Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0043—Nose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/26—Androgens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body

Definitions

• the present invention relates to intranasal testosterone gels for the controlled release of testosterone into the systemic circulation of males and females after pernasal application for providing constant effective testosterone blood levels, without causing unwanted testosterone blood level spikes, over dose life, which are suitable for use in testosterone replacement or supplemental therapy and effective to treat males and females in need of testosterone replacement or testosterone supplemental therapy to treat, for example, male testosterone deficiency or female sexual dysfunction.
• the present invention also relates to methods and pre-filled multi-dose applicator systems for pernasal administration of the nasal testosterone gels.
• Nasal drug delivery offers many advantages that include rapid adsorption due to abundant capillary vessels, fast onset of action, avoidance of hepatic first-pass metabolism, utility for chronic medication and ease of administration.
• Hussain et al therefore proposed the use of a water-soluble pro-drug, testosterone 17 ⁇ - ⁇ , ⁇ - dimethylglycinate, and found serum levels equal to intravenous administration with peak plasma concentrations within 12 min (25 mg dose) and 20 min (50 mg dose), respectively, and elimination half-lives of about 55 min. It should be mentioned that this speed is not necessary/desirable because sex hormone replacement or supplemental therapy is not an emergency therapy requiring peak plasma concentations immediately following adminsitration.
• testosterone formulation systems for controlling the release of testosterone into the systemic circulation of men and women that (a) are therapeutically effective when administered intranasally to male and female patients, (b) provide constant effective testosterone blood levels, without unwanted testosterone blood level spike, over dose life, and (c) are safe, convenient to use, well tolerated, stable and easily and reproducibly manufactured on scale up.
• the present invention overcomes the above-mentioned disadvantages and drawbacks associated with current testosterone replacement or supplemental therapy and is directed to novel sustained or controlled release testosterone gels, for pernasal administration, which uniquely provide constant effective testosterone blood levels, without causing undesired testosterone blood level spikes, over dose life when the novel intranasal testosterone gels are administered pernasal to males or females.
• the novel intranasal testosterone gels of the present invention are safe, convenient to use, well tolerated, stable and easily and reproducibly manufactured on scale up.
• the intranasal testosterone gels of the present invention mimic or restore testosterone blood levels to normal physiologic daily rhythmic testosterone levels when the novel intranasal testosterone gels of the present invention are administered pernasally
• the novel intranasal testosterone gels of the present invention are uniquely suited for testosterone replacement or supplemental therapy and are effective to treat males and females in need of testosterone replacement or testosterone supplemental therapy to treat, for example, male testosterone deficiency or female sexual dysfunction.
• the present invention is also directed to novel methods for pernasal administration of the nasal testosterone gels.
• the novel methods of the present invention involve depositing the intranasal testosterone gels topically into the nasal cavity of each nostril to deliver a therapeutically effective amount of testosterone over dose life for providing constant effective testosterone blood levels for use in testosterone replacement or supplemental therapy and for effectively treating males and females in need of testosterone replacement or testosterone supplemental therapy to treat, for example, male testosterone deficiency or female sexual dysfunction.
• 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.
• the outer nose is then preferably gently and carefully squeezed and/or rubbed by the patient, so that the deposited gel remains in contact with the mucosal membranes within the nasal cavity for sustained or controlled release of the testosterone over dose life.
• typical testosterone gel dosage amounts deposited pernasal application ranges from about 140 microliters to about 180 microliters.
• the novel topical intranasal gel formulations and methods of the present invention also contemplate the pernasal administration of any suitable testosterone formulations or any suitable active ingredient, either alone or in combination with testosterone or other active ingredients, such as neurosteroids or sexual hormones (e.g., androgens and progestins, like testosterone, estradiol, estrogen, oestrone, progesterone, etc.), neurotransmitters, (e.g., acetylcholine, epinephrine, norepinephrine, dopamine, serotonin, melatonin, histamine, glutamate, gamma aminobutyric acid, aspartate, glycine, adenosine, ATP, GTP, oxytocin, vasopressin, endorphin, nitric oxide, pregne
• neurosteroids or sexual hormones e.g., androgens and progestins, like testosterone, estradiol, estrogen, o
• the present invention is also directed to novel pre-filled, multi-dose applicator systems for pernasal administration to strategically and uniquely deposit the nasal testosterone gels at the preferred locations within the nasal cavity for practicing the novel methods and teachings of the present invention.
• the applicator systems of the present invention are, e.g., airless fluid, dip-tube fluid dispensing systems or pumps or any other system suitable for practicing the methods of the present invention.
• the applicator systems or pumps include, for example, a chamber, pre-filled with multiple doses of an intranasal testosterone gel of the present invention, that is closed by an actuator nozzle.
• the actuator nozzle may comprise an outlet channel and tip, wherein the actuator nozzle is shaped to conform to the interior surface of a user's nostril for (a) consistent delivery of uniform dose amounts of an intranasal testosterone gel of the present invention during pernasal application within the nasal cavity, and (b) deposition at the instructed location within each nostril of a patient as contemplated by the novel methods and teachings of the present invention.
• pre-filled, multi-dose applicator systems include the COMOD system available from Ursatec,maschine-GmbH, Schillerstr. 4, 66606 St. Wendel, Germany or the Albion or Digital airless applicator systems available from Airlessystems, RD 149 27380 Charleval, France or 250 North Route 303 Congers, NY 10950, as shown in Figs. 1-4
• the salient elements of the novel intranasal testosterone gels according to the present invention comprise (a) testosterone in an effective amount, e.g., an amount of between about 0.5% and about 10% or higher, by weight; (b) at least one lipophilic or partly lipophilic carrier; (c) a super solvent or a mixture of super solvents for increasing the solubility of the testosterone, (d) a gel-forming or viscosity regulating agent for controlling the release of the testosterone from the gels following intranasal administration, and, optionally, (e) a surface active agent or a mixture of surface active agents, i.e., surfactant(s), having surface tension decreasing activity.
• a surface active agent or a mixture of surface active agents i.e., surfactant(s) having surface tension decreasing activity.
• the testosterone drug can be in, for instance, crystalline, amorphous, micronized, non-micronized, powder, small particle or large particle form when formulating the intranasal testosterone gels of the present invention.
• An Exemplary range of testosterone particle sizes include from about 0.5 microns to about 200 microns.
• the testosterone particle size is in a range of from about 5 microns to about 100 microns, and the testosterone is in crystalline or amorphous and non-micronized or micronized form.
• the testosterone is in crystalline or amorphous micronized form.
• the lipophilic carrier is an oil, preferably, a liquid oil.
• the oil can be natural, synthetic, semi- synthetic, vegetal or mineral, mostly hydrophobic.
• the oils are any acceptable vegetable oil, such as, castor oil, almond oil, linseed oil, canola oil, coconut oil, corn oil, cottonseed oil, palm oil, peanutoil, poppy seed oil and soybean oil.
• the oils can be a mineral oil (light mineral or paraffin), synthetic or refined isopropyl myristate, isopropyl palmitate, capryl caprylate, methyl stearate, medium chain triglycerides, propylene glycol dicaprylocaprate, cetostearyl alcohol, stearyl alcohol and mixtures thereof.
• mineral oil light mineral or paraffin
• synthetic or refined isopropyl myristate isopropyl palmitate
• capryl caprylate methyl stearate
• medium chain triglycerides propylene glycol dicaprylocaprate
• cetostearyl alcohol cetostearyl alcohol
• stearyl alcohol and mixtures thereof.
• the oil is any acceptable vegetable oil.
• the oil is castor oil, such as Crystal O® or Crystal LC USP.
• the carrier is present in the intranasal testosterone gels in an amount of between about 30% and about 98% by weight, preferably, between about 42% and about 96% by weight, more preferably, between about 67% and about 95% by weight, even more preferably, between about 82% and about 95% by weight, and most preferably between about 87% and about 94.5% by weight of the testosterone gel.
• the intranasal testosterone gels of the present invention are uniquely formulated with at least one super solvent for enhancing testosterone solubility.
• the super solvents are generally characterized as non aqueous solvents that are miscible with the carrier or oil and are present in the intranasal testosterone gels in amounts suitable to form a gel during gel formulation or gel manufacture and in advance of pernasal application.
• intranasal gels of the present invention are not emulsified in situ following application of the gels into the nasal cavity.
• the super solvents are present in the intranasal testosterone gels in amounts ranging from about 1% to about 50% by weight.
• the super solvents as contemplated by the present invention can be characterized as (1) enhancing testosterone solubility in the intranasal testosterone gels, (2) being acceptable to the nasal mucosal within the nasal cavities and (3) having no surfactant activity.
• examples of super solvents in accordance with the present invention include dimethyl isosorbide, pharma grade, such as Super Refined® ArlasolveTM-DMI, diethylene glycol monoethyl ether, such as Transcutol-P®, glycerin, propylene glycol, 1-methyl 2-pyrrolidone, glycerol and satisfactory mixtures thereof.
• the super solvent comprises dimethyl isosorbide (Super Refined® ArlasolveTM-DMI.
• the super solvents of the present invention may be generally present within the intranasal testosterone gels in amounts ranging from about 1% to about 50% by weight, the preferable amounts range from about 1% to about 25% by weight, more preferably, from about 5% to about 20% by weight, and more preferably, from about 5% to about 15%. Most preferably, the super solvents of the present invention are present in the intranasal testosterone gels in an amount at about 15% by weight.
