The most interesting thing I heard at the ASM

[petech]

I was thinking about it today and don't know if I posted it prior...the technosphere particle display was very interesting for those that saw it.  It turns out the particle is actually incredibly non-aerodynamic.  Chad's explanation was something to the effect of: If you think about all the other forms of administration, they involve some sort of propellant to get drugs into the system.  If you think about how the lungs are set up, it goes to two main branches and then off into very small alveoli...and isn't exactly a straight shot.  So if you wanted maximum disbursement of your drug that has to go through a bunch of twists and turns, would you want it shot out of a cannon...or would you want it as slow as possible to get where it needs to go.  

He then said some statistics about the speed...and technosphere was a fraction of other methods.

Pretty damn smart.

I think about this when I hear about other methods of pulmonary delivery. 

[ezrasfund]

I did hear that discussion where it was explained that if the particles were moving too fast they would hit the bronchial walls and not be able to travel through the intricate system of the bronchial tree to reach the deep lungs.

[EveningOfTheDay]

I had missed this, so thank you very much for the post. It makes total sense though and it probably offers another level of protection against possible competitors.

[ezrasfund]

If you study the deceptively simple looking Dreamboat device you will see how the mouthpiece is flared. This is where the Venturi effect is employed to precisely regulate the speed at which the TI powder enters the lungs.

[rrtzmd]

I would argue that whoever you spoke to didn't know what they were talking about. Reaching the deepest alveoli requires maximizing airflow energy and minimizing turbulence. The lungs do this by effecting a vortex of the inhaled air as it moves through the upper airways.  A vortex with high rotational velocity possesses enough energy to push the airflow into the extremely narrow distal tubes.  The exubera "bong" effectively "extended" the upper airway allowing a better, stronger vortex to form. One reason that a "bong" is so effective at delivering smoke  is the way it generates a strong vortex:

bong gif

At each bifurcation of the lung "tube," turbulence is generated which results in a loss of energy and momentum.  The large amount of energy imparted by the vortex rotation helps overcome the bifurcation effect.  A second beneficial effect is that the rotation of the air forces the particles to  the center of the stream -- sort of similar to the way a figure skater increases her rate of spin by pulling her arms except, in this case, it's the the increasing rotation speed forces the "arms" in.  This prevents contact with the walls on the way to the alveoli. The energy of the afrezza particles themselves is so small relative to the air flow that their own aerodynamics are irrelevant. 

On the other hand, of primary importance is the method of inhaling. I suspect most afrezza users don't inhale properly. Most seem to think that exhaling as much as they can and then taking a sudden, huge breath is required. That is likely not the case. Indeed, it probably increases the amount of afrezza deposited in the upper airways. Taking a sudden huge breath imparts a great deal of turbulence to the powder which results in it being tossed about and collecting on the walls of the trachea.  An analogous situation exists with other inhalers:

inhaler difficulties

Arguably, the best way to use the afrezza inhaler -- although rather extreme -- would be first to bend over so that the torso is at 90 degrees to the legs, look forward parallel to the floor -- all this is to "straighten" out the airway as much as possible so as to reduce turbulence -- exhale normally, grip the inhaler with the lips, then slowly and steadily inhale, hold for a count of 5-10 and then slowly, steadily exhale -- particles are also deposited during the exhalation process.  An alternative might be the use of a "spacer" where the extended tube effects are similar to the "bong."

[petech]

I was speaking with Chad Smutney.  He has quite a few patents to his name, so I'd argue he knows what he's talking about.  Here's a list:


patents.justia.com/inventor/chad-c-smutney



The display at the ASM on this was enlightening. There was even a model that showed how the drug disbursed based on the breath taken / airway. I took a lot of things from this display. Ignorance from Chad and his team was definitely not one.

I don't think anyone is going to bend over to inhale Afrezza, but I do think the shorts may have to do so...metaphorically...because of Afrezza.

[ezrasfund]

An interesting fact about Chad is that before he worked for MannKind he worked for a company developing a new type of syringe. (See the earlier patents in petech's link.) One thing he pointed out is that the dreamboat inhaler has many fewer parts and is much less expensive to manufacture than a syringe (never mind one of those flexpens).

[rrtzmd]

Oct 19, 2015 12:53:32 GMT -5 petech said:

I was speaking with Chad Smutney.  He has quite a few patents to his name, so I'd argue he knows what he's talking about.  Here's a list:


patents.justia.com/inventor/chad-c-smutney



The display at the ASM on this was enlightening. There was even a model that showed how the drug disbursed based on the breath taken / airway. I took a lot of things from this display. Ignorance from Chad and his team was definitely not one.

