ExcelMale
Menu
Home
What's new
Latest activity
Forums
New posts
Search forums
What's new
New posts
Latest activity
Videos
Lab Tests
Doctor Finder
Buy Books
About Us
Men’s Health Coaching
Log in
Register
What's new
Search
Search
Search titles only
By:
New posts
Search forums
Menu
Log in
Register
Navigation
Install the app
Install
More options
Contact us
Close Menu
Forums
Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
My Experience On Jatenzo (Oral TRT) Log
JavaScript is disabled. For a better experience, please enable JavaScript in your browser before proceeding.
You are using an out of date browser. It may not display this or other websites correctly.
You should upgrade or use an
alternative browser
.
Reply to thread
Message
<blockquote data-quote="madman" data-source="post: 217775" data-attributes="member: 13851"><p>Regarding oral native T, this is where it stands as of now.</p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/ditest%E2%84%A2-oral-native-testosterone.24223/[/URL]</p><p></p><p></p><p><em><strong>*Diurnal’s is also developing a <u>novel formulation of testosterone</u> for the treatment of hypogonadism</strong></em></p><p><em><strong></strong></em></p><p><em><strong><em><strong>*Diurnal’s <u>DITEST</u>™ product is a <u>formulation of unmodified testosterone that seeks to avoid the issues of poor bioavailability by using a PROPRIETARY, oil-based excipient mixture</u></strong></em></strong></em></p><p><em></em></p><p><em>Oral testosterone supplements can avoid these issues of transference, although they make up a smaller portion of the market. <strong>Currently available oral products use an undecanoate ester of testosterone, which dramatically improves bioavailability over <u>uncodified testosterone</u> by avoiding first-pass metabolism. However, testosterone undecanoate has a substantial food effect: for instance, <a href="https://www.excelmale.com/forum/threads/fda-approves-new-oral-testosterone-capsule-called-jatenzo.18173/" target="_blank">Jatenzo</a> must be taken with a high-fat meal (30g of fat or more) to ensure complete absorption and this must be done twice a day.</strong> <strong>For reference, a tablespoon of butter has 12g of fat.</strong> Moreover, <a href="https://www.excelmale.com/forum/threads/fda-approves-new-oral-testosterone-capsule-called-jatenzo.18173/" target="_blank">Jatenzo</a> has a black box warning for cardiovascular side effects.</em></p><p><em></em></p><p><em><strong>Diurnal’s <u>DITEST</u>™ product is a formulation of unmodified testosterone that seeks to avoid the issues of poor bioavailability by using a <u>proprietary, oil-based excipient mixture</u>. </strong>It has not been reported on how this excipient mixture avoids the issue of first-pass metabolism, but Diurnal has reported results from a Phase I study (n=25, 24 completed treatment) that showed similar pharmacological parameters to testosterone undecanoate, but without the food effect.</em></p><p></p><p></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://www.excelmale.com/forum/threads/oral-native-testosterone.23914/[/URL]</p><p></p><p><em><strong>*There is no licensed oral testosterone because of challenges in formulation</strong></em></p><p></p><p></p><p></p><p></p><p></p><p><strong>Significance Statement</strong></p><p></p><p><em><strong>There is no licensed oral testosterone because of challenges in formulation,</strong> and the oral formulations of the ester, testosterone undecanoate, require a fatty meal for absorption and generate supraphysiological dihydrotestosterone levels. <strong><em>We have overcome the design challenges and formulated <u>oral native testosterone</u> which can be taken with or without food and provides physiological levels of testosterone and dihydrotestosterone in hypogonadal men. </em>This formulation, <u>DITEST</u>, has the potential advantage of being oral for patients who don’t tolerate injections and less risk of adverse events that might theoretically be associated with elevated dihydrotestosterone levels</strong>. Future studies will need to define the dosing regimen for replacement in hypogonadal men.</em></p><p></p><p></p><p></p><p></p><p><strong>Introduction</strong></p><p></p><p><em><strong>Testosterone was isolated, named, and synthesized in 1935 (1), but to date, no <u>oral native testosterone</u> has been licensed for testosterone replacement therapy.