Natesto: large shards UPDATE- batch is all bad.

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trax123

New Member
naa if look at actual results they seem pretty consistent. they fudged the data a wee bit as 10000% depends on WHEN they test.. perhaps start to metabolize slower as time goes on? the RANGE looks VERY similar accross those ranges.

testosterone is metabolized very quickly so some people are back to baseline 1 hr after application ie half life of 15 min.. saying median level is super inaccurate as its nothing to do with actual stabilization of free test. just 1 hr after application people range from 400-900 and fairly consistent is all that means. also should not equate that to benefits. ie compare month 1 range to month 6.. pretty much the same -/+ 70 or so....

BE VERY WARY of natesto data... be even more cautious about drawing conclusions from it.

new issue with natesto bottles is the shards get stuck so actuator does not depress all the way... "we will esculate this" yet no refund 7 months later, no answers, empty promises, was told they tested the crystalized product and would send results.... noda... people they had me speak to have left the company lol.. "restructured" have a feeling class action lawsuit is coming and no one wanted to be holding the bag they hired a shell company to manufacture so they dont have to be held accountable.

takes alot of complaints for FDA or health canada to actually do something particularly when no life or death risk as testosterone is pretty safe even if get 4x teh dosage your suppost to AND nearly impossible to gather data unless test 10 min after application AND hit a crystal that exact dose aswell (As 2 pumps 2-3 times a day) as by 1 hr + ur levels will be within range even if were 2500 for a small time. issue is of course causing damage to the HPTA axis having such high unintended spikes.
I take your points - I've not experienced any issues with the applicator not depressing though.

I may ask the pharmacy to try to exchange the unopened vials from the batch - one of them is riddled with crystals - I'm test/using the one that has the least but its obviously just not an optimal solution and appears to be a widespread manufacturing issue.

Physicians and several pharmacists alike profess total ignorance about this - they claim no one has ever reported it, so I don't know what to think exactly.

Any experience with Empower's 'generic' version of the gel?
 
Defy Medical TRT clinic doctor

trax123

New Member
Despite protestations from pharmacists - upon seeing the crystals they agreed it seemed possible but were incredulous that so many different lots could all have the issue... and that no other patients had ever reported it (also noting Natesto isn't that popular and they're not familiar with it either...)

But clearly Natesto in 2019 recalled the drug across 2 lots because "they deliver lower than labelled amount of product" which is alluding to - without specifically noting - this exact precipitation issue. After all what else could cause a homogenous gel in a tiny volume with 3 ingredients from dispensing one of them uniformly?

So I absolutely think Mr. Granger here is correct and they are all - in fact - wrong and rejecting what is plainly in front of them, namely that the company cannot solve its basic manufacturing problems, is in borderline receivership with a ghost operation, and clearly is shipping poor quality medication with no oversight or pushback. Indeed I wonder how many patients have even bothered peeling off the 2 layers of stickers and illuminating the vial to inspect the gel?

Very disappointing all around.
natesto recall.PNG
 

granger

Member
agreed, concern is mostly hitting crystals and getting TOO high of test levels and random dosages which of course may impact HPTA aXIS alot more than standard dosing. because you cannot OD its not a big deal to public safety HOWEVER very possibly negatively impacting HPTA axis and therefore marketing claims of such may be misleading.

FYI NATHAN BRYSON no longer works at ACERUS either lol... seems to have moved around ALOT for a guy with such high credentials... interesting that HE conducted alot of the research they did..... and left... I bet he isnt a shy sciency guy but a pretty quick witted salesman guy.. but im being negative and assuming.. could be they canned everyone vs some devious behaviour i suppose lol... just an annoyed particularly with this company being such a gong show. no ones asking the moon, simply follow through with what they had said AND fix product..

the reason pharmacists and DRs are confused is that they have not detailed this issue in the monograph.. as if its ok to use with shards they are suppost to say that or if shards are not ok they need to make that clear and accept loss for returned product.. they SAY its ok on the phone however interesting will never put that in print, also gave my pharmacy teh run around and feel bad for the lady as spent time on the phone, had to resend product after they sent it back after they gve her fedex # to send it too etc etc.


Thank you for posting the detailed information about test results... I do wish they posted individual data points or at least a few that we could see adrenal or testical pulses of testosterone staying intact between doses. while when suppression is of course folks with higher T will see greater AMOUNT of suppression, I dont think its a super great sign of keeping things functional.. but will take a closer read. a better sign would be all patients get similar low suppression in dose dependant manner and % of change may be helpful as MORE/greater is not uber informative IMO.

anyway, for investors i wouldn't be buying up stock lets say..
 

trax123

New Member
Agreed - frankly as this is the very first time I have ever used it, I'm more just trying to figure out whether it's a time issue (I need to use it for several weeks) or its the crystallization issue.

I 100% am convinced at this point that these crystals are not normal - see photos below. 6 vials all with crystals, 1 probably the best one with only 2 small visible ones, but of course just because they're not visible is irrelevant, it suggests the drug is not dissolved properly in the gel.

The Empower gel apparently is a much more complex mixture of 30 compounds - almost certainly either a patent issue OR a more expensive gel production method that Natesto uses unavailable for compounders.

