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  • 专利说明
  • 权利要求
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    • 专利摘要:
    APPLICATOR SYSTEM FOR APPLICATION OF VISCOSE LIQUID TO HUMAN SKIN. The present invention relates to an applicator system (1) for applying a viscous liquid, in particular a transdermal pharmaceutical formulation, to human skin comprising a dosing dispenser (2) in turn comprising a container containing the viscous liquid and a pump (5) for dosing the liquid and an applicator (3) removably connected to the dispenser (2) and comprising an application surface (6) to receive a metered amount of the liquid from the dispenser (2). The application surface (6) is convex.
    公开号:BR112013033061B1
    申请号:R112013033061-9
    申请日:2012-06-20
    公开日:2021-02-09
    发明作者:Dario Carrara；John Edward Burke；David George Robinson；Robert Peter Fernall
    申请人:Ferring B.V.；
    IPC主号:
    专利说明:

    [0001] The present invention relates to an applicator system for applying a viscous liquid, in particular a transdermal pharmaceutical formulation, to human skin comprising, a dosing dispenser in turn comprising a container containing the viscous liquid and a dosing pump the liquid and an applicator removably connected to the dispenser and comprising an application surface to receive a metered amount (dose) of the liquid from the dispenser.
    [0002] As explained in WO 2008/083423, topical liquids such as sunscreens or medicated liquids were presented in compressible containers or in containers with a pump operated by a finger by means of which a portion of the liquid is deposited on the surface to be be treated or on the free hand for subsequent application to the surface to be treated. In either case, the liquid is spread over the surface to be treated with the free hand, which results in the fact that the liquid is applied to a surface other than the surface to be treated. It is not always acceptable for the free hand to be treated with a medicated liquid since the volume dispensed from the container can be the prescribed dose. This is particularly the case when the liquid is intended to have a therapeutic effect at the prescribed dose.
    [0003] It is often desirable to offer an implement that temporarily retains the liquid to be applied to the surface to be treated. Implements tend to suffer from the tension between temporarily retaining the liquid and having to release the liquid on the surface to be treated. Implements such as brushes and sponges are effective in spreading the liquid over the surface to be treated, however they tend to retain a volume of residual liquid after application of the implement to the surface to be treated. The volume retained can vary from application to application and thus it is difficult to accurately apply a metered dose to a surface to be treated using an implement such as a brush or sponge.
    [0004] In WO 2008/083423, it is considered desirable to provide an implement that is capable of applying a liquid to a surface to be treated while minimizing the retention of residual liquid, and also an implement that is easy to clean after used. In WO 2008/083423, an implement is offered to apply a volume of liquid to a surface to be treated including a support means on which a defined receptacle is mounted, a reservoir space that receives the volume of liquid, the receptacle having a base and a wall. The wall is substantially transversal to the base and has a work surface that is used to spread the liquid over the surface to be treated. At least the wall is resiliently deformable so that in use the work surface maintains contact with the surface to be treated when the liquid is being spread.
    [0005] The applicator according to WO 2008/083423 is intended to apply low viscosity liquids, typically having a viscosity of "less than 300 centipoise and generally about 150 centipoise".
    [0006] It is an objective of the present invention to offer an improved applicator system that allows the exact transfer of measured amounts of viscous liquids, for example, gels, from the application surface to the skin.
    [0007] Therefore, in the applicator system according to the present invention, the application surface is convex.
    [0008] In one embodiment, the entire application surface is convex. In another embodiment, the application surface is continuous and in particular does not comprise orifices or porous regions for distributing the liquid to the surface of the volume contained therein.
    [0009] In another embodiment, the application surface is rigid, that is, non-deformable. More specifically, it is preferable that the material forming the surface has a Young's modulus of at least 1.5 GPa, preferably in the range of 2 to 4 GPa.
    [00010] The application surface according to the present invention enables substantially complete transfer of the metered viscous liquid to the skin.
    [00011] To further improve the transfer of the viscous liquid from the application surface to the skin, it is preferable that the application surface is smooth, preferably having a stage 21 texture (measured according to the VDI 3400 standard) or smoother .
    [00012] The applicator according to the present invention can be used in combination with standard metering pumps, made in large quantities and thus providing good accuracy at relatively low costs. As the applicator surface provides a substantially complete transfer of the metered viscous liquid, the precision of the metering pump extends to the effective application.
