Effect of cryoprotectants on the stability and aerosol performance of nebulized aviscumine, a 57-kDa protein

Steckel, Hartwig; Eskandar, Fadi; Witthohn, Klaus

doi:10.1016/s0939-6411(03)00044-4

Cited by 13 publications

(7 citation statements)

References 27 publications

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“…Moreover, protein solutions are commonly freeze‐dried to provide greater physicochemical stability . When sodium polyphosphate, calcium chloride or magnesium sulfate are used as cryoprotectants in a protein formulation (aviscumine), decreased surface tension and increased viscosity are seen . The droplet size of jet nebulized formulations was observed to be slightly decreased when containing these excipients as compared to normal saline.…”

Section: Established Nebulizersmentioning

confidence: 99%

The function and performance of aqueous aerosol devices for inhalation therapy

Carvalho

McConville

2016

Journal of Pharmacy and Pharmacology

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Objectives In this review paper, we explore the interaction between the functioning mechanism of different nebulizers and the physicochemical properties of the formulations for several types of devices, namely jet, ultrasonic and vibrating-mesh nebulizers; colliding and extruded jets; electrohydrodynamic mechanism; surface acoustic wave microfluidic atomization; and capillary aerosol generation. Key findings Nebulization is the transformation of bulk liquids into droplets. For inhalation therapy, nebulizers are widely used to aerosolize aqueous systems, such as solutions and suspensions. The interaction between the functioning mechanism of different nebulizers and the physicochemical properties of the formulations plays a significant role in the performance of aerosol generation appropriate for pulmonary delivery. Certain types of nebulizers have consistently presented temperature increase during the nebulization event. Therefore, careful consideration should be given when evaluating thermo-labile drugs, such as protein therapeutics. We also present the general approaches for characterization of nebulizer formulations. Summary In conclusion, the interplay between the dosage form (i.e. aqueous systems) and the specific type of device for aerosol generation determines the effectiveness of drug delivery in nebulization therapies, thus requiring extensive understanding and characterization.

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Section: Established Nebulizersmentioning

confidence: 99%

The function and performance of aqueous aerosol devices for inhalation therapy

Carvalho

McConville

2016

Journal of Pharmacy and Pharmacology

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“…Because nebulization requires rather severe cavitation, it has been found beneficial to protect the proteins by the addition of certain surfactant stabilizers [141,142]. These additives appear to complex with the proteins and protect them from degradative shear stresses and perhaps from free radical attack.…”

Section: Pulmonary Delivery By Ultrasonic Nebulizationmentioning

confidence: 99%

“…It is possible that the surfactants may form micelles or liposomes that sequester the proteins and protect them from cavitation stresses. A short list of ultrasonically nebulized protein delivery includes interferon [143], platelet-activating factor [144], lactate dehydrogenase [141], superoxide dismutase [145], alpha1 protease inhibitor [146,147], urokinase plasminogen activator [148], and aviscumine [142].…”

Section: Pulmonary Delivery By Ultrasonic Nebulizationmentioning

confidence: 99%

Ultrasonic drug delivery – a general review

Pitt

Husseini

Staples

2004

Expert Opinion on Drug Delivery

543

428

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Ultrasound (US) has an ever-increasing role in the delivery of therapeutic agents including genetic material, proteins, and chemotherapeutic agents. Cavitating gas bodies such as microbubbles are the mediators through which the energy of relatively non-interactive pressure waves is concentrated to produce forces that permeabilize cell membranes and disrupt the vesicles that carry drugs. Thus the presence of microbubbles enormously enhances delivery of genetic material, proteins and smaller chemical agents. Delivery of genetic material is greatly enhanced by ultrasound in the presence of microbubbles. Attaching the DNA directly to the microbubbles or to gas-containing liposomes enhances gene uptake even further. US-enhanced gene delivery has been studied in various tissues including cardiac, vascular, skeletal muscle, tumor and even fetal tissue. US-enhanced delivery of proteins has found most application in transdermal delivery of insulin. Cavitation events reversibly disrupt the structure of the stratus corneum to allow transport of these large molecules. Other hormones and small proteins could also be delivered transdermally. Small chemotherapeutic molecules are delivered in research settings from micelles and liposomes exposed to ultrasound. Cavitation appears to play two roles: it disrupts the structure of the carrier vesicle and releases the drug; it also makes the cell membranes and capillaries more permeable to drugs. There remains a need to better understand the physics of cavitation of microbubbles and the impact that such cavitation has upon cells and drug-carrying vesicles.