But in either case it is NOT simply a 'generic' equivalent but a completely different medication, in my mind.

Will try to contact Acerus about this...
 

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trax123

New Member
I used it for years. I assumed crystals were normal and never gave them any thought.
Hey - yes I had noticed you were a very active Natesto poster on here!

I've also noted though people DO report many instances of suspecting Natesto wasn't being dosed correctly or evenly? We also know Natesto did recall vials for this reason.

Finally, it's of course well known that IV solutions do crystallize, and warming them for dissolution is a well reported phenomenon.

That said, you obviously have had years of use, so that's quite interesting in itself. I don't believe the crystallization is normal since the gel only contains 3 components - the hormone, castor oil, and some glyceride substrates. So I MUST assume that the crystals represent Testosterone precipitating out of solution.

The pharmacist I showed this to concurred that he himself would probably not take such a drug believing it to have probably 'cooled down too much during storage' and that "wherever they are warehousing the Natesto they may be storing it in chilled rooms alongside other drugs or perhaps even mistakenly keeping it chilled believing that it requires it."

I do believe though that given the 3x a day use (meaning each vial is fully administered in 10 days), AND given the fact that effects can be difficult to detect on a dose-by-dose basis for some, obviously the drug IS being delivered somewhere over those 30 doses just probably very unevenly. I suspect this COULD explain a lot of the reported erratic responses to Natesto.

As Mr. Granger has noted above, he has experienced major spikes (explained by applying a full crystal of the hormone) on Natesto while other times experiencing nothing. This is consistent with the drug not being properly mixed.

I also note some that reported using Empower's Nasal gel (which is an entirely different formulation) reported that the Empower seemed to produce instant physiological responses / were clearly cognizant they had administered the drug. This would also make sense since perhaps Empower's formula keeps the hormone dissolved more readily.

I'm speculating of course, but I will say that Mr. Granger's experience as reported seems very supportive to me. Furthermore, I have experienced zero effects on Natesto after a week of dosings from crystallized gel. Yes of course it's possible I either am not responsive at all OR I need to keep using it for several weeks... but inevitably eventually I will extrude a crystal... and presumably have a response. I am exquisitely sensitive to clomiphene for instance and had physiological responses within a few hours of dosing it in the past during a trial.

All this said - I'd be very curious to know if ALL your vials over these years have been crystallized or not.
 

Fortunate

Well-Known Member
Hey - yes I had noticed you were a very active Natesto poster on here!

I've also noted though people DO report many instances of suspecting Natesto wasn't being dosed correctly or evenly? We also know Natesto did recall vials for this reason.

Finally, it's of course well known that IV solutions do crystallize, and warming them for dissolution is a well reported phenomenon.

That said, you obviously have had years of use, so that's quite interesting in itself. I don't believe the crystallization is normal since the gel only contains 3 components - the hormone, castor oil, and some glyceride substrates. So I MUST assume that the crystals represent Testosterone precipitating out of solution.

The pharmacist I showed this to concurred that he himself would probably not take such a drug believing it to have probably 'cooled down too much during storage' and that "wherever they are warehousing the Natesto they may be storing it in chilled rooms alongside other drugs or perhaps even mistakenly keeping it chilled believing that it requires it."

I do believe though that given the 3x a day use (meaning each vial is fully administered in 10 days), AND given the fact that effects can be difficult to detect on a dose-by-dose basis for some, obviously the drug IS being delivered somewhere over those 30 doses just probably very unevenly. I suspect this COULD explain a lot of the reported erratic responses to Natesto.

As Mr. Granger has noted above, he has experienced major spikes (explained by applying a full crystal of the hormone) on Natesto while other times experiencing nothing. This is consistent with the drug not being properly mixed.

I also note some that reported using Empower's Nasal gel (which is an entirely different formulation) reported that the Empower seemed to produce instant physiological responses / were clearly cognizant they had administered the drug. This would also make sense since perhaps Empower's formula keeps the hormone dissolved more readily.

I'm speculating of course, but I will say that Mr. Granger's experience as reported seems very supportive to me. Furthermore, I have experienced zero effects on Natesto after a week of dosings from crystallized gel. Yes of course it's possible I either am not responsive at all OR I need to keep using it for several weeks... but inevitably eventually I will extrude a crystal... and presumably have a response. I am exquisitely sensitive to clomiphene for instance and had physiological responses within a few hours of dosing it in the past during a trial.

All this said - I'd be very curious to know if ALL your vials over these years have been crystallized or not.
At some point, I can invest some more time at updating you and everyone interested on my prior experience. To summarize: you guys may be onto something.

I am no longer using Natesto for a few reasons. Fortunately, for me, I did not have your experience. I did have a positive response. However, looking back, I do believe it was inconsistent. I always assumed that that was due to the delivery method and the inherent potential inconsistencies of getting the exact same amount delivered each dose. But, it is altogether possible that the inconsistencies were due to what you guys are describing. I never really paid attention to the crystallization until it was brought up here. Perhaps I should have?
 

madman

Super Moderator
Despite protestations from pharmacists - upon seeing the crystals they agreed it seemed possible but were incredulous that so many different lots could all have the issue... and that no other patients had ever reported it (also noting Natesto isn't that popular and they're not familiar with it either...)