I don't think anyone is going to bend over to inhale Afrezza, but I do think the shorts may have to do so...metaphorically...because of Afrezza.

Mr. Chutney is a mechanical engineer who contributed to the inhaler design.  I certainly wouldn't argue that he's ignorant, nevertheless the "aerodynamics" of the particle are minimally relevant to their lung distribution. Think snowflakes versus dust in a hurricane and you realize that shape, size, weight make little difference to how the hurricane disperses the particles. In the case of afrezza, you already lose 60% of the insulin to upper airway deposition due to turbulence slowing the particles down and allowing them to be "captured." The slower they get, the more that are trapped where they can't have any effect.  

And, yes, my "instructions" were "extreme," but they were meant to illustrate the idea that straightening the airway allows more time for vortex formation and raises the energy of the airstream. This is one reason why "spacers" are recommended for most inhaler devices -- see the link in my previous comment.

[peppy]

aerodynamics of Afrezza was covered in a study done with afrezza. my eyes glazed over.
Afrezza, it likes the ph of the alveoli. a ph of 7.
it is excreted in the urine as inert.
no first pass liver.
2 micron is it.

every pharma needs technosphere delivery system.

[rrtzmd]

Oct 19, 2015 11:17:28 GMT -5 ezrasfund said:

If you study the deceptively simple looking Dreamboat device you will see how the mouthpiece is flared. This is where the Venturi effect is employed to precisely regulate the speed at which the TI powder enters the lungs.

No, that is incorrect. The Venturi effect increases the speed at which the air is moving in the channel but causes a decrease in pressure behind the channel and serves only to facilitate dispersal of the particles from the cartridge. This video illustrates well how it works, except he uses a blower while a patient uses inhalation:

how venturi effect is employed to disperse powder

The initial speed of the powder is depends on the rate of airflow with inspiration and the subsequent loss of velocity depends on the increasing turbulence effected by the bifurcations. 

[jpg]

rrtzmd,


As for many of the things you say above I respectfully disagree with much of what you are saying.

Be it about the 'uninformed' Mannkind expert, the reason for particle aerodynamics mattering in turbulent vs laminar airways (where does this matter and in what part of the airway and you didn't mention electrostatic interactions), the simply very wrong misunderstanding of laminar vs turbulent flow in a respiratory tree (and complete misunderstanding of how air does get to the alveoli. Hint: pressure gradients), explanation for need of aero chamber in many inhalation devices (not relavant to TS) and why the way they use the Ventori effect in the Dreamboat really is very important (as Erzasfund is possibly referring to).

Not that I want to be the scientific police (as this has very little bearing on the true prospects of Afrezza which we all know works regardless of how it works) and this may seem harsh but much of what you say sounds more like a scientific 'word cloud' than a scientific explanation. We seem to be having a run on this stuff recently!

[peppy]

In reply to the post directly above.
I like it when people start talking pressure gradients.

I am sorry moderators. so sorry.

[rrtzmd]

Oct 19, 2015 20:55:02 GMT -5 jpg said:

rrtzmd,


As for many of the things you say above I respectfully disagree with much of what you are saying.

Be it about the 'uninformed' Mannkind expert, the reason for particle aerodynamics mattering in turbulent vs laminar airways (where does this matter and in what part of the airway and you didn't mention electrostatic interactions), the simply very wrong misunderstanding of laminar vs turbulent flow in a respiratory tree (and complete misunderstanding of how air does get to the alveoli. Hint: pressure gradients), explanation for need of aero chamber in many inhalation devices (not relavant to TS) and why the way they use the Ventori effect in the Dreamboat really is very important (as Erzasfund is possibly referring to).

Not that I want to be the scientific police (as this has very little bearing on the true prospects of Afrezza which we all know works regardless of how it works) and this may seem harsh but much of what you say sounds more like a scientific 'word cloud' than a scientific explanation. We seem to be having a run on this stuff recently!

Airways are neither "turbulent" or "laminar." Air FLOW, on the other hand, is. Laminar air flow is AROUND an object and obviously doesn't apply to the lungs. Turbulent airflow, on the other hand, is important because of the bifurcations as I described. The particles of afrezza within the in the air flow are TINY relative to the total mass of the air flow and CANNOT affect the changes in resistance caused by bifurcations. For example, imagine what would happen if you dumped a bunch of sawdust into the middle of a river. Would the size, shape, interactions, etc, affect the overall movement of the particles within the flow of the river? 