    [00013] In one embodiment, the dispenser has a dispensing accuracy of +/- 15%, preferably +/- 10% of the stipulated amount and / or is configured to deliver a dosed amount per application in the range of 0.5 to 2.5 ml. In one embodiment, the dispenser delivers a metered amount per application in the range of 1.0 to 2.0 ml. In another embodiment, the dispenser delivers a metered amount of 1.25 ml per application.
    [00014] In a particularly practical modality, the applicator bends as a lid for the dispenser and / or comprises a sleeve for receiving and securing the dispenser, for example, by means of tightening or by means of a screw connection or bayonet.
    [00015] In another embodiment, the applicator has a total length of at least 6.5 centimeters, preferably at least 9 centimeters, and preferably no more than 15 centimeters and / or at least 50% of the applicator's length is suitable as a claw. Therefore, the applicator is sufficiently compressed to wrap and hold the dispenser and allow efficient and comfortable handling by the user. In one embodiment, the applicator has a total length of about 12 centimeters.
    [00016] In another embodiment, the dispenser contains a viscous liquid having a viscosity of at least 3000 centipoise (at 25 ° C), preferably in the range of 5000 to 50,000 centipoise, more preferably in the range of 17000 to 24000 centipoise. Thus, the viscous liquid, for example, a gel, will adhere to the application surface, reducing the risk that the gel distributed on the surface will drain for example as a result of the movements made by the user.
    [00017] The system is especially suitable for applying a viscous liquid comprising testosterone or a derivative thereof.
    [00018] Where testosterone is mentioned, it should be understood as indicating the androgen-like steroid hormone 17-β-hydroxyandrostenone also called (8R, 9S, 10R, 13S, 14S, 17S) -17-hydroxy-10,13-dimethyl- 1,2,6,7,8,9,11,12,14,15,16,17 dodecahydrocyclopenta [a] fenantren-3-one (CAS Registry Number 58-22-0).
    [00019] Examples of other androgens that can be administered with the applicator system of the invention include, but are not limited to, any testosterone esters (such as enanthate, propionate, cypionate, phenylacetate, acetate, isobutyrate, buciclate, heptanoate, decanoate esters, testosterone undecanoate, caprate and isocaprate), 4-dihydrotestosterone, and any pharmaceutically acceptable testosterone derivatives such as, for example, methyl testosterone, testolactone, oxymetholone and fluoxymesterone. These androgens can be used alone or in combinations of two or more of them.
    [00020] The system is also suitable for the application of transdermal pharmaceutical formulations comprising at least one active agent and a solvent system present in an amount sufficient to solubilize the at least one active ingredient.
    [00021] In one embodiment, the viscous liquid is a formulation comprising an active agent and a solvent system as specified in US 7,198,801. In a specific embodiment, the active agent in the formulation is testosterone or a derivative thereof.
    [00022] Examples of preferred testosterone formulations to be administered with an applicator of the invention are specified in PCT application No. PCT / EP2012 / 050695.
    [00023] In one embodiment, the viscous liquid is a formulation comprising a C2-C4 alkanol in an amount between about 5 - 50% by weight, polyalcohol in an amount between about 1 - 30% by weight, diethylene monoalkyl ether glycol in an amount between about 0.2 - 25% by weight, gelling agent in an amount between about 0.05 - 4% by weight, neutralizing agent in an amount between about 0.05 -1% by weight, and chelating agent in an amount between about 0.001 - 5.0% by weight.
    [00024] Unless expressly specified to the contrary, the term "comprising" is used in the context of this application to indicate that other members may optionally be present in addition to the explicitly mentioned members. We contemplate, however, as a specific embodiment of the present invention that the term "comprising" encompasses the possibility that no other member is present. In other words, for the purposes of this modality, "comprising" is interpreted as having the meaning "consisting of".
    [00025] The following detailed description discloses specific and / or preferred variants of the individual aspects of the invention. The present invention also contemplates as particularly preferred embodiments those which are generated by combining two or more of the specific and / or preferred variants described for two or more aspects of the present invention.
