WO2017035619A1 - Formulation pharmaceutique nasale de testostérone et « kit » sous forme de tablette de dispositifs nasaux unitaires pour application de monodose de testostérone - Google Patents

Formulation pharmaceutique nasale de testostérone et « kit » sous forme de tablette de dispositifs nasaux unitaires pour application de monodose de testostérone Download PDF

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Publication number
WO2017035619A1
WO2017035619A1 PCT/BR2016/050212 BR2016050212W WO2017035619A1 WO 2017035619 A1 WO2017035619 A1 WO 2017035619A1 BR 2016050212 W BR2016050212 W BR 2016050212W WO 2017035619 A1 WO2017035619 A1 WO 2017035619A1
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Prior art keywords
testosterone
formulation
air
chamber
nasal
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PCT/BR2016/050212
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English (en)
Portuguese (pt)
Inventor
Moisés Alves DE OLIVEIRA NETO
Brandão De Souza REZENDE
Marcelo Reis PERILLO
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F.B.M. Indústria Farmacêutica Ltda
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/06—Ampoules or carpules
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form

Definitions

  • This patent application is a set of devices comprising a device-shaped pharmaceutical kit for nasal testosterone administration consisting of a plurality of single dose single dose delivery devices. monodose, therapeutically measured.
  • Each device is provided for the administration of a single dose of a testosterone formulation to an individual in need of hormone treatment, and after use is discarded.
  • Each device releases an accurate volume amount of the testosterone formulation without leaving dead volume.
  • the testosterone formulation is such that it allows the device to release an accurate and substantially total amount of the testosterone formulation contained therein, without leaving any remaining volume.
  • the patient is a female patient undergoing hormone replacement treatment in which a minimal daily dose of the hormone testosterone is administered for this purpose.
  • the patient is also male and given an adequate minimum daily dose for the purpose of hormone replacement or supplementation.
  • Testosterone is usually thought of as a "male hormone" but is found in both men and women. women, although the amount of this hormone in the female body is usually about twenty (20) times lower than in men.
  • Testosterone the main androgen of the circulation, is responsible for the development and maintenance of male sexual characteristics and anabolic state of tissues.
  • the physiology and pathophysiology of testosterone are well differentiated in men and women.
  • Chemically testosterone is a spheroid hormone (formed from cholesterol).
  • Testosterone deficiency can have serious consequences, both physical and mental, impairing a woman's health and libido. In special cases this deficiency is even more prominent, as in the case of ovarian removal due to pathologies or various physiological situations, such as:
  • adrenal insufficiency (suprarenal); • Use (current or previous) of hormonal contraceptives, mainly orally;
  • Testosterone hormone depletion can occur in both postmenopausal women, either natural or for surgical reasons, leading to a large population of women needing to have their hormone levels measured, such as just as they need to become users of some form of hormone replacement.
  • the contraceptive decreases the amount of free testosterone as it stimulates the production by the liver of a protein called sex hormone binding globulin (SHBG).
  • SHBG sex hormone binding globulin
  • SHBG sex hormone binding globulin
  • the use of testosterone replacement is the preferred approach.
  • the lowest acceptable normal amount of total testosterone is 200 ng / dL [6.9 nmol / L]) and free testosterone is 40 ng / dL [1.8 nmol / L]).
  • the lowest acceptable normal amount of total testosterone is 20 ng / dL [6.9 nmol / L]) and free testosterone is 4 ng / dL [0.18 nmol / L]).
  • the lack of testosterone is also basically supplied by hormone replacement with testosterone and other testosterone precursors such as DHEA.
  • Supraphysiological testosterone levels may lead to the appearance of masculinizing signs.
  • the onset of hair and acne, or Adam's apple, clitoral enlargement, facial modification, excessive hair growth and acne, too much muscle mass, voice changes and menstrual changes are seen in women who use indiscriminate and uncontrolled of derivatives of this hormone, which in general use this hormone in much higher potency and in large unnatural amounts.