But clearly Natesto in 2019 recalled the drug across 2 lots because "they deliver lower than labelled amount of product" which is alluding to - without specifically noting - this exact precipitation issue. After all what else could cause a homogenous gel in a tiny volume with 3 ingredients from dispensing one of them uniformly?

So I absolutely think Mr. Granger here is correct and they are all - in fact - wrong and rejecting what is plainly in front of them, namely that the company cannot solve its basic manufacturing problems, is in borderline receivership with a ghost operation, and clearly is shipping poor quality medication with no oversight or pushback. Indeed I wonder how many patients have even bothered peeling off the 2 layers of stickers and illuminating the vial to inspect the gel?

Very disappointing all around.View attachment 42237

11/2019





1710106526924.png

1710106619258.png






pg. 8-10
1710106661857.png



*On August 2, 2019, the Corporation announced that it had identified four commercial lots of Natesto®released in the Canadian and South Korean markets that were found to be non-conforming during long term stability studies, even though such lots were fully in-specification at the time of release. This post release non-conformity is not harmful to the patient, but may result in difficulties in dispensing. At that time, the temporary shortage of the product in the Canadian and South Korean markets was expected to continue until the end of October 2019. The Corporation noted this shortage on the Drug Shortages Canada website and continued to dialogue with Health Canada to identify solutions to try to minimize the disruption to patients in the affected markets.

*On November 1, 2019, the Corporation provided an update on the temporary unavailability of Natesto® in Canada and South Korea, following the previous announcement of the voluntary recall of certain Natesto® lots released on the Canadian and South Korean markets

*The Corporation initially made minor modifications to the manufacturing process that appeared to have resolved the previously identified issues and has produced a batch of Natesto® (the “Revised Batch”).While Acerus believed the changes would have been classified by Health Canada as level III, thereby requiring only an annual notification update to Health Canada and allowing for product to be released in Q4-2019, Health Canada, after much deliberation, classified the modifications as level I, requiring the submission of a Supplemental New Drug Submission (“SNDS”) prior to the release of the Revised Batch in the Canadian market. Ultimately, the issue was resolved by the Corporation providing an internal corrective action plan in February 2021. The Corporation notified Health Canada of its intention to reactivate the DIN for Natesto® in July 2021.

*On July 28, 2020, the Corporation announced that production of new batches of Natesto® (testosterone nasal gel) was underway and that shipments were already in transit to several key markets in North America and Asia (the United States, Taiwan and South Korea).
The first country resupplied with Natesto® was the United States, ensuring that product is available to meet anticipated demand in support of the Acerus Specialty Sales Force. In addition, Eu HWA, a subsidiary of Orient EuroPharma (“OEP”) – The Corporation’s licensee across South Asia – officially introduced Natesto® to Taiwan at the Taiwanese Urology Association’s annual meeting on August 22-23, 2020 representing the second commercial launch of Natesto® outside North America. OEP is also preparing entry strategies for nearby markets including Hong Kong, the Philippines, Singapore, Malaysia & Vietnam. Supply of Natesto® in Canada is expected to resume in 2021.

*The Company also remains optimistic about a return of NATESTO® to Canada during 2021. The first batch of NATESTO® for this market has already been manufactured and is undergoing stability studies. At the same time, Acerus has begun the regulatory work and commercial preparations required to support the reintroduction of NATESTO® in Canada.


 

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Fortunate

Well-Known Member
11/2019





View attachment 42259
View attachment 42260





pg. 8-10
View attachment 42261


*On August 2, 2019, the Corporation announced that it had identified four commercial lots of Natesto®released in the Canadian and South Korean markets that were found to be non-conforming during long term stability studies, even though such lots were fully in-specification at the time of release. This post release non-conformity is not harmful to the patient, but may result in difficulties in dispensing. At that time, the temporary shortage of the product in the Canadian and South Korean markets was expected to continue until the end of October 2019. The Corporation noted this shortage on the Drug Shortages Canada website and continued to dialogue with Health Canada to identify solutions to try to minimize the disruption to patients in the affected markets.

*On November 1, 2019, the Corporation provided an update on the temporary unavailability of Natesto® in Canada and South Korea, following the previous announcement of the voluntary recall of certain Natesto® lots released on the Canadian and South Korean markets

*The Corporation initially made minor modifications to the manufacturing process that appeared to have resolved the previously identified issues and has produced a batch of Natesto® (the “Revised Batch”).While Acerus believed the changes would have been classified by Health Canada as level III, thereby requiring only an annual notification update to Health Canada and allowing for product to be released in Q4-2019, Health Canada, after much deliberation, classified the modifications as level I, requiring the submission of a Supplemental New Drug Submission (“SNDS”) prior to the release of the Revised Batch in the Canadian market. Ultimately, the issue was resolved by the Corporation providing an internal corrective action plan in February 2021. The Corporation notified Health Canada of its intention to reactivate the DIN for Natesto® in July 2021.