    [00026] Unless expressly specified to the contrary, all indications of relative quantities in this application are made in terms of weight / weight. Indications of the relative quantities of a component characterized by a generic term are intended to indicate the total quantity of all variants or specific members covered by that generic term. If it is specified that a particular component defined by a generic term is present in a certain relative quantity, and if that component is still characterized as being a specific variant or member covered by the generic term, then other variants or members covered by the generic term should not additionally be present in quantities that cause the total relative quantity of components covered by the generic term to exceed the specified relative quantity, more preferably, in that case, absolutely no other variant or member covered by the generic term is present.
    [00027] The term "C2 to C4 alkanol" as used in this report should be interpreted as covering one or more C2 to C4 alkanes substituted with a hydroxy group (-OH). In one embodiment, an alkanol comprised in a formulation to be administered by an applicator of the invention is one or more selected from the group consisting of ethanol, isopropanol and n-propanol. In another embodiment, said alkanol is ethanol. In another embodiment, said alkanol is ethanol present in an amount of about 44.0% by weight.
    [00028] The term "polyalcohol" as used in this report should be interpreted as covering one or more of a C2 to C6 alkane or C2 to C6 alkene, substituted with two or more hydroxy groups.
    [00029] In some embodiments, the polyalcohol comprised in a formulation to be administered by an applicator of the invention is one or more selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol, and hexylene glycol. In one embodiment, the polyalcohol is propylene glycol. In another embodiment, the polyalcohol is propylene glycol present in an amount of about 20.0% by weight.
    [00030] The term "diethylene glycol monoalkyl ether" as used in this report should be interpreted as encompassing one or more diethylene glycols substituted with a C1 to C6 alkyl ether.
    [00031] In one embodiment, diethylene glycol monoalkyl ether comprised in a formulation to be administered by an applicator of the invention is one or both of diethylene glycol monoethyl ether (DGME) and diethylene glycol monomethyl ether. In another embodiment, the diethylene glycol monoalkyl ether is diethylene glycol monoethyl ether. In yet another embodiment, said diethylene glycol monoalkyl ether is diethylene glycol monoethyl ether in an amount of about 5.0% by weight.
    [00032] The term "gelling agent" as used in this report should be interpreted as covering any agent capable of altering the viscosity of a formulation. The gelling agent used in a formulation to be administered by an applicator of the invention can be one or more selected from the group including: carbomer, carboxyethylene or polyacrylic acid such as carbomer or carbopol 980NF (CARBOPOLTM 980 NF) or 940 NF, 981 or 941 NF, 1382 or 1342 NF, 5984 or 934 NF, ETD 2020, 2050, 934P NF, 971P NF, 974P NF, and Noveon AA-1 USP, cellulose derivatives such as ethyl cellulose (EC), hydroxypropylmethylcellulose (HPMC), ethyl- hydroxyethylcellulose (EHEC), carboxymethylcellulose (CMC), hydroxypropylcellulose (HPC) (different grades of Klucel), hydroxyethylcellulose (HEC) (grades of Natrosol), HPMCP 55, and grades of Methocel, natural gums such as arabic gum, xanthan gum, gum guar, and alginates, polyvinylpyrrolidone derivatives such as Kollidon grades, polyoxyethylene-polyoxypropylene copolymers such as Lutrol F grades 68 and 127, chitosan, polyvinyl alcohols, pectins, and degrees of veegum. A tertiary amine, such as triethanolamine or trolamine, can also be included in the formulation to thicken and neutralize the system.
    [00033] In one embodiment, the gelling agent comprised in a formulation to be administered by an applicator of the invention is a carbomer. Carbomer refers to a class of acrylic acid homopolymers with a high molecular weight, which are cross-linked with any of several polyalcohyl alkyl ethers. Non-limiting examples of carbomers are carbomer 940, carbomer 973, carbomer 980NF, carbomer C980NF (where the number indicates the average molecular weight of the polymer chains. In a particular embodiment, the gelling agent comprised in a formulation to be administered by an applicator of the The invention is C980NF carbomer In yet another embodiment, the gelling agent is C980NF carbomer in an amount of 1.20% by weight.
    [00034] The term "neutralizing agent" as used in this report should be interpreted as encompassing one or more agents capable of neutralizing an acidic or basic component of a formulation to be administered by an applicator of the invention to obtain a stable and homogeneous formulation. Non-limiting examples of a neutralizing agent include: diethylamine, diisopropylamine, a tertiary amine such as triethanolamine or tromethamine, tetrahydroxypropylethylendiamine, and alkalis such as KOH or NaOH solution.
