The efficacy of hydrogel foams in talc Pleurodesis.

BACKGROUND: Malignant pleural effusions are a serious complication of many late stage cancers that adversely affect quality of life. Pleurodesis with talc slurry is a standard treatment option, but clinical failures occur, possible due to poor talc delivery. A novel drug-delivery system was developed that fills the entire thoracic cavity with a liquid foam containing talc. The foam is designed to gel and adhere to the tissue walls at body temperature, to improve talc deposition and efficacy. METHODS: Rheology, foam stability, and ex-vivo coating and bio-adhesion studies were performed on three concentrations of a novel hydrogel talc foam system that was developed to improve delivery of talc to the pleural surfaces. A New Zealand rabbit model of pleurodesis was used to evaluate effectiveness of the foams at inducing adhesion formation and compared to talc slurry. The rabbits were recovered after they had one of the test agents instilled into their pleura, and then sacrificed after 28 days. Pleurodesis was assessed by a blinded pathologist using a standardized pathological scoring system. RESULTS: All talc foam formulations produced foams that gelled at physiological temperatures and were relatively stable for at least two hours. As the concentration of the formulation increased the gelation temperature decreased and the foam adhesiveness increased. Rabbits that received talc foam had significantly greater adhesion formation than talc slurry (mean score of 2.21 vs. 1.18 (p < 0.05)). Rabbits that received the 20% foam developed the most adhesions. CONCLUSIONS: This study demonstrates that our triblock copolymer hydrogel foam delivery system enhances adhesion formation in an experimental model. This novel approach can have important clinical impact, potentially improving efficacy of existing therapies and reducing the need for more invasive treatments.

Needle-free delivery of macromolecules across the skin by nanoliter-volume pulsed microjets.

Needle-free liquid jet injectors were invented >50 years ago for the delivery of proteins and vaccines. Despite their long history, needle-free liquid jet injectors are not commonly used as a result of frequent pain and bruising. We hypothesized that pain and bruising originate from the deep penetration of the jets and can potentially be addressed by minimizing the penetration depth of jets into the skin. However, current jet injectors are not designed to maintain shallow dermal penetration depths. Using a new strategy of jet injection, pulsed microjets, we report on delivery of protein drugs into the skin without deep penetration. The high velocity (v >100 m/s) of microjets allows their entry into the skin, whereas the small jet diameters (50-100 mum) and extremely small volumes (2-15 nanoliters) limit the penetration depth ( approximately 200 mum). In vitro experiments confirmed quantitative delivery of molecules into human skin and in vivo experiments with rats confirmed the ability of pulsed microjets to deliver therapeutic doses of insulin across the skin. Pulsed microjet injectors could be used to deliver drugs for local as well as systemic applications without using needles.

Needle-free liquid jet injections: mechanisms and applications.

Liquid jet injections employ a high-speed jet to puncture the skin and deliver drugs without the use of a needle. They have been used to deliver a number of macromolecules including vaccines and insulin, as well as small molecules, such as anesthetics and antibiotics. This article reviews liquid jet injectors with respect to their historical perspective, clinical applications, mechanisms and future prospects. An overview of the use of jet injectors for delivery of vaccines, insulin and growth hormones is presented. Particular attention is paid to the mechanistic understanding of jet injections, especially the dependence of jet penetration on parameters such as nozzle diameter, velocity and jet power. Finally, gaps in the current understanding are presented and suggestions for future research and development are made.

Jet-induced skin puncture and its impact on needle-free jet injections: experimental studies and a predictive model.

Needle-free jet injections constitute an important method of drug delivery, especially for insulin and vaccines. This report addresses the mechanisms of interactions of liquid jets with skin. Liquid jets first puncture the skin to form a hole through which the fluid is deposited into skin. Experimental studies showed that the depth of the hole significantly affects drug delivery by jet injections. At a constant jet exit velocity and nozzle diameter, the hole depth increased with increasing jet volume up to an asymptotic value and decreased with increasing values of skin's uniaxial Young's modulus. A theoretical model was developed to predict the hole depth as a function of jet and skin properties. A simplified model was first verified with polyacrylamide gels, a soft material in which the fluid mechanics during hole formation is well understood. Prediction of the hole depth in the skin is a first step in quantitatively predicting drug delivery by jet injection.

Needle-free jet injections: dependence of jet penetration and dispersion in the skin on jet power.

Jet injection is a needle-free drug delivery method in which a high-speed stream of fluid impacts the skin and delivers drugs. Although a number of jet injectors are commercially available, especially for insulin delivery, a quantitative understanding of the energetics of jet injection is still lacking. Here, we describe the dependence of jet injections into human skin on the power of the jet. Dermal delivery of liquid jets was quantified using two measurements, penetration of a radiolabeled solute, mannitol, into skin and the shape of jet dispersion in the skin which was visualized using sulforhodamine B (SRB). The power of the jet at the nozzle was varied from 1 to 600 W by independently altering the nozzle diameter (30-560 microm) and jet velocity (100-200 m/s). The dependence of the amount of liquid delivered in the skin and the geometric measurements of jet dispersion on nozzle diameter and jet velocity was captured by a single parameter, jet power. Additional experiments were performed using a model material, polyacrylamide gel, to further understand the dependence of jet penetration on jet power. These experiments demonstrated that jet power also effectively describes gel erosion due to liquid impingement.

Jet injection into polyacrylamide gels: investigation of jet injection mechanics.

Jet injectors employ high-velocity liquid jets that penetrate into human skin and deposit drugs in the dermal or subdermal region. Although jet injectors have been marketed for a number of years, relatively little is known about the interactions of high-speed jets with soft materials such as skin. Using polyacrylamide gels as a model system, the mechanics of jet penetration, including the dependence of jet penetration on mechanical properties, was studied. Jets employed in a typical commercial injector, (orifice diameter: 152 microm, velocity: 170-180 m/s) were used to inject fluid into polyacrylamide gels possessing Young's moduli in the range of 0.06-0.77 MPa and hardness values in the range of 4-70 H(OO). Motion analysis of jet entry into polyacrylamide gels revealed that jet penetration can be divided into three distinct events: erosion, stagnation, and dispersion. During the erosion phase, the jet removed the gel at the impact site and led to the formation of a distinct cylindrical hole. Cessation of erosion induced a period of jet stagnation ( approximately 600 micros) characterized by constant penetration depth. This stage was followed by dispersion of the liquid into the gel. The dispersion took place by crack propagation and was nearly symmetrical with the exception of injections into 10% acrylamide (Young's modulus of 0.06 MPa). The penetration depth of the jets as well as the rate of erosion decreased with increasing Young's modulus. The mechanics of jet penetration into polyacrylamide gels provides an important tool for understanding jet injection into skin.