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Post by victoria on Mar 23, 2017 15:08:40 GMT -5
Re this patent, my instinct is that the aim is to establish that techno sphere insulin is a non-obvious step, ie that it is materially differect from exubera as to rapidity and pk pd profile. A patent can be refused if challenged as being an obvious development of an existing invention, so if the patent is allowed it will be open to anyone to say this is scientifically not similar to exubera. Obvious to us, who know that, but a patent would be handy to rebut those who try to point to exubera as a failure and to suggest this is just a rerun. It would establish techno sphere insulin as unique relative even to the only other inhaled insulin.
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Post by mango on Mar 23, 2017 15:39:32 GMT -5
In the olden days MannKind did a lot of basic science work that enabled them to create Afrezza so that it mimics the mealtime endogenous secretion of insulin. The early PK studies highlighting the correlations between patients' C-peptide and Afrezza are unqiue in that no one else created an insulin before Afrezza to mimic the endogenous profile in humans before. Instead, the insulin companies have continuously made unremarkable insulins that solve no unmet needs, nor even hint to suggest that they attempted to. MannKind definitely didn't slap together some stuff and call it a day. Really, really great technical and thoughtful science was done. Looking at the early studies and graphs, man, Al was just on another level. He solved a problem to multiple unmet needs with this insulin. I can't get over it. Maybe the veil will be lifted soon so others finally see it too.
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Post by peppy on Mar 23, 2017 16:01:08 GMT -5
Regarding the patent; thank you Victoria.
TECHNICAL FIELD
This invention relates to an improved apparatus and a method for cryogranulating a pharmaceutical composition during manufacturing of a drug product. In a particular embodiment, the apparatus and method are utilized in a process for manufacturing pharmaceutical products for pulmonary delivery. SUMMARY
The present invention relates to cryogranulation systems
DETAILED DESCRIPTION Disclosed herein are an apparatus and methods for cryogranulating or cryopelletizing a pharmaceutical composition.
In particular embodiments, the pharmaceutical substance can be a protein or peptide which is adsorbed onto carrier particles and contained in a medium such as a buffer, a solution, a suspension or a slurry.
Claims.
Filed: Oct 29, 2013 Date of Patent: Feb 14, 2017
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Post by mango on Mar 23, 2017 16:06:15 GMT -5
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Post by peppy on Mar 23, 2017 16:14:38 GMT -5
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Post by sayhey24 on Mar 23, 2017 18:44:34 GMT -5
Re this patent, my instinct is that the aim is to establish that techno sphere insulin is a non-obvious step, ie that it is materially differect from exubera as to rapidity and pk pd profile. A patent can be refused if challenged as being an obvious development of an existing invention, so if the patent is allowed it will be open to anyone to say this is scientifically not similar to exubera. Obvious to us, who know that, but a patent would be handy to rebut those who try to point to exubera as a failure and to suggest this is just a rerun. It would establish techno sphere insulin as unique relative even to the only other inhaled insulin. What do you mean if the patent is allowed? It has been. It was filed in 2012 and according to portal.uspto.gov/pair/PublicPair it was granted on 3/21/2017 Application Number: 13/357,821 Correspondence Address Customer Number: 45200 Filing or 371 (c) Date: 01-25-2012 Status: Patented Case Application Type: Utility Status Date: 03-01-2017 Examiner Name: CHANDRA, GYAN Location: What is a Location? ELECTRONIC Group Art Unit: 1646 Location Date: - Confirmation Number: 3450 Earliest Publication No: US 2012-0122775 A1 Attorney Docket Number: 1951300.00089 DIV Earliest Publication Date: 05-17-2012 Class / Subclass: 514/003 Patent Number: 9,597,374 First Named Inventor: Anders Hasager Boss , Princeton, NJ (US) all Inventors Issue Date of Patent: 03-21-2017
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Post by sayhey24 on Mar 23, 2017 18:46:40 GMT -5
Where did you get the afrezza/humalog graph above and the words first phase doesn't lower BG?
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Post by peppy on Mar 23, 2017 18:51:25 GMT -5
Compounds site Afrezza just breathe took me to Matt's site Afrezzadown under That work is Matt B afrezzadownunder. he has more work as well.