    [00035] In one embodiment, a neutralizing agent comprised in a formulation to be administered by an applicator of the invention is triethanolamine (also interchangeably called trolamine). In another embodiment, the neutralizing agent is triethanolamine in an amount of about 0.35% by weight.
    [00036] The term "chelating agent" as used in this report should be interpreted as encompassing one or more agents that complex and secrete residual traces of free multivalent cations susceptible to cause physical degradation of a gel matrix (thus causing loss of viscosity and decomposition of the formulation).
    [00037] In one embodiment, a chelating agent comprised in a formulation to be administered by an applicator of the invention is disodium edetate. In another embodiment, the chelating agent is disodium edetate in an amount of about 0.06% by weight.
    [00038] As used in this report the term "solvent" can cover any type of solvent suitable for use in transdermal formulations and can be the same or different from any other component of a formulation to be administered by an applicator of the invention, as already detailed Upper. In one embodiment, a solvent comprised in a formulation to be administered by an applicator of the invention is water.
    [00039] In one embodiment, a formulation to be administered by an applicator of the invention comprises 2% by weight of testosterone, C2 to C4 alkanol, polyalcohol, and monoalkyl ether of diethylene glycol, where said formulation is substantially free of fatty alcohols. long chain, long chain fatty acids, and long chain fatty esters.
    [00040] Omitting long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters provides formulations that do not have the unpleasant smell, irritation, and / or greasy texture caused by formulations that include one or more of these compounds, resulting in greater patient collaboration.
    [00041] "Long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters" as used in this report should be interpreted as encompassing fatty alcohols and fatty acids having a straight or branched carbon chain having 8 or more atoms carbon, and esters thereof, that is, fatty esters having a linear or branched acid moiety having 8 or more carbon atoms or having a linear or branched alcohol moiety having 8 or more carbon atoms.
    [00042] "Substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters" as used in this report should be interpreted as comprising fatty alcohols, fatty acids and / or fatty esters in a total amount less than to about 0.1% by weight.
    [00043] In one embodiment, a formulation to be administered by an applicator of the invention comprises 2% by weight of testosterone, 44.0% by weight of ethanol, 20.0% by weight of propylene glycol, and 5.0% by weight. weight of diethylene glycol monoethyl ether, where said formulation is substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters.
    [00044] In another embodiment, a formulation to be administered by an applicator of the invention comprises 2% by weight of testosterone, 44.0% by weight of ethanol, 20.0% by weight of propylene glycol, 5.0% by weight. weight of diethylene glycol monoethyl ether, 1.20% by weight of carbomer, 0.35% by weight of triethanolamine, 0.06% by weight of disodium edetate and water (qs) where said formulation is substantially free of fatty alcohols long-chain, long-chain fatty acids, and long-chain fatty esters.
    [00045] In another embodiment, a formulation to be administered by an applicator of the invention consists of 2% by weight of testosterone, 44.0% by weight of ethanol, 20.0% by weight of propylene glycol, 5.0% by weight of diethylene glycol monoethyl ether, 1.20% by weight of carbomer, 0.35% by weight of triethanolamine, 0.06% by weight of disodium edetate and water (qs).
    [00046] In yet another embodiment, a formulation to be administered by an applicator of the invention comprises 1% by weight of testosterone, C2 to C4 alkanol, polyalcohol, and diethylene glycol monoalkyl ether, wherein said formulation is substantially alcohol-free long-chain fatty acids, long-chain fatty acids, and long-chain fatty esters.
    [00047] In another embodiment, a formulation to be administered by an applicator of the invention comprises 1% by weight of testosterone, 44.0% by weight of ethanol, 20.0% by weight of propylene glycol, and 5.0% by weight of diethylene glycol monoethyl ether, wherein said formulation is substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters.
    [00048] In another embodiment, a formulation to be administered by an applicator of the invention comprises 1% by weight of testosterone, 44.0% by weight of ethanol, 20.0% by weight of propylene glycol, 5.0% by weight. weight of diethylene glycol monoethyl ether, 1.20% by weight of carbomer, 0.35% by weight of triethanolamine, 0.06% by weight of disodium edetate and water (qs) where said formulation is substantially free of fatty alcohols long-chain, long-chain fatty acids, and long-chain fatty esters.
