Challenges and Future

Prospects for Pulmonary

Delivery of Biologics

AAPS Annual Meeting Oct 2015

Sildes Acknowledgement

Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga Ashkan Yazdi

Questions to be addressed

bull Why are biologics important

bull Can inhaled biologics become a reality

bull What evidence is there that inhaled biologics are possible

bull How does one deliver and formulate inhaled biologics

bull What can we expect in the next few years for inhaled biologics

Growth of Biologics

bull Biologics currently represent approximately a

20 share of all global pharmaceutical sales [1]

bull There are more than 300 therapeutic biological

molecules approved worldwide and many more

in product development pipelines

bull Biopharmarsquos current annual growth rate is

approximately 8 and is double that of

conventional pharma [2]

1 httpwwwimshealthcomdeployedfilesimshealthGlobalContentCorporateIMS Health

InstituteReportsGlobal_Use_of_Meds_Outlook_2017Biologics_Marketpdf

2 Ralf Otto AS Ulf Schrader Rapid growth in biopharma Challenges and opportunities 2014 Available from

httpwwwmckinseycominsightshealth_systems_and_servicesrapid_growth_in_biopharma

Alternative Route Inhalation

The inhaled route is an attractive alternative

to the parenteral route of administration for a

multitude of reasons

ndash Local delivery

bull allows high doses of protein drugs to be delivered

while limiting potential systemic side effects

ndash Systemic delivery

Large Surface Area For Absorption

Mild MetabolicEnzymatic

Environment bull Metabolism in lungs differs

substantially from the

intestinalndashhepatic

metabolism

bull Expression levels of

enzymes are generally

lower and the expression

patterns differ

Bo Olsson Eva Bondesson et al Pulmonary Drug Metabolism Clearance

and Absorption in Controlled Pulmonary Drug Delivery HDC Smyth and AJ Hickey (eds) DOI 101007978-1-4419-9745-

6_2

Administration Stability

Example of the challenge Insulin

Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics

Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280

Ubiquitous biologic formulation issues

+ aerosolization + excipient limitations

Can inhaled biologics become a

reality bull The withdrawal of Exuberareg remains a

disappointment and has ―muddied the waters for potential investorsdevelopers

bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram

rather than international units very large device)

ndash apparent safety considerations

ndash marketing and sales inadequacies

ndash pricing and sales

1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529

2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113

3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013

Mixed Perception for Inhaled Biologics

bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics

bull Realityhellip

ndash Pulmozymereg bull Dornase alpha or DNase Genentech

bull Approved in 1993

bull A mainstay of therapy for cystic fibrosis

bull Therefore there is a history of protein delivery to the lungs routinely without adverse events

ndash Afrezza bull Inhaled insulin approved

ndash Many others in the pipeline

Inhaled Biologics ndash Locally Acting Drug Clinical application

Pitrakinra (recombinant human Interleukin-4) Asthma

vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis

Glutathione Cystic Fibrosis

granulocyte-macrophage colony-stimulating

factor (GM-CSF) pulmonary alveolar proteinosis

DAS181 Influenza virus

INF-γ Cystic fibrosis

Interleukin-2 (IL-2) Cancer

Sargramostin

Metastatic

cancer

sarcoma

α1 -antitrypsin Fibrosis

Inhaled Proteins ndash Systemically Acting Drug

Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Insulin (Exuberareg) Hypoglycemic

effect Type III diabetes

Approved disc2007 Bellary and Barnett (2006)

(NektarPfizer)

Insulin (AIR system) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Muchmore et al (2007)

(AlkermesEli Lilly)

Insulin ( Afrezzareg) Hypoglycemic

effect Type III diabetes

ϕ Approved Steiner et al (2002)

(MannKind)

Insulin (AERx IDMS) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Thipphawong et al (2002)

(Aradigm)

Human parathyroid hormone

(PTH)

Bone mineral

metabolism Osteoporosis

Pilot clinical trial

(MannKind) Pfuumltzner et al (2003)

Interferons (INF) Immune system

regulation Multiple sclerosis Pre-clinical

Patton et al (1994) Martin et

al (2002) Vallee et al(2012)

and Agu RU (2001) Niven et

al (1995)

Interleukin-2 (IL-2) Immune system

regulation

Cancer and

immunodeficiency including

HIV

Mayo Clinic

Foundation Ten et al (2002)

Recombinant-methionyl

human granulocyte colony-

stimulating factor( r-huG-

CSF)

Immune system

regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)

Human growth Hormon

(hGH) Bone growth Growth deficiency

ϕ I completed 2008

(AlkermesEli Lilly) Nelson et al (2009) and

Walvoord et al (2009)

EPO-Fc Erythrocyte

production Anaemia

ϕ I completed 2005

(SyntonixBI)

Dumont et al

2005 and Bitonti and

Dumont 2006

Questions to be addressed

bull Why are biologics important

bull Can inhaled biologics become a reality

bull What evidence is there that inhaled biologics are possible

bull How does one deliver and formulate inhaled biologics

bull What can we expect in the next few years for inhaled biologics

Growth of Biologics

bull Biologics currently represent approximately a

20 share of all global pharmaceutical sales [1]

bull There are more than 300 therapeutic biological

molecules approved worldwide and many more

in product development pipelines

bull Biopharmarsquos current annual growth rate is

approximately 8 and is double that of

conventional pharma [2]

1 httpwwwimshealthcomdeployedfilesimshealthGlobalContentCorporateIMS Health

InstituteReportsGlobal_Use_of_Meds_Outlook_2017Biologics_Marketpdf

2 Ralf Otto AS Ulf Schrader Rapid growth in biopharma Challenges and opportunities 2014 Available from

httpwwwmckinseycominsightshealth_systems_and_servicesrapid_growth_in_biopharma

Alternative Route Inhalation

The inhaled route is an attractive alternative

to the parenteral route of administration for a

multitude of reasons

ndash Local delivery

bull allows high doses of protein drugs to be delivered

while limiting potential systemic side effects

ndash Systemic delivery

Large Surface Area For Absorption

Mild MetabolicEnzymatic

Environment bull Metabolism in lungs differs

substantially from the

intestinalndashhepatic

metabolism

bull Expression levels of

enzymes are generally

lower and the expression

patterns differ

Bo Olsson Eva Bondesson et al Pulmonary Drug Metabolism Clearance

and Absorption in Controlled Pulmonary Drug Delivery HDC Smyth and AJ Hickey (eds) DOI 101007978-1-4419-9745-

6_2

Administration Stability

Example of the challenge Insulin

Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics

Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280

Ubiquitous biologic formulation issues

+ aerosolization + excipient limitations

Can inhaled biologics become a

reality bull The withdrawal of Exuberareg remains a

disappointment and has ―muddied the waters for potential investorsdevelopers

bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram

rather than international units very large device)

ndash apparent safety considerations

ndash marketing and sales inadequacies

ndash pricing and sales

1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529

2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113

3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013

Mixed Perception for Inhaled Biologics

bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics

bull Realityhellip

ndash Pulmozymereg bull Dornase alpha or DNase Genentech

bull Approved in 1993

bull A mainstay of therapy for cystic fibrosis

bull Therefore there is a history of protein delivery to the lungs routinely without adverse events

ndash Afrezza bull Inhaled insulin approved

ndash Many others in the pipeline

Inhaled Biologics ndash Locally Acting Drug Clinical application

Pitrakinra (recombinant human Interleukin-4) Asthma

vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis

Glutathione Cystic Fibrosis

granulocyte-macrophage colony-stimulating

factor (GM-CSF) pulmonary alveolar proteinosis

DAS181 Influenza virus

INF-γ Cystic fibrosis

Interleukin-2 (IL-2) Cancer

Sargramostin

Metastatic

cancer

sarcoma

α1 -antitrypsin Fibrosis

Inhaled Proteins ndash Systemically Acting Drug

Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Insulin (Exuberareg) Hypoglycemic

effect Type III diabetes

Approved disc2007 Bellary and Barnett (2006)

(NektarPfizer)

Insulin (AIR system) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Muchmore et al (2007)

(AlkermesEli Lilly)

Insulin ( Afrezzareg) Hypoglycemic

effect Type III diabetes

ϕ Approved Steiner et al (2002)

(MannKind)

Insulin (AERx IDMS) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Thipphawong et al (2002)

(Aradigm)

Human parathyroid hormone

(PTH)

Bone mineral

metabolism Osteoporosis

Pilot clinical trial

(MannKind) Pfuumltzner et al (2003)

Interferons (INF) Immune system

regulation Multiple sclerosis Pre-clinical

Patton et al (1994) Martin et

al (2002) Vallee et al(2012)

and Agu RU (2001) Niven et

al (1995)

Interleukin-2 (IL-2) Immune system

regulation

Cancer and

immunodeficiency including

HIV

Mayo Clinic

Foundation Ten et al (2002)

Recombinant-methionyl

human granulocyte colony-

stimulating factor( r-huG-

CSF)

Immune system

regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)

Human growth Hormon

(hGH) Bone growth Growth deficiency

ϕ I completed 2008

(AlkermesEli Lilly) Nelson et al (2009) and

Walvoord et al (2009)

EPO-Fc Erythrocyte

production Anaemia

ϕ I completed 2005

(SyntonixBI)

Dumont et al

2005 and Bitonti and

Dumont 2006

Growth of Biologics

bull Biologics currently represent approximately a

20 share of all global pharmaceutical sales [1]

bull There are more than 300 therapeutic biological

molecules approved worldwide and many more

in product development pipelines

bull Biopharmarsquos current annual growth rate is

approximately 8 and is double that of

conventional pharma [2]

1 httpwwwimshealthcomdeployedfilesimshealthGlobalContentCorporateIMS Health

InstituteReportsGlobal_Use_of_Meds_Outlook_2017Biologics_Marketpdf

2 Ralf Otto AS Ulf Schrader Rapid growth in biopharma Challenges and opportunities 2014 Available from

httpwwwmckinseycominsightshealth_systems_and_servicesrapid_growth_in_biopharma

Alternative Route Inhalation

The inhaled route is an attractive alternative

to the parenteral route of administration for a

multitude of reasons

ndash Local delivery

bull allows high doses of protein drugs to be delivered

while limiting potential systemic side effects

ndash Systemic delivery

Large Surface Area For Absorption

Mild MetabolicEnzymatic

Environment bull Metabolism in lungs differs

substantially from the

intestinalndashhepatic

metabolism

bull Expression levels of

enzymes are generally

lower and the expression

patterns differ

Bo Olsson Eva Bondesson et al Pulmonary Drug Metabolism Clearance

and Absorption in Controlled Pulmonary Drug Delivery HDC Smyth and AJ Hickey (eds) DOI 101007978-1-4419-9745-