  • a device which is a set of packaged carton devices to form a pharmaceutical monodose device kit.
  • testosterone for nasal administration whose pharmaceutical form allows the administration of single-dose testosterone, measured at a dosage corresponding to physiological conditions, for the replacement of this hormone to a patient in need of such replacement.
  • Testosterone deficiency is a relatively common pathological condition in both female and male populations [1-2].
  • the WHO, NIH, and FDA recommend that the primary goal of therapy is to replace deficient testosterone levels to levels as close to physiological concentrations as possible.
  • Testosterone patches another pharmaceutical form of medication used for hormone replacement, have a high rate of skin irritation [5,6].
  • testosterone gels despite being the most accepted hormone replacement medicine in the United States, are less irritating to human skin, but are not always considered convenient and may be at risk of gel transfer from one patient to another by skin-to-skin cross-contamination [7-13].
  • Oral testosterone undecanoate formulations need to be administered with a high fat meal and the absorption levels obtained are generally low [14-19].
  • Oral formulations are generally related to high levels of dihydrotestosterone because of the high levels of 5-reductase in the human intestine [20].
  • a formulation provided in a nasal drug delivery device was developed to allow a patient to supply testosterone in a single dose, metered without causing skin irritation, not promoting overdose, not requiring fat supply for absorption and without the need for metabolism via the gastric as with oral forms of hormone supplementation of testosterone.
  • Nasal testosterone formulations must have an ideal viscosity so that it does not drip and is swallowed, becoming an undesirable oral route.
  • Table 1 proposes an analysis by the researchers of the present patent, based on current knowledge of the state of the art, in order to evaluate the most appropriate pharmaceutical form for the presentation of the formulation of their drug, using of the minimum dose required to produce the testosterone hormone replacement effectiveness achieved by the present invention.
  • prostate gland rapidly; infertility, proportional to impotence, liver cancer technology, and pancreatic drug technology); employed in
  • Implant Does not pass through Does not mimic the Ineffective in the case of subcutaneous liver; daily secretion hormone replacement;
  • Pill is taken by 0 number of high cost of oral orally, but pills is treatment, versus
  • testosterone and its derivatives are the subject of frequent studies to define the best pharmaceutical form for proper administration in view of the therapeutic target and the gender of the patient to be treated.
  • a specific formulation is developed for the appropriate absorption of the therapeutic substance combined with the preferred route of administration.
  • the administration of the hormone as a function of the desired therapeutic outcome has greater or lesser therapeutic effects, as well as side effects and greater or lesser patient adherence to treatment.
  • the intramuscular route is the most common and least costly form of androgen replacement, but on the other hand, if employed more steadily and permanently, it may result in poor patient adherence. treatment.
  • these androgens - testosterone and its derivatives have low bioavailability and large hepatic inactivation, except for the 17-alpha-alkylated androgens, such as methyltestosterone. absorbed but have higher hepatotoxicity.
  • both testosterone enanthate and cypionate exhibit longer absorption and duration, 10 to 14 days after intramuscular 200 mg application, while caproate and testosterone isocaproate are longer, 14 and 28 days, in use for male patients and by injection.
  • testosterone derivatives when formulated in an oily vehicle, is already in common use in the prior art, particularly when the chosen form is injectable.
  • testosterone derivative to be used as an active ingredient is crucial to the achievement of the expected results, in view of the above stated objectives to be achieved by the present invention, to be packaged in the monodose device and for nasal application. .
  • testosterone butyrate associated with oily vehicle is reported in GB729808 published 11/05/1955, such as sesame oil, also for injectable use.
  • Prolonged-release implants as known in US5733565 published March 31, 1998, provide more stable testosterone levels for up to 6 months, but have complications such as extrusion, bleeding, and local infection in about 5% of users. .
  • Transdermal application of testosterone is an attractive alternative because it provides more stable circulating testosterone levels and avoid pain at the application site.
  • both the patch and the testosterone gel have a much higher final drug cost than injection.