    [00049] In another embodiment, a formulation to be administered by an applicator of the invention consists of 1% by weight of testosterone, 44.0% by weight of ethanol, 20.0% by weight of propylene glycol, 5.0% by weight of diethylene glycol monoethyl ether, 1.20% by weight of carbomer, 0.35% by weight of triethanolamine, 0.06% by weight of disodium edetate and water (qs).
    [00050] In some embodiments, a formulation to be administered by an application system of the invention further comprises at least one buffering agent, a wetting agent, a humectant, a surfactant, an antioxidant, an emollient, or a buffer.
    [00051] In a specific embodiment, the invention offers an applicator system for transdermally administering testosterone or a derivative of it to a patient in need of it, for example, for use in the treatment of a disease or disorder associated with the endogenous production of testosterone.
    [00052] "Diseases and disorders associated with endogenous testosterone production" should be interpreted as encompassing any disease or disorder that is directly or indirectly related to a condition of a mammalian individual where endogenous testosterone production is either reduced or substantially non-existent or ceased. Diseases and disorders associated with endogenous testosterone production refer to hormonal disorders such as, but not limited to, hypogonadism, female sexual disorder, hypoactive sexual disorder, and adrenal insufficiency.
    [00053] A viscous liquid, in particular a transdermal pharmaceutical formulation, can be topically applied by an application system of the invention to any part of the body, such as, but without limitation, the chest, thigh, inner thigh, abdomen, the shoulder, the upper claw, the upper torso, the back, the neck, the feet, the hands, the armpits, or scrotum. In one embodiment, a formulation in the form of a gel is applied to an area of skin from about 100 cm2 to about 1500 cm2.
    [00054] In another aspect the invention offers a kit comprising at least one application system of the invention comprising a formulation comprising testosterone as detailed above, and instructions for using it. In one embodiment, the instructions include at least the steps that the applicator must be removed from the dispenser, a dose of gel must be dosed on the application surface, and the dose must be applied on the skin.
    [00055] In one embodiment, a kit of the invention comprises an applicator system that is adapted to dispense a predetermined measured amount of said testosterone formulation. In a specific embodiment, the predetermined amount is 1.25 ml per application.
    [00056] In yet another specific embodiment, the application system of the invention dispenses 1.25 ml by applying a formulation consisting of 2% by weight of testosterone, 44.0% by weight of ethanol, 20.0% by weight of propylene glycol, 5.0% by weight of diethylene glycol monoethyl ether, 1.20% by weight of carbomer, 0.35% by weight of triethanolamine, 0.06% by weight of disodium edetate and water (qs).
    [00057] To enable a better understanding of the background of the present invention, we draw attention to the following patent publications.
    [00058] US 2005/0054991 relates to a dosing device for topically administering a pharmaceutical formulation directly to a mammal's skin. The device comprises a housing capable of storing at least one unit dose of a pharmaceutical formulation; an applicator adapted to topically administer a unit dose of the pharmaceutical formulation directly to the skin; and a trigger capable of dosing a single unit dose of the pharmaceutical formulation from a first position in which the unit dose is stored in the box to a second position in which the single unit dose is outside the device on the applicator so that the single dose unit can be administered topically.
    [00059] US 2007/0000946 relates to a dispenser for dispensing creamy medications comprising a cylinder, a base having a threaded rod extending from it, an elevator having at least one flexible seal that engages the cylinder , and an applicator cap with holes to spread the cream on the user's skin.
    [00060] EP 1 514 492 relates to a device for storing and dispensing a cosmetic product, comprising a refillable unit with a product distributed from a container. The refillable unit has an application unit, for example, a sponge.
    [00061] US 2007/0166361 relates to formulations for transdermal or transmucosal administration of an active agent such as estradiol.
    [00062] WO 2009/064762 discloses a dispenser including a body defining a supply chamber in it to retain a volume of a composition. The dispenser also includes an application portion having a front side with a concave application surface arranged on the outside and being large enough to receive the skin of a patient for application of the composition to it, and a conduit that allows the fluid communication of the chamber. supply with the application surface to distribute the composition to the application surface from the supply chamber.
