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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone Basics & Questions
Natesto: large shards UPDATE- batch is all bad.
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<blockquote data-quote="madman" data-source="post: 277301" data-attributes="member: 13851"><p>There should be no crystalized T in the viscous oily based formulation.</p><p></p><p>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.</p><p></p><p></p><p><strong><em>*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.</em></strong></p><p><strong><em></em></strong></p><p><strong><em>*Because <u>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</u>, testosterone gel formulations of the invention.</em></strong><em> <em><strong>The manufacturability of testosterone gel formulations of the invention, however is <u>influenced by the particle size of testosterone</u>. When using a particle size of 50% i25 microns, 90% 550 microns the solubility of the drug substance in the matrix is especially favorable</strong></em></em></p><p><em><em><strong></strong></em></em></p><p><em><em><strong>*The drug product, TBS-1, is a <u>viscous and thixotropic, oil-based formulation containing solubilized testosterone</u> 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.</strong></em></em></p><p><em><em><strong></strong></em></em></p><p><em><em><strong>*Overall, stability data provided in this section are concluded to support a <u>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)]</u>. <u>The data also show that special storage conditions for the drug product are not required</u>. <u>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</u>. 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.</strong></em></em></p><p></p><p></p><p></p><p></p><p></p><p>Only 2 lots in Canada were identified back in 2019.</p><p></p><p></p><p><strong><em>*Acerus has received a small number of complaints over the past few months relating to this <u>actuation problem</u>. There has been no change in any other type of complaints relating to safety or efficacy.</em></strong></p><p><strong><em></em></strong></p><p><strong><em>*Two commercial lots of NATESTO released in the Canadian market were found to be <u>non-conforming during long-term stability studies, even though such lots were fully in- specification at the time of release</u>. The impacted lots do not <u>consistently meet the delivered dose uniformity specification (they deliver lower than labelled amount of product)</u>. This post-release non-conformity does not pose any safety concerns for patients, but can <u>result in the patient receiving a lower dose of the active ingredient, impacting efficacy</u></em></strong></p><p></p><p>[ATTACH=full]42266[/ATTACH]</p><p>[ATTACH=full]42267[/ATTACH]</p><p>[ATTACH=full]42268[/ATTACH]</p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p></p><p>[URL unfurl="true"]https://patents.google.com/patent/AU2020210227A1/en[/URL]</p><p></p><h3>Intranasal testosterone gel formulations and use thereof for treating male hypogonadism</h3><p></p><p><em>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.<strong> More specifically, testosterone is rapidly absorbed following pernasal administration with a <u>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</u>. 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.</strong> <strong><u>The formulations containing 4% and 4.5% testosterone by weight provide surprising properties</u>. <u>Importantly, the solubility of testosterone in castor oil pure is 3.6% maximum, falling to 3.36% about with 4% Labrafil</u>. <u>Addition of fumed silica (Aerosil, CabOsil) can increase the solubility of testosterone in castor oil up to 4.5% even with 4.0% Labrafil</u>. This is counter intuitive for a person skilled in the art. However, without wishing to be bound by any particular theory, <u>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</u>.</strong> 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.</em></p><p><em></em></p><p><em>*As used herein a "testosterone gel formulation for nasal administration" <strong>means a formulation comprising testosterone in combination with a solvent, a wetting agent, and a viscosity increasing agent.</strong></em></p><p><em></em></p><p><em>*The testosterone gel formulations of the invention are <strong>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.</strong> <strong><u>Other pharmacologically inactive ingredients in the testosterone intranasal gel are castor oil USP, oleoyl macrogolglycerides EP and colloidal silicon dioxide NF</u>.</strong> 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.</em></p><p></p><p></p><p></p><p></p><p><strong>Table 2: General Properties of Testosterone</strong></p><p></p><p><em>*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</em></p><p><em></em></p><p><em>*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. <strong>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.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Because <u>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</u>.</strong> <strong>The manufacturability of testosterone gel formulations of the invention, however is <u>influenced by the particle size of testosterone</u>. When using a particle size of 50% i25 microns, 90% 550 microns the solubility of the drug substance in the matrix is especially favorable</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Other pharmacologically inactive ingredients in the testosterone intranasal gel are castor oil USP, oleoyl macrogolglycerides EP and colloidal silicon dioxide NF. </strong>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"<strong> 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).</strong> 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.</em></p><p><em></em></p><p><em><strong>*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 <u>disadvantage of being hydrophobic</u>. <u>The nasal mucosa contains 95-97% water</u>. <u>Without the oleoyl macrogol-glycerides, the castor oil containing the active ingredient would form a non interactive layer on the mucous membrane</u>. <u>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</u>.</strong> Oleoyl macrogolglycerides are used in semi-solids at concentrations ranging from about 3 to 20%, depending on the application. <strong>The amount of oleoyl macrogol glycerides in testosterone gel formulations of the invention is <u>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</u>. A favourable concentration of oleoyl microgol-glycerides in testosterone gel formulations of the invention is found to be 4% of the formulation.