug-delivery systems for treatment of solid tumors: a review.

Technological advancements in the field of biomaterials, polymer chemistry and drug-delivery techniques have aided the development of a number of new drug-delivery systems for targeting to solid tumors. Numerous research groups have explored the possibility of utilizing tumor-specific drug-delivery systems using nanoparticles. In this review we have attempted to highlight the achievements of some research groups actively involved in nanoparticulate drug delivery systems. The manuscript presents an in-depth discussion for nanoparticle systems such as micelles, liposomes, dendrimers, nanoemulsion, solid lipid nanoparticles and carbon fullerenes as chemotherapeutic options. The review reiterates the importance of the basic fundamentals of targeted drug delivery using nanoparticles and the influence of physiological parameters on their efficacy.

Evaluation of novel vanilloid-based hemostatic agents in rats.

BACKGROUND: : Hemostatic dressings containing clotting factors, biodegradable matrices, and recombinant proteins have been developed to control bleeding for battlefield trauma and trauma in clinical settings. Our present study evaluates the use of a vanilloid compound in biodegradable hemostatic dressings in a rat model of trauma. METHODS: : Male Sprague-Dawley rats (n = 180) were randomly divided into treatment groups and control groups and subjected to a lethal groin injury at 30 degrees C and 37 degrees C. Treatment groups included hemostatic matrices consisting of Protosan and graded doses of 2.5%, 5%, 10%, 15%, and 20% of the vanilloid agonist CAP-305. Powder or bilayer patch formulations were applied to the injury site. The seal integrity was assessed by reperfusion of the animal to a minimum mean-arterial pressure (MAP) of 80 mm Hg and monitoring for 60 minutes postinjury. RESULTS: : Powder and patch formulations loaded with varying concentrations of CAP-305 were evaluated. Powders containing 2.5% to 20% drug by weight showed 40% to 80% seal rates at 37 degrees C (p < 0.0001), whereas no significant results were obtained at 30 degrees C compared with the control animals. Conversely, bilayer patches loaded with 5% to 20% drug exhibited a consistent 70% seal rate (p < 0.0001) at 37 degrees C and 70% to 90% seal rates (p < 0.0001) in hypothermic animals when compared with controls. CONCLUSIONS: : Our study demonstrates the efficacy of CAP-305 loaded hemostatic dressings in the rat model of lethal groin injury. This study provides relevant proof of concept for the development of vanilloid agonists as hemostatic agents.

Design and synthesis of novel tri-aryl CB2 selective cannabinoid ligands.

A novel series of cannabinoid ligands with a structurally unique tri-aryl core has been designed, synthesized and assayed. Receptor binding assays show that these compounds possess CB2 receptor sub-type selectivity with binding affinities ranging from 1.07 (+/-0.05) for 7 to 4.77 (+/-0.57) nM for 6. The selectivity of the compounds was enhanced 9-600-fold for the CB2 receptor over the CB1 receptor. The results of our present study identify a novel, highly selective cannabinoid scaffold with a non-classical core.