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The expanding role of aerosols in systemic drug delivery, gene therapy and vaccination: an update.

Laube BL - Transl Respir Med (2014)

Bottom Line: The early promise of aerosolized systemic drug delivery and its outlook for future success will be highlighted.Finally, progress in the development of aerosolized vaccination will be presented.The continued expansion of the role of aerosol therapy in the future will depend on: (1) improving the bioavailability of systemically delivered drugs; (2) developing gene therapy vectors that can efficiently penetrate the mucus barrier and cell membrane, navigate the cell cytoplasm and efficiently transfer DNA material to the cell nucleus; (3) improving delivery of gene vectors and vaccines to infants; and (4) developing formulations that are safe for acute and chronic administrations.

View Article: PubMed Central - PubMed

Affiliation: The Johns Hopkins Medical Institutions, Suite 3015, The David M. Rubenstein Building, 200 North Wolfe Street, Baltimore, MD 21287 USA.

ABSTRACT
Until the late 1990s, aerosol therapy consisted of beta2-adrenergic agonists, anti-cholinergics, steroidal and non-steroidal agents, mucolytics and antibiotics that were used to treat patients with asthma, COPD and cystic fibrosis. Since then, inhalation therapy has matured to include drugs that: (1) are designed to treat diseases outside the lung and whose target is the systemic circulation (systemic drug delivery); (2) deliver nucleic acids that lead to permanent expression of a gene construct, or protein coding sequence, in a population of cells (gene therapy); and (3) provide needle-free immunization against disease (aerosolized vaccination). During the evolution of these advanced applications, it was also necessary to develop new devices that provided increased dosing efficiency and less loss during delivery. This review will present an update on the success of each of these new applications and their devices. The early promise of aerosolized systemic drug delivery and its outlook for future success will be highlighted. In addition, the challenges to aerosolized gene therapy and the need for appropriate gene vectors will be discussed. Finally, progress in the development of aerosolized vaccination will be presented. The continued expansion of the role of aerosol therapy in the future will depend on: (1) improving the bioavailability of systemically delivered drugs; (2) developing gene therapy vectors that can efficiently penetrate the mucus barrier and cell membrane, navigate the cell cytoplasm and efficiently transfer DNA material to the cell nucleus; (3) improving delivery of gene vectors and vaccines to infants; and (4) developing formulations that are safe for acute and chronic administrations.

No MeSH data available.


Related in: MedlinePlus

Results from recent clinical trial with inhaled Technosphere insulin plus insulin glargine.(A) Glycosylated hemoglobin (HbA1c) values over 52 weeks for patients who were treated with inhaled Technosphere insulin plus insulin glargine versus patients who were treated with Biaspart insulin by SC; (B) Change in fasting plasma glucose from baseline for two patient groups over 52 weeks (from Reference [36] with Permission).
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Fig2: Results from recent clinical trial with inhaled Technosphere insulin plus insulin glargine.(A) Glycosylated hemoglobin (HbA1c) values over 52 weeks for patients who were treated with inhaled Technosphere insulin plus insulin glargine versus patients who were treated with Biaspart insulin by SC; (B) Change in fasting plasma glucose from baseline for two patient groups over 52 weeks (from Reference [36] with Permission).

Mentions: AFREZZA® is a pocket-size device developed by MannKind Corporation (Valencia, CA, USA) (Figure 1) [34]. It is a second generation delivery system for inhaled insulin with several advantages over earlier generations. First, it delivers microparticles (Technospheres™) of insulin. Technosphere™ insulin particles (human regular insulin loaded onto a fumaryl diketopiperazine molecule) are optimized for deposition in the alveolar region of the lung. Greater than 90% of the particles are in the respirable range, with a mean particle diameter of 2.5 μm [35]. Bioavailability of this new formulation is also estimated to be 24-28% of SC [36] which is higher than for human regular insulin delivered by the Exubera® device. Unlike the Exubera®, it is small and portable and appears to be easier to use. In a recent clinical trial, the change in HBA1C for 211 type 2 patients after 52 weeks on prandial inhaled Technosphere plus bedtime insulin glargine was similar and non-inferior to that of 237 patients who were injected twice daily with biaspart insulin (70% insulin aspart protamine suspension and 30% insulin aspart) (Figure 2A and 2B) [36]. In addition, weight gain was lower and hypoglycemic events were fewer on Technoshpere compared to patients on injected insulin. Thirty-two percent of patients treated with Technosphere reported cough compared to 14% of patients treated with injected insulin. Most cough events occurred during the first 10 minutes of inhalation and declined to about 2/week by week 6. There were no differences between treatment groups in terms of pulmonary function changes. A recent review based on a MEDLINE search of studies relevant to Technosphere insulin concludes that it is has a pharmacokinetic profile suitable to meet prandial insulin needs in patients with diabetes [37]. The company is awaiting FDA approval for mealtime glucose control only. If approved, it could lead to earlier treatment of diabetes with insulin for patients who have resisted such treatment due to fear of, or pain associated with, injection therapy.Figure 1


The expanding role of aerosols in systemic drug delivery, gene therapy and vaccination: an update.