*On July 28, 2020, the Corporation announced that production of new batches of Natesto® (testosterone nasal gel) was underway and that shipments were already in transit to several key markets in North America and Asia (the United States, Taiwan and South Korea).
The first country resupplied with Natesto® was the United States, ensuring that product is available to meet anticipated demand in support of the Acerus Specialty Sales Force. In addition, Eu HWA, a subsidiary of Orient EuroPharma (“OEP”) – The Corporation’s licensee across South Asia – officially introduced Natesto® to Taiwan at the Taiwanese Urology Association’s annual meeting on August 22-23, 2020 representing the second commercial launch of Natesto® outside North America. OEP is also preparing entry strategies for nearby markets including Hong Kong, the Philippines, Singapore, Malaysia & Vietnam. Supply of Natesto® in Canada is expected to resume in 2021.

*The Company also remains optimistic about a return of NATESTO® to Canada during 2021. The first batch of NATESTO® for this market has already been manufactured and is undergoing stability studies. At the same time, Acerus has begun the regulatory work and commercial preparations required to support the reintroduction of NATESTO® in Canada.
@madman, I remember this, but do you think it has anything to do with what the guys are describing here? As I alluded to above, I have crystals in most of my tubes. I always assumed it was normal for them to be there. It is altogether possible that I was wrong and never knew it. I have a crap ton of unopened Natesto. Maybe I should go through all of them and see if there are some with and some without crystals out of curiosity.

I have been off Natesto for while now. To be honest, I am glad to be off. I for sure noticed some inconsistencies in how I felt while I was on it. There are so many variables that could have explained it, but I always had a suspicion that I was not getting the same dose every time I applied it.
 

trax123

New Member
Interesting that you have so many vials! I have only 1 out of 6 that was mostly clean - 1-2 visible crystals, this is the one I'm trial-using right now.

The 'gentleness' of Natesto in terms of its rapid half-life and relatively low dose I believe makes determining the dosing (on a physiology basis) even more difficult. Testing is also - as was mentioned above - highly inaccurate because of the pulsatile nature and the differential absorption through the nasal membranes for different people - it's very difficult to 'time' a blood test to catch the T peak as such.

1. I think a better experiment is to compare against Empower's nasal gel. Clearly this less sophisticated 30-compound mixture 'cream' formulation is very different and I guess might be more stable (though it may also be slower to absorb if I had to guess), BUT it might be a more accurate representation of the effects and efficiacy of pulsed low-dose nasal delivered T. i.e. the cruder formulary version might be superior to the fancier patented Natesto gel because Natesto's manufacturing/shelf stability is so poor/temperature fragile.

2. I may try Empower's formulation given I doubt I will have ANY hope of getting Acerus to do anything about this, let alone to pick up the phone.

3. While I LOVE the concept of a nasal gel - really smart - I'm also beginning to wonder if JATENZO might just be easier all around and actually more effective. It's becoming more appealing due to these Natesto manufacturing/quality issues which I don't see really getting resolved.

I have seen VERY FEW reports from people online about JATENZO. Other than the hypertension black box warning apparently it does increase HCT more than desirable in some people - almost certainly because of its longer half-life; the nasal gels don't do that at all. OTOH Jatenzo seems 'stronger' in terms of clinical response.


(My completely unsupported hypothesis is that PO TRT-related drugs like Jatenzo or Clomiphene/enclomiphene work faster (even faster than IM injections or gels) because the GI to bloodstream pathway - portal or lymphatic - is the 2nd fastest possible systemic route of admin (aside from IV of course) and more rapidly achieves saturation esp. at the doses easily achievable in pills. This isn't really apropos of anything but it's something I've noticed from reports.
 

madman

Super Moderator
@madman, I remember this, but do you think it has anything to do with what the guys are describing here? As I alluded to above, I have crystals in most of my tubes. I always assumed it was normal for them to be there. It is altogether possible that I was wrong and never knew it. I have a crap ton of unopened Natesto. Maybe I should go through all of them and see if there are some with and some without crystals out of curiosity.

I have been off Natesto for while now. To be honest, I am glad to be off. I for sure noticed some inconsistencies in how I felt while I was on it. There are so many variables that could have explained it, but I always had a suspicion that I was not getting the same dose every time I applied it.

There should be no crystalized T in the viscous oily based formulation.

Hard to say for sure whether it was due to crystalized T in the formulation which may have prevented the full dose from being delivered.


*The testosterone gel formulations of the invention are stored at room temperature (20 250C or 68 to 770F). Temperature excursions from 15 to 300C or 59 to 86F are permissible for the testosterone gel formulations of the inventions. The stability data supports a 12-month shelf life.

*Because testosterone is fully dissolved within the formulations of the present invention, physical characteristics of the drug substance do not influence the performance of the drug product, testosterone gel formulations of the invention.
The manufacturability of testosterone gel formulations of the invention, however is influenced by the particle size of testosterone. When using a particle size of 50% i25 microns, 90% 550 microns the solubility of the drug substance in the matrix is especially favorable

*The drug product, TBS-1, is a viscous and thixotropic, oil-based formulation containing solubilized testosterone intended for intranasal application for the treatment of hypogonadism in men. The drug product is formulated with the following compendial inactive ingredients: castor oil, oleoyl macrogolglycerides, and colloidal silicon dioxide.

