Designing Inhaled Drugs - Wall Street Journal
Apr 9, 2023 8:50:15 GMT -5
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Post by ronw77077 on Apr 9, 2023 8:50:15 GMT -5
By Dominique MosbergenFollow
April 9, 2023 5:17 am ET
Treatments for asthma have long been delivered through the airways. Now researchers are developing inhalable therapies to target a wider range of ailments from cancer to diabetes.
Constantly exposed to the outside world as we breathe, the lungs are a first line of defense against infection. They also provide a direct pathway to the circulatory system as they send oxygen to the blood. Researchers hope that delivering medicines directly to the lungs can exploit those characteristics and make drugs that are more efficient and effective than oral or injectable drugs—and maybe easier to take.
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They are harnessing technologies ranging from nanomedicine to gene-editing tools to particle engineering to improve how medicines interact with the lungs, targeting lung diseases such as cystic fibrosis and lung cancer as well as less obvious conditions including schizophrenia, migraines and Parkinson’s disease.
“We’re pushing the boundaries of delivery,” said Philip Santangelo, a professor of biomedical engineering at Emory University.
Respiratory diseases that spread through the air are a key target. Dr. Santangelo and colleagues are developing inhalable drugs that use an RNA-editing tool known as CRISPR-Cas13 and messenger RNA to kill viruses such as Covid-19, influenza and respiratory syncytial virus or RSV. Using nebulizers that dispense medicine as mist via a mask, they have tested the delivery of some of the medicines on rhesus monkeys, cows, horses and pigs. The tests in pigs showed that getting the drugs to the lungs reduces the severity and spread of infections, Dr. Santangelo said.
“If you want it in the lung, we thought we should get it into the lung,” he said.
Researchers are also applying that logic to other conditions, including some cancers. Oncologists at the University of California, Davis are investigating an inhaled immunotherapy for cancer that would boost the ability of special immune cells in the lungs to fight disease.
Nanomedicine researchers at Johns Hopkins University are developing an inhalable gene therapy that aims to cure cystic fibrosis, a genetic condition that damages the lungs and digestive system. Cystetic Medicines Inc. is making an inhalable version of amphotericin B, an antifungal, to treat the disease. Amphotericin B’s usually severe side effects are reduced when the drug is targeted to the lungs, where it can change the way some cells function to counteract the disease, the company said.
People have been inhaling medicines for millennia. A papyrus scroll dated to around 1554 B.C., discovered with an Egyptian mummy described patients inhaling vapor from herbs heated on hot bricks. The Greek physician Hippocrates, who lived around 400 B.C., detailed the therapeutic use of boiling herbs and resins in vinegar and oil and inhaling the fumes through a reed.
Inhalable medicines have come a long way.
Exubera, launched in 2006 by Pfizer Inc., was one of the first inhalable drugs the Food and Drug Administration approved for a disease not specific to the lungs. It was shown in clinical trials to be as effective as other insulin products but patients and doctors were hesitant to use it, drug-delivery experts said, partly because of safety concerns and it required a bulky inhaler that resembled a bong. Pfizer stopped marketing Exubera in 2007. The company said that while the drug was safe and effective, it hadn’t met customer or financial expectations.
Take a Deep Breath
Inhalable drugs and vaccines can be deployed in different ways. In one method, researchers target the lungs directly, using nanomedicine and other technologies to get treatments to tumors, microbes or immune cells. Another approach is to send drugs through the alveoli, tiny air sacs deep in the lungs, to reach the bloodstream quickly.
Pathway to bloodstream:
Localized delivery:
1
2
Here, nanoparticles carrying an immunotherapy drug or vaccine target a lung immune cell.
Through the alveoli, medicine can reach systemic circulation rapidly. In this example, an insulin molecule is shown passing through the wall of an alveolus into a capillary.