</strong> <strong>The reason being that oral native testosterone, although absorbed through the intestine, undergoes extensive presystemic metabolism along the gastrointestinal tract (2), as well as rapid first-pass metabolism in the liver (3). </strong>The oral absorption of testosterone is also dependent on the dosing vehicle, wherein a lipophilic vehicle may increase the proportion of testosterone absorbed via the lymphatic route (4). It is thus difficult to achieve adequate bioavailability of testosterone in order to maintain consistent physiological testosterone levels via the oral route. </em><strong><em>To address this, different routes of administration for testosterone have been used and <u>native testosterone replacement therapy</u> has been licensed as implants, transdermal, transbuccal, and intranasal therapies (5).</em></strong></p><p></p><p><em>Oral 17α-alkylated androgens such as methyltestosterone and oxymetholone were proved to be effective androgen replacement therapies but were associated with severe liver damage including the development of jaundice, peliosis hepatis, and liver tumors (6). <strong><em>This toxic effect on the liver appears to be specific to oral modified (i.e. non-native) testosterones, particularly methylated testosterone, and was not seen with native testosterone in animal models assessing liver toxicity (7).</em></strong> Testosterone undecanoate (TU) is an ester prodrug of testosterone and has a mid-chain length fatty acid at the 17β position and when given orally undergoes absorption in part through the intestinal lymphatic pathway, so circumventing some of the first-pass metabolism through the liver (4). <strong><em>Oral testosterone undecanoate is presented as an oily capsule and has been available in Europe since the 1970s (1); however, TU has to be taken with a meal two or three times daily, has an unpredictable absorption pattern, and generates high dihydrotestosterone (DHT) to testosterone ratio (8-10).</em></strong> <strong><em>An oral self-emulsifying formulation of TU has recently been approved in the US (<a href="https://www.excelmale.com/forum/threads/fda-approves-new-oral-testosterone-capsule-called-jatenzo.18173/" target="_blank">Jatenzo</a>®, Clarus Therapeutics Inc., USA). </em></strong>The formulation promotes solubilization and intestinal lymphatic absorption of the lipophilic testosterone ester. Deesterification of TU by nonspecific esterases in liver, blood, and tissue results in the production of testosterone. The liberated undecanoic acid moiety is metabolized via beta-oxidation. 5-Alpha reduction of testosterone undecanoate in the gut produces dihydrotestosterone undecanoate (DHTU) and DHT (11). The testosterone undecanoate formulation has to be taken with food, patients have higher than normal DHT levels on treatment and the label is associated with a black box warning regarding an increase in blood pressure (12). These data support the need for new developments in this area.</em></p><p></p><p><strong><em>Various oral formulations of native testosterone have been tested in man although none have been licensed (13-20). </em></strong><em>Soon after testosterone’s identification and characterization, oral testosterone administration was disregarded as a viable route of administration and replacement because of poor oral absorption (21). <strong>In the 1970s, a micronized form of free testosterone was demonstrated to be absorbed in hypogonadal men but absorption was not reliable enough to progress as therapy (14). Further research, particularly by Amory and coworkers, showed that native testosterone administered as a suspension in oil, provided potentially therapeutic levels of testosterone in healthy men (15), and combined with 5αreductase inhibitors provided physiological testosterone levels both in the fasted and fed state (16).<u> Native testosterone is practically insoluble in water and in fatty oil vehicles (22), and the challenge has been to develop a solution formulation that contains sufficient testosterone concentration to provide reproducible physiological testosterone levels in hypogonadal men</u>. Building upon the previous observations, we have developed a <u>lipidic solution formulation of native testosterone</u> and have tested it in dogs and humans in the fasted and fed state.</strong></em></p><p></p><p></p><p></p><p></p><p><strong>Formulation:</strong> <em><u><strong>Lipidic Native Testosterone (NT) formulations</strong></u> were developed and assessed in vitro for dispersion behavior in gastric and intestinal media and for physical stability. A single formulation of NT, <u>DITEST</u>, was selected to take forward into pre-clinical trials (Table 1). The formulation used digestible lipids (oils with carbon chain length > 10 carbons atoms) with the addition of short-medium chain oils and ethanol as a polar co-solvent to assist with solubilization. The formulation was encapsulated in size 00 soft gelatin capsules with 40mg per capsule inside an aluminum foil blister pack and was stable for 2 years at ambient temperature (25°C).</em></p></blockquote><p></p>