  • Scrotal patches require depilation and may cause deleterious effects on the prostate due to excessive increase in local DHT production.
  • Non-scrotal adhesives have similar efficacy, are more practical and do not generate an excessive increase in DHT levels.
  • testosterone gel (1%) for daily application at doses of 5 to 10 g on shoulders, arms and / or abdomen has efficacy and the same problems presented similarly by adhesives.
  • Testosterone use may be contraindicated in hypogonadic patients with prostate or breast carcinoma.
  • Testosterone replacement in addition to the aforementioned side effects, especially when administered at supraphysiological doses, can cause water retention, gynecomastia, cholestatic jaundice, liver damage, acne, priapism, aggressive behavior, and increased hematocrit.
  • bioidentical hormones Individual dosing that optimizes response and limits undesirable effects is possible when using bioidentical hormones, and the exact dose and most appropriate pharmaceutical form, such as the dermal form, may be formulated via the nasal route.
  • An example of the use of bioidentical testosterone in hormone therapy using bioidentical hormones is seen in US7563565 published 21/07/2009.
  • bioidentical hormone monodose such as micronized testosterone.
  • the use in the formulation of the present invention of bioidentical testosterone in its micronized form, finely divided to a powder, is essential for increasing the solubility and bioavailability of the drug, notably in the preparation of the preferred formulation in view of its application via the nasal route.
  • the hormonal active agent of the present invention is presented as a particulate powder in an average particle diameter range of less than 5 ⁇ obtained by laser diffraction.
  • Modern pharmacotechnics use particle size reduction of the active compound of formulations to obtain an increase in the specific surface of the powder, that is, the surface area to weight ratio. Both drug dissolution and absorption rates, content uniformity and stability of the pharmaceutical form are directly dependent on the degree of particle size variation, size distribution and interactions between solid surfaces.
  • the testosterone of the present invention in its micronized form has a high specific surface and thus dissolves with greater speed in the patient's medium of administration, which has as a differentiated technical effect with respect to known testosterone preparations of the state of the art. by promoting the absorption of the drug by passive diffusion.
  • the adjuvants chosen for the preparation of the formulation are not suitable, even if the solids have adequate particle sizes, the dissolution rate of the drug may be affected.
  • the set of devices constituting the pharmaceutical kit is characterized by a set of individual devices (1) containing low viscosity, high viscosity, micronized testosterone-based gel formulation to provide the a patient, whether female or male, precisely measured and physiologically appropriate unit doses of testosterone.
  • the device after use is immediately discarded by the user without residual hormone losses even when administered via the nasal route, due to the high viscosity of the formulation coupled with the air pumping system of the drug contained in the device, ensures the release of virtually all of your content.
  • Each device is provided with a hollow chamber (2), where the medicine is packed, and an air column area that acts as a plunger to expel the volume of medicine contained in the chamber (2).
  • Expulsion air chamber (3) provides user-pressurized air into the hollow chamber (2), which acts as compressed air in the face of passing through the neck (6) provided between the hollow chamber (2) and the inner tube (3).
  • Tear lines (8 - 9 - 12) are provided to facilitate the removal of each device from the card for use.
  • the formulation of the present invention in order to avoid the drawbacks of the art, for example making the hydrophobic formulation undesirable, since the chosen route of administration of the formulation of the present invention is nasal, the formulation was prepared as a gel using the semi-solid hormone. Other precautions have been observed so that particle size does not affect content uniformity since the testosterone dosage of the formulation of the present invention is significantly low, and thus tight control has been maintained in the preparation of the formulation, since such inconvenience would not occur as long as the interaction between the particles was ensured and the flow characteristics of the drug were maintained.
  • the nasal formulation of the present invention employed micronized bioidentical testosterone, with a mean diameter of 5 ⁇ , employed in a gel preparation at a dosage of 0, 08% w / w 3.33% w / w, containing testosterone in appropriate doses according to the formulation for female or male use respectively.
  • the formulation of the present invention is therefore provided for nasal delivery via a rigidly metered "ampoule” applicator device containing up to 200 mg of a micronized testosterone formulation.