</strong> <strong>According to the "Handbook of Pharmaceutical Additives" <u>colloidal silicon dioxide is used as an oil adsorbent, thermal stabiliser and gellant</u>.</strong> 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.<strong> 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). </strong>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.</em></p><p><em></em></p><p><em><strong>*The oil in testosterone gel formulations of the invention is thickened with colloidal silicon dioxide, which acts as a gel-forming agent.</strong> This compound is used commonly for stiffening oleogels.<strong> The intended dosage form for testosterone gel formulations of the invention is a semi-solid, not a liquid. <u>The formulation is thickened with colloidal silicon dioxide</u>. <u>It is believed that colloidal silicon dioxide contributes to the thixotropic properties of the gel, simplifying drug delivery to the nostril</u>.</strong> 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%. <strong>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.</strong> 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.</em></p><p></p><p></p><p></p><p></p><p><strong>Table 3: Composition of a testosterone gel formulation of the invention</strong></p><p><strong></strong></p><p><strong><em>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%</em></strong></p><p><strong><em></em></strong></p><p><strong><em>*<u>The testosterone gel formulations of the invention are stored at room temperature (20 250C or 68 to 770 F)</u>. Temperature excursions from 15 to 300C or <u>59 to 86F are permissible for the testosterone gel formulations of the inventions</u>. <u>The stability data supports a 12-month shelf life</u>. </em></strong></p><p><strong><em>*</em></strong><em>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.</em> <em>The syringes body is moulded from polypropylene, the plunger is moulded from polyethylene and the cap is HDPE.</em><strong><em> These syringes are designed and manufactured to deliver sterile and non-sterile solutions, liquids and gels at low volumes. <u>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</u>. </em></strong><em>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. </em><strong><em>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. </em></strong><em>It is manufactured by Floeter Flexibles GmbH, and supplied under the name "CLIMAPAC || 12-12-75". <strong>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.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*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. <u>Mixture II is then screened through a sieve to remove any un-dissolved Testosterone aggregates</u>.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Mixture III is prepared by adding the colloidal silicon dioxide to Mixture II and mixing for 15 minutes while maintaining product temperature below 500C. <u>A visual check is conducted after this step, to ensure that the gel is clear</u>. 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. <u>Following the application of the label, two syringes are packaged in a pre-formed foil pouch and the pouch is sealed</u>. <u>Each pouch is labelled</u>.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*The drug product, TBS-1, is a <u>viscous and thixotropic, oil-based formulation containing solubilized testosterone</u> 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.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*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.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Overall, stability data provided in this section are concluded to support a <u>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)]</u>. <u>The data also show that special storage conditions for the drug product are not required</u>. <u>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</u>. 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.</strong></em></p><p><em><strong></strong></em></p><p><em><strong>*Content: Active ingredient: <u>Testosterone. Excipients: Silicon dioxide, castor oil, Labrafil</u>*. Mode of administration: Nasally, as a single dose to each nostril. Manufacturer: <u>Haupt Pharma Amareg. Batch numbers: 0744, 0942, and 0943</u> Storage conditions: <u>Between 20 - 25°C</u>.</strong></em></p></blockquote><p></p>
[QUOTE="madman, post: 277301, member: 13851"] 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. [B][I]*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 [U]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[/U], testosterone gel formulations of the invention.[/I][/B][I] [I][B]The manufacturability of testosterone gel formulations of the invention, however is [U]influenced by the particle size of testosterone[/U]. 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 [U]viscous and thixotropic, oil-based formulation containing solubilized testosterone[/U] 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 [U]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)][/U]. [U]The data also show that special storage conditions for the drug product are not required[/U]. [U]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[/U]. 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.[/B][/I][/I] Only 2 lots in Canada were identified back in 2019. [B][I]*Acerus has received a small number of complaints over the past few months relating to this [U]actuation problem[/U]. 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 [U]non-conforming during long-term stability studies, even though such lots were fully in- specification at the time of release[/U]. The impacted lots do not [U]consistently meet the delivered dose uniformity specification (they deliver lower than labelled amount of product)[/U]. This post-release non-conformity does not pose any safety concerns for patients, but can [U]result in the patient receiving a lower dose of the active ingredient, impacting efficacy[/U][/I][/B] [ATTACH type="full" alt="Screenshot (33602).png"]42266[/ATTACH] [ATTACH type="full" alt="Screenshot (33603).png"]42267[/ATTACH] [ATTACH type="full" alt="Screenshot (33604).png"]42268[/ATTACH] [URL unfurl="true"]https://patents.google.com/patent/AU2020210227A1/en[/URL] [HEADING=2]Intranasal testosterone gel formulations and use thereof for treating male hypogonadism[/HEADING] [I]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.