    [00063] WO 2006/005135 discloses a container including a receptacle (number 6 in the Figures of WO 2006/005135) for holding a substance, drug or liquid, and having an opening 7 for receptacle 6 through which the substance it can be dispensed and having a circular and domed spreading surface 15 adjacent to the opening for spreading and precise distribution of a thin layer of liquid over an area of the skin. In the embodiment shown in Figure 15, the spreading surface 15 is slightly convex with rounded edges and a circular shape. The receptacle 6 preferably retains between 50μl and 500μl of liquid having a viscosity of approximately 2.5 centipoises at an ambient temperature of 20 ° C.
    [00064] WO 2007/140542 discloses an applicator (number 2 in the Figures of WO 2007/140542) for dispensing a lotion from a dispensing device 1. The applicator includes a receptacle 13 for receiving a metered volume of lotion dispensed from the dispensing device 1. The receptacle 13 includes a retractable reservoir space 15. The retraction of the reservoir space 15 causes the lotion to pass through a passage formed by the holes 18 in an outer member 14. An outer surface 21 of the outer member 14 provides a spreading surface, preferably substantially convex, for spreading the lotion over the surface to be treated 20 of the user.
    [00065] In the context of the present invention, the term "viscous liquid" includes, but is not limited to, gels, emulsions, creams, lotions and pastes.
    [00066] The invention will now be explained in more detail with reference to the drawings, which schematically show a preferred embodiment according to the present invention.
    [00067] Figure 1 is a perspective view of an applicator and dispenser according to the present invention.
    [00068] Figure 2 is an exploded view of the applicator shown in Figure 1.
    [00069] Figures 3A to 3D illustrate the steps of a method of applying a viscous liquid to human skin.
    [00070] Figures 1 and 2 show an applicator system 1 for applying a transdermal pharmaceutical formulation to human skin, in accordance with the present invention. The system comprises a dispenser dispenser 2 and an applicator 3 attached to the dispenser.
    [00071] Dispenser 2 is a so-called airless dispenser comprising a cylindrical housing 4 and a metering pump 5. The housing contains a pouch (not shown), for example, made of a multilayer sheet of aluminum and polyethylene, to ensure the protection of the liquid inside against oxygen and UV rays. The metering pump is driven by pressure and delivers a constant and accurate dose of, for example, 1.25 ml +/- 5% with each actuation. Suitable airless metering pumps are commercially available, for example, at Lablabo.
    [00072] The applicator comprises a continuous and convex application surface 6 to receive a metered amount of the viscous liquid from the dispenser 2. In this example, the surface is part of an insert 7 which is clamped and / or welded at the end distal of a sleeve 8. The insertion is made of a plastomer, for example, acrylonitrile butadiene styrene (ABS), having a Young modulus of for example 3 GPa. The application surface is smooth, with a 21 stage texture (measured according to the VDI 3400 standard) or smoother.
    [00073] Surface 6 is provided with a symbol 9 on it to indicate the ideal location for measuring viscous liquid. In this example, the symbol comprises a drop and a circle surrounding the drop to indicate the limit of the ideal location.
    [00074] As shown in Figure 1, the applicator bends as a lid for the dispenser. For this purpose, the sleeve 8, with its proximal end, fits tightly around the dispenser 2.
    [00075] In this example, the applicator has a length of 118 millimeters and approximately 90% of the length of the sleeve is provided with an elastomeric claw 10. The handle ends at some distance from the application surface to provide a barrier between the two.
    [00076] To prevent any residues from splashing onto other surfaces, for example, towels or people, such as family members of the user of the applicator system, a hygienic cover 11, made for example of polycarbonate, is provided to cover the application surface after use. use.
    [00077] Figures 3A to 3D illustrate the typical steps of a method of applying a gel to human skin with the present applicator. The hygienic cover is removed from the application surface (Figure 3A) and the applicator is removed from the dispenser (Figure 3B), in no specific order. A single dose of gel is measured on the application surface (Figure 3C) and the dose is applied to the skin, preferably spreading the gel over a much larger area (Figure 3D) to facilitate absorption. When double or triple the quantity is indicated, these last two steps can therefore be repeated.