6_2

Administration Stability

Example of the challenge Insulin

Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics

Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280

Ubiquitous biologic formulation issues

+ aerosolization + excipient limitations

Can inhaled biologics become a

reality bull The withdrawal of Exuberareg remains a

disappointment and has ―muddied the waters for potential investorsdevelopers

bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram

rather than international units very large device)

ndash apparent safety considerations

ndash marketing and sales inadequacies

ndash pricing and sales

1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529

2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113

3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013

Mixed Perception for Inhaled Biologics

bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics

bull Realityhellip

ndash Pulmozymereg bull Dornase alpha or DNase Genentech

bull Approved in 1993

bull A mainstay of therapy for cystic fibrosis

bull Therefore there is a history of protein delivery to the lungs routinely without adverse events

ndash Afrezza bull Inhaled insulin approved

ndash Many others in the pipeline

Inhaled Biologics ndash Locally Acting Drug Clinical application

Pitrakinra (recombinant human Interleukin-4) Asthma

vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis

Glutathione Cystic Fibrosis

granulocyte-macrophage colony-stimulating

factor (GM-CSF) pulmonary alveolar proteinosis

DAS181 Influenza virus

INF-γ Cystic fibrosis

Interleukin-2 (IL-2) Cancer

Sargramostin

Metastatic

cancer

sarcoma

α1 -antitrypsin Fibrosis

Inhaled Proteins ndash Systemically Acting Drug

Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Insulin (Exuberareg) Hypoglycemic

effect Type III diabetes

Approved disc2007 Bellary and Barnett (2006)

(NektarPfizer)

Insulin (AIR system) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Muchmore et al (2007)

(AlkermesEli Lilly)

Insulin ( Afrezzareg) Hypoglycemic

effect Type III diabetes

ϕ Approved Steiner et al (2002)

(MannKind)

Insulin (AERx IDMS) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Thipphawong et al (2002)

(Aradigm)

Human parathyroid hormone

(PTH)

Bone mineral

metabolism Osteoporosis

Pilot clinical trial

(MannKind) Pfuumltzner et al (2003)

Interferons (INF) Immune system

regulation Multiple sclerosis Pre-clinical

Patton et al (1994) Martin et

al (2002) Vallee et al(2012)

and Agu RU (2001) Niven et

al (1995)

Interleukin-2 (IL-2) Immune system

regulation

Cancer and

immunodeficiency including

HIV

Mayo Clinic

Foundation Ten et al (2002)

Recombinant-methionyl

human granulocyte colony-

stimulating factor( r-huG-

CSF)

Immune system

regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)

Human growth Hormon

(hGH) Bone growth Growth deficiency

ϕ I completed 2008

(AlkermesEli Lilly) Nelson et al (2009) and

Walvoord et al (2009)

EPO-Fc Erythrocyte

production Anaemia

ϕ I completed 2005

(SyntonixBI)

Dumont et al

2005 and Bitonti and

Dumont 2006

Alternative Route Inhalation

The inhaled route is an attractive alternative

to the parenteral route of administration for a

multitude of reasons

ndash Local delivery

bull allows high doses of protein drugs to be delivered

while limiting potential systemic side effects

ndash Systemic delivery

Large Surface Area For Absorption

Mild MetabolicEnzymatic

Environment bull Metabolism in lungs differs

substantially from the

intestinalndashhepatic

metabolism

bull Expression levels of

enzymes are generally

lower and the expression

patterns differ

Bo Olsson Eva Bondesson et al Pulmonary Drug Metabolism Clearance

and Absorption in Controlled Pulmonary Drug Delivery HDC Smyth and AJ Hickey (eds) DOI 101007978-1-4419-9745-

6_2

Administration Stability

Example of the challenge Insulin

Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics

Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280

Ubiquitous biologic formulation issues

+ aerosolization + excipient limitations

Can inhaled biologics become a

reality bull The withdrawal of Exuberareg remains a

disappointment and has ―muddied the waters for potential investorsdevelopers

bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram

rather than international units very large device)

ndash apparent safety considerations

ndash marketing and sales inadequacies

ndash pricing and sales

1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529

2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113

3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013

Mixed Perception for Inhaled Biologics

bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics

bull Realityhellip

ndash Pulmozymereg bull Dornase alpha or DNase Genentech

bull Approved in 1993

bull A mainstay of therapy for cystic fibrosis

bull Therefore there is a history of protein delivery to the lungs routinely without adverse events

ndash Afrezza bull Inhaled insulin approved

ndash Many others in the pipeline

Inhaled Biologics ndash Locally Acting Drug Clinical application

Pitrakinra (recombinant human Interleukin-4) Asthma

vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis

Glutathione Cystic Fibrosis

granulocyte-macrophage colony-stimulating

factor (GM-CSF) pulmonary alveolar proteinosis

DAS181 Influenza virus

INF-γ Cystic fibrosis

Interleukin-2 (IL-2) Cancer

Sargramostin

Metastatic

cancer

sarcoma

α1 -antitrypsin Fibrosis

Inhaled Proteins ndash Systemically Acting Drug

Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Insulin (Exuberareg) Hypoglycemic

effect Type III diabetes

Approved disc2007 Bellary and Barnett (2006)

(NektarPfizer)

Insulin (AIR system) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Muchmore et al (2007)

(AlkermesEli Lilly)

Insulin ( Afrezzareg) Hypoglycemic

effect Type III diabetes

ϕ Approved Steiner et al (2002)

(MannKind)

Insulin (AERx IDMS) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Thipphawong et al (2002)

(Aradigm)

Human parathyroid hormone

(PTH)

Bone mineral

metabolism Osteoporosis

Pilot clinical trial

(MannKind) Pfuumltzner et al (2003)

Interferons (INF) Immune system

regulation Multiple sclerosis Pre-clinical

Patton et al (1994) Martin et

al (2002) Vallee et al(2012)

and Agu RU (2001) Niven et

al (1995)

Interleukin-2 (IL-2) Immune system

regulation

Cancer and

immunodeficiency including

HIV

Mayo Clinic

Foundation Ten et al (2002)

Recombinant-methionyl

human granulocyte colony-

stimulating factor( r-huG-

CSF)

Immune system

regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)

Human growth Hormon

(hGH) Bone growth Growth deficiency

ϕ I completed 2008

(AlkermesEli Lilly) Nelson et al (2009) and

Walvoord et al (2009)

EPO-Fc Erythrocyte

production Anaemia

ϕ I completed 2005

(SyntonixBI)

Dumont et al

2005 and Bitonti and

Dumont 2006

Large Surface Area For Absorption

Mild MetabolicEnzymatic

Environment bull Metabolism in lungs differs

substantially from the

intestinalndashhepatic

metabolism

bull Expression levels of

enzymes are generally

lower and the expression

patterns differ

Bo Olsson Eva Bondesson et al Pulmonary Drug Metabolism Clearance

and Absorption in Controlled Pulmonary Drug Delivery HDC Smyth and AJ Hickey (eds) DOI 101007978-1-4419-9745-

6_2

Administration Stability

Example of the challenge Insulin

Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics

Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280

Ubiquitous biologic formulation issues

+ aerosolization + excipient limitations

Can inhaled biologics become a

reality bull The withdrawal of Exuberareg remains a

disappointment and has ―muddied the waters for potential investorsdevelopers

bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram

rather than international units very large device)

ndash apparent safety considerations

ndash marketing and sales inadequacies

ndash pricing and sales

1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529

2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113

3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013

Mixed Perception for Inhaled Biologics

bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics

bull Realityhellip

ndash Pulmozymereg bull Dornase alpha or DNase Genentech

bull Approved in 1993

bull A mainstay of therapy for cystic fibrosis

bull Therefore there is a history of protein delivery to the lungs routinely without adverse events

ndash Afrezza bull Inhaled insulin approved

ndash Many others in the pipeline

Inhaled Biologics ndash Locally Acting Drug Clinical application

Pitrakinra (recombinant human Interleukin-4) Asthma

vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis

Glutathione Cystic Fibrosis

granulocyte-macrophage colony-stimulating

factor (GM-CSF) pulmonary alveolar proteinosis

DAS181 Influenza virus

INF-γ Cystic fibrosis

Interleukin-2 (IL-2) Cancer

Sargramostin

Metastatic

cancer

sarcoma

α1 -antitrypsin Fibrosis

Inhaled Proteins ndash Systemically Acting Drug

Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Insulin (Exuberareg) Hypoglycemic

effect Type III diabetes

Approved disc2007 Bellary and Barnett (2006)

(NektarPfizer)

Insulin (AIR system) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Muchmore et al (2007)

(AlkermesEli Lilly)

Insulin ( Afrezzareg) Hypoglycemic

effect Type III diabetes

ϕ Approved Steiner et al (2002)

(MannKind)

Insulin (AERx IDMS) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Thipphawong et al (2002)

(Aradigm)

Human parathyroid hormone

(PTH)

Bone mineral

metabolism Osteoporosis

Pilot clinical trial

(MannKind) Pfuumltzner et al (2003)

Interferons (INF) Immune system

regulation Multiple sclerosis Pre-clinical

Patton et al (1994) Martin et

al (2002) Vallee et al(2012)

and Agu RU (2001) Niven et

al (1995)

Interleukin-2 (IL-2) Immune system

regulation

Cancer and

immunodeficiency including

HIV

Mayo Clinic

Foundation Ten et al (2002)

Recombinant-methionyl

human granulocyte colony-

stimulating factor( r-huG-

CSF)

Immune system

regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)

Human growth Hormon

(hGH) Bone growth Growth deficiency

ϕ I completed 2008

(AlkermesEli Lilly) Nelson et al (2009) and

Walvoord et al (2009)

EPO-Fc Erythrocyte

production Anaemia

ϕ I completed 2005

(SyntonixBI)

Dumont et al

2005 and Bitonti and

Dumont 2006

Mild MetabolicEnzymatic

Environment bull Metabolism in lungs differs

substantially from the

intestinalndashhepatic

metabolism

bull Expression levels of

enzymes are generally

lower and the expression

patterns differ

Bo Olsson Eva Bondesson et al Pulmonary Drug Metabolism Clearance

and Absorption in Controlled Pulmonary Drug Delivery HDC Smyth and AJ Hickey (eds) DOI 101007978-1-4419-9745-

6_2

Administration Stability

Example of the challenge Insulin

Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics

Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280

Ubiquitous biologic formulation issues

+ aerosolization + excipient limitations

Can inhaled biologics become a

reality bull The withdrawal of Exuberareg remains a

disappointment and has ―muddied the waters for potential investorsdevelopers

bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram

rather than international units very large device)

ndash apparent safety considerations

ndash marketing and sales inadequacies

ndash pricing and sales

1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529

2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113

3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013

Mixed Perception for Inhaled Biologics

bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics

bull Realityhellip

ndash Pulmozymereg bull Dornase alpha or DNase Genentech

bull Approved in 1993

bull A mainstay of therapy for cystic fibrosis

bull Therefore there is a history of protein delivery to the lungs routinely without adverse events

ndash Afrezza bull Inhaled insulin approved

ndash Many others in the pipeline

Inhaled Biologics ndash Locally Acting Drug Clinical application

Pitrakinra (recombinant human Interleukin-4) Asthma

vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis

Glutathione Cystic Fibrosis

granulocyte-macrophage colony-stimulating

factor (GM-CSF) pulmonary alveolar proteinosis

DAS181 Influenza virus

INF-γ Cystic fibrosis

Interleukin-2 (IL-2) Cancer

Sargramostin

Metastatic

cancer

sarcoma

α1 -antitrypsin Fibrosis

Inhaled Proteins ndash Systemically Acting Drug

Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Insulin (Exuberareg) Hypoglycemic

effect Type III diabetes

Approved disc2007 Bellary and Barnett (2006)