• the intranasal testosterone gels of the present invention include a gel-forming or viscosity regulating agent to (1) form a gel, (2) enhance gel viscosity, and (3) control the release of the testosterone from an intranasal testosterone gel following pernasal administration, as contemplated herein by the present invention, i.e., to provide a gel with suitable viscosity and having a slow constant rate of release of the testosterone from the intranasal testosterone gel following pernasal administration, so that a constant effective testosterone blood level or profile, without testosterone spike, is achieved and maintained over dose life in a male or female patient in need of testosterone replacement therapy to treat, e.g., male testosterone deficiency or female sexual dysfunction, respectively.
• a gel-forming or viscosity regulating agent to (1) form a gel, (2) enhance gel viscosity, and (3) control the release of the testosterone from an intranasal testosterone gel following pernasal administration, as contemplated herein by the present invention, i.e.,
• a viscosity regulating agent of the present invention comprises a thickener or gelling agent and examples include cellulose and cellulose derivatives, e.g., hydroxypropyl cellulose and hydroxyethyl cellulose, polysaccharides, carbomers, acrylic polymers, such as Carbopol®, polyvinyl alcohol and other vinylic polymers, povidone, colloidal silicon dioxide, such as Aerosil® 200 or Cab-O-Sil®, lipophilic silicon dioxide, such as Aerosil® R972, cetyl alcohols, stearic acid, glyceryl behenate, wax, beeswax, petrolatum, lipophilic gum, triglycerides, lanolin, inulin and suitable mixtures thereof.
• the gel-forming or viscosity increasing agent is colloidal silicon dioxide, and even more preferably, Si0 2 and polyvinyl alcohol.
• the gel-forming or viscosity regulating agent is present within the intranasal testosterone gels in amounts generally ranging from about 0.5% to about 10% by weight, preferably, about 0.5% to about 5% by weight, more preferably, about 1% to about 4% by weight, and most preferably, at about 3% by weight.
• 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.
• the intranasal testosterone gels of the present invention may optionally, but not necessarily, be formulated with at least one surfactant, such as lecithin, fatty acid esters of polyvalent alcohols, fatty acid esters of sorbitanes, fatty acid esters of polyoxyethylensorbitans, fatty acid esters of polyoxyethylene, fatty acid esters of sucrose, fatty acid esters of polyglycerol, sorbitol, glycerine, polyethylene glycol, macrogol glycerol fatty acid ester and satisfactory mixtures thereof.
• surfactant such as lecithin, fatty acid esters of polyvalent alcohols, fatty acid esters of sorbitanes, fatty acid esters of polyoxyethylensorbitans, fatty acid esters of polyoxyethylene, fatty acid esters of sucrose, fatty acid esters of polyglycerol, sorbitol, glycerine, polyethylene glycol, macrogol glycerol fatty
• surfactants suitable for use in accordance with the present invention include those illustrated in U.S. Patent Nos. 5,578,588, 5,756,071, and 5,576,071 and in U.S. Patent Publication Nos. 2005/0100564, 2007/0149454 and 2009/0227550, all of which are incorporated herein by reference in their entireties.
• the amount of testosterone in an intranasal testosterone gel of the present invention that will be therapeutically effective in a specific situation will depend upon such things as the dosing regimen, the application site, the particular gel formulation, dose longevity and the condition being treated. As such, it is generally not practical to identify specific administration amounts herein; however, it is believed that those skilled in the art will be able to determine appropriate therapeutically effective amounts based on the guidance provided herein, information available in the art pertaining to testosterone replacement or supplemental therapy, and routine testing.
• a therapeutically effective amount means an amount of testosterone sufficient to induce a therapeutic or prophylactic effect (1) for use in testosterone replacement or supplemental therapy, and/or (2) to treat (a) males diagnosed with male testosterone deficiency, namely, low sexual libido, drive or sexual activity, low fertility, low spermatogenesis, aspermatogenesis, depression and/or hypogonadism in males, and (b) female sexual dysfunction ("FSD”), namely, low sexual libido, drive or sexual activity, low amygdala reactivity, low sexual stimulation, female sexual arousal disorder, hypoactive sexual desire disorder ("HSDD”) and/or female orgasmic disorder ("anorgasmia”) in females.
• males diagnosed with male testosterone deficiency namely, low sexual libido, drive or sexual activity, low fertility, low spermatogenesis, aspermatogenesis, depression and/or hypogonadism in males
• FSD female sexual dysfunction
• HSDD hypoactive sexual desire disorder
• the amount of testosterone present in an intranasal gel formulation of the present invention will be an amount effective to treat a targeted condition, to prevent recurrence of the condition, or to promote sexual stimulation and/or reproduction in males or amygdala reactivity or sexual stimulation in females, as indicated above and herein throughout.
• the amount or concentration of testosterone is at least about 0.5% by weight, such as, for example, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, and at least about 10% by weight based on the total weight of the intranasal testosterone gel formulation.
• the amount of testosterone is at most about 10% by weight, such as, for example, at most about 9%, at most about 8%, at most about 7%, at most about 6%, at most about 5%, at most about 4%, at most about 3%, at most about 2%, at most about 1%, and at most about 0.5%, including any and all increments there between including about 0.25% increments, more or less, by weight based on the total weight of the intranasal testosterone gel formulation.
• the amount or concentration of testosterone is at least about 0.1% by weight, such as, for example, at least about 0.125%, at least about 0.15%, at least about 0.175%, at least about 0.2%, at least about 0.225%, at least about 0.25%, at least about 0.275%, at least about 0.3%, at least about 0.325%, at least about 0.35%, at least about 0.375%, at least about 0.4%, at least about 0.425%, at least about 0.45%, at least about 0.475%, at least about 0.5%, at least about 0.525%, at least about 0.55%, at least about 0.575%, at least about 0.6%, at least about 0.625%, at least about 0.65%, at least about 0.675%, at least about 0.7%, at least about 0.725%, at least about 0.75%, at least about 0.775%, at least about 0.8%, at least about 0.825%, at least about 0.85%, at least about 0.875%, at least about 0.9%, at least about 0.925%, at least about 0.95%, at least
• the testosterone may be present in each pernasal dosage of the intranasal testosterone gels of the present invention in amounts ranging from about 0.5 to about 10% by weight, preferably from about 1% to about 9% by weight, more preferably, for male treatment, from about 7% to about 9%, and more preferably, from about 7.5% to about 8.5% by weight, and most preferably, at about 8% by weight, and for female treatment, from about 0.1% to about 2% by weight, from about 0.5% to 1% by weight, from about 1% to about 2% by weight,, from about 2% to about 3% by weight, from about 3% to about 4% by weight, from about 4% to about 5% by weight, etc., wherein each pernasal dosage is in the general size range of between about 140 microliters and 180 microliters,
• an effective amount of testosterone drug is preferably present within the intranasal testosterone gels of the present invention in amounts generally ranging from at least about 0.05 mg to about 0.13 mg or more per microliter dose, e.g., about 140 microliters to about 180 microliters, administered in each nostril (pernasal) for a total intranasal testosterone dose of at least about 20 mg to about 36 mg pernasal application.
• each 140 microliter dose should contain about 0.07 mg of testosterone, whereas a 180 microliter dose should have about 0.55 mg of testosterone. If total dose of about 28 mg testosterone is desired, each 140 microliter dose should contain about 0.1 mg of testosterone, whereas a 180 microliter dose should have about 0.78 mg of testosterone. If, however, about 36 mg testosterone is desired as a total dose, each 180 microliter dose should contain about 0.1 mg of testosterone, whereas each 140 microliter dose should contain about 0.13 mg of testosterone.
• an 8% intranasal testosterone gel in a pernasal dosage amount of about 140 microliters is preferred for delivering a total combined testosterone dose of about 22.4 mg per application (about 11.2 mg of testosterone pernasal application), or for delivering a total combined testosterone daily dose of about 22.4 mg and about 44.8 mg when administered once or twice per day pernasal, respectively, to treat a male testosterone deficiency to restore testosterone to normal testosterone blood levels observed in healthy young males, i.e., from about 200 nanograms/dl to about 1500 nanograms/dl of testosterone.
• examples of rates of diffusion of the testosterone in the intranasal gels of the present invention through a Franz cell membrane range from between about 28 and 100 slope/mgT%, and preferably about 30 and 95 slope/mgT%.
• the preferred rates of diffusion of testosterone are between about 28 and 35 slope/mgT%. See, for example, Examples 9 and 10.
• the total testosterone dosage amount delivered each day to increase amygdala reactivity in middle age women, i.e., ages between about 40 and about 65 , or to restore testosterone to normal testosterone levels comparable to that of healthy young women, i.e., ages between about 30 and about 45 , e.g., from a low of about 30 nanograms/dl to a high of about 150 nanograms/dl, to treat FSD may be, for example, in the general range of from about 100 micrograms to about 5000 micrograms or more.
• Fig. 1 is a side view of a first embodiment of the invention.
• FIG. 2 is a cross-sectional side view of the distributor pump of the first embodiment of the invention.
• FIG. 3 is a side view of a second embodiment of the invention.
• Fig. 4 is a cross-sectional side view of the distributor pump of the second embodiment of the invention.