  • Gels are defined as semi-solid systems composed of dispersions of small inorganic particles or large organic molecules enclosed by a liquid.
  • Nasal preparations are often used for the administration of drugs that need to be employed for both local and systemic effects.
  • the nasal route is the focus of interest because of the need to develop a non-oral and non-parenteral route for the absorption of biologically active testosterone from the formulation of the present invention.
  • Testosterone like other drugs, is subject to destruction by gastrointestinal fluids as it is intensely metabolized by the liver. Most testosterone-based medicines are now injected.
  • nasal route of administration for achieving systemic effects in certain drug preparations is known to be very satisfactory as the nasal mucosa is amenable to systemic absorption of certain non-peptide drugs, including testosterone.
  • the nose serves as an important barrier to the entry of bacteria into the lungs by acting as a protective mechanism of the organism. To this end, its surface is covered by a mucosa with a pH value between 5.5 and 6.5.
  • nasal tissue is highly vascularized, it becomes a suitable site for rapid and efficient systemic absorption.
  • a major advantage of this absorption pathway is that it avoids first pass metabolism through the liver.
  • the nasal preparation of the present invention has been designed to maintain bioidentical pH levels to those of the nasal mucosa where the formulation of the present invention will be administered.
  • Another essential feature that the formulation of the present invention had to take into account was that it was not irritating to the nasal mucosa, and mainly did not interfere with the ciliary movement that normally occurs in the nasal cavities, and would have as a function of driving the medicine for deeper airway regions for its full absorption.
  • Nasal gels are semi-solid preparations for nasal application and may be used to obtain local or systemic effect. Absorption of the drug is ensured to achieve the desired systemic effect of absorption of testosterone since the nose cavity has a capacity of approximately 20mL with a large surface area of about 180.00cm 2 , The desired absorption is ensured by the micro villi located along the pseudo stratified columnar epithelial cells of the nasal mucosa.
  • the formulation of the present invention is made from a reduced amount of micronized testosterone, preferably bioidentical testosterone, in dosage ranging from 0.05% w / w to 3.5% w / w, relative to the total weight of the gel formulation.
  • the semisolid form of micronized testosterone is provided in powders of less than 5 ⁇ .
  • Excipients constituted to promote the reach of the gel form of the formulation such as at least one thickener, chosen from colloidal silicon dioxide, polyvinyl alcohol hydroxyethylcellulose, sodium carboxymethylcellulose, starch, and gelatin, are further employed.
  • colloidal silicon dioxide is used which is already presented as a very fine amorphous submicroscopic powder, less than 15 ⁇ promoting optimal aggregation to testosterone in its micronized form.
  • the chosen viscosity agent is employed in a range of 2.5 to 4% by weight with respect to the total weight of the formulation.
  • the colloidal silicon dioxide viscosity agent whose pH according to USP 26 must be in the range 3 , 5 and 5,5 is effective in increasing the viscosity of the formulation when administered to the patient via the nasal route, which is particularly favorable for drug administration without loss of product dripping out of the user's nose.
  • the viscosity of the formulation of the present invention is thus within a range of 30,000 to 150,000 mPa * s.
  • the formulation of the present invention further provides for the use of a surfactant chosen from benzalkonium chloride, oleoyl macrogolglycerides, nonoxynol 10 (nonionic surfactant), polysorbate 80, sodium lauryl sulfate.
  • a surfactant chosen from benzalkonium chloride, oleoyl macrogolglycerides, nonoxynol 10 (nonionic surfactant), polysorbate 80, sodium lauryl sulfate.
  • N-9 Nonoxynol-9
  • oleoyl macrogolglyceride is preferred because of its best suitability for a gel formulation.
  • the surfactant of the present invention is employed in amounts ranging from 3.5 to 4.5%, and more preferably 4% of the total formulation weight.