*Overall, stability data provided in this section are concluded to support a 24 month "use by" period for TBS-1 stored at controlled room temperature conditions [i.e., 25 °C (77°F); excursions 15 - 30 °C (59-86°F)]. The data also show that special storage conditions for the drug product are not required. The packaging configuration is adequate to protect the drug product from light and the drug product does not degrade or change physically following exposure to temperature cycling stress. The clinical supplies are applied a 1 year re-test period, when stored at controlled room temperature conditions [i.e., 25 °C (77°F); excursions 15 -30 °C (59-86°F)], to reflect the duration of the trial and the data available. As additional data is available the re-test period will be extended as appropriate.






Only 2 lots in Canada were identified back in 2019.


*Acerus has received a small number of complaints over the past few months relating to this actuation problem. There has been no change in any other type of complaints relating to safety or efficacy.

*Two commercial lots of NATESTO released in the Canadian market were found to be non-conforming during long-term stability studies, even though such lots were fully in- specification at the time of release. The impacted lots do not consistently meet the delivered dose uniformity specification (they deliver lower than labelled amount of product). This post-release non-conformity does not pose any safety concerns for patients, but can result in the patient receiving a lower dose of the active ingredient, impacting efficacy


Screenshot (33602).png

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Intranasal testosterone gel formulations and use thereof for treating male hypogonadism​


Generally speaking, the intranasal testosterone gel formulations of the present invention are formulated with about 4% and 4.5% testosterone by weight, and the testosterone is well absorbed when such gel formulations are administered pernasally to hypogonadal subjects. More specifically, testosterone is rapidly absorbed following pernasal administration with a peak concentration reached within 36 minutes to 1 hour 6 minutes (mean Tmax) following intra-nasal administration and maximal serum concentration is reached after about 1-2 hours post nasal administration. The maximum Testosterone concentration over a 24-hour interval is observed during the first administration (0-10 hours) in approximately 57% to 71% of the hypogonadal men while approximately 29% to 43% of the subjects had their maximum 24-h Testosterone concentration during subsequent administrations. The formulations containing 4% and 4.5% testosterone by weight provide surprising properties. Importantly, the solubility of testosterone in castor oil pure is 3.6% maximum, falling to 3.36% about with 4% Labrafil. Addition of fumed silica (Aerosil, CabOsil) can increase the solubility of testosterone in castor oil up to 4.5% even with 4.0% Labrafil. This is counter intuitive for a person skilled in the art. However, without wishing to be bound by any particular theory, it is believed that this increase in solubility in the presence of silica is due, at least in part, to the fact that SiO 2 adsorbs about 10% of the testosterone. In accordance with the novel methods of the present invention, the intranasal testosterone gels are topically deposited on the outer external walls (opposite the nasal septum) inside the naval cavity of each nostril, preferably at about the middle to about the upper section of the outer external wall (opposite the nasal septum) just under the cartilage section of the outer external wall inside the naval cavity of each nostril. Once gel deposition is complete within each nostril of the nose, the outer nose is then gently and carefully squeezed and/or rubbed by the subject, so that the deposited gel remains in contact with the mucosal membranes within the nasal cavity for sustained release of the testosterone over dose life. Typical testosterone gel dosage amounts deposited pernasal application is between about 50 to about 150 microliters per nostril, and preferably about 125 to about 150 microliters per nostril. In carrying out the methods of the present invention, approximately between about 50 microliters and about 150 microliters of an intranasal testosterone gel of the present invention is applied to each nostril of a subject once or twice daily or three times a day, e.g., for one, two, three, four or more consecutive weeks, or for two, three, four, five or six consecutive days or more, or intermittently such as every other day or once, twice or three times weekly, or on demand once or twice during the same day, as TRT or to treat male testosterone deficiency, including male hypogonadism.

*As used herein a "testosterone gel formulation for nasal administration" means a formulation comprising testosterone in combination with a solvent, a wetting agent, and a viscosity increasing agent.

*The testosterone gel formulations of the invention are viscous and thixotropic, oil based formulations containing a solution of testosterone intended for intranasal application. The non-irritating formulation is designed to adhere to the inner nose. In addition, it acts as a controlling matrix, thus allowing sustained drug delivery through the nasal mucosa. Other pharmacologically inactive ingredients in the testosterone intranasal gel are castor oil USP, oleoyl macrogolglycerides EP and colloidal silicon dioxide NF. None of these excipients are of human or animal origin. All excipients are well-known and listed in the "Inactive Ingredient" list for Approved Drug Products issued by the FDA.





Table 2: General Properties of Testosterone

*Appearance White or slightly creamy white crystals or crystalline powder..It.is odorless, and.stable in air. Solubility Practically insoluble in water (0.024 g/L), freely soluble in dehydrated alcohol, chloroform and in methylene chloride, soluble in dioxane and in vegetable oils; slightly soluble.in. ether. Melting range 153°C 0 to 157°C Specific rotation +101° to +105°0 (dioxane) Loss on drying Nte than 1.0% g

*Testosterone, for testosterone gel formulations of the invention, appears as white or slightly creamy white crystals or crystalline powder. Itis freely soluble in methanol and ethanol, soluble in acetone and isopropanol and insoluble in n-heptane. It can also be considered as insoluble in water (S 2 0 c=2.41 x10 2g/L±0.04 x10 2g/L); its n Octanol/Water partition coefficient (log Pow determined by HPLC) is 2.84. The solubility of testosterone in oils was determined to be 0.8% in isopropyl myristate, 0.5% in peanut oil, 0.6% in soybean oil, 0.5% in corn oil, 0.7% in cottonseed oil and up to 4% in castor oil.