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Post by sayhey24 on Mar 23, 2017 19:03:40 GMT -5
Compounds site Afrezza just breathe took me to Matt's site Afrezzadown under That work is Matt B afrezzadownunder. he has more work as well. OK - he is misunderstanding afrezza's first phase insulin release. It should read something like "afrezza identically mimics the pancreas's first phase insulin release which shuts off liver glucose production and immediately blunts rising blood sugar in addition to immediately beginning to lower blood sugar". One puff of afrezza has no second phase release. Thats why its always better to Go Big on the first puff. The patent talks to this in detail but the point of the 90 minute BG testing is to determine if you need more for a second phase response. The body/healthy pancreas will start naturally doing this about 15 minutes after first phase. Second phase is the only drawback of afrezza. You may need a second dose. Some people are trying to delay the first puff to about 20 minutes for some slow digesting foods. But if you are eating something like pizza - the perfect storm of high fat and high carb, a few hours later you will need the second dose. Notice he never talks about Humalog first phase. No Analog has a first phase release. What they do provide is a second phase which lasts too too long.
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Post by peppy on Mar 23, 2017 19:22:04 GMT -5
Compounds site Afrezza just breathe took me to Matt's site Afrezzadown under That work is Matt B afrezzadownunder. he has more work as well. OK - he is misunderstanding afrezza's first phase insulin release. It should read something like "afrezza identically mimics the pancreas's first phase insulin release which shuts off liver glucose production and immediately blunts rising blood sugar in addition to immediately beginning to lower blood sugar". One puff of afrezza has no second phase release. Thats why its always better to Go Big on the first puff. The patent talks to this in detail but the point of the 90 minute BG testing is to determine if you need more for a second phase response. The body/healthy pancreas will start naturally doing this about 15 minutes after first phase. Second phase is the only drawback of afrezza. You may need a second dose. Some people are trying to delay the first puff to about 20 minutes for some slow digesting foods. But if you are eating something like pizza - the perfect storm of high fat and high carb, a few hours later you will need the second dose. Notice he never talks about Humalog first phase. No Analog has a first phase release. What they do provide is a second phase which lasts too too long. I know you are busy. It is a video
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Post by victoria on Mar 23, 2017 19:25:03 GMT -5
Thanks, I misread: yes its a grant, not just publication. Thats good. I dont know enough US law about whether a patent can be challenged after grant or whether thats the end of it. However I see this as good news since ultra rapid insulin plus basal now exists as an invention and is a distinct from exubera plus basal, and TI insulin therefore deemed not simply an obvious variation on the existing inhaled drug. I expect but don't know, that this presumably means mnkd can refer to the combined therapy as being a use of 'ultra rapid insulin', given that TI is FDA approved, basals are FDA approved, and the combined regime is a patented invention concerning one type of use of ultra rapid insulin.
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Post by mango on Mar 23, 2017 19:29:23 GMT -5
This is from MannKind's 2009 patient study in the link above.
CONCLUSIONS
The relationship between C-peptide and insulin has been explored since the mechanism of insulin secretion was first elucidated. The focus has been on how to use the pharmcokinetic profile of C-peptide to understand and predict pancreatic insulin secretion. Because C-peptide does not undergo hepatic uptake after secretion into the portal vein while insulin is extracted by the liver, its plasma profile levels might be useful to determine the pancreatic response to various stimuli which enhance insulin secretion. Although many studies have been done and progress has been made using C-peptide, the use of simultaneous plasma C-peptide and insulin values for evaluation has not been extensively studied. Clearance mechanisms for insulin and C-peptide are very different. Insulin undergoes a “first pass” effect in the liver and subsequent elimination which has been described by several authors as mono- or bi-exponential (one-compartment or two-compartment models). C-peptide is not extracted to a significant degree by the liver before it undergoes bi-exponential elimination (two-compartment model). Several authors have noted these differences and stated that analyzing the relationship would be limited because of their different kinetic profiles7, or can only be approximated when insulin and C-peptide levels are changing in response to a stimulus.8 Many studies which evaluated insulin and C-peptide used the administration of bolus glucose in a step-function manner which rapidly induced insulin and C-peptide release. This is not consistent with insulin and C-peptide secretions observed with the administration of a meal to the GI tract. While the alteration in “first-phase” insulin secretion from a glucose infusion is diminished in subjects with type 2 diabetes compared to healthy subjects, some authors question how this may relate to insulin secretion secondary to a meal in both populations.9 Whether the methodology in these studies may have affected the relationship is unknown. This method may not have been used because of its perceived limited utility. We developed this method to specifically address the problem of distinguishing the pharmacokinetic profiles of exogenously administered human insulin from endogenous human insulin. This method has proven to be useful in understanding and describing the pharmacokinetic profile of inhaled insulin. Baseline levels of insulin are corrected to very low levels. Endogenous levels of insulin diminish during exposure to exogenous insulin and return towards normal when the administered exogenous insulin has been cleared from the body. This has facilitated the study of bioavailability, bioequivalence, and pharmacokinetics/pharmacodynamics using healthy volunteers who are given meals sufficient to prevent hypoglycemia. These studies can be performed safely and rapidly provide useful and accurate data during the development of a human insulin product. Of further interest is the C-peptide:insulin relationship in the context of severity and stage of disease, and the evaluation of hepatic insulin extraction in relationship to meals, disease, and other therapies.