  • An oily vehicle made up of vegetable oil is also envisaged for the better solubility of the hormone in an oily environment, while still considering that the more liquid formulation, such as an aqueous formulation, unlike the gel formulation. of the present invention, is more prone to runny nose of the user under nasal testosterone administration.
  • the vegetable oil employed as an oily or lipid carrier in the present invention may be one or a combination of oils selected from the group represented by cottonseed oil, sesame oil, castor oil, or castor oil; wheat germ oil, among others.
  • castor oil or castor oil is chosen for its favorable performance in the gel formulation of the present invention in view of its high concentration of unsaturated fatty acids.
  • Vegetable oil is employed in the present formulation in an amount ranging from 85 to 95%, and more specifically ranging from 88.67 to 93.42%,
  • Example IA - Gel formulation to be packaged in a single dose nasal device for employment by female patient. Testosterone concentration 0.16%.
  • Example 2 Gel formulation to be packaged in a single dose nasal device for use by a male patient. Testosterone concentration at 3.33%.
  • the graph in Figure 5 shows the pharmaceutically acceptable variants of the filled ampoule volumes and the mediator (y) of these variants per dose, compared to the same occurrence of pharmaceutical variants for the applied doses, demonstrating that the variations are minimum volume and volume applied. Keeping any ampoule volume versus applied volume losses below acceptable limits, it can be ensured that the proposed minimum dose delivery system to be administered to the patient therapeutically serves the purpose of the present invention.
  • the average dose dispensed was 149.34 mg and the standard deviation was 6.49 (max / min 158.5-134.4) with a delta of 24.1. These data show a high precision and accuracy of the dispensed doses in this device that was predicted to dispense 150mg of the formulation.
  • the main focus of the present invention therefore lies on the nasal administration of a minimal dose. of micronized testosterone, in a semi-solid gel formulation, to a patient in need of this drug by the use of an ampoule-shaped device with its constituent elements, anatomical parts and facilitating the fullest possible dispensation , of the medicament packaged in such a device.
  • a set of sequentially identifiable devices for controlling the administration of individual doses of testosterone constitutes the drug kit of the present invention, allowing the patient to organize and adhere to and control while minimizing the risk of loss of subsequent doses.
  • EP0150751 published 07/08/1985 discloses a liquid dispenser or pharmaceutical or cosmetic preparation having opposite side flaps on the dispenser body, thin parts to be fractured at the neck height and axially elongated to form and where the outlet opening of the pharmaceutical or cosmetic content of the dispenser is arranged.
  • the prior art dispenser is more specifically provided for ophthalmic preparation application whereby the thin and elongated neck where the discharge opening is arranged and the side flaps are more suitable for such application. Said side flaps are intended to assist the user to hold the device. The only break lines are provided to release the fluid discharge opening without any pumping aid from the dispenser contents. Thus, more viscous fluids, such as the present invention, are not adequately dispensed by this device, resulting in a random amount not retained in the container, which prevents the effective administration of the desired dose or prescribed for the patient's treatment.
  • US5761885 published on 09/06/1988 deals with a method of manufacturing a plastic container, which consists of a polyethylene or polypropylene ampoule in which a separate piston is manufactured, preferably made of polyfluoroethylene.
  • Said piston acts as a plunger pushing the contents of the ampoule into a discharge opening, when a rectangular area constituting a chamber is pressed pushing the air contained therein, which in turn pushes the plunger to move fluid from the ampoule into the opening.
  • discharge Said opening it is released by breaking a fragile area to be broken at the time of administration.
  • the ampoule is individual and is not provided as a set of devices for programmed administration of a viscous medicament, such as the device of the present invention.
  • WO2011001275 published 06/11/2011, refers to a single container made of two components of plastics material for use with pharmaceutical or cosmetic preparations, provided with a breakable element for the discharge opening release. fluid and a hollow monolithic body formed of a flexible plastics material having a concavity to be compressed to release the contents of the vial.
  • the prior art container is not intended to be provided as a set of units of a carton, constituting a monodose "KIT", and does not have an adjacent, non-integral pump element to the device body, to promote virtually complete emptying of the device by ensuring delivery of the intended dose to be administered to a patient, as proposed in the present invention.