*Because testosterone is fully dissolved within the formulations of the present invention, physical characteristics of the drug substance do not influence the performance of the drug product, testosterone gel formulations of the invention.
The manufacturability of testosterone gel formulations of the invention, however is influenced by the particle size of testosterone. When using a particle size of 50% i25 microns, 90% 550 microns the solubility of the drug substance in the matrix is especially favorable

*Other pharmacologically inactive ingredients in the testosterone intranasal gel are castor oil USP, oleoyl macrogolglycerides EP and colloidal silicon dioxide NF.
None of these excipients are of human or animal origin. All excipients are well-known and listed in the "Inactive Ingredient" list for Approved Drug Products issued by the FDA. According to the "Handbook of Pharmaceutical Additives" oleoyl polyoxylglycerides are used as hydrophilic oil for topicals, injectables and nasals. In FDA-approved medicinal products it is used as co-emulsifier in topical emulsions/lotions/creams and in vaginal emulsions/creams. In France this excipient is approved for nasal preparations such as "Rhino-Sulforgan" (Laboratoire Jolly-Jatel, France; containing 10% oleoyl polyoxylglycerides) and "Huile Gomenolee 2% ("Laboratoire Gom6nol, France; containing 10% oleoyl polyoxylglycerides). Hence, like for castor oil it can be deduced that oleoyl polyoxylglycerides is suitable for an application route where safety and tolerability are of highest importance (e.g. injectables and nasal or vaginal preparations). Oleoyl macrogolglycerides are also referred to as Labrafil M 1944 CS, apricot kernel oil PEG-6 esters, Peglicol-5-oleate, mixture of glycerides and polyethylene esters.

*The castor oil, which is used as a solvent for testosterone gel formulations of the invention, is a fixed oil. Such oils have the advantage of being non-volatile or spreading (in contrast to essential oils or liquid paraffin), but have the disadvantage of being hydrophobic. The nasal mucosa contains 95-97% water. Without the oleoyl macrogol-glycerides, the castor oil containing the active ingredient would form a non interactive layer on the mucous membrane. In order to achieve adequate contact between the castor oil layer and the mucous membrane, the hydrophilic oleoyl macrogol-glycerides oil is added to the formulation to form an emulsion between the castor oil and the mucosa fluid. Oleoyl macrogolglycerides are used in semi-solids at concentrations ranging from about 3 to 20%, depending on the application. The amount of oleoyl macrogol glycerides in testosterone gel formulations of the invention is high enough to allow for a better contact of the carrier oil with the mucous membrane and low enough to have minimal impact on the amount of testosterone that can be incorporated into the carrier oil. A favourable concentration of oleoyl microgol-glycerides in testosterone gel formulations of the invention is found to be 4% of the formulation. According to the "Handbook of Pharmaceutical Additives" colloidal silicon dioxide is used as an oil adsorbent, thermal stabiliser and gellant. In FDA-approved medicinal products it is used in dental gels, sublingual tablets, endocervical gel, suppositories, vaginal emulsions/creams/tablets/tampons and capsules for inhalation. Furthermore, it is used as an excipient in "Testoderm with adhesives" (Alza Corporation, approved in 1996) a testosterone transdermal patch. Hence, it can be deduced that colloidal silicon dioxide is suitable for an application route where safety and tolerability are of highest importance (e.g. inhalations, endocervical, vaginal or rectal preparations). For clinical trial supplies, testosterone intranasal gel is supplied in unit-dose syringes consisting of a syringe body made from polypropylene, a plunger moulded from polyethylene and a syringe cap made from high density polyethylene. The syringes are wrapped in aluminum foil as secondary packaging. The pre-filled unit-dose syringes used in accordance with the study in the Examples are filled as follows: (a) 4% testosterone intranasal bio-adhesive gel - 148 microliters and 5.92 mgs of testosterone; (b) 4.5% testosterone intranasal bio-adhesive gel - 148 microliters and 6.66 mgs of testosterone; and (c) 4.5% testosterone intranasal bio-adhesive gel - 148 microliters and 7.785 mgs of testosterone.

*The oil in testosterone gel formulations of the invention is thickened with colloidal silicon dioxide, which acts as a gel-forming agent. This compound is used commonly for stiffening oleogels. The intended dosage form for testosterone gel formulations of the invention is a semi-solid, not a liquid. The formulation is thickened with colloidal silicon dioxide. It is believed that colloidal silicon dioxide contributes to the thixotropic properties of the gel, simplifying drug delivery to the nostril. Colloidal silicon dioxide is generally an inert material which is well tolerated as an excipient in mucosal applications such as suppositories. Colloidal silicon dioxide is typically used in these preparations at concentrations ranging from about 0.5 to 10%. The concentration of colloidal silicon dioxide in testosterone gel formulations of the invention is high enough to achieve gel formation but at a level that has minimal impact on testosterone incorporation into the carrier oil. Preferably, the intranasal testosterone gels of the present invention have in general, a viscosity in the range of between about 3,000 cps and about 27,000 cps. It should nevertheless be understood by those versed in this art that, while the above mentioned viscosity range is believed to be a preferred viscosity range, any suitable viscosities or viscosity ranges that do not defeat the objectives of the present invention are contemplated. A detailed description of batches of a testosterone gel formulation of the invention is shown in Table 3.