[QUOTE="madman, post: 217775, member: 13851"] Regarding oral native T, this is where it stands as of now. [URL unfurl="true"]https://www.excelmale.com/forum/threads/ditest%E2%84%A2-oral-native-testosterone.24223/[/URL] [I][B]*Diurnal’s is also developing a [U]novel formulation of testosterone[/U] for the treatment of hypogonadism [I][B]*Diurnal’s [U]DITEST[/U]™ product is a [U]formulation of unmodified testosterone that seeks to avoid the issues of poor bioavailability by using a PROPRIETARY, oil-based excipient mixture[/U][/B][/I][/B] Oral testosterone supplements can avoid these issues of transference, although they make up a smaller portion of the market. [B]Currently available oral products use an undecanoate ester of testosterone, which dramatically improves bioavailability over [U]uncodified testosterone[/U] by avoiding first-pass metabolism. However, testosterone undecanoate has a substantial food effect: for instance, [URL='https://www.excelmale.com/forum/threads/fda-approves-new-oral-testosterone-capsule-called-jatenzo.18173/']Jatenzo[/URL] must be taken with a high-fat meal (30g of fat or more) to ensure complete absorption and this must be done twice a day.[/B] [B]For reference, a tablespoon of butter has 12g of fat.[/B] Moreover, [URL='https://www.excelmale.com/forum/threads/fda-approves-new-oral-testosterone-capsule-called-jatenzo.18173/']Jatenzo[/URL] has a black box warning for cardiovascular side effects. [B]Diurnal’s [U]DITEST[/U]™ product is a formulation of unmodified testosterone that seeks to avoid the issues of poor bioavailability by using a [U]proprietary, oil-based excipient mixture[/U]. [/B]It has not been reported on how this excipient mixture avoids the issue of first-pass metabolism, but Diurnal has reported results from a Phase I study (n=25, 24 completed treatment) that showed similar pharmacological parameters to testosterone undecanoate, but without the food effect.[/I] [URL unfurl="true"]https://www.excelmale.com/forum/threads/oral-native-testosterone.23914/[/URL] [I][B]*There is no licensed oral testosterone because of challenges in formulation[/B][/I] [B]Significance Statement[/B] [I][B]There is no licensed oral testosterone because of challenges in formulation,[/B] and the oral formulations of the ester, testosterone undecanoate, require a fatty meal for absorption and generate supraphysiological dihydrotestosterone levels. [B][I]We have overcome the design challenges and formulated [U]oral native testosterone[/U] which can be taken with or without food and provides physiological levels of testosterone and dihydrotestosterone in hypogonadal men. [/I]This formulation, [U]DITEST[/U], has the potential advantage of being oral for patients who don’t tolerate injections and less risk of adverse events that might theoretically be associated with elevated dihydrotestosterone levels[/B]. Future studies will need to define the dosing regimen for replacement in hypogonadal men.[/I] [B]Introduction[/B] [I][B]Testosterone was isolated, named, and synthesized in 1935 (1), but to date, no [U]oral native testosterone[/U] has been licensed for testosterone replacement therapy.[/B] [B]The reason being that oral native testosterone, although absorbed through the intestine, undergoes extensive presystemic metabolism along the gastrointestinal tract (2), as well as rapid first-pass metabolism in the liver (3). [/B]The oral absorption of testosterone is also dependent on the dosing vehicle, wherein a lipophilic vehicle may increase the proportion of testosterone absorbed via the lymphatic route (4). It is thus difficult to achieve adequate bioavailability of testosterone in order to maintain consistent physiological testosterone levels via the oral route. [/I][B][I]To address this, different routes of administration for testosterone have been used and [U]native testosterone replacement therapy[/U] has been licensed as implants, transdermal, transbuccal, and intranasal therapies (5).