Ann: Phosphagenics Arbitration Award Issued, page-221

@playez

Thanks for the link to start. Been pretty busy w/end so only really getting a chance to review & research this arvo.

There is definite merit in what you are saying re something like TPGS however, there also appears to be one distinct difference - TPGS has been developed for & used primarily in oral applications not transdermal / injectable.

So, with that in mind, it must be taken into consideration that whilst both formula / compounds provide evidence & studies to support permeability & absorption advantages they don't play in the same DDS backyard as yet. One has been optimised for internal absorption / permeability and one being optimised for external.

That's not to say they won't be in the same backyard at some stage as there are a number of studies / papers I have reviewed evidencing TPGS as a possible pathway for transdermal / injectable pharmaceuticals but at this stage, it is just that, from what I can find, studies.

These studies have also primarily identified TPGS' possible benefits in cancer & MDR capabilities which is where they seem to focusing their attention so far.

Their was one 16/17 study I located on TPGS trasndermal possibilities and the conclusion is as below with ref link. They concluded "combined" with other enhancing techniques etc. Indicates to me that as a standalone it may not be as potent in transdermal / injectable....yet (of course)

https://slideheaven.com/application-of-d-tocopheryl-polyethylene-glycol-1000-succinate-tpgs-in-transderm.html

Conclusions: TPGS can be combined with other enhancing technique toformulate novel formulations with higher effective, precise,and safe drug delivery drug through skin or inside in skin.

As you also pointed out, it is difficult to find any studies / papers to support superiority (as you put it) however, in establishing that both formula / compounds are essentially involved in different DDS, it seems logical that they would not necessarily go head to head. The other item that appears to be a common thread is that it is not a "one size fits all" scenario whereby just beacuse TPGS does this or TPM does that, that the delivery will be as effective with one drug as another so again, there are differences where one may provide a positive, the other may not be as effective.

Are they peers or are they competitors?

A peer loosely by default of sharing some similar properties as to what they are trying to achieve in their respective DDS, a competitor, not at this stage imo for the same reasons above - different DDS.

So, back to trying to find any type of overlap anywhere. One that I did spot (from the same transdermal paper linked above), was a test done on diclofenac in 2001. Of course there may be possible enhancements to the formula by now but couldn't find any - maybe not bothered given first pass result? If you review the paper, there are a number of others in the table for positive & negative for various tests as to what the role of TPGS was.

Diclofenac sodium Transdermal PenetrationenhancerAbdominal ratskinNo effect Mohammed (2001)

As diclofenac appeared to be the only cross match I could find in attempting to provide benefits to transdermal applications, below is the apparent results for the same. POH claims evidence TPM provided an enhancement whereas Mohammed claimed no effect.

http://www.phosphagenics.com/research/pain/

TPM®/Diclofenac GelPhosphagenics’ TPM® pharmaceutical delivery technology can be used as a targeted, localized delivery system, to increase the delivery of actives such as diclofenac to targeted areas, while minimizing exposure to the rest of the body. A Phase 1b human study was completed in 2009 and demonstrated that Phosphagenics’ TPM®/Diclofenac Gel results in more effective permeation of diclofenac into the skin than the currently available Voltaren® gel (see chart below). The study showed that dermal absorption of diclofenac was increased compared with Voltaren® gel (about 2 to 4 fold increase), while maintaining similar levels of systemic exposure (see chart below).

Does TPGS have an advantage - in already having FDA approval for "oral", the you have to say yes in that regard. Though, this approval does not extend to injectables at this stage (refer a ref below).

Does that make the upcoming POH / FDA meeting important - absolutely. "If" it still proceeds of course and has a positive outcome to go forward with.

Does TPM have an advantage - in already being developed, advanced and partly commercialised for transdermal - then I would say ye,s in having a slight first mover advantage in that DDS.

Ref - part conclusion / perspective (my bold) - Recent developments in d-α-tocopheryl polyethylene glycol-succinate-based nanomedicine for cancer therapy

https://www.tandfonline.com/doi/full/10.1080/10717544.2017.1406561

Safety is an important feature of TPGS. Although the original preparation approved by the FDA is an oral formulation, i.v. injection of TPGS has not been reported to cause any side effects. We have also evaluated the safety of TPGS after i.v. injection in healthy Kunming mice at a dose of 200 mg/kg. (Yin et al., 2017bYin M, Tan S, Bao Y, Zhang Z.(2017b). Enhanced tumor therapy via drug co-delivery and in situ vascular-promoting strategy. J Control Release 258:108–20.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]) The results showed that compared with saline, the TPGS group exhibited almost the same body weight changes, main organ/body index and ALT, AST, and BUN levels. H&E staining of the main organs (heart, liver, spleen, lung, and kidney) further confirmed that there were no significant differences between the two groups. TPGS was also reported to prevent hemolysis (0.32%), after being added in a positive charged dendrime, G4 PAMA (Pooja et al., 2014Pooja D, Kulhari H, Singh MK, et al. (2014). Dendrimer-TPGS mixed micelles for enhanced solubility and cellular toxicity of taxanes. Colloids Surf B Biointerfaces 121:461–8.[Crossref], [PubMed], [Web of Science ®], [Google Scholar]). However, to achieve the clinical translation, researchers should focus on several TPGS-based DDSs that are easy to be scaled-up and can be manufactured with reproducible physicochemical properties (e.g. drug loading, particle size, stability). Advanced study on safety and efficacy in clinical research is also needed. Anyway, taken together with its unique bio-functions, TPGS could serve as an effective drug carrier component that may greatly reduce ‘carrier material burden’ Thus, it could be utilized to develop a simple, but multi-functional DDS that could be applied clinically for cancer treatment.

in conclusion, does TPGS provide a direct competitor formula here & now, not imo but potentially for the future if POH does not surmount the hurdles ahead.

On that, the bottom line now regardless of the TPGS (or similar) vs TPM concerns is the impending costs award, the csh on hand and what contingency plans management had / have to move forward.

With the costs award, it must also be remembered (as per one of my earlier post links) that there doesn't seem to be a black / white approach. Will it be a simple yep, all to Mylan or was there other mitigating factors the tribunal will consider as per their want as described in the costs ref link. Was the race closer than expected and Mylan got over the line operating better within the legal framework with POH's claims have sound merit hence why it took some time, or did Mylan drag it deliberately looking to try cripple POH? These sorts of things the tribunal is supposed to consider though not holding my breath on that either 

Am I concerned for my pilot buy into a high RvR - nope. If it had gone the other way, I would looked to pyramid up. Will I hold till whatever is decided - yep. Was prepared to lose what was there. Do I feel for LT holders still holding - absolutely. They stumped up hard earned and are still in limbo for the time being. Do I feel for those who dumped out - nope, They have a made a conscious decision to crystallize any losses as per their want.

Ref links ( though most have prob been done to death already) and will leave it all now till we see what the future holds. GLA

https://slideheaven.com/tocopheryl-phosphate-mixture-tpm-as-a-novel-lipid-based-transdermal-drug-deliver.html

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622802/?tool=pmcentrez&report=abstract

http://www.thno.org/v08p0464.htm

https://www.tandfonline.com/doi/full/10.1080/10717544.2017.1406561

https://slideheaven.com/application-of-d-tocopheryl-polyethylene-glycol-1000-succinate-tpgs-in-transderm.html