The only purpose of the Venturi effect is to disperse the afrezza powder. That is simply ALL it can do. The properties of the particles themselves can affect how the powder "de-agglomerates" but the Venturi does NOTHING more than create a vacuum to suck up the particles.
 
And "pressure gradients"? What do you think a pressure gradient does to a tube of air -- "Hint": blow on a straw and feel what comes out the other end. When you inhale, the pressure gradient is produced by expansion of the chest wall lowering the pressure inside the chest cavity and causing air to rush in until there is no longer a gradient. Try for a few minutes to breathe without moving your chest wall and see what happens. 

The only IMPORTANT place where particle properties matter is in the "de-agglomerization" from inside the cartridge. It's important that afrezza gets broken up as much as possible into the smallest fragments possible in order to assure maximum distribution. Consequently, things like electrostatic attraction, geometry, weight, etc, contribute to how well it "de-agglomerates."  But once broken into its smallest fragments and in the air flow, nothing specific to the particles matters much in terms of affecting distribution to the distal lung.

[jpg]

Oct 19, 2015 22:47:25 GMT -5 rrtzmd said:

Oct 19, 2015 20:55:02 GMT -5 jpg said:

rrtzmd,

Airways are neither "turbulent" or "laminar." Air FLOW, on the other hand, is. Laminar air flow is AROUND an object and obviously doesn't apply to the lungs. Turbulent airflow, on the other hand, is important because of the bifurcations as I described. The particles of afrezza within the in the air flow are TINY relative to the total mass of the air flow and CANNOT affect the changes in resistance caused by bifurcations. For example, imagine what would happen if you dumped a bunch of sawdust into the middle of a river. Would the size, shape, interactions, etc, affect the overall movement of the particles within the flow of the river? 

The only purpose of the Venturi effect is to disperse the afrezza powder. That is simply ALL it can do. The properties of the particles themselves can affect how the powder "de-agglomerates" but the Venturi does NOTHING more than create a vacuum to suck up the particles.
 
And "pressure gradients"? What do you think a pressure gradient does to a tube of air -- "Hint": blow on a straw and feel what comes out the other end. When you inhale, the pressure gradient is produced by expansion of the chest wall lowering the pressure inside the chest cavity and causing air to rush in until there is no longer a gradient. Try for a few minutes to breathe without moving your chest wall and see what happens. 

The only IMPORTANT place where particle properties matter is in the "de-agglomerization" from inside the cartridge. It's important that afrezza gets broken up as much as possible into the smallest fragments possible in order to assure maximum distribution. Consequently, things like electrostatic attraction, geometry, weight, etc, contribute to how well it "de-agglomerates."  But once broken into its smallest fragments and in the air flow, nothing specific to the particles matters much in terms of affecting distribution to the distal lung.

Rivers, sawdust etc. More scientific 'word fest'.

I apologize for the harsh terms but at best you are a scientific novice. Again sorry but you are probably (or hopefully) well meaning (and motivated) but sadly simply wrong and uninformed. Airways have distinct and very important laminar and turbulent properties. That is the basis of gas exchange and pulmonary function.

Again airways have distinct regional properties (depending on location and distance from the mouth). I refer you to West (the 'bible' of pulmonary physiology):
books.google.ca/books?id=eLRjk-VDF3cC&pg=PA110&lpg=PA110&dq=west+physiology+laminar+and+turbulent+flow&source=bl&ots=RmTO8sKnAV&sig=8bdtDJ-yvY_ruloMDHHeUpqTcXk&hl=en&sa=X&ved=0CCcQ6AEwAWoVChMIo5qV1KHQyAIVTDeICh0RUQTh#v=onepage&q=west%20physiology%20laminar%20and%20turbulent%20flow&f=false

As for pressure gradients: yes you are starting to grasp the simple most basic concepts of air movements. Why did you not mention this most important fact in your previous word cloud?

As for your last statement it is sadly more scientific gibberish. Sorry. Do you know another poster I recently called out for the same sort of pseudo scientific gibberish? Same sort of scientific 'logic'. Hmmm? I wonder?

[ezrasfund]

I am not really sure what the argument is here. Surely rrtzmd is not suggesting that Afrezza does not reach the deep lungs. Is the suggestion that the dreamboat design is somehow inferior and substandard? It is well know that some of the TI powder is left in the mouth and throat, but that is accounted for in the cartridges that do not contain 4 units of insulin, but a 4 unit equivalent, for example.

I am not a scientist, but that bong gif did remind me of a certain device made by Nektar Therapeutics.