Inhalable device
LUNG EPITHELIUM
ALVEOLI
Nanoparticle
aerosol carrier
Mucus
barrier
Nanoparticle
passes through
barrier
Alveolus
Detail below
Alveolar wall
Insulin passes
through lining
Immune cell
Capillary wall
Capillary
Red blood cells
Source: Catherine A. Fromen, University of Delaware
Jemal R. Brinson/THE WALL STREET JOURNAL
Afrezza, an inhalable insulin from MannKind Corp. that the FDA approved in 2014, is administered with an inhaler about the size of a referee’s whistle. Afrezza isn’t recommended for smokers and people with lung conditions like asthma, and there may be less dosing flexibility compared with injectable insulins which can be dosed in smaller increments, said Dr. Jennifer Goldman, a professor of pharmacy practice at Massachusetts College of Pharmacy and Health Sciences.
MannKind said its inhaled insulin acts faster than injectable mealtime insulin and precise dosing wasn’t a problem in clinical trials. The company said it is enrolling children aged 4 to 17 for a pediatric trial for Afrezza.
At the University of Delaware, biomolecular engineer Catherine Fromen is exploring ways to design custom inhalers. Using 3D-printed lungs and also a robot lung made from plastic tubes and inflatable containers, Dr. Fromen is developing computational models to customize inhalers based on how deeply people breathe and how diseased their lungs are.
“My lungs are different from your lungs,” she said.
A drug’s path from the lungs into the bloodstream is determined in part by its particle size and aerodynamic properties as well as the type of inhaler. The link to the circulatory system involves a network of air-carrying tubes ending in millions of one-cell-thick sacs called alveoli that move oxygen and carbon dioxide in and out of the bloodstream. The smaller the particle, the deeper the drug tends to go into this network.
PHOTO: LIZ DESOUSA FOR THE WALL STREET JOURNAL
But there is a limit. If a particle is smaller than about a micrometer, more of it might be exhaled than deposited in the lungs. Depending on its target, drugs are designed to stick to, penetrate or evade the various mechanisms in the lungs—such as the protective mucus barrier—that work to clear contaminants from the airways, drug-delivery experts said.
Inbrija, an inhalable version of the Parkinson’s drug levadopa, is inhaled into the deep lungs and quickly enters the bloodstream thanks to its design, said Ron Cohen, president and CEO of its developer Acorda Therapeutics Inc. Created using a spray-drying technique, the powdered drug is made of microscopic particles that resemble crumpled balls of paper with a lot of surface area, Dr. Cohen said. The FDA approved Inbrija in 2018.
“It is extremely light and gets absorbed extremely quickly,” Dr. Cohen said.
Pulmatrix Inc. is using spray-drying and other particle-engineering techniques to develop potential inhalable drugs for migraines and aspergillosis, a fungal infection. Alexza Pharmaceuticals Inc., which makes an inhaled drug that treats agitation associated with schizophrenia and bipolar disorder, is exploring other inhalable treatments including one that could stop epileptic seizures. Alexza has developed an inhaler that turns a solid drug into vapor using rapid heating.
SHARE YOUR THOUGHTS
What do you think is the future for inhalable therapies?
InhaTarget Therapeutics is conducting a clinical trial in five hospitals in Belgium to investigate inhalable cisplatin, a chemotherapy drug that is toxic to cells, in advanced lung-cancer patients. Cisplatin is conventionally delivered intravenously.
“By changing the route of administration, we reduce the systemic toxicities while increasing the frequency of treatments,” CEO Fréderic De Coninck said. “We get more drug exposure in the lungs.”
Researchers at The University of Texas MD Anderson Cancer Center are exploring an inhaled version of the chemotherapy drug gemcitabine for patients aged 10 to 50 with tumors that have spread to the lungs from other parts of the body.
“Patients are happy because they don’t lose their hair and are avoiding other systemic side effects,” said Dr. Najat Daw, a pediatric oncologist at MD Anderson.