(NektarPfizer)

Insulin (AIR system) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Muchmore et al (2007)

(AlkermesEli Lilly)

Insulin ( Afrezzareg) Hypoglycemic

effect Type III diabetes

ϕ Approved Steiner et al (2002)

(MannKind)

Insulin (AERx IDMS) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Thipphawong et al (2002)

(Aradigm)

Human parathyroid hormone

(PTH)

Bone mineral

metabolism Osteoporosis

Pilot clinical trial

(MannKind) Pfuumltzner et al (2003)

Interferons (INF) Immune system

regulation Multiple sclerosis Pre-clinical

Patton et al (1994) Martin et

al (2002) Vallee et al(2012)

and Agu RU (2001) Niven et

al (1995)

Interleukin-2 (IL-2) Immune system

regulation

Cancer and

immunodeficiency including

HIV

Mayo Clinic

Foundation Ten et al (2002)

Recombinant-methionyl

human granulocyte colony-

stimulating factor( r-huG-

CSF)

Immune system

regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)

Human growth Hormon

(hGH) Bone growth Growth deficiency

ϕ I completed 2008

(AlkermesEli Lilly) Nelson et al (2009) and

Walvoord et al (2009)

EPO-Fc Erythrocyte

production Anaemia

ϕ I completed 2005

(SyntonixBI)

Dumont et al

2005 and Bitonti and

Dumont 2006

Administration Stability

Example of the challenge Insulin

Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics

Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280

Ubiquitous biologic formulation issues

+ aerosolization + excipient limitations

Can inhaled biologics become a

reality bull The withdrawal of Exuberareg remains a

disappointment and has ―muddied the waters for potential investorsdevelopers

bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram

rather than international units very large device)

ndash apparent safety considerations

ndash marketing and sales inadequacies

ndash pricing and sales

1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529

2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113

3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013

Mixed Perception for Inhaled Biologics

bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics

bull Realityhellip

ndash Pulmozymereg bull Dornase alpha or DNase Genentech

bull Approved in 1993

bull A mainstay of therapy for cystic fibrosis

bull Therefore there is a history of protein delivery to the lungs routinely without adverse events

ndash Afrezza bull Inhaled insulin approved

ndash Many others in the pipeline

Inhaled Biologics ndash Locally Acting Drug Clinical application

Pitrakinra (recombinant human Interleukin-4) Asthma

vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis

Glutathione Cystic Fibrosis

granulocyte-macrophage colony-stimulating

factor (GM-CSF) pulmonary alveolar proteinosis

DAS181 Influenza virus

INF-γ Cystic fibrosis

Interleukin-2 (IL-2) Cancer

Sargramostin

Metastatic

cancer

sarcoma

α1 -antitrypsin Fibrosis

Inhaled Proteins ndash Systemically Acting Drug

Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Insulin (Exuberareg) Hypoglycemic

effect Type III diabetes

Approved disc2007 Bellary and Barnett (2006)

(NektarPfizer)

Insulin (AIR system) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Muchmore et al (2007)

(AlkermesEli Lilly)

Insulin ( Afrezzareg) Hypoglycemic

effect Type III diabetes

ϕ Approved Steiner et al (2002)

(MannKind)

Insulin (AERx IDMS) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Thipphawong et al (2002)

(Aradigm)

Human parathyroid hormone

(PTH)

Bone mineral

metabolism Osteoporosis

Pilot clinical trial

(MannKind) Pfuumltzner et al (2003)

Interferons (INF) Immune system

regulation Multiple sclerosis Pre-clinical

Patton et al (1994) Martin et

al (2002) Vallee et al(2012)

and Agu RU (2001) Niven et

al (1995)

Interleukin-2 (IL-2) Immune system

regulation

Cancer and

immunodeficiency including

HIV

Mayo Clinic

Foundation Ten et al (2002)

Recombinant-methionyl

human granulocyte colony-

stimulating factor( r-huG-

CSF)

Immune system

regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)

Human growth Hormon

(hGH) Bone growth Growth deficiency

ϕ I completed 2008

(AlkermesEli Lilly) Nelson et al (2009) and

Walvoord et al (2009)

EPO-Fc Erythrocyte

production Anaemia

ϕ I completed 2005

(SyntonixBI)

Dumont et al

2005 and Bitonti and

Dumont 2006

Example of the challenge Insulin

Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics

Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280

Ubiquitous biologic formulation issues

+ aerosolization + excipient limitations

Can inhaled biologics become a

reality bull The withdrawal of Exuberareg remains a

disappointment and has ―muddied the waters for potential investorsdevelopers

bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram

rather than international units very large device)

ndash apparent safety considerations

ndash marketing and sales inadequacies

ndash pricing and sales

1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529

2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113

3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013

Mixed Perception for Inhaled Biologics

bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics

bull Realityhellip

ndash Pulmozymereg bull Dornase alpha or DNase Genentech

bull Approved in 1993

bull A mainstay of therapy for cystic fibrosis

bull Therefore there is a history of protein delivery to the lungs routinely without adverse events

ndash Afrezza bull Inhaled insulin approved

ndash Many others in the pipeline

Inhaled Biologics ndash Locally Acting Drug Clinical application

Pitrakinra (recombinant human Interleukin-4) Asthma

vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis

Glutathione Cystic Fibrosis

granulocyte-macrophage colony-stimulating

factor (GM-CSF) pulmonary alveolar proteinosis

DAS181 Influenza virus

INF-γ Cystic fibrosis

Interleukin-2 (IL-2) Cancer

Sargramostin

Metastatic

cancer

sarcoma

α1 -antitrypsin Fibrosis

Inhaled Proteins ndash Systemically Acting Drug

Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Insulin (Exuberareg) Hypoglycemic

effect Type III diabetes

Approved disc2007 Bellary and Barnett (2006)

(NektarPfizer)

Insulin (AIR system) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Muchmore et al (2007)

(AlkermesEli Lilly)

Insulin ( Afrezzareg) Hypoglycemic

effect Type III diabetes

ϕ Approved Steiner et al (2002)

(MannKind)

Insulin (AERx IDMS) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Thipphawong et al (2002)

(Aradigm)

Human parathyroid hormone

(PTH)

Bone mineral

metabolism Osteoporosis

Pilot clinical trial

(MannKind) Pfuumltzner et al (2003)

Interferons (INF) Immune system

regulation Multiple sclerosis Pre-clinical

Patton et al (1994) Martin et

al (2002) Vallee et al(2012)

and Agu RU (2001) Niven et

al (1995)

Interleukin-2 (IL-2) Immune system

regulation

Cancer and

immunodeficiency including

HIV

Mayo Clinic

Foundation Ten et al (2002)

Recombinant-methionyl

human granulocyte colony-

stimulating factor( r-huG-

CSF)

Immune system

regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)

Human growth Hormon

(hGH) Bone growth Growth deficiency

ϕ I completed 2008

(AlkermesEli Lilly) Nelson et al (2009) and

Walvoord et al (2009)

EPO-Fc Erythrocyte

production Anaemia

ϕ I completed 2005

(SyntonixBI)

Dumont et al

2005 and Bitonti and

Dumont 2006

Can inhaled biologics become a

reality bull The withdrawal of Exuberareg remains a

disappointment and has ―muddied the waters for potential investorsdevelopers

bull There has been considerable speculation explaining the demise of this product ndash formulation and device issues (dose in milligram

rather than international units very large device)

ndash apparent safety considerations

ndash marketing and sales inadequacies

ndash pricing and sales

1 Heinemann L 2008 The failure of Exubera Are we beating a dead horse J Diabetes Sci Technol 2518ndash529

2 Siekmeier R Scheuch G 2008 Inhaled insulinmdashDoes it become a reality J Physiol Pharmacol 59(Suppl 6)81ndash113

3 Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013

Mixed Perception for Inhaled Biologics

bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics

bull Realityhellip

ndash Pulmozymereg bull Dornase alpha or DNase Genentech

bull Approved in 1993

bull A mainstay of therapy for cystic fibrosis

bull Therefore there is a history of protein delivery to the lungs routinely without adverse events

ndash Afrezza bull Inhaled insulin approved

ndash Many others in the pipeline

Inhaled Biologics ndash Locally Acting Drug Clinical application

Pitrakinra (recombinant human Interleukin-4) Asthma

vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis

Glutathione Cystic Fibrosis

granulocyte-macrophage colony-stimulating

factor (GM-CSF) pulmonary alveolar proteinosis

DAS181 Influenza virus

INF-γ Cystic fibrosis

Interleukin-2 (IL-2) Cancer

Sargramostin

Metastatic

cancer

sarcoma

α1 -antitrypsin Fibrosis

Inhaled Proteins ndash Systemically Acting Drug

Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Insulin (Exuberareg) Hypoglycemic

effect Type III diabetes

Approved disc2007 Bellary and Barnett (2006)

(NektarPfizer)

Insulin (AIR system) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Muchmore et al (2007)

(AlkermesEli Lilly)

Insulin ( Afrezzareg) Hypoglycemic

effect Type III diabetes

ϕ Approved Steiner et al (2002)

(MannKind)

Insulin (AERx IDMS) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Thipphawong et al (2002)

(Aradigm)

Human parathyroid hormone

(PTH)

Bone mineral

metabolism Osteoporosis

Pilot clinical trial

(MannKind) Pfuumltzner et al (2003)

Interferons (INF) Immune system

regulation Multiple sclerosis Pre-clinical

Patton et al (1994) Martin et

al (2002) Vallee et al(2012)

and Agu RU (2001) Niven et

al (1995)

Interleukin-2 (IL-2) Immune system

regulation

Cancer and

immunodeficiency including

HIV

Mayo Clinic

Foundation Ten et al (2002)

Recombinant-methionyl

human granulocyte colony-

stimulating factor( r-huG-

CSF)

Immune system

regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)

Human growth Hormon

(hGH) Bone growth Growth deficiency

ϕ I completed 2008

(AlkermesEli Lilly) Nelson et al (2009) and

Walvoord et al (2009)

EPO-Fc Erythrocyte

production Anaemia

ϕ I completed 2005

(SyntonixBI)