• Fig. 5 is a side view of a second embodiment of the invention concerning an airless bottle assembly of the invention
• Fig. 6 is a side view of a second embodiment of the invention concerning digital actuator and rounded cap
• Fig. 7A depicts the right nostril of subject #1 after a single dose syringe
• Fig.7B depicts the left nostril of subject #1 after a multiple dose dispenser
• Fig. 8A depicts the right nostril of subject #2 after a single dose syringe
• Fig. 8B depicts the left nostril of subject #2 after a multiple dose dispenser
• FIG. 9A depicts the right nostril of subject #3 after a single dose syringe
• Fig. 9B depicts the left nostril of subject #3 after a multiple dose dispenser
• Figs. 10A and 10B illustrate use of a multiple dose dispenser in accordance with the present invention
• Fig. 11 illustrates a multiple dose dispenser in accordance with the present invention
• Fig. 13 depicts a Franz Cell apparatus position layouts for comparing testing in accordance with Example 5;
• Fig. 14 depicts individual amount of testosterone released from the compositions in acoordance with Example 5;
• Fig. 16 depicts individual (blue) and median (black) testosterone concentration versus time (linear y-axis), that are grouped by treatment;
• Fig. 17 depicts the probability density of the log ratio of testosterone levels that are reached with the multiple dose dispenser over levels tht are reached with the syringe;
• Fig. 18 depicts solubility of testosterone in different vehicles at 32°C and at 50°C;
• Fig. 19 depicts Ternary solvent mixture optimization: Contour plot shows that, in order to achieve more than 6% testosterone solubility, higher levels of DMI and Transcutol are required;
• Fig. 20 depicts a flow diagram for manufacturing TBS-1.
• Figs 21A and 21B depict a flow diagram of a manufacturing process of an antranasal testosterone gel of the present invention
• Fig. 23 depicts testosterone diffusion rate of intranasal testosterone gel formulations of Example 6 using Franz cells method;
• Fig. 24 depicts the pharmacokinetic profiles of 15 male subjects using the formulas of Example 6;
• Fig. 25 depicts a comparison between TBS 1 A 8% (Part I); Fig. 26 depicts a comparison between TBS 1 A 8% (Part I); Fig. 27 depicts a comparison between 6 hours and 24 hours run (RD11101 and RD11102) Fig. 28 depicts a comparison between TBS 1 A 4% (Part I); Fig. 29 depicts a comparison between TBS 1 A 4% (Part II); Fig. 30 depicts a comparison between TBS 1 A 4% (Part III); Fig. 31 depicts a comparison slower diffusion;
• Fig. 32 depicts a comparison between 6 hours and 24 hours run (RD11063 and RD11085).
• Fig. 33 depicts a comparison between 400mg and 1 gram of gel (RD11063).
• the present invention relates to an intranasal testosterone gel pharmaceutical composition
• a pharmaceutically acceptable vehicle for testosterone which vehicle comprises a super solvent or suitable mixtures of super solvents, a gel-forming or viscosity regulating agent to control the release of testosterone from the intranasal testosterone gels and, optionally, a surface active agent or a mixture of surface active agents, i.e., surfactant(s), having surface tension decreasing activity.
• the present invention is drawn to intranasal testosterone gels for topical pernasal administration, e.g., onto the mucosal membranes inside the nasal cavity for each nostril, for the sustained or controlled release of testosterone into the systemic circulations of males and females for providing constant effective testosterone blood levels, without testosterone spike, over dose life, which are effective to effectively treat males and females in need of testosterone replacement or testosterone supplemental therapy who, for example, have been diagnosed with or suffer from either male testosterone deficiency or female sexual dysfunction
• the intranasal testosterone gels comprise: (a) a testosterone drug in an amount effective to achieve constant effective testosterone blood levels, for example, between about 0.5% and about 10% by weight; (b) at least one lipophilic or partly lipophilic carrier, such as a liquid oil, to solubilize the testosterone drug; (c) a super solvent or a mixture of super solvents for increasing or enhancing testosterone solubility, especially at higher testosterone drug concentrations, (d) a gel-forming or viscosity
• intranasal testosterone gels of the present invention are chemically and physically stable and can in the dosage form of, for example, a suspension or a solution of the pharmacologically active substance.
• the intranasal testosterone gels are filled into a preservative-free, airless multi-dose device able to accurately deliver doses of the above testosterone gel, also at higher viscosities.
• testosterone will be efficiently trapped at the deposition site and be absorbed at a predictable rate across the mucous membrane of the patient, thereby limiting possible deactivation by metabolizing enzymes and/or protein-binding and testosterone spike.
• the intranasal testosterone gels of the present invention comprise (a) the hormone, testosterone, in an amount of from about 0.5% up to about 10% by weight; (b) at least one lipophilic or partly lipophilic carrier; (c) a super solvent or a mixture of super solvents for increasing the solubility of testosterone, (d) a gel-forming or viscosity regulating agent in order to create a sustained release effect regarding testosterone release from the intranasal testosterone gels following pernasal administration and, optionally, (e) a surface active agent or a mixture of surface active agents, i.e., surfactant(s), having surface tension decreasing activity.
• the testosterone hormonal drug of this invention may be introduced into the intranasal testosterone gels in a processed form such as microspheres, liposomes, micronized, etc.
• the term "lipophilic carrier” shall comprise, but not limited to, a vegetable oil such as castor oil, soybean oil, sesame oil or peanut oil, fatty acid ester such as ethyl- and oleyloleat, isopropylmyristate, medium chain triglycerides, glycerol esters of fatty acids, or polyethylene glycol, phospholipids, white soft paraffin, or hydrogenated castor oil. Particularly preferred is castor oil, such as Crystal O® or Crystal LC USP.
• the incorporation of the testosterone is also possible into an oil mixture and contemplated by the present invention.
• the particular amount of oil that constitutes an effective amount is dependent on the particular viscosity regulating agent (see below) used in the testosterone gel. It is therefore not practical to enumerate specific amounts for use with specific formulations of the invention.
• the lipophilic part can be present in a formulation in an amount between about 30% and about 98% by weight, preferably between about 42% and about 96% by weight, more preferably between about 67% and about 94% by weight, even more preferably between about 82% and about 95% by weight and most preferably between about 87% and about 94.5% by weight of the testosterone gel.
• the intranasal testosterone gels of the present invention include at least one super solvent for enhancing testosterone solubility.
• the super solvents are generally characterized as non aqueous solvents that are miscible with the carrier or oil and are present in the intranasal testosterone gels in amounts suitable to form a gel during gel formulation or gel manufacture and in advance of pernasal application (the gels do not emulsifiy in situ following application into the nasal cavity).
• the super solvents as contemplated by the present invention are characterized as (1) enhancing testosterone solubility in the intranasal testosterone gels, (2) being acceptable to the nasal mucosal within the nasal cavities and (3) having no surfactant activity.
• super solvents examples include dimethyl isosorbide, pharma grade, such as Super Refined Aralasolve®-DMI, diethylene glycol monoethyl ether, such as Transcutol-P®, glycerin, propylene glycol, 1 -methyl 2-pyrrolidone, glycerol and satisfactory mixtures thereof.
• a preferred super solvent for use in accordance with the present invention is a dimethyl isosorbide, such as Super Refined® ArlasolveTM- DMI.
• the super solvents of the present invention may be generally present within the intranasal testosterone gels in amounts ranging from about 1% to about 80% by weight, preferable ranges are from about 1% to about 70% by weight, from about 1% to about 60% by weight, from about 1% to about 50% by weight, from about 1% to about 40% by weight, from about 1% to about 30% by weight, from about 1% to about 20% by weight and from about 1% to about 10% by weight.
• a more preferable range is from about 1% to about 25% by weight, whereas an even more preferable range is from about 5% to about 20% by weight, and an even more preferable range is from about 5% to about 15%.
• One preferable concentration for a super solvent formulated in an intranasal testosterone gel of the present invention is about 15% by weight. See Fig.19.
• viscosity regulating agent shall mean a thickener or gelling agent.
• examples are, but not limited to, cellulose and cellulose derivatives thereof, such as hydroxypropyl cellulose and hydroxyethyl cellulose, polysaccharides, carbomers, acrylic polymers, such as Carbopol®, polyvinyl alcohol and other vinylic polymers, povidone, Co-Polyvidone (Kollidon VA64) colloidal silicon dioxide, such as Aerosil® 200 or Cab-O-Sil®, such as Cab-O-Sil® M-5P, lipophilic silicon dioxide, such as Aerosil® R972, cetyl alcohols, stearic acid, glyceryl behenate, wax, beeswax, petrolatum, triglycerides, lanolin and suitable mixtures thereof. It is believed, however, that colloidal silicon dioxide (such as Aerosil® 200, as available from Degussa), Si0 2 and polyvinyl alcohol are particularly useful.
• testosterone drug is also possible into a mixture of thickeners or gelling agents.
• the particular amount of thickener/gelling agent that constitutes an effective amount is dependent on the particular oil or oil mixture (see above) used in the formulation. It is therefore not practical to enumerate specific amounts for use with specific formulations of the invention. Generally, however, the thickener/gelling agent(s) can be present in a formulation in an amount from about 0.5 to about 10% by weight, preferably about 0.5 to about 5% by weight, more preferably about 1 to about 3% by weight, and most preferably at about 3% by weight.
• the Testosterone gel may further optionally, but not necessarily, include a surfactant such as, but not limited to, lecithin, fatty acid ester of polyvalent alcohols, of sorbitanes, of polyoxyethylensorbitans, of polyoxyethylene, of sucrose, of polyglycerol and/or at least one humectant such as sorbitol, glycerine, polyethylene glycol, or macrogol glycerol fatty acid ester.
• a surfactant such as, but not limited to, lecithin, fatty acid ester of polyvalent alcohols, of sorbitanes, of polyoxyethylensorbitans, of polyoxyethylene, of sucrose, of polyglycerol and/or at least one humectant such as sorbitol, glycerine, polyethylene glycol, or macrogol glycerol fatty acid ester.
• oleoyl macrogolglycerides such as Labrafil® M 1944
• testosterone drug is also possible into a surfactant mixture.