Table 3: Composition of a testosterone gel formulation of the invention

Amount Amount Component (%w/w) (%w/w) 4.0% 0.45% Testosterone 4.0% 4.5% Castor oil 88% 87.5% Oleoyl macrogol- 4.0% 4.0% glycerides Colloidal silicon dioxide 4.0% 4.0%

*The testosterone gel formulations of the invention are stored at room temperature (20 250C or 68 to 770 F). Temperature excursions from 15 to 300C or 59 to 86F are permissible for the testosterone gel formulations of the inventions. The stability data supports a 12-month shelf life.
*
Unit dose syringes are chosen for the primary packaging of the clinical materials for the clinical trial described below to allow for ease of dosing, ability to generate multiple doses by varying the fill volume and consistency of dose delivered. The syringe consists of a syringe body, a plunger and a syringe cap. The syringes body is moulded from polypropylene, the plunger is moulded from polyethylene and the cap is HDPE. These syringes are designed and manufactured to deliver sterile and non-sterile solutions, liquids and gels at low volumes. For additional protection from the environment (i.e., exposure to dirt, light, humidity and oxygen), the syringes are packed in a foil-laminate overwrap pouch. The syringes and caps are designed for use in a clinical setting and meet the requirements of the EU Medical Devices Directive 93/42/EEC of June 14, 1993 and as amended. As this container closure is only intended for use in this portion of the clinical program, no additional studies will be performed on the syringe and syringe components. For a further element of protection, two syringes are contained in secondary packaging consisting of an aluminium foil pouch. Two syringes are packaged in the aluminium foil pouch and each pouch is sealed. The pouch consists of a flexible, 3-layered-foil-laminate of a) polyester 12 micron, b) aluminum 12 micron and c) a polyethylene 75 micron. It is manufactured by Floeter Flexibles GmbH, and supplied under the name "CLIMAPAC || 12-12-75". The invention provides for intranasal bio-adhesive gel formulations of testosterone to be administered intranasally, wherein the dosage of the formulation is from about 4.0% or 4.5% testosterone by weight of said gel.

*Mixing of the Ingredients - Bulk Gel The Pre-Mix is prepared by mixing, with a propeller mixer, the full amount of Testosterone with portion 1 of the castor oil for 10 minutes. Mixture I is prepared by adding the Pre-Mix to the remaining castor oil and mixing for 60 minutes. The product temperature is maintained below 50°C 0 for the entire mixing process. The oleoyl polyxoyl glycerides are pre-heated to 40 -50°C and mixed for 10 minutes before being added to Mixture1. This is identified as Mixture II. It is mixed for minutes while maintaining product temperature below 50°C. Mixture II is then screened through a sieve to remove any un-dissolved Testosterone aggregates.

*Mixture III is prepared by adding the colloidal silicon dioxide to Mixture II and mixing for 15 minutes while maintaining product temperature below 500C. A visual check is conducted after this step, to ensure that the gel is clear. At the completion of mixing the gel is stirred and cooled to a product temperature below 300C. The product is then discharged into stainless steel drums and the bulk gel sample is taken for analytical testing. Filling and Packaging - Clinical Supplies After release of the final gel mixture by the quality control laboratory, the filling and packaging process is carried out by filling a pre-determined volume into the syringe followed by the application of the syringe cap. Two syringes are packaged into a foil pouch. The syringes are filled using a pipette with the gel taken from a holding tank. The tip of the pipette is discarded after the syringe is filled and the syringe cap is applied. Each syringe is individually labelled. Following the application of the label, two syringes are packaged in a pre-formed foil pouch and the pouch is sealed. Each pouch is labelled.

*The drug product, TBS-1, is a viscous and thixotropic, oil-based formulation containing solubilized testosterone intended for intranasal application for the treatment of hypogonadism in men. The drug product is formulated with the following compendial inactive ingredients: castor oil, oleoyl macrogolglycerides, and colloidal silicon dioxide.

*Stability [TBS-1, Gel] Stability Summary and Conclusions [TBS-1, Gel] This section has been amended to include additional data on the on-going stability studies for the initial stability batches and to provide stability data on the drug product in the syringes utilized for the Phase II clinical study. Only the updated sections and new information have been included for review. All stability studies of TBS-1 gel have been performed by ACC GmbH Analytical Clinical Concepts, Sch6ntalweg 9-11, 63849 Leidersbach/Aschaffenburg, Germany. Stability studies that meet ICH requirements are on-going.