Write to Dominique Mosbergen at dominique.mosbergen@wsj.com
April 9, 2023 5:17 am ET
Treatments for asthma have long been delivered through the airways. Now researchers are developing inhalable therapies to target a wider range of ailments from cancer to diabetes.
Constantly exposed to the outside world as we breathe, the lungs are a first line of defense against infection. They also provide a direct pathway to the circulatory system as they send oxygen to the blood. Researchers hope that delivering medicines directly to the lungs can exploit those characteristics and make drugs that are more efficient and effective than oral or injectable drugs—and maybe easier to take.
NEWSLETTER SIGN-UP
The Future of Everything
A look at how innovation and technology are transforming the way we live, work and play.
Preview
Subscribe
They are harnessing technologies ranging from nanomedicine to gene-editing tools to particle engineering to improve how medicines interact with the lungs, targeting lung diseases such as cystic fibrosis and lung cancer as well as less obvious conditions including schizophrenia, migraines and Parkinson’s disease.
“We’re pushing the boundaries of delivery,” said Philip Santangelo, a professor of biomedical engineering at Emory University.
Respiratory diseases that spread through the air are a key target. Dr. Santangelo and colleagues are developing inhalable drugs that use an RNA-editing tool known as CRISPR-Cas13 and messenger RNA to kill viruses such as Covid-19, influenza and respiratory syncytial virus or RSV. Using nebulizers that dispense medicine as mist via a mask, they have tested the delivery of some of the medicines on rhesus monkeys, cows, horses and pigs. The tests in pigs showed that getting the drugs to the lungs reduces the severity and spread of infections, Dr. Santangelo said.
“If you want it in the lung, we thought we should get it into the lung,” he said.
Researchers are also applying that logic to other conditions, including some cancers. Oncologists at the University of California, Davis are investigating an inhaled immunotherapy for cancer that would boost the ability of special immune cells in the lungs to fight disease.
Nanomedicine researchers at Johns Hopkins University are developing an inhalable gene therapy that aims to cure cystic fibrosis, a genetic condition that damages the lungs and digestive system. Cystetic Medicines Inc. is making an inhalable version of amphotericin B, an antifungal, to treat the disease. Amphotericin B’s usually severe side effects are reduced when the drug is targeted to the lungs, where it can change the way some cells function to counteract the disease, the company said.
People have been inhaling medicines for millennia. A papyrus scroll dated to around 1554 B.C., discovered with an Egyptian mummy described patients inhaling vapor from herbs heated on hot bricks. The Greek physician Hippocrates, who lived around 400 B.C., detailed the therapeutic use of boiling herbs and resins in vinegar and oil and inhaling the fumes through a reed.
Inhalable medicines have come a long way.
Exubera, launched in 2006 by Pfizer Inc., was one of the first inhalable drugs the Food and Drug Administration approved for a disease not specific to the lungs. It was shown in clinical trials to be as effective as other insulin products but patients and doctors were hesitant to use it, drug-delivery experts said, partly because of safety concerns and it required a bulky inhaler that resembled a bong. Pfizer stopped marketing Exubera in 2007. The company said that while the drug was safe and effective, it hadn’t met customer or financial expectations.
Take a Deep Breath
Inhalable drugs and vaccines can be deployed in different ways. In one method, researchers target the lungs directly, using nanomedicine and other technologies to get treatments to tumors, microbes or immune cells. Another approach is to send drugs through the alveoli, tiny air sacs deep in the lungs, to reach the bloodstream quickly.
Pathway to bloodstream:
Localized delivery:
1
2
Here, nanoparticles carrying an immunotherapy drug or vaccine target a lung immune cell.
Through the alveoli, medicine can reach systemic circulation rapidly. In this example, an insulin molecule is shown passing through the wall of an alveolus into a capillary.