• the particular amount of surfactant that constitutes an effective amount is dependent on the particular oil or oil mixture (see above) used in the testosterone gel. It is therefore not practical to enumerate specific amounts for use with specific formulations of the invention. Generally, however, the surfactant can be present in a formulation in an amount of from between about 0.5 to about 10% by weight, preferably about 0.5 to about 5% by weight, more preferably 1 to 4% by weight, and most preferably at about 3% by weight.
• the intranasal testosterone gels of the present invention can be applied once a day ("QD"), twice a day (“BID”), three times a day (“TID”), four times-a-day ("QID”) or as needed ("prn").
• the intranasal testosterone gels are topically applied onto the nasal mucosal in the nasal cavity, preferably, of each nostril per application ("pernasal"). More specifically, the intranasal testosterone gels are topically applied to 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) or at about under the cartilage section of the outer external wall (opposite the nasal septum) inside the naval cavity of each nostril.
• the gel dosages will unfortunately wash into the throat or, if the gels are applied to shallow down in the forefront or adjacent the external openings of the nostrils, the gel dosages will unfortunately flow out from inside the naval cavity possibly leading, in either situation, to ineffective dosing and poor compliance.
• an intranasal testosterone gel of the present invention has been topically applied or deposited onto the appropriate designated region on the outer external walls (opposite the nasal septum) in the nasal cavity of each nostril of a male or female patient in need of testosterone replacement or supplemental therapy, it is preferable for the male or female patient to message the outer skin of his/her nose to distribute the applied or deposited intranasal testosterone gel dose evenly and throughout the nasal cavity of each nostril.
• the intranasal testosterone gels once formulated, are preferably filled into a preservative-free, airless nasal spray or dispensing multi-dose device, such as the COMOD system available from Ursatec,maschine-GmbH, Schillerstr.
• the airless nasal pre-filled spray or applicator multi-dose device includes a dispensing element for topically applying the intranasal testosterone gel dose at about a location within each nostril as described herein above.
• the dispensing element by way of example is bent or curved- shape to strategically permit consistent topical applications of the intranasal testosterone gels in about the prescribed amounts and at about the preferred location within each nostril (pernasal) to maximize effectiveness in the treatment of female sexual dysfunction in females patients and testosterone deficiency in male patients with the intranasal testosterone gels of the present invention.
• the serum level of testosterone in a male or female patient in need of testosterone replacement or supplemental therapy is higher than baseline, i.e., the testosterone serum level is either (a) restored to, (b) approaching or (c) is very similar to, resembles or closely mimics normal testosterone blood levels found in healthy young men such as, by way of example, a male testosterone blood level of between about 200 nanograms and about 1500 nanograms of testosterone per deciliter of blood, or more particularly a male testosterone blood level of between about 300 ng/dl and about 1200 ng/dl, or more particularly a male testosterone blood level of between about 350 ng/dl and about 800 ng/dl, or more particularly a male testosterone blood level of between about 350 ng/dl and about 600 ng/dl, or more particularly a male testosterone blood level of between about
• testosterone is nearly insoluble in water, liberation from the formulation is the speed-limiting step for adsorption. It has been surprisingly found that the incorporation of testosterone in an oily formulation containing a suitable surfactant according to the invention leads to physiologic serum levels and to a steady, sustained action of testosterone over time.
• the testosterone's release is controlled or slowed by properties containing the testosterone.
• a gel-forming or viscosity regulating agent added to the intranasal testosterone gels of the present invention to create a desired gel viscosity, the dissolution pattern of the testosterone from the intranasal testosterone gels becomes more favorable and effective because there is no testosterone spike variability in dissolution ensuring constant effective testosterone blood levels or constant testosterone dose bioequivalence over dose life.
• the intranasal testosterone gels of the present invention can be manufactured as follows.
• a lipophilic carrier e.g., castor oil
• the testosterone can then be slowly added to the lipophilic carrier and homogenized until mixing is complete to form an intermediate product.
• the intermediate homogenate is allowed to cool to about room temperature, the super solvent and optionally, a surfactant, can then be added to the intermediate product to form a basic mixture.
• the gel-forming or viscosity regulating agent can then be added to the cooled basic mixture and mixed under vacuum to achieve a final product with a desired gel viscosity.
• the starting materials should be are kept in quarantine and sterile. After each manufacturing step (e.g., dissolution, homogenization), the resulting product should be stored in quarantine until next production step. Samples for quality control may be taken at different stages of the manufacturing process. The batch of a finished product should likewise be stored in quarantine until use.
• manufacturing step e.g., dissolution, homogenization
• the necessary amount of the testosterone for the bulk mixture is calculated on the basis of content determination of a respective batch. This determination is part of the quarantine procedure for the starting material. The amount is calculated in such a way that the necessary content of 100% testosterone will be reached in the bulk mixture.
• a lipophilic carrier e.g., castor oil
• a super solvent e.g., DMI
• Step 1 A lipophilic carrier, e.g., castor oil
• a super solvent e.g., DMI
• Control of temperature of the carrier and super solvent mixture is necessary in the following steps to prevent a significant increase in temperature due to the shear intensity applied to dissolve testosterone.
• Homogenization of the Intermediate Product is done by controlling the temperature of the mixture not to exceed about 50°C. Three (3) such cycles are believed to be necessary until the testosterone is completely dissolved. Each cycle has the following course: Homogenization in dispersing mode for a specified mix cycle.
• a surfactant such as an oleoyl macrogol-glycerides, (Step 5) is added to the Intermediate Product to give the basic mixture.
• the Basic Mixture (Step 6) should be checked for content of testosterone taking care that the dissolution of testosterone is complete. The content can be examined by UV method and the Basic Mixture should have a testosterone amount in mg equivalent to the selected testosterone concentration. [0098] After the last homogenization step, the Basic Mixture should be cooled until a temperature of about 40°C ( ⁇ 2°) or less is reached. Thereafter, the gel-forming agent, such as colloidal silicon dioxide, (Step 7) can be added to the Basic Mixture.
• the gel-forming agent such as colloidal silicon dioxide
• the resulting homogeneous intranasal testosterone gel is then ready for discharge into stainless steel holding tanks. Before closing the container, the Final Bulk mixture can be coated or covered with nitrogen of about 0.5 to about 1.5 bar.
• the intranasal testosterone gels of the present invention it is preferable to use multi-dose devices that allow delivery of precise dosage amounts to the external wall in each nostril of the middle-upper nasal cavity (under cartilage) for depositing the dosage thereon.
• the outer nose should be gently messaged with fingers to evenly distribute the intranasal testosterone gel throughout the nasal cavity without or minimal dosage loss into the throat or outside the nose.
• multi-dose devices for pernasal deposition at the preferred location within the nose in accordance with the present invention include the COMOD system available from Ursatec,maschine-GmbH, Schillerstr. 4, 66606 St.
• a nasal multi-dose dispenser device such as the Albion or Digital airless applicator systems available from Airlessystems, is comprised of a fluid container and a distributor pump for delivery of multiple doses of a gel or other topical formulation.
• the nasal multi-dose dispenser device is adapted for an airless fluid dispensing system.
• the nasal multi-dose dispenser device is adapted for a dip tube fluid dispensing system.
• an airless system that is contemplated by the present invention is one that will deliver a liquid, including gel, without the need for a pressured gas or air pump to be in contact with the liquid (or gel).
• an airless system of the present invention comprises a flexible pouch containing the liquid, a solid cylindrical container a moving piston, an aspirating pump, a dosing valve and a delivery nozzle, as depicted, for example, in Figs. 1-4.
• the multi-dose dispenser 100 of Fig. 1 is provided with a fluid container 120, a distributor pump 140 and a cap 102.
• the fluid container 120 comprises a container body 122, a base 124 and a neck 126.
• the distributor pump 140 is fastened to the neck by a sleeve 128.
• the top end of the container body 122 is closed by the distributor pump 140.
• the sleeve 128 tightly pinches a neck gasket 150 against the top end of the container body 122.
• the container body 122 forms a vacuum and houses the fluid to be dispensed.
• the distributor pump 140 is closed by its actuator nozzle 130, which retains the stem 144 at the stem head.
• the actuator nozzle 130 comprises an outlet channel 132 and tip 134.
• the actuator nozzle 130 is shaped to conform with the interior surface of a user's nostril.
• the actuator nozzle 130 is moveable between a downward open position and upward closed position. The user removes the cap 102 and inserts the actuator nozzle 130 in the user's nostril.
• fluid in the dosing chamber 180 is withdrawn by the distributor pump 140 and exits at the tip 134 via the outlet channel 132 of the actuator nozzle 130.
• FIG. 2 shows a cross-sectional view of the distributor pump 140.
• the distributor pump has a body 142 provided with a bottom intake having an inlet valve 160 with a ball 162 as its valve member.
• the ball 162 is held in place by a cage 164 and by a return spring 170.
• the stem 144 At its bottom end, the stem 144 carries a spring cap 172.
• a piston 174 is located above the spring cap 172. The stem 144 passes through an axial orifice of the piston base 176.
• the side walls of the piston 174 seals against the distributor pump body 142 via lips.
• the sleeve 128 tightly pinches a stem gasket 152 against the stem collar 146, distributor pump body 142 and top of the piston 174.
• a precompression spring 178 placed between the piston base 176 and the stem collar 146.
• the precompression spring 178 biases the actuator nozzle 130 via the stem 144 to the closed position.
• the return spring 170 which returns the piston 174 back upwards, is compressed between two opposed seats on the cage 164 and the spring cap 172.
• the distributor pump 140 has a dosing chamber 180 formed between the cage 164 and piston 174. When the user pushes the actuator nozzle downwards to the open position, fluid in the dosing chamber is withdrawn by the distributor pump 140 and dispensed from the tip of the actuator nozzle 130. [0116] When the user releases the actuator nozzle 130 upwards to the closed position, a fluid in the container body 122 is withdrawn into the dosing chamber 180 by the distributor pump 140. Thus, a dose of fluid is ready for the next actuation of the actuator nozzle by the user. [0117] In another embodiment of the present invention, the dispenser 200 of Fig. 3 is provided with a fluid container 220, a distributor pump 240 and a cap 202.