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“…8) Formulations for efficient nebulization are usually designed using empirical methods that consider pharmacological effects and physicochemical properties, including viscosity, surface tension, and drug concentrations. [9][10][11][12][13][14] However, N-siRNA delivery by aerosol inhalation may result in marked losses in transfection efficiency because of the nebulization process. Higher concentrations of N-siRNA are necessary for the therapeutic application of aerosol inhalation techniques than for siRNA carrier systems, including cationic lipids and polymers.…”

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confidence: 99%

Inhalation Properties and Stability of Nebulized Naked siRNA Solution for Pulmonary Therapy

2016

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The use of naked unmodified small interfering RNA (N-siRNA) without vector has previously been investigated as a pulmonary therapy. However, little is known regarding stabilities and aerodynamic particle sizes of N-siRNA-containing droplets; nebulizers have not yet been optimized for N-siRNA solutions. Thus, in this study, we investigated the feasibility of inhaled N-siRNA solutions for pulmonary therapy using nebulization. Various nebulizers and N-siRNA concentrations were assessed in terms of siRNA integrity after nebulization, and inhalation properties including aerodynamic particle size were examined. In comparison with ultrasonic-, air-jet-, and vibrating-mesh nebulizers, N-siRNA integrity was not affected by nebulization. Thus, in further experiments, performances of N-siRNA aerosols with different nebulizers and N-siRNA concentrations were evaluated and screened using an aerodynamic particle sizer (APS) which employed the time-of-flight principle or a cascade impactor. Mean mass aerodynamic diameters of N-siRNA-containing droplets from vibrating-mesh nebulizers tended to decrease with increasing N-siRNA concentrations, reflecting the influence of N-siRNA solutions on surface tension, as indicated by contact angles. These data indicate the utility of APS instruments for investigating the nebulized characteristics of expensive drugs including siRNAs and may facilitate the development of N-siRNA inhalation formulations.Key words small interfering RNA (siRNA); vibrating-mesh nebulizer; aerodynamic particle size; surface tension; contact angle Small interfering RNA (siRNA) has a great therapeutic potential as a tool for the post-transcriptional silencing of target gene expression. 1) Recently, the field of siRNA delivery has rapidly progressed, and the local pulmonary delivery of siRNA has been investigated for various lung diseases. 2,3)Inhalation is the most popular noninvasive method for delivering therapeutic siRNA agents to the lungs 4); local siRNA inhalation therapy reduced virus titers in the lung and attenuated local pulmonary chemokine production after acute lung injury and infection.5,6) However, naked (unmodified) siRNA (N-siRNA) is susceptible to nuclease degradation; siRNA delivery systems facilitating gene silencing efficiency, including those using cationic materials, can have cytotoxic effects. N-siRNA has been delivered with some success to the lung, although systemic delivery of N-siRNA generally fails to produce significant gene silencing effects.3,7) N-siRNA lacks delivery vectors that produce toxicity and inflammation; thus, N-siRNA formulation for pulmonary delivery offers advantages for safety and simplicity. However, few developments of N-siRNA formulations have been reported. Direct pulmonary N-siRNA delivery has been achieved in humans following the inhalation of aerosols generated by inhalers or nebulizers. Three types of inhalation devices are currently available for pulmonary drug delivery, including metered dose inhalers, dry powder inhalers, and nebulizers. Liquid nebulization e...

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Effect of cryoprotectants on the stability and aerosol performance of nebulized aviscumine, a 57-kDa protein

Cited by 13 publications

References 27 publications

The function and performance of aqueous aerosol devices for inhalation therapy

The function and performance of aqueous aerosol devices for inhalation therapy

Ultrasonic drug delivery – a general review

Inhalation Properties and Stability of Nebulized Naked siRNA Solution for Pulmonary Therapy

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