  • Figure 1 is a front view of a carton or set of devices constituting the pharmaceutical testosterone administration kit for a hormone replacement therapy to a patient;
  • Figure 2 is a longitudinal section (B - B ' ) of a pharmaceutical kit card of Figure 1;
  • Figure 3 is a cross-sectional view of a device (A - A ' ) from the pharmaceutical kit card of Figure 1; and
  • Figure 4 is a perspective view of a carton or set of devices for nasal testosterone administration as shown in Figure 1.
  • the present invention is comprised of a set of devices in the form of a carton (1) for nasal administration of testosterone to a female and / or male patient in need for hormone replacement therapy.
  • Said card consists of an appropriate amount of unitary devices sequentially labeled.
  • each device is embossed on the underside of the tear tab (7) of the closure head (5) of the device.
  • the card (1) is formed of plastic such as low density polyethylene (LDPE). Said devices of the card (1) are provided with hollow body (2), and are obtained by extrusion molding.
  • LDPE low density polyethylene
  • Each device consists of a hollow body (2) into which the medicament is introduced under aseptic conditions prior to sealing the closure (5-7) of the hollow cylindrical body (2) of the device.
  • a closure head (5) is provided on the medicine discharge portion of the hollow body (2).
  • Said printhead (5) and tear tab (7) are anatomically arranged in the hollow body (2), in accordance with This allows the user to disconnect the device in a single simple two-finger movement from the adjacent ones, to which it was interconnected by means of a cut line (9).
  • the device unit of the Device Kit assembly (1) is provided to be filled to a height "H" with the micronized testosterone gel formulation so as to remain a residual internal area of the hollow device filled with trapped air and not filled with the medicine.
  • This air column properly calculated as a function of the height "H” of the device and the thickness "e", exerts a downward pressure that will press, like a plunger, the drug upon administration.
  • the height "H" of the medicinal product contained in the container is directly proportional to the volume of formulation to be contained in said hollow chamber (2).
  • the container is provided with a total internal volume of 250mg.
  • the volume of the drug packaged in said device ranges from a total of 158.5mg to a total of 134.4 mg, which corresponds to a range of about 61 to 72% of the total volume of the device to be filled with the hormone formulation to ensure that the air column provides positive pressure on the upper area of the gel formulation to fully push it down and out of the device at administration of the drug to the patient.
  • the dosage to be administered of the hormone is on average around 148.6 mg, it can be considered that the average mass of air capable of promoting the proper emptying pressure of the device is about 72 mg / 28, 27 mm 2 , or 2,546 mPa, since the hollow chamber dimension "e" of the device is about 6 mm.
  • total device emptying in addition to the viscosity index provided for in the gel formulation of micronized testosterone hormone, is ensured by providing an additional air pumping arrangement in the body of each unitary device of the present invention. , such as an isosceles, broad-based pyramidal trunk (3) extrusion chamber (3), extruded molded.
  • the walls of the tube (3) result from the extrusion operation at the time of molding, which are substantially thinner than the walls of the hollow container (2), so that when compressed by the user's fingers they produce an effect. pumping air contained in said chamber (3).
  • the expulsion or pumping chamber (3) has a height "B" substantially equal to the diameter "e" of the hollow cylindrical body (2) of the nasal delivery device, in which the hormone medicine is contained. the testosterone base.
  • V 2X (Si X B / 2)
  • Si is the area of the pyramidal base of the chamber (3)
  • FIG. 2 it is a longitudinal section BB ', which shows the trapezoidal air-discharge chambers (3), with a larger base (4), which are part of a set of devices. molded into a carton comprising a Kit (1) having a plurality of individual, separable elements provided for application of micronized testosterone-based drug monodoses.
  • Said device is configured such that the larger base of the expulsion chamber "L” is substantially equal to the distance "d" between the longitudinal axes of the devices, arranged in the form of a carton or packing kit of unitary elements. for the administration of the drug.