[B] More specifically, testosterone is rapidly absorbed following pernasal administration with a [U]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[/U]. 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.[/B] [B][U]The formulations containing 4% and 4.5% testosterone by weight provide surprising properties[/U]. [U]Importantly, the solubility of testosterone in castor oil pure is 3.6% maximum, falling to 3.36% about with 4% Labrafil[/U]. [U]Addition of fumed silica (Aerosil, CabOsil) can increase the solubility of testosterone in castor oil up to 4.5% even with 4.0% Labrafil[/U]. This is counter intuitive for a person skilled in the art. However, without wishing to be bound by any particular theory, [U]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[/U].[/B] 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" [B]means a formulation comprising testosterone in combination with a solvent, a wetting agent, and a viscosity increasing agent.[/B] *The testosterone gel formulations of the invention are [B]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.[/B] [B][U]Other pharmacologically inactive ingredients in the testosterone intranasal gel are castor oil USP, oleoyl macrogolglycerides EP and colloidal silicon dioxide NF[/U].[/B] 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.[/I] [B]Table 2: General Properties of Testosterone[/B] [I]*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. [B]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 [U]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[/U].[/B] [B]The manufacturability of testosterone gel formulations of the invention, however is [U]influenced by the particle size of testosterone[/U]. 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. [/B]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"[B] 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).[/B] 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. [B]*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 [U]disadvantage of being hydrophobic[/U]. [U]The nasal mucosa contains 95-97% water[/U]. [U]Without the oleoyl macrogol-glycerides, the castor oil containing the active ingredient would form a non interactive layer on the mucous membrane[/U]. [U]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[/U].[/B] Oleoyl macrogolglycerides are used in semi-solids at concentrations ranging from about 3 to 20%, depending on the application. [B]The amount of oleoyl macrogol glycerides in testosterone gel formulations of the invention is [U]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[/U]. A favourable concentration of oleoyl microgol-glycerides in testosterone gel formulations of the invention is found to be 4% of the formulation.[/B] [B]According to the "Handbook of Pharmaceutical Additives" [U]colloidal silicon dioxide is used as an oil adsorbent, thermal stabiliser and gellant[/U].[/B] 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.[B] 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). [/B]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. [B]*The oil in testosterone gel formulations of the invention is thickened with colloidal silicon dioxide, which acts as a gel-forming agent.[/B] This compound is used commonly for stiffening oleogels.[B] The intended dosage form for testosterone gel formulations of the invention is a semi-solid, not a liquid. [U]The formulation is thickened with colloidal silicon dioxide[/U]. [U]It is believed that colloidal silicon dioxide contributes to the thixotropic properties of the gel, simplifying drug delivery to the nostril[/U].[/B] 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%. [B]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.[/B] 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.[/I] [B]Table 3: Composition of a testosterone gel formulation of the invention [I]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% *[U]The testosterone gel formulations of the invention are stored at room temperature (20 250C or 68 to 770 F)[/U]. Temperature excursions from 15 to 300C or [U]59 to 86F are permissible for the testosterone gel formulations of the inventions[/U]. [U]The stability data supports a 12-month shelf life[/U]. *[/I][/B][I]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.[/I] [I]The syringes body is moulded from polypropylene, the plunger is moulded from polyethylene and the cap is HDPE.[/I][B][I] These syringes are designed and manufactured to deliver sterile and non-sterile solutions, liquids and gels at low volumes. [U]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[/U]. [/I][/B][I]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. [/I][B][I]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. [/I][/B][I]It is manufactured by Floeter Flexibles GmbH, and supplied under the name "CLIMAPAC || 12-12-75". [B]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. [U]Mixture II is then screened through a sieve to remove any un-dissolved Testosterone aggregates[/U]. *Mixture III is prepared by adding the colloidal silicon dioxide to Mixture II and mixing for 15 minutes while maintaining product temperature below 500C. [U]A visual check is conducted after this step, to ensure that the gel is clear[/U]. 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. [U]Following the application of the label, two syringes are packaged in a pre-formed foil pouch and the pouch is sealed[/U]. [U]Each pouch is labelled[/U]. *The drug product, TBS-1, is a [U]viscous and thixotropic, oil-based formulation containing solubilized testosterone[/U] 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 [U]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)][/U]. [U]The data also show that special storage conditions for the drug product are not required[/U]. [U]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[/U]. 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: [U]Testosterone. Excipients: Silicon dioxide, castor oil, Labrafil[/U]*. Mode of administration: Nasally, as a single dose to each nostril. Manufacturer: [U]Haupt Pharma Amareg. Batch numbers: 0744, 0942, and 0943[/U] Storage conditions: [U]Between 20 - 25°C[/U].[/B][/I] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
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