*Overall, stability data provided in this section are concluded to support a 24 month "use by" period for TBS-1 stored at controlled room temperature conditions [i.e., 2 5 °C (77°F); excursions 1 5 - 3 0 °C (59-86°F)]. The data also show that special storage conditions for the drug product are not required. The packaging configuration is adequate to protect the drug product from light and the drug product does not degrade or change physically following exposure to temperature cycling stress. The clinical supplies are applied a 1 year re-test period, when stored at controlled room temperature conditions [i.e., 2 5 °C (77°F); excursions 1 5 -3 0 °C (59-86°F)], to reflect the duration of the trial and the data available. As additional data is available the re-test period will be extended as appropriate.

*Content: Active ingredient: Testosterone. Excipients: Silicon dioxide, castor oil, Labrafil*. Mode of administration: Nasally, as a single dose to each nostril. Manufacturer: Haupt Pharma Amareg. Batch numbers: 0744, 0942, and 0943 Storage conditions: Between 20 - 25°C.
 

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granger

Member
@trax123 having more ingredients in empower compounded doesnt make it better. sometimes its just a bulk base gel that is used for several other things and they just add a solvent and teh test for example to it. somethings can be in there for other reasons when used with other products for example.. i dont know specific formulation of compounded nasal gel... little more familiar with other topical/trans drugs/hormones though.

i get the idea of natesto with the silicon once hits moisture it basically turns to normal booger consistency and sticks inside the nose instead of being swallowed. i dont know about the empower so would be interested to hear your experience!
 

madman

Super Moderator
Interesting that you have so many vials! I have only 1 out of 6 that was mostly clean - 1-2 visible crystals, this is the one I'm trial-using right now.

The 'gentleness' of Natesto in terms of its rapid half-life and relatively low dose I believe makes determining the dosing (on a physiology basis) even more difficult. Testing is also - as was mentioned above - highly inaccurate because of the pulsatile nature and the differential absorption through the nasal membranes for different people - it's very difficult to 'time' a blood test to catch the T peak as such.

1. I think a better experiment is to compare against Empower's nasal gel. Clearly this less sophisticated 30-compound mixture 'cream' formulation is very different and I guess might be more stable (though it may also be slower to absorb if I had to guess), BUT it might be a more accurate representation of the effects and efficiacy of pulsed low-dose nasal delivered T. i.e. the cruder formulary version might be superior to the fancier patented Natesto gel because Natesto's manufacturing/shelf stability is so poor/temperature fragile.

2. I may try Empower's formulation given I doubt I will have ANY hope of getting Acerus to do anything about this, let alone to pick up the phone.

3. While I LOVE the concept of a nasal gel - really smart - I'm also beginning to wonder if JATENZO might just be easier all around and actually more effective. It's becoming more appealing due to these Natesto manufacturing/quality issues which I don't see really getting resolved.

I have seen VERY FEW reports from people online about JATENZO. Other than the hypertension black box warning apparently it does increase HCT more than desirable in some people - almost certainly because of its longer half-life; the nasal gels don't do that at all. OTOH Jatenzo seems 'stronger' in terms of clinical response.


(My completely unsupported hypothesis is that PO TRT-related drugs like Jatenzo or Clomiphene/enclomiphene work faster (even faster than IM injections or gels) because the GI to bloodstream pathway - portal or lymphatic - is the 2nd fastest possible systemic route of admin (aside from IV of course) and more rapidly achieves saturation esp. at the doses easily achievable in pills. This isn't really apropos of anything but it's something I've noticed from reports.


Compounded Testosterone Nasal Gel-cream

Non-medicinal ingredients: 29

1710134202508.png












 

granger

Member
never a fan of EDTA(the empower nasal gel), its what gives hydroponic veggies the weird hydroponic taste/smell and is not super great for you even in low doses IMO. hormone disruptor bad for kidneys heart etc etc.
 

trax123

New Member
My point was basically my guess is the formulary compounding method is simpler and not refined, though this could mean less crystallization - this is why they use so many different binders and solvents, whereas Natesto's manufacturing process may be more labor intensive to dissolve the hormone in castor oil which is why they're able to produce a much 'cleaner' end-product.

Thank you Madman for posting all the links to related discussions (you don't need to keep posting them by the way).

Jatenzo obviously causes more suppression and has some more classical TRT side fx which the nasal gel does not. So it's a consideration for me personally and perhaps for others having issues with the gel.

I will investigate Empower's gel. My physician has also been able to contact Acerus through their representative (apparently it was difficult but they got to them).

//Aside
So I will comment if I hear anything. I'm not expecting much though, my sense is they probably consider this within tolerances since the entire vial - something like 330mg of Testosterone - gets delivered over 10 days. If you graph the variance against an expected mean of 33mg/day (3x dosing daily) you'll see zeroes and some 100mg doses probably but it's probably true that in 5 days you'll probably get about half of it.

Given it's already a low dose with a very short half life AND clinical effects with most people average out over time, I suspect they're 1) well aware of the issue and 2) don't care because ultimately the drug is getting delivered. I agree Granger's point that this could actually interfere with the stated HPG axis pulsing that Natesto is meant to preserve, but I'm also thinking the dose is so low it might not matter in - MOST - people b/c the half life is vanishingly fast.

Ergo, I would basically consider Natesto safe/ok from a drug standpoint but very low quality from a product standpoint. And I absolutely don't see this getting fixed, esp. given the comments above about dozens of vials all having crystals and all of mine also having crystals.
 
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