Dumont et al

2005 and Bitonti and

Dumont 2006

Mixed Perception for Inhaled Biologics

bull ―Exubera proves itrsquos just too hard too expensive and too risky to develop inhaled biologics

bull Realityhellip

ndash Pulmozymereg bull Dornase alpha or DNase Genentech

bull Approved in 1993

bull A mainstay of therapy for cystic fibrosis

bull Therefore there is a history of protein delivery to the lungs routinely without adverse events

ndash Afrezza bull Inhaled insulin approved

ndash Many others in the pipeline

Inhaled Biologics ndash Locally Acting Drug Clinical application

Pitrakinra (recombinant human Interleukin-4) Asthma

vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis

Glutathione Cystic Fibrosis

granulocyte-macrophage colony-stimulating

factor (GM-CSF) pulmonary alveolar proteinosis

DAS181 Influenza virus

INF-γ Cystic fibrosis

Interleukin-2 (IL-2) Cancer

Sargramostin

Metastatic

cancer

sarcoma

α1 -antitrypsin Fibrosis

Inhaled Proteins ndash Systemically Acting Drug

Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Insulin (Exuberareg) Hypoglycemic

effect Type III diabetes

Approved disc2007 Bellary and Barnett (2006)

(NektarPfizer)

Insulin (AIR system) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Muchmore et al (2007)

(AlkermesEli Lilly)

Insulin ( Afrezzareg) Hypoglycemic

effect Type III diabetes

ϕ Approved Steiner et al (2002)

(MannKind)

Insulin (AERx IDMS) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Thipphawong et al (2002)

(Aradigm)

Human parathyroid hormone

(PTH)

Bone mineral

metabolism Osteoporosis

Pilot clinical trial

(MannKind) Pfuumltzner et al (2003)

Interferons (INF) Immune system

regulation Multiple sclerosis Pre-clinical

Patton et al (1994) Martin et

al (2002) Vallee et al(2012)

and Agu RU (2001) Niven et

al (1995)

Interleukin-2 (IL-2) Immune system

regulation

Cancer and

immunodeficiency including

HIV

Mayo Clinic

Foundation Ten et al (2002)

Recombinant-methionyl

human granulocyte colony-

stimulating factor( r-huG-

CSF)

Immune system

regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)

Human growth Hormon

(hGH) Bone growth Growth deficiency

ϕ I completed 2008

(AlkermesEli Lilly) Nelson et al (2009) and

Walvoord et al (2009)

EPO-Fc Erythrocyte

production Anaemia

ϕ I completed 2005

(SyntonixBI)

Dumont et al

2005 and Bitonti and

Dumont 2006

Inhaled Biologics ndash Locally Acting Drug Clinical application

Pitrakinra (recombinant human Interleukin-4) Asthma

vasoactive intestinal peptide asthma pulmonary hypertension and sarcoidosis

Glutathione Cystic Fibrosis

granulocyte-macrophage colony-stimulating

factor (GM-CSF) pulmonary alveolar proteinosis

DAS181 Influenza virus

INF-γ Cystic fibrosis

Interleukin-2 (IL-2) Cancer

Sargramostin

Metastatic

cancer

sarcoma

α1 -antitrypsin Fibrosis

Inhaled Proteins ndash Systemically Acting Drug

Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Insulin (Exuberareg) Hypoglycemic

effect Type III diabetes

Approved disc2007 Bellary and Barnett (2006)

(NektarPfizer)

Insulin (AIR system) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Muchmore et al (2007)

(AlkermesEli Lilly)

Insulin ( Afrezzareg) Hypoglycemic

effect Type III diabetes

ϕ Approved Steiner et al (2002)

(MannKind)

Insulin (AERx IDMS) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Thipphawong et al (2002)

(Aradigm)

Human parathyroid hormone

(PTH)

Bone mineral

metabolism Osteoporosis

Pilot clinical trial

(MannKind) Pfuumltzner et al (2003)

Interferons (INF) Immune system

regulation Multiple sclerosis Pre-clinical

Patton et al (1994) Martin et

al (2002) Vallee et al(2012)

and Agu RU (2001) Niven et

al (1995)

Interleukin-2 (IL-2) Immune system

regulation

Cancer and

immunodeficiency including

HIV

Mayo Clinic

Foundation Ten et al (2002)

Recombinant-methionyl

human granulocyte colony-

stimulating factor( r-huG-

CSF)

Immune system

regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)

Human growth Hormon

(hGH) Bone growth Growth deficiency

ϕ I completed 2008

(AlkermesEli Lilly) Nelson et al (2009) and

Walvoord et al (2009)

EPO-Fc Erythrocyte

production Anaemia

ϕ I completed 2005

(SyntonixBI)

Dumont et al

2005 and Bitonti and

Dumont 2006

Inhaled Proteins ndash Systemically Acting Drug

Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Insulin (Exuberareg) Hypoglycemic

effect Type III diabetes

Approved disc2007 Bellary and Barnett (2006)

(NektarPfizer)

Insulin (AIR system) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Muchmore et al (2007)

(AlkermesEli Lilly)

Insulin ( Afrezzareg) Hypoglycemic

effect Type III diabetes

ϕ Approved Steiner et al (2002)

(MannKind)

Insulin (AERx IDMS) Hypoglycemic

effect Type III diabetes

ϕ III disc 2008 Thipphawong et al (2002)

(Aradigm)

Human parathyroid hormone

(PTH)

Bone mineral

metabolism Osteoporosis

Pilot clinical trial

(MannKind) Pfuumltzner et al (2003)

Interferons (INF) Immune system

regulation Multiple sclerosis Pre-clinical

Patton et al (1994) Martin et

al (2002) Vallee et al(2012)

and Agu RU (2001) Niven et

al (1995)

Interleukin-2 (IL-2) Immune system

regulation

Cancer and

immunodeficiency including

HIV

Mayo Clinic

Foundation Ten et al (2002)

Recombinant-methionyl

human granulocyte colony-

stimulating factor( r-huG-

CSF)

Immune system

regulation Immunodeficiency Pre-clinical Niven et al (1993 and 1994)

Human growth Hormon

(hGH) Bone growth Growth deficiency

ϕ I completed 2008

(AlkermesEli Lilly) Nelson et al (2009) and

Walvoord et al (2009)

EPO-Fc Erythrocyte

production Anaemia

ϕ I completed 2005

(SyntonixBI)

Dumont et al

2005 and Bitonti and

Dumont 2006

Inhaled Peptides ndash Systemically Acting

Drug Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Calcitonin Bone mineral

metabolism

Osteoporosis Pagets

disease

ϕ I completed 1996

(Dura Pharm) Deftos et al (1997)

Leuprolide

Regulation of

estradiol and

testosterone

Hormone-responsive

cancers estrogen-

dependent conditions

precocious puberty and in

vitro fertilization

TAP

Pharmaceuticals

Abbott Laboratories

Adjei A et al

(1990 and 1992)

Cetrorelix Mimetic of

leuprolide

Hormone-responsive

cancers estrogen-

dependent conditions

precocious puberty and in

vitro fertilization

Pre-clinical Lizio et al (2000)

PYY(3-36) Weight reduction Obesity Pre-clinical Kuehl et al (2015)

Glucagon-like peptide-

1 (GLP-1)

Hypoglycemic

effect Type II diabetes

ϕ I completed 2008

ϕ II ongoing

(MannKind)

NCT00642538

Lee et al (2009)

Inhaled Vaccines Drug

Biological

class

Biological

functions Clinical application

Clinical status

(sponsor)

RefTrial registry

number

Hepatitis B vaccine Immune system

stimulation Hepatitis B Pre-clinical

Thomas et al (2010 and

2011) Muttil et al (2010)

Diphtheria vaccine Immune system

stimulation Diphtheria Pre-clinical Muttil et al (2010)

HPV vaccine Immune system

stimulation Cervical cancer

Department of

Gynecology Centre

Hospitalier

Universitaire

Vaudois

Switzerland

Nardelli-Haefliger et al

(2005)

Influenza vaccine Immune system

stimulation Influenza Pre-clinical

Saluja et al (2010) and

Amorij et al (2007)

HIV vaccine Immune system

stimulation HIV Pre-clinical

Corbett et al (2007) and

Hunter et al (2009)

Live attenuated measles

virus vaccine

Immune system

stimulation Measles vaccine

Early pilot trials in

Mexico and ϕ I

ongoing 2012

(Serum Institute of

India Limited)

Sabin et al (1983 and

1984) Hiremath et al

(2005) Low et al (2007)

Agarkhedkar et al (2014)

NCT01557699

Live attenuated

Mycobacterium

bovis bacillus

vaccine Immune system

stimulation Tuberculosis vaccine

ϕ I ongoing 2012

(University of

Oxford)

NCT01497769

ApprovedLate stage Systemically

Acting Brand Name

(Company) Drug

Regulatory

Status Dosage Freq Tmax MW (Da) LogP Site of Action Refs

Exuberareg (Pfizer) Insulin Approved

Withdrawn

1 3 mg (~3 8

units) tid ~ 15 hr 5808 NA Systemic Mack(2007) Patton (2015)

Adasuvereg (Alexza) Loxapine Approved 10 mg PRN 10 min 3278 36 CNS Teva Pharms USA Inc-

Adasuve (R) [package Insert]

Afrezzareg

MannKind Insulin Approved

4 8 12 u

cartridges tid 15 min 5808 NA Systemic Cassidy (2011) Boss (2012)

Dance 501reg Dance Insulin Phase III Liq tid NA 5808 NA Systemic Dancebiopharmcom

Semprana

(Allergan)

Dihydro-

ergotamine

Pending

Approval 1 mginh PRN 10 min 67978 2

Cerebral arteries brain

stem Selberstein (2012) Cook

(2009)

Fludasereg (Ansun) DAS181 Phase III 10 mg qday NA 45 KDa NA LocalSystemic Fernanda (2014)

Relenzareg (GSK) Zanamivir Approved 5 mg qday-bid 1 - 2 hr 3323 -3 LocalSystemic Leung (2015)

NA (Vectura) Apomorphine Phase II Multidose

inhaler NA 2-7min 2673 31 CNS Morton (2008)

NA (Civitas) Levodopa Phase III 35 mg 50 mg NA 15 min 1972 -239 CNS Poewe (2015)

NA (GSK) Oxytocin Pre-clinical NA NA NA 1007 NA Uterus Prankerd (2013)

Enthusiasm

bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics

Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013

Challenges

Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics

Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280

0

90

180

0

90

180

0

90

180

0

90

180

Oropharyngeal

Trachea

Sedimentation 1-5 μm

Diffusion lt 1 μm

Air Velocity Anatomical

Region

Bronchial

Bronchiolar

Alveolar

Effective cross-sectional area

Inertial Impaction

5-30 μm

Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153

Aerodynamic Barriers

Sticky Van der Waals world

Gravity dominates

less cohesion

So What Happens to ParticlesDrug

After Deposition in the Airways

bull Mechanical

ndash Mucociliary clearance

ndash Cough

bull Cellular

ndash Alveolar macrophages

ndash Epithelial cells

ndash Partitioningabsorption

Mucocillary Clearance

bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains

bull In effect a combinatorial library

Phagocytosis

bull Particles penetrating

down to the

respiratory airways

are rapidly cleared

by alveolar

macrophages

bull 12-14

Macrophages05

billion alveoli

Phagocytosis is complex

bull Phagocytosis requires bull (1) binding of the particle to the macrophage

bull (2) activation of receptors (signal transfer)

bull (3) functional actin and

bull (4) phagosomes engulf material

bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator

bull Influenced by disease (eg incr in asthma)

bull Influence by particle size (Tabata amp Ikada 1988)

bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora

et al 1998)