• the fluid container 220 comprises a container body 222, a base 224 and a neck 226.
• the distributor pump 240 is fastened to the neck by a sleeve 228.
• the top end of the container body 222 is closed by the distributor pump 240.
• the sleeve 228 tightly pinches a neck gasket 250 against the top end of the container body 222.
• the container body 222 houses the fluid to be dispensed.
• the distributor pump 240 is closed by its actuator nozzle 230, which retains the stem 244 at the stem head.
• the actuator nozzle 230 comprises an outlet channel 232 and tip 234.
• the actuator nozzle 230 is shaped to conform with the interior surface of a user's nostril.
• the actuator nozzle 230 is moveable between a downward open position and upward closed position.
• the user removes the cap 202 and inserts the actuator nozzle 230 in the user's nostril.
• fluid in the dosing chamber 280 is withdrawn by the distributor pump 240 and exits at the tip 234 via the outlet channel 232 of the actuator nozzle 230.
• Fig. 4 shows a cross-sectional view of the distributor pump 240.
• the distributor pump has a body 242 provided with a bottom intake having an inlet valve 260 with a ball 262 as its valve member.
• the ball 262 is held in place by a cage 264 and by a return spring 270.
• a dip tube 290 can extend downward from the inlet valve 260 and is immersed in the liquid contained in the container body.
• the stem 244 carries a spring cap 272.
• a piston 274 is located above the spring cap 272.
• the stem 244 passes through an axial orifice of the piston base 276.
• the side walls of the piston 274 seals against the distributor pump body 242 via lips.
• the sleeve 228 tightly pinches a stem gasket 252 against the stem collar 246, distributor pump body 242 and top of the piston 274.
• a precompression spring 278 placed between the piston base 276 and the stem collar 246.
• the precompression spring 278 biases the actuator nozzle 230 via the stem 244 to the closed position.
• the return spring 270 which returns the piston 274 back upwards, is compressed between two opposed seats on the cage 264 and the spring cap 272.
• the distributor pump 240 has a dosing chamber 280 formed between the cage 264 and piston 274. When the user pushes the actuator nozzle downwards to the open position, air enters the dosing chamber 280, which forces the fluid in the dosing chamber to be withdrawn by the distributor pump 240 and dispensed from the tip of the actuator nozzle 230.
• the amount of fluid withdrawn by the distributor pump into the dosing chamber may be a fixed volume.
• the distributor pumps may be of a variety of sizes to accommodate a range of delivery volumes.
• a distributor pump may have a delivery volume of 140 ⁇ .
• the dispensers of the present invention may dispense topical intranasal gel or other topical intranasal formulations, preferably pernasally, which contain alternative or additional active ingredients, such as neurosteroids or sexual hormones (e.g., androgens and progestins, like testosterone, estradiol, estrogen, oestrone, progesterone, etc.), neurotransmitters, (e.g., acetylcholine, epinephrine, norepinephrine, dopamine, serotonin, melatonin, histamine, glutamate, gamma aminobutyric acid, aspartate, glycine, adenosine, ATP, GTP, oxytocin, vasopressin, endorphin, nitric oxide, pregnenolone, etc.), prostaglandin, benzodiazepines like diazepam, midazolam, lorazepam, etc.
• the dispensers may be suitable for cosmetic, dermatological or pharmaceutical applications.
• topical intranasal formulations for topical pernasal application which can be dispensed in accordance with the present invention include the pernasal testosterone gels of the present invention or other intranasal topical gels wherein the testosterone is replaced or combined with a another active ingredient in effective amounts, such as those active ingredients discussed herein above.
• other testosterone formulations suitable and contemplated for dispensing from the dispensers and/or in accordance with the methods of the present invention include the formulations dislcosed in, for example, U.S. Patent Nos. 5,578,588, 5,756,071 and 5,756,071 and U.S. Patent Publication Nos. 2005/0100564, 2007/0149454 and 2009/0227550, all of which are incorporated herein by reference in their entirties.
• Intranasal testosterone gel formulations 14-21 are further examples of gel formulations contemplated by the present invention (Per Hundred parts).
• Testosterone in micronized form is preferred.
• Transcutol® 5 (Diethylene glycol monoethyl ether)
• Labrafac® PG P-glycol dicaproylate 40 DMI 25
• Carbopol® 934 0.5 Glyceryl Behenate 5.0
• Arlasolve. May limit batch size to 1 kg (or 1.5 kg) to assure sufficient material on hand in case of having to repeat an IMP batch.
• Copolyvidone - solvating polymer (Kollidon VA 64 or Plasdone S630)
• HPC Hydroxypropyl cellulose
• SR agent Shinel XHF or G250
• Silicon Dioxide - viscosifying agent (Aerosil)
• Test product Testosterone gel for pernasal administration.
• Nasobol® syringes pre-filled with 4.5% testosterone gel to deliver 6.75mg of testosterone per each nostril (manufactured by Trimel Biopharma, Inc. Canada).
• the Nasobol® formulation is as follows:
• the firm Prior to conducting studies for submission to the AND A, the firm should determine appropriate loading weight, length of time the loading weight is applied to press the buccal tablet into contact with the base plate of the tensiometer, and the rate at which the buccal tablet is pulled away from the base plate. These studies should be conducted to assure the appropriateness of the test conditions to the test and reference products. See, for example, HE Junginger et al:
• Dissolution Methods Database is available to the public at the OGD website at http://www.fda.gov/cder/ogd/index.htm. Please find the dissolution information for this product at this website. Please conduct
• Testosterone is indicated as a hormone replacement therapy for males having conditions associated with a deficiency or absence of endogenous testosterone. Lack of testosterone may cause sexual dysfunction, muscle loss, increase in fat, infertility, decreased beard and body hair and other conditions.
• CornpleoTM is a semi-solid Castor oil-based bioadhesive gel formulation containing the hormone Testosterone. CornpleoTM is being assessed as a treatment for
• a multiple dose dispenser with a tip for nasal deposition has been designed to deliver CornpleoTM to the nasal mucosa.
• the key components of the multiple dose dispenser include a barrel, piston, base, pump and actuator.
• the dispenser utilises atmospheric pressure and is designed to deliver the required dose.
• a valve is opened in the pump mechanism when the digital actuator is pressed. This allows atmospheric pressure to act on the piston via the base of the barrel, forcing it upwards.
• This study was designed to compare the placement properties for the multiple dose dispenser and the single dose syringe. The study was conducted to examine the placement of the gel from each dispenser, the ease of use for each device and the size of the gel droplet. Three healthy subjects were included in the study (two male and one female), with each subject testing both the single dose syringe and the multiple dose dispenser filled with placebo gel. Placement location and droplet size were observed and recorded by the principle investigator. A photograph was taken following each administration for comparison purposes. After administration, the subjects are asked for feedback on ease of use for each dispenser.
• the primary objective of this study was to compare the placement of the gel following intranasal administration from the two different dispensers
• the study drug is administered according to the following schedule:
• nostril Dispenser/Left nostril Following gel administration in each nostril, a photograph is taken of the nasal cavity using the KarlStorz 0° rigid endoscope and the Storz AIDA image capture platform. A visual observation is made and recorded by the principle investigator on the location of the gel deposit and the size of the gel droplet. Each subject is then asked about the ease of use of the dispenser.
• the single dose syringe are capable of depositing the gel in the correct
• dispenser is equivalent to the single dose syringe and is capable of
• dosing instructions for patients A copy of this dosing pamphlet can be
• test (T) product and reference (R) product in each run is randomized or pre-assigned in a mixed arrangement.
• the two different formulations of the testosterone gel products are applied on 12 cells of the modified Franz-Cell apparatus system: 6 cells for reference product (R) and 6 cells for test product (T), as depicted in Fig. 13.
• the two gel products 20 Testosterone Nasabol Gel 4%, lot# E10-007, and TBS 1A Testosterone Nasal Gel 4%, lot# IMP 11002, are described in Example 6 and designated as 4% TSA-1 A and TBS1.
• a table with six rows and seven columns is generated and reference slopes (RS) are listed across the first row and test slopes (TS) are listed down the first column of Table 2.
• RS reference slopes
• TS test slopes
• Individual T R ratios (30) between each test slope and each reference slope are computed and the corresponding values are entered in the table.
• T R ratios are ranked from lowest to highest.
• the sixth and twenty-fifth ordered ratios represent low and upper limits of the 90% CI for the ratios of median release rates.
• Standard criteria Test and reference product are considered to be the same if the 90% CI falls within the limits of 75% - 133.3%.
• Testosterone Nasabol Gel 4% Two batches of Testosterone Nasabol Gel 4%, lot# E10-007, and TBSIA Testosterone Nasal Gel 4%, lot# IMP 11002, are tested and evaluated for sameness.
• a statistical comparison is carried out by taking the ratio of release rates from 6 cells of the reference lot # E10-007 (R) against 5 cells of the test batch lot# IMP 11002 (T).
• the reference batch and the test batch are applied in a randomized manner on the cells on Apparatus A and B of the modified Franz Cell System.
• the 90% Confidence Interval is represented by the sixth and twenty-fifth Release Rate ratios
• Testosterone Nasal Gel 4%, lot# IMP 11002, are tested and evaluated for sameness.
• the Mean Release Rate (slope) for the Test lot# IMP 11002 is about 1.8 times higher than for the Reference lot# E 10-007. The two tested products are found to be not the same.