I also enjoy watching the videos on youtube of Al. Of all his scientific and medical accomplishments, it is so clear that Afrezza was his greatest achievement, IMO. The short bio of himself that he always told, starting out with how the DoD approached him and his work with solar cells, all the way to this new prandial insulin his company made, the excitement in his voice and expressions are priceless. The ending is something one wouldn't expect to see—a small inhaler for diabetes. Al's vision and thinking was so ahead of everyone else's that had been making diabetes drugs for decades (or maybe it was the result of him truly caring and having true compassion for people? I don't know). This is the kind of impact revolutionary people has on society. Every waking day that man devoted himself to trying to make the world a better place. This is who I would trust and would want my medications from.
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Post by mango on Mar 23, 2017 19:32:03 GMT -5
Thanks, I misread: yes its a grant, not just publication. Thats good. I dont know enough US law about whether a patent can be challenged after grant or whether thats the end of it. However I see this as good news since ultra rapid insulin plus basal now exists as an invention and is a distinct from exubera plus basal, and TI insulin therefore deemed not simply an obvious variation on the existing inhaled drug. I expect but don't know, that this presumably means mnkd can refer to the combined therapy as being a use of 'ultra rapid insulin', given that TI is FDA approved, basals are FDA approved, and the combined regime is a patented invention concerning one type of use of ultra rapid insulin. I'm just curious but who challenges a patent? The US patent office or outside parties? There are some bizarre patents out there. Things one would only find if they were already in the rabbit hole. I don't think the patent office cares as long as they get paid? Maybe. Just a guess.
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Post by sayhey24 on Mar 23, 2017 19:34:08 GMT -5
OK - he is misunderstanding afrezza's first phase insulin release. It should read something like "afrezza identically mimics the pancreas's first phase insulin release which shuts off liver glucose production and immediately blunts rising blood sugar in addition to immediately beginning to lower blood sugar". One puff of afrezza has no second phase release. Thats why its always better to Go Big on the first puff. The patent talks to this in detail but the point of the 90 minute BG testing is to determine if you need more for a second phase response. The body/healthy pancreas will start naturally doing this about 15 minutes after first phase. Second phase is the only drawback of afrezza. You may need a second dose. Some people are trying to delay the first puff to about 20 minutes for some slow digesting foods. But if you are eating something like pizza - the perfect storm of high fat and high carb, a few hours later you will need the second dose. Notice he never talks about Humalog first phase. No Analog has a first phase release. What they do provide is a second phase which lasts too too long. I know you are busy. It is a video
I am busy but no problem I had to take a break. He has a misunderstanding. If you compare the afrezza graphs to the c-peptide "natural insulin" release graphs what you will see is a little bump where the line flattens just a little which afrezza does not have. It will show up 15-20 minutes after initial first phase release. That is the beginning of the natural second phase release which will happen about every 5 minutes after it starts until the BG drops below 100 mg/dl. This natural second phase is the only reason afrezza and the pancreas natural release graphs are not identical. otherwise they would be exactly the same. They are the exact same monomer molecule 51 amino acid 5808 Da. Identical, no difference. Even the liver thinks they are the same. Thats why metformin just gets in the way when using afrezza. You want the liver working in its natural state and to provide glucose release going below 80 mg/dl. Metformin disturbs this natural harmony.
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Post by slugworth008 on Mar 23, 2017 19:34:19 GMT -5
Finally - the new dosing instructions for the new label from the clamp studies. I would have liked it better if they went stronger after metformin and said just throw it in the trash as it will just mess up proper liver function. Now, the next step are the associated computer models which take all this info on dosing and marry it with real time data from the CGMs and tell the PWD how to dose so they don't need to read all that "label" stuff and figure it out on their own. What did Josh Riff say at the Digital Diabetes Congress the other week about the future - easy ways to tell PWD how to dose and a new way to take insulin. Sehey, The problem with your idea is that Metformin cost nothing so Doctors/Insurance companies use it as its cheap. McDonalds is cheap too - try living on it though
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