Absorption bull 70 ndash 100 m2 surface area for absorption

bull Small hydrophobic molecules are rapidly

absorbed (within seconds) by passive diffusion

bull Transporters tight junctions or via

transcytosis through caveoli

Patton et al Proceedings of the American

Thoracic Society 1338-344 (2004)

Enthusiasm

bull ―The continued interest in the delivery of alpha-1-antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada) human growth hormone and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx PharmaNostrum Pharmaceuticals) is indicators of the enthusiasm for development of protein and peptide therapeutics

Hickey A Back to the Future Inhaled Drug Products J Pharm Sci 2013

Challenges

Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics

Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280

0

90

180

0

90

180

0

90

180

0

90

180

Oropharyngeal

Trachea

Sedimentation 1-5 μm

Diffusion lt 1 μm

Air Velocity Anatomical

Region

Bronchial

Bronchiolar

Alveolar

Effective cross-sectional area

Inertial Impaction

5-30 μm

Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153

Aerodynamic Barriers

Sticky Van der Waals world

Gravity dominates

less cohesion

So What Happens to ParticlesDrug

After Deposition in the Airways

bull Mechanical

ndash Mucociliary clearance

ndash Cough

bull Cellular

ndash Alveolar macrophages

ndash Epithelial cells

ndash Partitioningabsorption

Mucocillary Clearance

bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains

bull In effect a combinatorial library

Phagocytosis

bull Particles penetrating

down to the

respiratory airways

are rapidly cleared

by alveolar

macrophages

bull 12-14

Macrophages05

billion alveoli

Phagocytosis is complex

bull Phagocytosis requires bull (1) binding of the particle to the macrophage

bull (2) activation of receptors (signal transfer)

bull (3) functional actin and

bull (4) phagosomes engulf material

bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator

bull Influenced by disease (eg incr in asthma)

bull Influence by particle size (Tabata amp Ikada 1988)

bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora

et al 1998)

Absorption bull 70 ndash 100 m2 surface area for absorption

bull Small hydrophobic molecules are rapidly

absorbed (within seconds) by passive diffusion

bull Transporters tight junctions or via

transcytosis through caveoli

Patton et al Proceedings of the American

Thoracic Society 1338-344 (2004)

Challenges

Flore Depreter Gabrielle Pilcer Karim Amighi International Journal of Pharmaceutics

Volume 447 Issues 1ndash2 15 April 2013 Pages 251ndash280

0

90

180

0

90

180

0

90

180

0

90

180

Oropharyngeal

Trachea

Sedimentation 1-5 μm

Diffusion lt 1 μm

Air Velocity Anatomical

Region

Bronchial

Bronchiolar

Alveolar

Effective cross-sectional area

Inertial Impaction

5-30 μm

Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153

Aerodynamic Barriers

Sticky Van der Waals world

Gravity dominates

less cohesion

So What Happens to ParticlesDrug

After Deposition in the Airways

bull Mechanical

ndash Mucociliary clearance

ndash Cough

bull Cellular

ndash Alveolar macrophages

ndash Epithelial cells

ndash Partitioningabsorption

Mucocillary Clearance

bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains

bull In effect a combinatorial library

Phagocytosis

bull Particles penetrating

down to the

respiratory airways

are rapidly cleared

by alveolar

macrophages

bull 12-14

Macrophages05

billion alveoli

Phagocytosis is complex

bull Phagocytosis requires bull (1) binding of the particle to the macrophage

bull (2) activation of receptors (signal transfer)

bull (3) functional actin and

bull (4) phagosomes engulf material

bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator

bull Influenced by disease (eg incr in asthma)

bull Influence by particle size (Tabata amp Ikada 1988)

bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora

et al 1998)

Absorption bull 70 ndash 100 m2 surface area for absorption

bull Small hydrophobic molecules are rapidly

absorbed (within seconds) by passive diffusion

bull Transporters tight junctions or via

transcytosis through caveoli

Patton et al Proceedings of the American

Thoracic Society 1338-344 (2004)

0

90

180

0

90

180

0

90

180

0

90

180

Oropharyngeal

Trachea

Sedimentation 1-5 μm

Diffusion lt 1 μm

Air Velocity Anatomical

Region

Bronchial

Bronchiolar

Alveolar

Effective cross-sectional area

Inertial Impaction

5-30 μm

Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153

Aerodynamic Barriers

Sticky Van der Waals world

Gravity dominates

less cohesion

So What Happens to ParticlesDrug

After Deposition in the Airways

bull Mechanical

ndash Mucociliary clearance

ndash Cough

bull Cellular

ndash Alveolar macrophages

ndash Epithelial cells

ndash Partitioningabsorption

Mucocillary Clearance

bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains

bull In effect a combinatorial library

Phagocytosis

bull Particles penetrating

down to the

respiratory airways

are rapidly cleared

by alveolar

macrophages

bull 12-14

Macrophages05

billion alveoli

Phagocytosis is complex

bull Phagocytosis requires bull (1) binding of the particle to the macrophage

bull (2) activation of receptors (signal transfer)

bull (3) functional actin and

bull (4) phagosomes engulf material

bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator

bull Influenced by disease (eg incr in asthma)

bull Influence by particle size (Tabata amp Ikada 1988)

bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora

et al 1998)

Absorption bull 70 ndash 100 m2 surface area for absorption

bull Small hydrophobic molecules are rapidly

absorbed (within seconds) by passive diffusion

bull Transporters tight junctions or via

transcytosis through caveoli

Patton et al Proceedings of the American

Thoracic Society 1338-344 (2004)

Patton and Byron Nature Reviews Drug Discovery 6 67ndash74 (January 2007) | doi101038nrd2153

Aerodynamic Barriers

Sticky Van der Waals world

Gravity dominates

less cohesion

So What Happens to ParticlesDrug

After Deposition in the Airways

bull Mechanical

ndash Mucociliary clearance

ndash Cough

bull Cellular

ndash Alveolar macrophages

ndash Epithelial cells

ndash Partitioningabsorption

Mucocillary Clearance

bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains

bull In effect a combinatorial library

Phagocytosis

bull Particles penetrating

down to the

respiratory airways

are rapidly cleared

by alveolar

macrophages

bull 12-14

Macrophages05

billion alveoli

Phagocytosis is complex

bull Phagocytosis requires bull (1) binding of the particle to the macrophage

bull (2) activation of receptors (signal transfer)

bull (3) functional actin and

bull (4) phagosomes engulf material

bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator

bull Influenced by disease (eg incr in asthma)

bull Influence by particle size (Tabata amp Ikada 1988)

bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora

et al 1998)

Absorption bull 70 ndash 100 m2 surface area for absorption

bull Small hydrophobic molecules are rapidly

absorbed (within seconds) by passive diffusion

bull Transporters tight junctions or via

transcytosis through caveoli

Patton et al Proceedings of the American

Thoracic Society 1338-344 (2004)

So What Happens to ParticlesDrug

After Deposition in the Airways

bull Mechanical

ndash Mucociliary clearance

ndash Cough

bull Cellular

ndash Alveolar macrophages

ndash Epithelial cells

ndash Partitioningabsorption

Mucocillary Clearance

bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains

bull In effect a combinatorial library

Phagocytosis

bull Particles penetrating

down to the

respiratory airways

are rapidly cleared

by alveolar

macrophages

bull 12-14

Macrophages05

billion alveoli

Phagocytosis is complex

bull Phagocytosis requires bull (1) binding of the particle to the macrophage

bull (2) activation of receptors (signal transfer)

bull (3) functional actin and

bull (4) phagosomes engulf material

bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator

bull Influenced by disease (eg incr in asthma)

bull Influence by particle size (Tabata amp Ikada 1988)

bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora

et al 1998)

Absorption bull 70 ndash 100 m2 surface area for absorption

bull Small hydrophobic molecules are rapidly

absorbed (within seconds) by passive diffusion

bull Transporters tight junctions or via

transcytosis through caveoli

Patton et al Proceedings of the American

Thoracic Society 1338-344 (2004)

Mucocillary Clearance

bull Mucins are well adapted to trapping bull Extraordinary diversity of carbohydrate side chains

bull In effect a combinatorial library

Phagocytosis

bull Particles penetrating

down to the

respiratory airways

are rapidly cleared

by alveolar

macrophages

bull 12-14

Macrophages05

billion alveoli

Phagocytosis is complex

bull Phagocytosis requires bull (1) binding of the particle to the macrophage

bull (2) activation of receptors (signal transfer)

bull (3) functional actin and

bull (4) phagosomes engulf material

bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator

bull Influenced by disease (eg incr in asthma)

bull Influence by particle size (Tabata amp Ikada 1988)

bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora

et al 1998)

Absorption bull 70 ndash 100 m2 surface area for absorption

bull Small hydrophobic molecules are rapidly

absorbed (within seconds) by passive diffusion

bull Transporters tight junctions or via

transcytosis through caveoli

Patton et al Proceedings of the American

Thoracic Society 1338-344 (2004)

Phagocytosis

bull Particles penetrating

down to the

respiratory airways

are rapidly cleared

by alveolar

macrophages

bull 12-14

Macrophages05

billion alveoli

Phagocytosis is complex

bull Phagocytosis requires bull (1) binding of the particle to the macrophage

bull (2) activation of receptors (signal transfer)

bull (3) functional actin and

bull (4) phagosomes engulf material

bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator

bull Influenced by disease (eg incr in asthma)

bull Influence by particle size (Tabata amp Ikada 1988)

bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora

et al 1998)

Absorption bull 70 ndash 100 m2 surface area for absorption

bull Small hydrophobic molecules are rapidly

absorbed (within seconds) by passive diffusion

bull Transporters tight junctions or via

transcytosis through caveoli

Patton et al Proceedings of the American

Thoracic Society 1338-344 (2004)

Phagocytosis is complex

bull Phagocytosis requires bull (1) binding of the particle to the macrophage

bull (2) activation of receptors (signal transfer)

bull (3) functional actin and

bull (4) phagosomes engulf material

bull Macrophages migrate out of the alveoli and also reach the mucociliary escalator

bull Influenced by disease (eg incr in asthma)

bull Influence by particle size (Tabata amp Ikada 1988)

bull Shape surface chemistry (Champion amp Mitragotri 2006) (Evora

et al 1998)

Absorption bull 70 ndash 100 m2 surface area for absorption

bull Small hydrophobic molecules are rapidly

absorbed (within seconds) by passive diffusion

bull Transporters tight junctions or via

transcytosis through caveoli

Patton et al Proceedings of the American

Thoracic Society 1338-344 (2004)