  • a median line joining identical parts of the device (13) indicates and facilitates demoulding of parts.
  • FIG. 3 there is shown a longitudinal section AA 'of an individual device, where the tear tab (7) and the closure head (5) of the device are joined by the weakening line (1). 8).
  • a neck (6) is provided between the hollow chamber (2) containing the medicated gel and the air expulsion chamber (3) so as to create a device acting as a pressure valve to provide greater pressure of the air contained in the chamber (3) to provide a flow of compressed air to the air pressure of the chamber (2) so that it acts as an air piston, carrier of the total volume of the hollow chamber contents (2), ensuring the total expulsion of the drug during its administration to the patient.
  • An upper flap (10), of larger surface and substantially thinner than the device and its hollow parts, is arranged externally and complementary to the device to allow it to be embossed thereon (14) , on each device, health information such as date and batch of manufacture of the drug and expiration date. Weakening or Tearing Lines
  • each flap 10 are disposed between each flap 10 and adjacent thereof to facilitate detachment of each device from its respective card.
  • Testosterone Gel Study Group Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab 2000; 85: 3020-3023.

Abstract

L'invention concerne une formulation pharmaceutique nasale de testostérone et un ensemble de dispositifs constituant un kit pharmaceutique sous forme de tablette, destiné à l'administration de testostérone par voie nasale, formé d'une pluralité de dispositifs d'application d'une dose unique ou monodose, mesurée thérapeutiquement. L'ensemble de dispositifs constituant le kit pharmaceutique est caractérisé par un ensemble de dispositifs individuels (1) contenant une formulation en gel à base de testostérone micronisée, à haute viscosité, à faible dosage en hormone, de manière à fournir à un patient, de sexes féminin ou masculin, des doses unitaires de testostérone précisément mesurées de physiologiquement appropriées. Après utilisation, le dispositif est immédiatement jeté par l'utilisateur, sans pertes résiduelles de l'hormone, y compris lors d'une administration par voie nasale, compte tenu de la haute viscosité de la formulation qui, associée au système de pompage d'air du médicament contenu dans le dispositif, assure la libération du contenu dans sa quasi-totalité. Chaque dispositif est doté d'une chambre creuse (2) où est conditionné le médicament, et d'une zone de colonne d'air qui agit comme un piston pour l'expulsion du volume de médicament contenu dans la chambre (2). La chambre à air (3) d'expulsion fournit de l'air mis sous pression par l'utilisateur à l'intérieur de la chambre creuse (2), agissant comme de l'air comprimé lorsqu'il est mis sous pression et passe par le col (6) situé entre la chambre creuse (2) et la chambre à air (3). Des lignes de ruptures (8 - 9 - 12) sont prévues pour faciliter le retrait de chaque dispositif de la tablette en vue d'une utilisation.
PCT/BR2016/050212 2015-08-28 2016-08-26 Formulation pharmaceutique nasale de testostérone et « kit » sous forme de tablette de dispositifs nasaux unitaires pour application de monodose de testostérone WO2017035619A1 (fr)

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BR102015020878A BR102015020878B1 (pt) 2015-08-28 2015-08-28 formulação farmacêutica nasal de testosterona e “kit” em forma de cartela de dispositivos nasais unitários para aplicação de monodose de testosterona.

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DE3244403A1 (de) * 1982-12-01 1984-06-07 Hansen, Gerhard, 7166 Sulzbach-Laufen Behaelter aus einem elastischen kunststoff
BR8101650U (pt) * 2001-03-15 2002-11-05 Equiplex Ind Farmaceutica Ltda Ampola em polietileno
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Publication number Priority date Publication date Assignee Title
CN112936934A (zh) * 2021-01-29 2021-06-11 重庆嘉涌电子有限公司 Vr眼镜框加工系统
CN112936934B (zh) * 2021-01-29 2022-08-23 重庆嘉涌电子有限公司 Vr眼镜框加工系统

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