• the In Vitro Release Rate (IVRT) testing results and raw data are in Tables 3-8 below and Fig. 14.
• Tastostsrwe TBS 1 A Tsstostsrorse Sstssas. Gei 4%
• Test toiVia3# B#S at 2 hour was Hfesing injection. Comparison catenated i>y 53 ⁇ 4S*3 ⁇
• Testosterone replacement therapy aims to correct testosterone deficiency in hypogonadal men.
• Trimel BioPharma has developed an intranasal testosterone gel (TBS-1) as alternative to the currently available testosterone administration forms.
• TBS-1 intranasal testosterone gel
• Trimel identified a multiple dose dispenser intended for commercial use. The purpose of this study was to demonstrate the relative performance of the multiple dose dispenser in comparison to the syringe used previously in clinical trials.
• TBS-1 testosterone nasal gel This was an open label, balanced, randomized, crossover, two-group, two -treatment, two-period, pharmacokinetic study of TBS-1 testosterone nasal gel in healthy, male subjects aged 18 to 28.
• Treatment consisted of 4.5% TBS-1 testosterone gel as a single dose of 5.5 mg of testosterone per nostril, delivered using either a syringe or the multiple dose dispenser, for a total dose of 11.0 mg given at 21:00 hours.
• Prior to first administration subjects were admitted to the unit for blood sampling in order to determine a baseline testosterone profile. Wash-out between drug administrations was at least 48 hours.
• Endogenous androgens are responsible for the normal growth and development of the male sex organs as well as promoting secondary sex characteristics including the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as beard, pubic, chest, and axillary hair, laryngeal enlargements, vocal cord thickening, alterations in body musculature, and fat distribution.
• hypogonadism in men is characterized by a reduced concentration of serum testosterone resulting in signs and symptoms that may include decreased libido, erectile dysfunction, decreased volume of ejaculate, loss of body and facial hair, decreased bone density, decreased lean body mass, increased body fat, fatigue, weakness and anaemia.
• hypogonadism can be primary or secondary in nature.
• primary hypogonadism congenital or acquired testicular failure can be caused by cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchidectomy, Klinefelter' s syndrome, chemotherapy, or toxic damage from alcohol or heavy metals.
• FSH, LH serum gonadotropin levels
• Secondary hypogonadism In secondary hypogonadism (Hypogonadotropic Hypogonadism (congenital or acquired)) the defects reside outside the testes, and are usually at the level of the hypothalamus or the pituitary gland. Secondary hypogonadism can be caused by Idiopathic Gonadotropin or LHRH deficiency, or pituitary hypothalamic injury from tumors, trauma, or radiation. These men have low serum testosterone levels but have serum gonadotropin levels in the normal or low ranges. Testosterone hormone therapy is indicated as a hormone replacement therapy in males for conditions associated with a deficiency or absence of endogenous testosterone. The currently available options for administration of testosterone are oral, buccal, injectable, and transdermal.
• Trimel BioPharma has developed an intranasal testosterone gel (TBS-1) as a hormone replacement therapy for the treatment of male hypogonadism.
• TSS-1 intranasal testosterone gel
• the nasal mucosa offers an alternative route of administration that is not subjected to first pass metabolism, has high permeability, with rapid absorption into the systemic circulation.
• the advantages of the testosterone intranasal gel when compared to other formulations include ease of administration and no transference of testosterone to other family members.
• TBS-1 an intranasal testosterone dosage form.
• a description of its physical, chemical and pharmaceutical properties can be found in the Investigator's Brochure. Summary of Non-clinical and Clinical Studies
• TBS-1-2010-01 The most recently conducted study, TBS-1-2010-01, is described below and the other studies are summarized in the Investigator's Brochure.
• the objective of study TBS-1-2010-01 is to examine the efficacy and tolerability of 4.0% and 4.5% TBS-1 testosterone gel in hypogonadal men.
• TBS-1 is administered using a syringe, not the commercial multiple dose dispenser.
• the doses and dosing regimens that were used in study TBS-1-2010-01 are described in Table 1 below.
• Testosterone replacement therapy for hypogonadal men should correct the clinical abnormalities of testosterone deficiency. Since this was a Phase I study enrolling normal healthy men between the ages of 18 - 45, for a short period of time, it was not anticipated that these volunteers would directly benefit by taking part in this study. Volunteers were financially compensated for their participation.
• TBS-1 The risk to the subject by participating in this study was considered to be minimal.
• Testosterone replacement therapy is indicated for the treatment of hypogonadism and TBS-1 has been administered to over 100 men with minimal side effects.
• TBS-1 is an investigational drug that is in clinical development, the complete side effect profile was not fully known. Epistaxis, nasal congestion, nasal discomfort, nasal dryness and nasal inflammation have been reported following use of TBS-1.
• the main benefit of the intranasal drug delivery route is that with this method many of the different disadvantages observed with other products would not be expected. This would include skin-to-skin transfer, stickiness, unpleasant smell (gels), skin irritation (patches), elevated DHT (patches and oral), injection pain and high T and DHT peaks (intramuscular injection), food interaction (oral).
• Trimel identified a multiple dose dispenser that was intended as the commercial dispenser to be used in this clinical trial program.
• a syringe has been used to deliver TBS-1 in the previous clinical trials.
• the purpose of this study was to demonstrate the comparability of the pharmacokinetic results obtained with a multiple dose dispenser or a syringe.
• the primary study objective is to compare a pharmacokinetic profile of testosterone after administration of TBS-1 using two different dispensers in healthy male subjects.
• the secondary objective is to assess the safety of TBS-1.
• Subject with active allergies such as rhinitis, rhinorrhea, or nasal congestion
• nasal disorders e.g. polyposis, recurrent epistaxis (> 1 nose bleed per month), abuse of nasal decongestants) or sleep apnea
• nasal corticosteroids and oxymetazoline containing nasal sprays e.g. Dristan 12- Hour Nasal Spray
• TBS-1 For the drug administration, subjects are instructed on how TBS-1 is applied intranasally with the pre-filled syringes or the multiple dose dispensers. Self- administration of TBS-1 is monitored by the study personnel. Each subject is instructed not to sniff or blow his nose for the first hour after administration.
• Treatment 1 consists of TBS-1 syringes that are pre-filled with 4.5% testosterone gel to deliver a single dose of 5.5 mg of testosterone per nostril, for a total dose of 11.0 mg that is administered at 21:00 hours (+ 30 minutes) on Day 2 of Period I for Group A and Day 4 of Period II for Group B.
• Treatment 2 consists of a TBS-1 multiple dose dispensers that are pre-filled with 4.5% testosterone gel to deliver a single dose of 5.5 mg of testosterone per nostril, for a total dose of 11.0 mg that is administered at 21:00 hours (+ 30 minutes) on Day 2 of Period I for Group B and Day 4 of Period II for Group A. Identity of Investigational Produces )
• TBS-1 an intranasal testosterone dosage form.
• Study medication consists of TBS-1 gel and is packed either in a single use syringe that is designed to expel 125 ⁇ of gel, with two syringes packaged per foil pouch, or in a multiple dose dispenser that is designed to expel 125 ⁇ of gel/actuation .
• Study medication is dispensed by the study pharmacist who prepares the individual study kits which contained two syringes in a pouch or the multiple dose dispenser.
• Treatment assignment is determined according to the randomization schedule at the end of Visit 1. Subjects who met the entry criteria are assigned randomly on a 1:1 basis to one of the two treatment groups (Group A or Group B). The randomization is balanced and the code is kept under controlled access. The personnel that are involved in dispensing of study drug is accountable for ensuring compliance to the randomization schedule.
• the screening visit (visit 1) takes place at a maximum of 21 days before the first study day. After giving informed consent, the suitability of the subject for study participation is assessed at screening which consists of the following items:
• a fasting blood sample is taken to determine the following: Complete Blood Count, Chemistry profile; testing for HBV, HCV, HIV and PSA.
• a 12 hour baseline testosterone profile is measured. Blood for the 12 hour baseline testosterone profile is drawn according to the following schedule: first sample at 20:45 hours and then at 0.33, 0.66, 1.00, 1.50, 2.00, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, and 12.00 hours relative to 21:00 time point (a total of 13 samples). On Day 2 vital signs are measured and safety parameters (symptoms, AEs) recorded before check-out.
• Dosing is performed on the evenings of Day 2 and 4, at 21:00 hr. Before dosing an ENT examination is performed and a pre-dose, baseline serum testosterone blood sample is drawn. After dosing, a 12 hour testosterone PK profile is measured. The blood samples are drawn according to the following schedule after the 21:00 hour dosing: 0.33, 0.66, 1.00, 1.50, 2.00, 3.00, 4.00, 5.00, 6.00, 8.00, 10.00, and 12.00 hr time points (a total of 13 samples per period).
• Blood samples for analysis of testosterone levels are collected in 4ml standard clotting tubes using an intravenous cannula. Tubes are left to clot for 30-45 minutes. Samples are centrifuged within one hour at 2000g for 10 minutes at 4°C. The serum is then transferred directly to two aliquots of 1 ml each and frozen at -40 °C.
• Blood samples for hematology are collected in 4ml EDTA tubes and sent to the hematology laboratory of the Leiden University Medical Center (LUMC) for routine analysis.
• Blood samples for blood chemistry are collected in 4 ml Heparin tubes and sent to the clinical chemistry laboratory for routine analysis.
• Frozen serum samples for PK analysis are stored in the freezer at -40°C and are shipped on dry ice to the laboratory, at the end of the study. Samples are analyzed using a validated LC-MS method for the determination of testosterone levels. It is not possible to discriminate endogenous and exogenous testosterone from each other using this method. Quality Assurance
• AUC Area under the concentration curve
• PK parameters could be performed as necessary.