Absorption bull 70 ndash 100 m2 surface area for absorption

bull Small hydrophobic molecules are rapidly

absorbed (within seconds) by passive diffusion

bull Transporters tight junctions or via

transcytosis through caveoli

Patton et al Proceedings of the American

Thoracic Society 1338-344 (2004)

Physicochemical Properties and

Dose

Cipolla amp Gonda 2011 Drug Disc Today ―Formulation technology to repurpose drugs for inhalation delivery

bull What biologics are susceptible to which

barriers

ndash DEPENDS - need to study each new case

Airway

anatomy

Disease

state

Breathing

Patterns

Particle

Size

Site of

Deposition

Physicochemical

Properties

Release

Rate

Pulmonary

Absorption

Pulmonary

Clearance

Mucociliary

escalator

Complexity of Lung Clearance

Pressurized Metered Dose Inhalers

bull Brief description HFA propellants device

valve actuator

bull Limitations Efficiency formulation design

space stability dose coordination

bull Advantages Portability pt acceptance

bull Is it practical to use this device

ndash Perhaps more evidence required to

determine platform applicability

Nebulizers

bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip

bull Limitations Efficiency stability (prior amp during neb) dose times

bull Advantages Aqueous formulations

bull Is it practical to use this device

ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary

Dry Powder Inhalers

bull Brief description Diverse devices passive active particle engineering

bull Limitations Formulationexcipient design window patient driven performance efficiency

bull Advantages Dose no coordination stability

bull Is it practical to use this device

ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary

ndash Newer devices achieve higher efficiencies less pt dependence

Peptideprotein Device Reference clinical trial number

Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]

Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization

NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]

IgG1 Nebulization DPI [23] and [41][42] [43] and [44]

BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II

IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II

rh-IL-4 receptor AERx [47]

Bikunin (Aerolyticreg) Nebulization Aerovance Phase II

Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]

Interferon-alpha Nebulizer AERx [50] and [51][52]

Interferon-beta i-neb AAD NCT01126177 Synairgen phase II

Interferon-gamma i-neb AAD [53]

Interferon-omega Respimatreg [54]

Interleukin-2 Jet nebulizer [55] and [56]

Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]

Catalase [59]

Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]

Mn-Superoxide dismutase Respimatreg [54]

Calcitonin DPI [61]

Parathyroid hormone it [62]

Human growth hormone DPI [63]

Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34

Insulin-like growth factor-I Nebulizer [66]

GLP-1 it [67]

rhG-CSF Nebulizer [68]

Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015

Are there ways of overcoming these

cellular and extracellular barriers

bull Epithelia ndash some evidence

bull Mucus ndash only a few technologies

bull Alveolar Macrophages ndash only a few

technologies

bull Pulmonary surfactant ndash some evidence

bull Enzymatic barrier ndash some evidence

Formulation approaches Surfactants

bull May increase the absorption of biologics through several mechanisms

bull alteration of mucus layer

bull protection against the enzymatic degradation

bull dissociation of proteins into oligomers or monomers

bull increase paracellular transport due to openings of tight junction

bull formation of micelles which facilitate protein transcellular transport

bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]

bull surfactant lauryl ether (rG-CSF) [99]

bull Span 85 for the administration of insulin [100 101]

97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43

98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71

99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6

100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73

102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110

Formulation approaches

bull Liposomes bull Protection from enzymatic deg enhance

absorption via surfactant recycling some peptides

hindered

bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin

bull Polymers bull Chitosan amp derivatives polyoxyethylene

Cryan AAPSJ 2005

Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14

Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44

Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats

J Pharm Sci 2008 97(12) p 5176-85

Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control

Release 2012 157(3) p 383-90

Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50

Formulation approaches Fusion Proteins

bull Receptor mediated transport across the

lung epithelium was successfully achieved

by fusing different proteins with the Fc

domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc

bull bioavailability retention of biological activity after

lung absorption and increased half-life

Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011

Formulation approaches Protease inhibitors

bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders

bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane

Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

Formulation approaches Mucus

bull Most work focused on improving nanoparticle

transport

bull PEG coatings specific density mw (Hanes

JHU Kala Pharma)

bull Mucolytics in formulations

Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007

Formulation approaches Macrophages

bull Using particle shape and size

ndash Low density porous particles (Edwards et al 1997)

ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug

delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release

2007)

ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC

(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm

Sci 99 2343ndash2356 doi 101002jps22003)

ndash PEGylation (Patton et al Pulmonary administration of chemically modified

insulin US 6838076 B2)

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Airway

anatomy

Disease

state

Breathing

Patterns

Particle

Size

Site of

Deposition

Physicochemical

Properties

Release

Rate

Pulmonary

Absorption

Pulmonary

Clearance

Mucociliary

escalator

Complexity of Lung Clearance

Pressurized Metered Dose Inhalers

bull Brief description HFA propellants device

valve actuator

bull Limitations Efficiency formulation design

space stability dose coordination

bull Advantages Portability pt acceptance

bull Is it practical to use this device

ndash Perhaps more evidence required to

determine platform applicability

Nebulizers

bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip

bull Limitations Efficiency stability (prior amp during neb) dose times

bull Advantages Aqueous formulations

bull Is it practical to use this device

ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary

Dry Powder Inhalers

bull Brief description Diverse devices passive active particle engineering

bull Limitations Formulationexcipient design window patient driven performance efficiency

bull Advantages Dose no coordination stability

bull Is it practical to use this device

ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary

ndash Newer devices achieve higher efficiencies less pt dependence

Peptideprotein Device Reference clinical trial number

Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]

Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization

NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]

IgG1 Nebulization DPI [23] and [41][42] [43] and [44]

BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II

IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II

rh-IL-4 receptor AERx [47]

Bikunin (Aerolyticreg) Nebulization Aerovance Phase II

Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]

Interferon-alpha Nebulizer AERx [50] and [51][52]

Interferon-beta i-neb AAD NCT01126177 Synairgen phase II

Interferon-gamma i-neb AAD [53]

Interferon-omega Respimatreg [54]

Interleukin-2 Jet nebulizer [55] and [56]

Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]

Catalase [59]

Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]

Mn-Superoxide dismutase Respimatreg [54]

Calcitonin DPI [61]

Parathyroid hormone it [62]

Human growth hormone DPI [63]

Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34

Insulin-like growth factor-I Nebulizer [66]

GLP-1 it [67]

rhG-CSF Nebulizer [68]

Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015

Are there ways of overcoming these

cellular and extracellular barriers

bull Epithelia ndash some evidence

bull Mucus ndash only a few technologies

bull Alveolar Macrophages ndash only a few

technologies

bull Pulmonary surfactant ndash some evidence

bull Enzymatic barrier ndash some evidence

Formulation approaches Surfactants

bull May increase the absorption of biologics through several mechanisms

bull alteration of mucus layer

bull protection against the enzymatic degradation

bull dissociation of proteins into oligomers or monomers

bull increase paracellular transport due to openings of tight junction

bull formation of micelles which facilitate protein transcellular transport

bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]

bull surfactant lauryl ether (rG-CSF) [99]

bull Span 85 for the administration of insulin [100 101]

97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43

98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71

99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6

100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73

102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110

Formulation approaches

bull Liposomes bull Protection from enzymatic deg enhance

absorption via surfactant recycling some peptides

hindered

bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin

bull Polymers bull Chitosan amp derivatives polyoxyethylene

Cryan AAPSJ 2005

Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14

Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44

Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats

J Pharm Sci 2008 97(12) p 5176-85

Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control

Release 2012 157(3) p 383-90

Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50

Formulation approaches Fusion Proteins

bull Receptor mediated transport across the

lung epithelium was successfully achieved

by fusing different proteins with the Fc

domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc

bull bioavailability retention of biological activity after

lung absorption and increased half-life

Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011

Formulation approaches Protease inhibitors

bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders

bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane

Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

Formulation approaches Mucus

bull Most work focused on improving nanoparticle

transport

bull PEG coatings specific density mw (Hanes

JHU Kala Pharma)

bull Mucolytics in formulations

Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007

Formulation approaches Macrophages

bull Using particle shape and size

ndash Low density porous particles (Edwards et al 1997)

ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug

delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release

2007)

ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC

(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm

Sci 99 2343ndash2356 doi 101002jps22003)

ndash PEGylation (Patton et al Pulmonary administration of chemically modified

insulin US 6838076 B2)

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Pressurized Metered Dose Inhalers

bull Brief description HFA propellants device

valve actuator

bull Limitations Efficiency formulation design

space stability dose coordination

bull Advantages Portability pt acceptance

bull Is it practical to use this device

ndash Perhaps more evidence required to

determine platform applicability

Nebulizers

bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip

bull Limitations Efficiency stability (prior amp during neb) dose times

bull Advantages Aqueous formulations

bull Is it practical to use this device

ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary

Dry Powder Inhalers

bull Brief description Diverse devices passive active particle engineering

bull Limitations Formulationexcipient design window patient driven performance efficiency

bull Advantages Dose no coordination stability

bull Is it practical to use this device

ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary

ndash Newer devices achieve higher efficiencies less pt dependence

Peptideprotein Device Reference clinical trial number

Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]

Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization

NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]

IgG1 Nebulization DPI [23] and [41][42] [43] and [44]

BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II

IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II

rh-IL-4 receptor AERx [47]

Bikunin (Aerolyticreg) Nebulization Aerovance Phase II

Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]

Interferon-alpha Nebulizer AERx [50] and [51][52]

Interferon-beta i-neb AAD NCT01126177 Synairgen phase II

Interferon-gamma i-neb AAD [53]

Interferon-omega Respimatreg [54]

Interleukin-2 Jet nebulizer [55] and [56]

Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]

Catalase [59]

Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]

Mn-Superoxide dismutase Respimatreg [54]

Calcitonin DPI [61]

Parathyroid hormone it [62]

Human growth hormone DPI [63]

Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34

Insulin-like growth factor-I Nebulizer [66]

GLP-1 it [67]

rhG-CSF Nebulizer [68]

Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015

Are there ways of overcoming these

cellular and extracellular barriers

bull Epithelia ndash some evidence

bull Mucus ndash only a few technologies

bull Alveolar Macrophages ndash only a few

technologies

bull Pulmonary surfactant ndash some evidence

bull Enzymatic barrier ndash some evidence

Formulation approaches Surfactants

bull May increase the absorption of biologics through several mechanisms

bull alteration of mucus layer

bull protection against the enzymatic degradation

bull dissociation of proteins into oligomers or monomers

bull increase paracellular transport due to openings of tight junction

bull formation of micelles which facilitate protein transcellular transport

bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]

bull surfactant lauryl ether (rG-CSF) [99]

bull Span 85 for the administration of insulin [100 101]