[/I][/B] [I]Oral 17α-alkylated androgens such as methyltestosterone and oxymetholone were proved to be effective androgen replacement therapies but were associated with severe liver damage including the development of jaundice, peliosis hepatis, and liver tumors (6). [B][I]This toxic effect on the liver appears to be specific to oral modified (i.e. non-native) testosterones, particularly methylated testosterone, and was not seen with native testosterone in animal models assessing liver toxicity (7).[/I][/B] Testosterone undecanoate (TU) is an ester prodrug of testosterone and has a mid-chain length fatty acid at the 17β position and when given orally undergoes absorption in part through the intestinal lymphatic pathway, so circumventing some of the first-pass metabolism through the liver (4). [B][I]Oral testosterone undecanoate is presented as an oily capsule and has been available in Europe since the 1970s (1); however, TU has to be taken with a meal two or three times daily, has an unpredictable absorption pattern, and generates high dihydrotestosterone (DHT) to testosterone ratio (8-10).[/I][/B] [B][I]An oral self-emulsifying formulation of TU has recently been approved in the US ([URL='https://www.excelmale.com/forum/threads/fda-approves-new-oral-testosterone-capsule-called-jatenzo.18173/']Jatenzo[/URL]®, Clarus Therapeutics Inc., USA). [/I][/B]The formulation promotes solubilization and intestinal lymphatic absorption of the lipophilic testosterone ester. Deesterification of TU by nonspecific esterases in liver, blood, and tissue results in the production of testosterone. The liberated undecanoic acid moiety is metabolized via beta-oxidation. 5-Alpha reduction of testosterone undecanoate in the gut produces dihydrotestosterone undecanoate (DHTU) and DHT (11). The testosterone undecanoate formulation has to be taken with food, patients have higher than normal DHT levels on treatment and the label is associated with a black box warning regarding an increase in blood pressure (12). These data support the need for new developments in this area.[/I] [B][I]Various oral formulations of native testosterone have been tested in man although none have been licensed (13-20). [/I][/B][I]Soon after testosterone’s identification and characterization, oral testosterone administration was disregarded as a viable route of administration and replacement because of poor oral absorption (21). [B]In the 1970s, a micronized form of free testosterone was demonstrated to be absorbed in hypogonadal men but absorption was not reliable enough to progress as therapy (14). Further research, particularly by Amory and coworkers, showed that native testosterone administered as a suspension in oil, provided potentially therapeutic levels of testosterone in healthy men (15), and combined with 5αreductase inhibitors provided physiological testosterone levels both in the fasted and fed state (16).[U] Native testosterone is practically insoluble in water and in fatty oil vehicles (22), and the challenge has been to develop a solution formulation that contains sufficient testosterone concentration to provide reproducible physiological testosterone levels in hypogonadal men[/U]. Building upon the previous observations, we have developed a [U]lipidic solution formulation of native testosterone[/U] and have tested it in dogs and humans in the fasted and fed state.[/B][/I] [B]Formulation:[/B] [I][U][B]Lipidic Native Testosterone (NT) formulations[/B][/U] were developed and assessed in vitro for dispersion behavior in gastric and intestinal media and for physical stability. A single formulation of NT, [U]DITEST[/U], was selected to take forward into pre-clinical trials (Table 1). The formulation used digestible lipids (oils with carbon chain length > 10 carbons atoms) with the addition of short-medium chain oils and ethanol as a polar co-solvent to assist with solubilization. The formulation was encapsulated in size 00 soft gelatin capsules with 40mg per capsule inside an aluminum foil blister pack and was stable for 2 years at ambient temperature (25°C).[/I] [/QUOTE]
Insert quotes…
Verification
Post reply
Share this page
Facebook
Twitter
Reddit
Pinterest
Tumblr
WhatsApp
Email
Share
Link
Sponsors
Forums
Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
My Experience On Jatenzo (Oral TRT) Log
This site uses cookies to help personalise content, tailor your experience and to keep you logged in if you register.
By continuing to use this site, you are consenting to our use of cookies.
Accept
Learn more…
Top