• the relative pharmacokinetic profile of the pre-filled syringe and the multiple dose dispenser is determined using the AUCo-i2h and Cmax 0 _i2h corrected for the endogenous serum testosterone concentration.
• the relative mean of the dispenser to the pre-filled syringe using log transformed data for AUCo i2h and Cmax 0 -i2h is corrected for the endogenous serum testosterone concentration is determined to be between 80% to 125%.
• Clinical chemistry profile sodium, potassium, chloride, glucose, urea, creatinine, calcium, phosphate, uric acid, total bilirubin, albumin, AST, ALT, ALP, GGT, CK and cholesterol.
• the nasal gel is self-administered by subjects. All administrations are successful.
• Fig. 15 shows the individual and median testosterone concentration versus time grouped by treatment.
• AUCo-12 Area under the serum concentration-time curve (ng hr/dL) for each occasion from 21:00 to 9:00 hrs, is calculated using the linear trapezoidal method.
• C me a n Mean concentration (ng/dL) during each occasion from 21:00 to 9:00 hrs, is calculated as AUC_0-12 /12.
• Tables 5 to 7 below summarize the primary pharmacokinetic parameters for endogenous testosterone during the baseline visit when no treatment is administered, for TBS-1 when administered using the multiple dose dispenser, and for TBS-1 when administered using a syringe.
• Table 6 Testosterone, TBS-1 multiple dose dispenser
• Total testosterone exposure is estimated by the mean area under the serum concentration-time curve (AUCo-12 in ng-hr/dL) is higher after TBS-1 administration using the dispenser or syringe than endogenous levels alone (7484 and 7266, respectively, versus 4911ng*h/dL). Between the methods of administration, the difference in mean AUCo-12 is small. The significance of this difference is explored below.
• t max Two subjects reach t max of testosterone only 10 and 12 hours after administration with the dispenser. In three subjects, t max is 10 and 12 hours after administration with the syringe, and t max is 5 and 6 hours in two others. Most likely, the endogenous testosterone peak fluctuation exceeded levels that is caused by exogenous testosterone administration. Thus, the calculated mean t max may be faster when testosterone is dosed high enough that the peak caused by exogenous administration exceeds the endogenous peak.
• Ratio AUCo-i2_dru g % ratio between AUCo-i2_dru g using dispenser and syringe
• Tables 8 and 9 below show the AUC and C max for the different TBS-1 delivery methods after subtracting baseline levels of testosterone.
• Table 8 Testosterone level using TBS-1 multiple dose dispenser, baseline subtracted
• Table 10 shows the ratio of serum testosterone levels that are reached with the dispenser or syringe, after subtracting baseline testosterone levels. There is clearly a difference in C max between the administration forms (mean ratio dispenser over syringe C max 2.057), but the AUCs are comparable (mean ratio dispenser over syringe AUC 1.12).
• Table 10 Testosterone, ratio of TBS-1 multiple dose dispenser over syringe
• Ratio AUCo.12 drug 1.122 0.580 0.940 0.550 2.572 12
• Table 11 shows the log of the ratio of serum testosterone levels that are reached when administering using the multiple dose dispenser over syringe, after subtracting baseline testosterone levels, with 95%, 90% and 80% confidence intervals.
• Table 11 Testosterone TBS-1 log ratios with different confidence intervals
• Treatment is well tolerated. There are 12 adverse event reports in total. Three events had their onset before the first administration of study medication and are therefore unrelated. Four reports of mild complaints such as sore throat are considered unlikely to be caused by study medication when considering the nature of the complaints and the time lapse after administration. One subject reschedules one occasion because of gastro-intestinal complaints that are unlikely to be related to study medication, onset of symptoms is days after study drug administration. Symptoms resolve without treatment.
• This study compares the pharmacokinetic profile of TBS-1 testosterone nasal gel administered using a multiple dose dispenser to the profile of TBS-1 delivery using a syringe.
• the order of administration is randomized.
• subjects are admitted to the unit for blood sampling in order to determine a baseline testosterone profile.
• t max Two subjects reach t max of testosterone only 10 and 12 hours after administration with the dispenser. In three subjects, t max is 10 and 12 hours after the syringe, and t max is 5 and 6 hours in two others. Most likely, the endogenous testosterone peak fluctuation exceed levels that are caused by exogenous testosterone administration. Thus, the calculated mean t max may be faster when testosterone is dosed high enough that the peak caused by exogenous administration exceeds the endogenous peak.
• TBS-1 and TBS-IA have been developed as a hormone replacement therapy for the treatment of hypogonadism. It is believed that TBS- 1/TBS-lA gel will offer significant safety and efficacy over existing therapies for the treatment of hypogonadism.
• TBS-1/TBS-1A are an innovative galenic formulation of testosterone for nasal administration.
• the advantages of TBS-1/TBS-1A nasal gel include a reduced amount of active ingredient in comparison to other testosterone replacement therapies and lack of transference to other family members.
• the testosterone intranasal gels are referred to as Nasobol or TBS-1 (for the treatment of hypogonadism in males).
• the investigational drugs, TBS-1 and TBS-IA, are an intranasal formulation of testosterone.
• Testosterone belongs to the pharmacological class of androgens.
• Table 2 Summary of the Active IMP, TBS-IA
• Impurity I ⁇ 0.2% Impurity C ⁇ 0.5% Impurity J ⁇ 0.1% any other ⁇ 0.1% Total impurities ⁇ 0.6%
• Testosterone is dispensed into polyethylene bags; each polyethylene bag is then sealed and placed in a polyethylene-aluminum-laminated bag.
• the polyethylene- aluminum-laminated bag is placed in a plastic container which is shipped within a fiber drum that is closed with a tamperproof metallic seal.
• Testosterone USP has a retest period of five (5) years.
• TBS-1 gel is a viscous and thixotropic, oil-based formulation containing solubilized testosterone intended for intranasal application.
• the drug product is formulated with the compendial inactive ingredients: castor oil, oleoyl polyoxylglycerides, and colloidal silicon dioxide.
• compositions of the drug product to be administered in this clinical trial are provided in Tables 2.1. P.1-1.
• TBS-1 gel is supplied in unit-dose polypropylene syringes. Two syringes of each dosage are packaged in a protective aluminium foil pouch.
• TBS-l/TBS-lA gel Because testosterone is fully dissolved within the formulation, physical characteristics of the drug substance do not influence the performance of the drug product TBS- 1/TBS-lA gel. The manufacturability of TBS-l/TBS-lA gel however is influenced by the particle size of testosterone. When using a particle size of 50% ⁇ 25 microns, 90% ⁇ 50 microns the solubility of the drug substance in the matrix is especially favorable.
• testosterone contains no functional groups that can be protonated or deprotonated in the physiological pH-range. Therefore, testosterone is to be considered as a neutral molecule with no pKa value in the range 1-14. Because it is neutral, testosterone is compatible with excipients.
• the excipients used in the formulation of the TBS-1/TBS-1A drug product are inactive ingredients used in semi-solid dosage forms.
• the ingredients are monographed in NF and/or USP/Ph. Eur. (except dimethyl isosorbide which is subject to a specific monograph) and are all listed in the "Inactive Ingredient” list for Approved Drug Products issued by the FDA.
• the main excipient in TBS-1/TBS-1A gel is castor oil which amounts to approximately 50 to 65% of the formulation and serves as a solvent for testosterone.
• the characteristics of oil which can influence drug product performance are: the ability to solubilize drug substance, viscosity which influences the amount of gellant required, odor/taste which may impact patient compliance, and acid/hydroxyl/iodine/saponification value which impacts the potential for skin irritation.
• the solubility of testosterone is highest in castor oil compared to other solvents suitable for nasal application and castor oil is not irritating to mucous membrane.
• a testosterone semisolid dosage form for nasal application would require a dose of 2.5 to 5 mg of the active per 100 ⁇ ⁇ per nostril.
• An aqueous solution of testosterone can contain only 0.002 mg per 100 uL while a castor oil solution, in contrast, can contain up to about 4.5mg per 100 ⁇ L.
• Oleoyl polyoxylglycerides 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 TBS-1 gel, 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 polyoxylglycerides, the castor oil containing the active ingredient would form a non-interactive layer on the mucous membrane.
• the hydrophilic oleoyl polyoxylglyceride is added to the formulation to form an emulsion between the castor oil and the mucosa fluid.
• Oleoyl polyoxylglycerides have a slight disadvantage of causing a minor decrease in the solubility of testosterone in castor oil.
• Oleoyl polyoxylglycerides are used in semi- solids at concentrations ranging from about 3 to 20%, depending on the application.
• the amount of oleoyl polyoxylglycerides in TBS-1 gel 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 favorable concentration of oleoyl polyoxylglycerides in TBS-1 gel is found to be 4% of the formulation.
• Oleoyl polyoxylglycerides show good mucosal tolerance and are used as an excipient in approved nasal and vaginal preparations. This oil is used in nasal sprays/drops together with other excipients such as olive oil, peanut oil, eucalyptol, niauli oil and in vaginal creams together with mineral oil, and tefose 63 (PEG-6-32 stearate and glycol stearate).
• Testosterone solubility in the oil based TBS-1A gel is limited to about 4.5%. There is a need to increase the solubility of testosterone to higher levels in order to reduce the volume of gel delivered as the recommend volume of gel to the nasal cavity should not preferably exceed about 150 ⁇ L ⁇ .
• Diethyleneglycol ethyl ether alone can dissolve more than 10% testosterone, and is used with DMI to increase the overall solubility of testosterone in the gel.