97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43

98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71

99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6

100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73

102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110

Formulation approaches

bull Liposomes bull Protection from enzymatic deg enhance

absorption via surfactant recycling some peptides

hindered

bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin

bull Polymers bull Chitosan amp derivatives polyoxyethylene

Cryan AAPSJ 2005

Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14

Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44

Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats

J Pharm Sci 2008 97(12) p 5176-85

Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control

Release 2012 157(3) p 383-90

Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50

Formulation approaches Fusion Proteins

bull Receptor mediated transport across the

lung epithelium was successfully achieved

by fusing different proteins with the Fc

domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc

bull bioavailability retention of biological activity after

lung absorption and increased half-life

Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011

Formulation approaches Protease inhibitors

bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders

bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane

Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

Formulation approaches Mucus

bull Most work focused on improving nanoparticle

transport

bull PEG coatings specific density mw (Hanes

JHU Kala Pharma)

bull Mucolytics in formulations

Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007

Formulation approaches Macrophages

bull Using particle shape and size

ndash Low density porous particles (Edwards et al 1997)

ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug

delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release

2007)

ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC

(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm

Sci 99 2343ndash2356 doi 101002jps22003)

ndash PEGylation (Patton et al Pulmonary administration of chemically modified

insulin US 6838076 B2)

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Nebulizers

bull Brief description Aqueous diverse devices air jet ultrasonic vibrating mesh hellip

bull Limitations Efficiency stability (prior amp during neb) dose times

bull Advantages Aqueous formulations

bull Is it practical to use this device

ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary

Dry Powder Inhalers

bull Brief description Diverse devices passive active particle engineering

bull Limitations Formulationexcipient design window patient driven performance efficiency

bull Advantages Dose no coordination stability

bull Is it practical to use this device

ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary

ndash Newer devices achieve higher efficiencies less pt dependence

Peptideprotein Device Reference clinical trial number

Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]

Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization

NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]

IgG1 Nebulization DPI [23] and [41][42] [43] and [44]

BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II

IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II

rh-IL-4 receptor AERx [47]

Bikunin (Aerolyticreg) Nebulization Aerovance Phase II

Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]

Interferon-alpha Nebulizer AERx [50] and [51][52]

Interferon-beta i-neb AAD NCT01126177 Synairgen phase II

Interferon-gamma i-neb AAD [53]

Interferon-omega Respimatreg [54]

Interleukin-2 Jet nebulizer [55] and [56]

Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]

Catalase [59]

Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]

Mn-Superoxide dismutase Respimatreg [54]

Calcitonin DPI [61]

Parathyroid hormone it [62]

Human growth hormone DPI [63]

Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34

Insulin-like growth factor-I Nebulizer [66]

GLP-1 it [67]

rhG-CSF Nebulizer [68]

Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015

Are there ways of overcoming these

cellular and extracellular barriers

bull Epithelia ndash some evidence

bull Mucus ndash only a few technologies

bull Alveolar Macrophages ndash only a few

technologies

bull Pulmonary surfactant ndash some evidence

bull Enzymatic barrier ndash some evidence

Formulation approaches Surfactants

bull May increase the absorption of biologics through several mechanisms

bull alteration of mucus layer

bull protection against the enzymatic degradation

bull dissociation of proteins into oligomers or monomers

bull increase paracellular transport due to openings of tight junction

bull formation of micelles which facilitate protein transcellular transport

bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]

bull surfactant lauryl ether (rG-CSF) [99]

bull Span 85 for the administration of insulin [100 101]

97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43

98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71

99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6

100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73

102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110

Formulation approaches

bull Liposomes bull Protection from enzymatic deg enhance

absorption via surfactant recycling some peptides

hindered

bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin

bull Polymers bull Chitosan amp derivatives polyoxyethylene

Cryan AAPSJ 2005

Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14

Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44

Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats

J Pharm Sci 2008 97(12) p 5176-85

Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control

Release 2012 157(3) p 383-90

Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50

Formulation approaches Fusion Proteins

bull Receptor mediated transport across the

lung epithelium was successfully achieved

by fusing different proteins with the Fc

domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc

bull bioavailability retention of biological activity after

lung absorption and increased half-life

Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011

Formulation approaches Protease inhibitors

bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders

bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane

Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

Formulation approaches Mucus

bull Most work focused on improving nanoparticle

transport

bull PEG coatings specific density mw (Hanes

JHU Kala Pharma)

bull Mucolytics in formulations

Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007

Formulation approaches Macrophages

bull Using particle shape and size

ndash Low density porous particles (Edwards et al 1997)

ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug

delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release

2007)

ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC

(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm

Sci 99 2343ndash2356 doi 101002jps22003)

ndash PEGylation (Patton et al Pulmonary administration of chemically modified

insulin US 6838076 B2)

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Dry Powder Inhalers

bull Brief description Diverse devices passive active particle engineering

bull Limitations Formulationexcipient design window patient driven performance efficiency

bull Advantages Dose no coordination stability

bull Is it practical to use this device

ndash Yes complexity of formulation and stability means preformulation formulation and device screening necessary

ndash Newer devices achieve higher efficiencies less pt dependence

Peptideprotein Device Reference clinical trial number

Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]

Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization

NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]

IgG1 Nebulization DPI [23] and [41][42] [43] and [44]

BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II

IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II

rh-IL-4 receptor AERx [47]

Bikunin (Aerolyticreg) Nebulization Aerovance Phase II

Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]

Interferon-alpha Nebulizer AERx [50] and [51][52]

Interferon-beta i-neb AAD NCT01126177 Synairgen phase II

Interferon-gamma i-neb AAD [53]

Interferon-omega Respimatreg [54]

Interleukin-2 Jet nebulizer [55] and [56]

Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]

Catalase [59]

Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]

Mn-Superoxide dismutase Respimatreg [54]

Calcitonin DPI [61]

Parathyroid hormone it [62]

Human growth hormone DPI [63]

Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34

Insulin-like growth factor-I Nebulizer [66]

GLP-1 it [67]

rhG-CSF Nebulizer [68]

Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015

Are there ways of overcoming these

cellular and extracellular barriers

bull Epithelia ndash some evidence

bull Mucus ndash only a few technologies

bull Alveolar Macrophages ndash only a few

technologies

bull Pulmonary surfactant ndash some evidence

bull Enzymatic barrier ndash some evidence

Formulation approaches Surfactants

bull May increase the absorption of biologics through several mechanisms

bull alteration of mucus layer

bull protection against the enzymatic degradation

bull dissociation of proteins into oligomers or monomers

bull increase paracellular transport due to openings of tight junction

bull formation of micelles which facilitate protein transcellular transport

bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]

bull surfactant lauryl ether (rG-CSF) [99]

bull Span 85 for the administration of insulin [100 101]

97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43

98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71

99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6

100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73

102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110

Formulation approaches

bull Liposomes bull Protection from enzymatic deg enhance

absorption via surfactant recycling some peptides

hindered

bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin

bull Polymers bull Chitosan amp derivatives polyoxyethylene

Cryan AAPSJ 2005

Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14

Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44

Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats

J Pharm Sci 2008 97(12) p 5176-85

Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control

Release 2012 157(3) p 383-90

Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50

Formulation approaches Fusion Proteins

bull Receptor mediated transport across the

lung epithelium was successfully achieved

by fusing different proteins with the Fc

domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc

bull bioavailability retention of biological activity after

lung absorption and increased half-life

Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011

Formulation approaches Protease inhibitors

bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders

bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane

Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

Formulation approaches Mucus

bull Most work focused on improving nanoparticle

transport

bull PEG coatings specific density mw (Hanes

JHU Kala Pharma)

bull Mucolytics in formulations

Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007

Formulation approaches Macrophages

bull Using particle shape and size

ndash Low density porous particles (Edwards et al 1997)

ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug

delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release

2007)

ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC

(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm

Sci 99 2343ndash2356 doi 101002jps22003)

ndash PEGylation (Patton et al Pulmonary administration of chemically modified

insulin US 6838076 B2)

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Peptideprotein Device Reference clinical trial number

Dornase alfa (DNase) Approved for nebulization Genzyme NCT01712334 [33] [34] [35] [36] [37][38]

Recombinant alpha-1-antitrypsin (rAAT) alpha-1-proteinase inhibitor Nebulization

NCT00486837 Talecris Phase III [25] NCT01217671 Kamada Phase III [39] and [40]

IgG1 Nebulization DPI [23] and [41][42] [43] and [44]

BIO-11006 Nebulization NCT00648245 [45] BioMarck Phase II

IL-4IL-13 antagonist (Pitrakinra) DPI NCT00801853 [46][43] Aerovance Phase II

rh-IL-4 receptor AERx [47]

Bikunin (Aerolyticreg) Nebulization Aerovance Phase II

Secretory leukoprotease inhibitor (SLPI) Nebulization DPI [48][49]

Interferon-alpha Nebulizer AERx [50] and [51][52]

Interferon-beta i-neb AAD NCT01126177 Synairgen phase II

Interferon-gamma i-neb AAD [53]

Interferon-omega Respimatreg [54]

Interleukin-2 Jet nebulizer [55] and [56]

Anti-IgE mAb (Omalizumabreg) Jet nebulizer DPI [57][58]

Catalase [59]

Liposomal rhldquoCuZnldquosuperoxide dismutase eFlow [60]

Mn-Superoxide dismutase Respimatreg [54]

Calcitonin DPI [61]

Parathyroid hormone it [62]

Human growth hormone DPI [63]

Insulin Exubera Afrezza Adagio DPI nebulizer Mannkind approved by FDA Dance Biopharm IncEudraCT 2012-002071-34

Insulin-like growth factor-I Nebulizer [66]

GLP-1 it [67]

rhG-CSF Nebulizer [68]

Sebastian P Hertel Gerhard Winter Wolfgang Friess Adv Drug Del Rev 2015

Are there ways of overcoming these

cellular and extracellular barriers

bull Epithelia ndash some evidence

bull Mucus ndash only a few technologies

bull Alveolar Macrophages ndash only a few

technologies

bull Pulmonary surfactant ndash some evidence

bull Enzymatic barrier ndash some evidence

Formulation approaches Surfactants

bull May increase the absorption of biologics through several mechanisms

bull alteration of mucus layer

bull protection against the enzymatic degradation

bull dissociation of proteins into oligomers or monomers

bull increase paracellular transport due to openings of tight junction

bull formation of micelles which facilitate protein transcellular transport

bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]

bull surfactant lauryl ether (rG-CSF) [99]

bull Span 85 for the administration of insulin [100 101]

97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43

98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71

99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6

100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73

102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110

Formulation approaches

bull Liposomes bull Protection from enzymatic deg enhance

absorption via surfactant recycling some peptides

hindered

bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin

bull Polymers bull Chitosan amp derivatives polyoxyethylene

Cryan AAPSJ 2005

Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14

Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44

Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats

J Pharm Sci 2008 97(12) p 5176-85

Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control

Release 2012 157(3) p 383-90

Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50

Formulation approaches Fusion Proteins

bull Receptor mediated transport across the

lung epithelium was successfully achieved

by fusing different proteins with the Fc

domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc

bull bioavailability retention of biological activity after

lung absorption and increased half-life

Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011

Formulation approaches Protease inhibitors

bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders

bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane

Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

Formulation approaches Mucus

bull Most work focused on improving nanoparticle

transport

bull PEG coatings specific density mw (Hanes

JHU Kala Pharma)

bull Mucolytics in formulations

Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007

Formulation approaches Macrophages

bull Using particle shape and size

ndash Low density porous particles (Edwards et al 1997)

ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug

delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release

2007)

ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC

(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm

Sci 99 2343ndash2356 doi 101002jps22003)

ndash PEGylation (Patton et al Pulmonary administration of chemically modified

insulin US 6838076 B2)

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Are there ways of overcoming these

cellular and extracellular barriers

bull Epithelia ndash some evidence

bull Mucus ndash only a few technologies

bull Alveolar Macrophages ndash only a few

technologies

bull Pulmonary surfactant ndash some evidence

bull Enzymatic barrier ndash some evidence

Formulation approaches Surfactants

bull May increase the absorption of biologics through several mechanisms

bull alteration of mucus layer

bull protection against the enzymatic degradation

bull dissociation of proteins into oligomers or monomers

bull increase paracellular transport due to openings of tight junction

bull formation of micelles which facilitate protein transcellular transport

bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]

bull surfactant lauryl ether (rG-CSF) [99]

bull Span 85 for the administration of insulin [100 101]

97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43

98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71

99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6

100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73

102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110

Formulation approaches

bull Liposomes bull Protection from enzymatic deg enhance

absorption via surfactant recycling some peptides

hindered

bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin

bull Polymers bull Chitosan amp derivatives polyoxyethylene

Cryan AAPSJ 2005

Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14

Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44

Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats

J Pharm Sci 2008 97(12) p 5176-85

Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control

Release 2012 157(3) p 383-90

Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50

Formulation approaches Fusion Proteins

bull Receptor mediated transport across the

lung epithelium was successfully achieved

by fusing different proteins with the Fc

domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc

bull bioavailability retention of biological activity after

lung absorption and increased half-life

Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011

Formulation approaches Protease inhibitors

bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders

bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane

Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

Formulation approaches Mucus

bull Most work focused on improving nanoparticle

transport

bull PEG coatings specific density mw (Hanes

JHU Kala Pharma)

bull Mucolytics in formulations

Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007

Formulation approaches Macrophages

bull Using particle shape and size

ndash Low density porous particles (Edwards et al 1997)

ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug

delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release

2007)

ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC

(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm

Sci 99 2343ndash2356 doi 101002jps22003)

ndash PEGylation (Patton et al Pulmonary administration of chemically modified

insulin US 6838076 B2)

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Formulation approaches Surfactants

bull May increase the absorption of biologics through several mechanisms

bull alteration of mucus layer

bull protection against the enzymatic degradation

bull dissociation of proteins into oligomers or monomers

bull increase paracellular transport due to openings of tight junction

bull formation of micelles which facilitate protein transcellular transport

bull Examples bull taurocholic acid with salmon calcitonin [97] and insulin [98]

bull surfactant lauryl ether (rG-CSF) [99]

bull Span 85 for the administration of insulin [100 101]

97Kobayashi S S Kondo and K Juni Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers Pharm Res 1994 11(9) p 1239-43

98Johansson F et al Mechanisms for absorption enhancement of inhaled insulin by sodium taurocholate Eur J Pharm Sci 2002 17(1-2) p 63-71

99Machida M M Hayashi and S Awazu The effects of absorption enhancers on the pulmonary absorption of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in rats Biol Pharm Bull 2000 23(1) p 84-6

100Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

101Okumura K et al Intratracheal delivery of insulin absorption from solution and aerosol by rat lung International journal of pharmaceutics 1992 88(1) p 63-73

102Todo H et al Effect of additives on insulin absorption from intratracheally administered dry powders in rats International journal of pharmaceutics 2001 220(1) p 101-110

Formulation approaches

bull Liposomes bull Protection from enzymatic deg enhance

absorption via surfactant recycling some peptides

hindered

bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin

bull Polymers bull Chitosan amp derivatives polyoxyethylene

Cryan AAPSJ 2005

Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14

Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44

Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats

J Pharm Sci 2008 97(12) p 5176-85

Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control

Release 2012 157(3) p 383-90

Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50

Formulation approaches Fusion Proteins

bull Receptor mediated transport across the

lung epithelium was successfully achieved

by fusing different proteins with the Fc

domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc

bull bioavailability retention of biological activity after

lung absorption and increased half-life

Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011

Formulation approaches Protease inhibitors

bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders

bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane

Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

Formulation approaches Mucus

bull Most work focused on improving nanoparticle

transport

bull PEG coatings specific density mw (Hanes

JHU Kala Pharma)

bull Mucolytics in formulations

Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007

Formulation approaches Macrophages

bull Using particle shape and size

ndash Low density porous particles (Edwards et al 1997)

ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug

delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release

2007)

ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC

(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm

Sci 99 2343ndash2356 doi 101002jps22003)

ndash PEGylation (Patton et al Pulmonary administration of chemically modified

insulin US 6838076 B2)

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Formulation approaches

bull Liposomes bull Protection from enzymatic deg enhance

absorption via surfactant recycling some peptides

hindered

bull Cyclodextrins bull Shown to improve bioavailability for rhGH insulin

bull Polymers bull Chitosan amp derivatives polyoxyethylene

Cryan AAPSJ 2005

Huang YY and CH Wang Pulmonary delivery of insulin by liposomal carriers J Control Release 2006 113(1) p 9-14

Ten RM et al Interleukin-2 liposomes for primary immune deficiency using the aerosol route Int Immunopharmacol 2002 2(2-3) p 333-44

Jalalipour M et al Effect of dimethyl-beta-cyclodextrin concentrations on the pulmonary delivery of recombinant human growth hormone dry powder in rats

J Pharm Sci 2008 97(12) p 5176-85

Al-Qadi S et al Microencapsulated chitosan nanoparticles for pulmonary protein delivery in vivo evaluation of insulin-loaded formulations J Control

Release 2012 157(3) p 383-90

Li HY and J Birchall Chitosan-modified dry powder formulations for pulmonary gene delivery Pharm Res 2006 23(5) p 941-50

Formulation approaches Fusion Proteins

bull Receptor mediated transport across the

lung epithelium was successfully achieved

by fusing different proteins with the Fc

domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc

bull bioavailability retention of biological activity after

lung absorption and increased half-life

Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011

Formulation approaches Protease inhibitors

bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders

bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane

Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

Formulation approaches Mucus

bull Most work focused on improving nanoparticle

transport

bull PEG coatings specific density mw (Hanes

JHU Kala Pharma)

bull Mucolytics in formulations

Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007

Formulation approaches Macrophages

bull Using particle shape and size

ndash Low density porous particles (Edwards et al 1997)

ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug

delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release

2007)

ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC

(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm

Sci 99 2343ndash2356 doi 101002jps22003)

ndash PEGylation (Patton et al Pulmonary administration of chemically modified

insulin US 6838076 B2)

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Formulation approaches Fusion Proteins

bull Receptor mediated transport across the

lung epithelium was successfully achieved

by fusing different proteins with the Fc

domain of IgG immunoglobulin bull EPO-fc INF-α-fc INF-β-fc and FSH-fc

bull bioavailability retention of biological activity after

lung absorption and increased half-life

Sakagami amp Gumbleton in Controlled Pulmonary Drug Delivery 2011

Formulation approaches Protease inhibitors

bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders

bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane

Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

Formulation approaches Mucus

bull Most work focused on improving nanoparticle

transport

bull PEG coatings specific density mw (Hanes

JHU Kala Pharma)

bull Mucolytics in formulations

Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007

Formulation approaches Macrophages

bull Using particle shape and size

ndash Low density porous particles (Edwards et al 1997)

ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug

delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release

2007)

ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC

(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm

Sci 99 2343ndash2356 doi 101002jps22003)

ndash PEGylation (Patton et al Pulmonary administration of chemically modified

insulin US 6838076 B2)

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Formulation approaches Protease inhibitors

bull Various enzymes are present in the lungs including aminopeptidases serine inhibitors and trypsin which are responsible for the degradation of both unwanted proteinaceous invaders

bull nafamostat mesilate bacitracin soybean trypsin inhibitor chymostatin potato carboxy peptidase inhibitor (PCPI) phosphoramidon foroxymithin amastatin aprotonin Tos-Phe-chloromethylketone 34-dichloroisocumarin trans-epoxysuccinyl-leucylamido (4-guanido) butane

Hussain A et al Absorption enhancers in pulmonary protein delivery J Control Release 2004 94(1) p 15-24

Formulation approaches Mucus

bull Most work focused on improving nanoparticle

transport

bull PEG coatings specific density mw (Hanes

JHU Kala Pharma)

bull Mucolytics in formulations

Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007

Formulation approaches Macrophages

bull Using particle shape and size

ndash Low density porous particles (Edwards et al 1997)

ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug

delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release

2007)

ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC

(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm

Sci 99 2343ndash2356 doi 101002jps22003)

ndash PEGylation (Patton et al Pulmonary administration of chemically modified

insulin US 6838076 B2)

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Formulation approaches Mucus

bull Most work focused on improving nanoparticle

transport

bull PEG coatings specific density mw (Hanes

JHU Kala Pharma)

bull Mucolytics in formulations

Min Liu Jian Zhang Wei Shan Yuan Huang httpdxdoiorg101016jajps201412007

Formulation approaches Macrophages

bull Using particle shape and size

ndash Low density porous particles (Edwards et al 1997)

ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug

delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release

2007)

ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC

(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm

Sci 99 2343ndash2356 doi 101002jps22003)

ndash PEGylation (Patton et al Pulmonary administration of chemically modified

insulin US 6838076 B2)

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Formulation approaches Macrophages

bull Using particle shape and size

ndash Low density porous particles (Edwards et al 1997)

ndash Shape (Particle shape a new design parameter for micro-and nanoscale drug

delivery carriers JA Champion YK Katare S Mitragotri - Journal of Controlled Release

2007)

ndash Swellable particles (El-Sherbiny I M McGill S and Smyth H DC

(2010) Swellable microparticles as carriers for sustained pulmonary drug delivery J Pharm

Sci 99 2343ndash2356 doi 101002jps22003)

ndash PEGylation (Patton et al Pulmonary administration of chemically modified

insulin US 6838076 B2)

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Future Prospects

bull Appears ~ 50 product pipelines are biologics

bull Appears ~ 50 FDA submissions are biologics

bull Appears ~ 50 commercial pre-clinical inhalation studies are biologics

bull Renewed interest in gene therapy new gene editing technologies

bull siRNA amp miRNA

bull Its probably a great time to be working in inhaled biologics

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research

Acknowledgements

bull Javier Morales Jason McConville AAPS

bull Kristin Fathe PhD Silvia Ferrati PhD Daniel Moraga

Ashkan Yazdi

The author of this presentation has received research support from Respira Therapeutics and also holds stock in consults

for Respira Therapeutics The terms of this arrangement have been reviewed and approved by the University of Texas at

Austin in accordance with its policy on objectivity in research