Inhalable device
LUNG EPITHELIUM
ALVEOLI
Nanoparticle
aerosol carrier
Mucus
barrier
Nanoparticle
passes through
barrier
Alveolus
Detail below
Alveolar wall
Insulin passes
through lining
Immune cell
Capillary wall
Capillary
Red blood cells
Source: Catherine A. Fromen, University of Delaware
Jemal R. Brinson/THE WALL STREET JOURNAL
Afrezza, an inhalable insulin from MannKind Corp. that the FDA approved in 2014, is administered with an inhaler about the size of a referee’s whistle. Afrezza isn’t recommended for smokers and people with lung conditions like asthma, and there may be less dosing flexibility compared with injectable insulins which can be dosed in smaller increments, said Dr. Jennifer Goldman, a professor of pharmacy practice at Massachusetts College of Pharmacy and Health Sciences.
MannKind said its inhaled insulin acts faster than injectable mealtime insulin and precise dosing wasn’t a problem in clinical trials. The company said it is enrolling children aged 4 to 17 for a pediatric trial for Afrezza.
At the University of Delaware, biomolecular engineer Catherine Fromen is exploring ways to design custom inhalers. Using 3D-printed lungs and also a robot lung made from plastic tubes and inflatable containers, Dr. Fromen is developing computational models to customize inhalers based on how deeply people breathe and how diseased their lungs are.
“My lungs are different from your lungs,” she said.
A drug’s path from the lungs into the bloodstream is determined in part by its particle size and aerodynamic properties as well as the type of inhaler. The link to the circulatory system involves a network of air-carrying tubes ending in millions of one-cell-thick sacs called alveoli that move oxygen and carbon dioxide in and out of the bloodstream. The smaller the particle, the deeper the drug tends to go into this network.
PHOTO: LIZ DESOUSA FOR THE WALL STREET JOURNAL
But there is a limit. If a particle is smaller than about a micrometer, more of it might be exhaled than deposited in the lungs. Depending on its target, drugs are designed to stick to, penetrate or evade the various mechanisms in the lungs—such as the protective mucus barrier—that work to clear contaminants from the airways, drug-delivery experts said.
Inbrija, an inhalable version of the Parkinson’s drug levadopa, is inhaled into the deep lungs and quickly enters the bloodstream thanks to its design, said Ron Cohen, president and CEO of its developer Acorda Therapeutics Inc. Created using a spray-drying technique, the powdered drug is made of microscopic particles that resemble crumpled balls of paper with a lot of surface area, Dr. Cohen said. The FDA approved Inbrija in 2018.
“It is extremely light and gets absorbed extremely quickly,” Dr. Cohen said.
Pulmatrix Inc. is using spray-drying and other particle-engineering techniques to develop potential inhalable drugs for migraines and aspergillosis, a fungal infection. Alexza Pharmaceuticals Inc., which makes an inhaled drug that treats agitation associated with schizophrenia and bipolar disorder, is exploring other inhalable treatments including one that could stop epileptic seizures. Alexza has developed an inhaler that turns a solid drug into vapor using rapid heating.
SHARE YOUR THOUGHTS
What do you think is the future for inhalable therapies?
InhaTarget Therapeutics is conducting a clinical trial in five hospitals in Belgium to investigate inhalable cisplatin, a chemotherapy drug that is toxic to cells, in advanced lung-cancer patients. Cisplatin is conventionally delivered intravenously.
“By changing the route of administration, we reduce the systemic toxicities while increasing the frequency of treatments,” CEO Fréderic De Coninck said. “We get more drug exposure in the lungs.”
Researchers at The University of Texas MD Anderson Cancer Center are exploring an inhaled version of the chemotherapy drug gemcitabine for patients aged 10 to 50 with tumors that have spread to the lungs from other parts of the body.
“Patients are happy because they don’t lose their hair and are avoiding other systemic side effects,” said Dr. Najat Daw, a pediatric oncologist at MD Anderson.
Write to Dominique Mosbergen at dominique.mosbergen@wsj.com