• Diethyleneglycol ethyl ether is used in many dermal formulations approved in Europe, USA, Canada and several other countries.
• DMI Dimethyl isosorbide
• Arlasolve is also a super solvent and is able to dissolve more than 12% testosterone. Used in conjunction with the other excipients, DMI allows for testosterone levels in the gel up to at leat about 8.0%.
• the safety profile for DMI is made public by, for example, the Australian Ministry of Health:
• Povidone (Kollidon K or Plasdone K) is a vinylic polymer used for decades in various pharmaceutical dosage forms. Povidone functions as a binder and is also used as a film former in sprays and an inhibitor of crystal growth in saturated solutions. Povidone is only partly soluble in the TBS-1A mixture and its amount is limited.
• Copovidone known as Kollidon VA 64 or Plasdone S 630 is a copolymer of vinyl acetate and pyrrolidone. Copovidone is similar in function to Povidone in that it is used as a binder in dozens of oral formulation but can also be found in topical formulation (Erythromycin dermal or clotrimazole vaginal) approved in Germany, and an anti-acne cream approved in UK).
• Copovidone is somewhat more soluble than Povidone in the TBS-1A mixture, its activity on crystal growth is somewhat less than Povidone, but, unlike Povidone, Copovidone helps increase the viscosity of the gel.
• TBS-1/TBS-1A gel The oil in TBS-1/TBS-1A gel is thickened with a gel-forming agent, colloidal silicon dioxide. This compound is used commonly for thickening oleogels.
• the intended dosage form for TBS-1/TBS-1A gel is a semi-solid, not a liquid.
• the formulation is thickened with colloidal silicon dioxide; instead of a solid fat as the viscosity obtained with the latter highly depend on of temperature, while the viscosity obtained with Si0 2 remains stable with temperature.
• 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 TBS-1/TBS-1A gel is high enough to achieve gel formation but at a level that has minimal impact on testosterone incorporation into the carrier oil. Hydroxypropyl cellulose Ph. Eur./USP (Hyprolose)
• Hydroxypropyl cellulose (Klucel or Nisso HPC) is a cellulose derivative used as a viscosity agent in pharmaceutical products.
• Hyprolose has been cited in literature as able to improve and prolong the absorption of hydrophilic drugs through the nasal route in animals (Dopamine).
• Hyprolose is also soluble in many organic solvent or semi-hydrophilic oils and therefore can be used as a secondary thickening agent in TBS-1A.
• Hyprolose is added to TBS-1A as DMI and Transcutol reduce the gelling efficiency of silicon dioxide as these amphiphilic solvents are believed to reduce the hydrogen bonds between the silica and the oil.
• TBS1 and TBS-1A gel are formulations of testosterone in an intranasal gel proposed for a Phase I clinical trial to compare the delivery of 125 ⁇ (5.0 mg) of a 4.0% w/w TBS-1 gel to 125 ⁇ (5.0 mg) of a 4.0% w/w TBS-1A gel and 62.5 ⁇ 1 (5.0 mg) of a 8.0% w/w TBS-1A gel.
• the quantity of testosterone per dose that is much lower than that administered via currently approved testosterone-containing dosage forms is selected.
• the initial dose is selected by considering the doses used for other orally administered drugs that have also been formulated for nasal delivery.
• a 4% testosterone- containing formulation that delivers about 5.6 mg testosterone in 140 ⁇ _, to each nostril is evaluated.
• This 4% formulation and a 4.5% testosterone-containing formulation are further used in a Phase II clinical study per the dosing regimen presented in Table 2.1. P.2.2.1-1.
• Table 2.1.P.2.2.1-1 TBS-1 Formulations used in a Phase II Clinical Study
• the proposed clinical study will compare 125 ⁇ (5.0 mg) of a 4.0% w/w TBS-1 gel to 125 ⁇ (5.0 mg) of a 4.0% w/w TBS-1A gel and 62.5 ⁇ 1 (5.0 mg) of a 8.0% w/w TBS- 1A gel packaged in HDPE syringes sealed in an aluminium foil.
• the first approach to developing a nasal delivery formulation of testosterone is to create a purely aqueous-based product.
• the formulation of a microcrystalline suspension of testosterone initially developed (referred to as "Formulation 1") is listed in Table 2.1.P.2.2.1-2.
• Avicel RC 591 is a mixture of microcrystalline cellulose and carboxymethyl cellulose sodium
• Formulation 1 is filled into a device that allowed preservative-free application of testosterone to the nose. Each actuation of the device delivered 5.6 mg of testosterone from the nasal actuator.
• Formulation 1 a proof-of-concept study is conducted in hypogonadal men; the study is an open label, multiple-dose, parallel, dose-ranging study in 5 subjects.
• a purely oil-based formulation of testosterone is developed.
• the 5.6 mg per nostril dose evaluated with Formulation 1 in the proof-of-concept study results in a relatively high C max value. Therefore, to achieve a lower C max from the oily formulation, the quantity of testosterone is lowered for the oil-based formulations.
• the formulation is filled into individual containers.
• the first trial laboratory scale batch (Batch No. 100304) is filled into glass vials. After production of the preliminary batch, non-clinical, stability and clinical batches are packaged in LDPE packaging using blow-fill- seal technology. The clinical product for this trial will be packaged into syringes with a syringe cap.
• Formulation 2A The quantity of testosterone in Formulation 2A is targeted at 3.5%.
• the exact formulation is listed in Table 2.1.P.2.2.1-3.
• Formulation 2A is used in one in vitro and two in vivo preliminary safety studies.
• Formulation 2B The quantity of testosterone in Formulation 2B is reduced from 3.5% to 3.2% along with an adjustment of the amount of castor oil.
• the exact formulation is listed in Table 2.1.P.2.2.1-3.
• Formulation 2B is used in the 3-month safety study in animals and in two clinical studies in Europe (i.e., a Phase I 24-hr kinetic and a Phase II dose ranging study).
• the quantity of testosterone in Formulation 2C is increased from 3.5% to 4.0% along with an adjustment of the amount of castor oil.
• the exact formulation is listed in Table 2.1. P.2.2.1-3.
• Formulation 2C is used in a Phase II clinical study.
• the TBS-1 formulation exhibits a rapid peak to trough profile. It is decided to reformulate the product with the addition of small amounts of polymer to possibly increase the elimination half-life of testosterone in vivo thus minimizing the peak to trough profile.
• the formulations, based on testosterone solubility and gel formation are listed in Table 2.1.P.2.2.1-4.
• a relevant parameter for the performance of the drug product is viscosity.
• the viscosity is important because it facilitates maintenance of the gel in the nasal cavity in contact with the nasal mucosa.
• TBS-1 Manufacturing Process Development
• TBS-1/TBS-1A gel is supplied in unit-dose polypropylene syringes.
• Syringes have been used as the primary packaging of the clinical materials for TBS-1 clinical trial as they allow for ease of dosing, ability to generate multiple doses by varying the fill volume and consistency of dose delivered.
• 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.
• TAMC total aerobic microbial count
• TYMC total yeast and mould count
• the drug is not administered with a diluent, another drug product or a dosage device and therefore compatibility studies were not performed.
• TBS-1 One batch of the bulk finished product, 4.0% TBS-1, has been manufactured for the proposed clinical trial.
• the batch formula is presented in Table 2.1. P.3.2-1.
• the clinical trial material is manufactured according to the following process as depicted in Fig. 20.
• the in-process controls comprise the entire manufacturing process of the product, from the incoming inspection and release of drug substance and excipients to the packaging of the drug product. Description of Manufacturing Process
• the Pre-Mix is prepared by mixing, with a propeller mixer, the full amount of Testosterone with 25.0 kg of castor oil for 5 minutes.
• Mixture I is prepared by adding the Pre-Mix to the remaining castor oil amount and mixing for 10 minutes to fully dissolve the Testosterone.
• the product temperature is maintined below 50°C for the entire mixing process.
• the oleoyl polyxoylglycerides are pre-heated to 50°C and added to Mixture I. It is mixed for 10 minutes while maintaining product temperature below 50°C. This is identified as Mixture II.
• Mixture III is prepared by adding the colloidal silicon dioxide to Mixture II and mixing for 10 minutes while maintaining product temperature below 50°C. A visual check is conducted after this step, to ensure that all of the Testosterone is dissolved and the gel is homogeneous. If the solution is clear and no undissolved Testosterone remains the cooling and discharge steps are initiated. In the event that undissolved Testosterone remains, the gel is mixed for an additional 10 minutes while maintaining product temperature below 50°C and the visual check is repeated.
• the gel is stirred and cooled to a product temperature below 30°C.
• the product is then discharged into stainless steel drums and the bulk gel sample is taken for analytical analysis.
• 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 sterile 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 package product is stored in quarantine and samples are presented to the quality control laboratory to control the finished product.
• the control of the finished product includes all parameters of the specification. All parameters have to conform to the release specification. After passing the quality control, the product TBS-1 gel is released.
• TBS-1 gel None of the excipients in TBS-1 gel is of human or animal origin.
• the TBS-1 bulk gel is tested to the following specifications for batch release.
• TBS-1 gel is packaged in unit dose syringes or the multiple dose dispensers and is tested to the following specifications for batch release.
• TBS-1 RC5 - 17a -hydroxyandrost-4-en-3-one (Epitestosterone); EP Impurity C Analytical Procedures (TBS-1, Gel)
• the identification by UV is determined in the Assay method using a HPLC equipped with a Diode Array Detector (DAD).
• DAD Diode Array Detector
• TBS-l/TBS-lA The measurement of the viscosity of TBS-l/TBS-lA is performed using a rotational viscosimeter

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