Laube BL - Transl Respir Med (2014)

Results from recent clinical trial with inhaled Technosphere insulin plus insulin glargine.(A) Glycosylated hemoglobin (HbA1c) values over 52 weeks for patients who were treated with inhaled Technosphere insulin plus insulin glargine versus patients who were treated with Biaspart insulin by SC; (B) Change in fasting plasma glucose from baseline for two patient groups over 52 weeks (from Reference [36] with Permission).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215822&req=5

Fig2: Results from recent clinical trial with inhaled Technosphere insulin plus insulin glargine.(A) Glycosylated hemoglobin (HbA1c) values over 52 weeks for patients who were treated with inhaled Technosphere insulin plus insulin glargine versus patients who were treated with Biaspart insulin by SC; (B) Change in fasting plasma glucose from baseline for two patient groups over 52 weeks (from Reference [36] with Permission).
Mentions: AFREZZA® is a pocket-size device developed by MannKind Corporation (Valencia, CA, USA) (Figure 1) [34]. It is a second generation delivery system for inhaled insulin with several advantages over earlier generations. First, it delivers microparticles (Technospheres™) of insulin. Technosphere™ insulin particles (human regular insulin loaded onto a fumaryl diketopiperazine molecule) are optimized for deposition in the alveolar region of the lung. Greater than 90% of the particles are in the respirable range, with a mean particle diameter of 2.5 μm [35]. Bioavailability of this new formulation is also estimated to be 24-28% of SC [36] which is higher than for human regular insulin delivered by the Exubera® device. Unlike the Exubera®, it is small and portable and appears to be easier to use. In a recent clinical trial, the change in HBA1C for 211 type 2 patients after 52 weeks on prandial inhaled Technosphere plus bedtime insulin glargine was similar and non-inferior to that of 237 patients who were injected twice daily with biaspart insulin (70% insulin aspart protamine suspension and 30% insulin aspart) (Figure 2A and 2B) [36]. In addition, weight gain was lower and hypoglycemic events were fewer on Technoshpere compared to patients on injected insulin. Thirty-two percent of patients treated with Technosphere reported cough compared to 14% of patients treated with injected insulin. Most cough events occurred during the first 10 minutes of inhalation and declined to about 2/week by week 6. There were no differences between treatment groups in terms of pulmonary function changes. A recent review based on a MEDLINE search of studies relevant to Technosphere insulin concludes that it is has a pharmacokinetic profile suitable to meet prandial insulin needs in patients with diabetes [37]. The company is awaiting FDA approval for mealtime glucose control only. If approved, it could lead to earlier treatment of diabetes with insulin for patients who have resisted such treatment due to fear of, or pain associated with, injection therapy.Figure 1

Bottom Line: The early promise of aerosolized systemic drug delivery and its outlook for future success will be highlighted.Finally, progress in the development of aerosolized vaccination will be presented.The continued expansion of the role of aerosol therapy in the future will depend on: (1) improving the bioavailability of systemically delivered drugs; (2) developing gene therapy vectors that can efficiently penetrate the mucus barrier and cell membrane, navigate the cell cytoplasm and efficiently transfer DNA material to the cell nucleus; (3) improving delivery of gene vectors and vaccines to infants; and (4) developing formulations that are safe for acute and chronic administrations.

View Article: PubMed Central - PubMed

Affiliation: The Johns Hopkins Medical Institutions, Suite 3015, The David M. Rubenstein Building, 200 North Wolfe Street, Baltimore, MD 21287 USA.

ABSTRACT
Until the late 1990s, aerosol therapy consisted of beta2-adrenergic agonists, anti-cholinergics, steroidal and non-steroidal agents, mucolytics and antibiotics that were used to treat patients with asthma, COPD and cystic fibrosis. Since then, inhalation therapy has matured to include drugs that: (1) are designed to treat diseases outside the lung and whose target is the systemic circulation (systemic drug delivery); (2) deliver nucleic acids that lead to permanent expression of a gene construct, or protein coding sequence, in a population of cells (gene therapy); and (3) provide needle-free immunization against disease (aerosolized vaccination). During the evolution of these advanced applications, it was also necessary to develop new devices that provided increased dosing efficiency and less loss during delivery. This review will present an update on the success of each of these new applications and their devices. The early promise of aerosolized systemic drug delivery and its outlook for future success will be highlighted. In addition, the challenges to aerosolized gene therapy and the need for appropriate gene vectors will be discussed. Finally, progress in the development of aerosolized vaccination will be presented. The continued expansion of the role of aerosol therapy in the future will depend on: (1) improving the bioavailability of systemically delivered drugs; (2) developing gene therapy vectors that can efficiently penetrate the mucus barrier and cell membrane, navigate the cell cytoplasm and efficiently transfer DNA material to the cell nucleus; (3) improving delivery of gene vectors and vaccines to infants; and (4) developing formulations that are safe for acute and chronic administrations.

No MeSH data available.


Related in: MedlinePlus