    [00078] The applicator system according to the present invention allows the use of traditional metering pumps, made in large quantities and, therefore, providing good accuracy at relatively low costs, and allows the substantially complete transfer of the amount of viscous liquid measured over the application surface from that surface to the skin. Experiences
    [00079] A phase 2, open label, sequential dose escalation study in 18 adult hypogonadal males, ie, men having a morning baseline serum testosterone concentration <300 ng / dL, was performed to assess the pharmacokinetics of three volumes (1.25, 2.50 and 3.75 mL) of a gel testosterone formulation. The gel formulation consisted of 2% by weight of testosterone, 44% by weight of ethanol, 20.0% by weight of propylene glycol, 5% by weight of diethylene glycol monoethyl ether, 1.20% by weight of carbomer, 0.35% by weight of triethanolamine, 0.06% by weight of disodium edetate and water (hereinafter "the gel"). It was administered to the shoulder / upper arm either with the applicator shown in the Figures and described above or by application with the hand.
    [00080] The objectives of the study in adult hypogonadic men were: 1. to investigate the steady-state pharmacokinetics of total testosterone (and dihydrotestosterone (DHT)) after 7 days of treatment with each of the three volumes (1.25, 2.50 and 3.75 ml) of the gel applied with an applicator of the invention to the shoulder / upper arm; 2. Investigate the steady-state pharmacokinetics of total testosterone (and DHT) after 7 days of treatment with a volume (2.50 mL) of the gel applied by hand to the shoulder / upper arm.
    [00081] The gel, when administered by an applicator of the invention, was distributed in 1.25 ml aliquots (23 mg / pump drive). A total of 1.25 mL (23 mg, 1 pump drive), 2.50 mL (46 mg, 2 pump drives) or 3.75 mL (70 mg, 3 pump drives) were administered per application.
    [00082] The subjects applied 2.50 ml of the gel by hand for 7 days, followed by a wash period of 7 days. After washing, the subjects applied three volumes of the gel (1.25, 2.50 and 3.75 ml) in a sequentially staggered manner with an applicator of the invention, with no washing period between the treatment phases (seven days each). Blood levels of total testosterone and DHT were determined before application and after 2, 4, 6, 8, 10, 12 and 24 hours of application at visits 4 (2.50 mL, hand), 7 (1.25 mL , applicator), 9 (2.50 mL, applicator) and 11 (3.75 mL, applicator) for the determination of AUCT (Area under the Curve), Cmax (maximum concentration), Cavg (average concentration), and estimated index of respondents (percentage of patients having a total testosterone concentration in the therapeutic range, 300 to 1050 ng / dL). The patient was also asked to say which particular method of application he preferred.
    [00083] The duration of the treatment period for each individual from the screening visit to the last visit was approximately 70 days.
    [00084] The results are shown in Tables 1 and 2 below.



    [00085] Table 1 shows a substantially proportional increase in AUCT, Cmax, and Cavg with increased dosage, confirming that the applicator provides an accurate transfer of the measured amounts of the gel from the application surface to the skin. This proportionality can be used to establish the correct dosage for a particular patient relatively quickly.
    [00086] Table 2 shows a reduced variability of AUCt, Cmax, and Cavg, when the gel is applied with the applicator and not with the hand. This also confirms a more accurate transfer. In addition, the Table shows a higher rate of respondents indicating an increased effectiveness of the gel when it is applied with the applicator according to the present invention.
    [00087] Also, 15 of the 18 individuals preferred to use the applicator instead of the application by hand, that is, the applicator offers an incentive for the correct and effective administration of the gel.
    [00088] The invention is not restricted to the modalities described above which can be varied in numerous ways within the scope of the claims.
    权利要求:
    Claims (21)
    [0001]
    1. Applicator system (1) for applying a viscous liquid, in particular a transdermal pharmaceutical formulation, to human skin comprising a dispenser dispenser (2) in turn comprising a container containing the viscous liquid and a pump (5) for dosing the liquid and an applicator (3) removably connected to the dispenser (2) and comprising an application surface (6) to receive a metered amount of liquid from the dispenser (2), characterized by the fact that the application surface (6) is convex and continuous, and a hygienic cover (11) is provided to cover the application surface (6).
    [0002]
    2. Application system (1), according to claim 1, characterized by the fact that the application surface (6) is rigid.
    [0003]
    3. Applicator system (6), according to claim 2, characterized by the fact that the material forming the application surface (6) has a Young's modulus of at least 1.5 GPa, preferably at least 2, 0 GPa.
    [0004]
    4. Application system (1) according to claim 2 or 3, characterized in that the application surface (1) is smooth, preferably having a stage 21 or smoother texture.
    [0005]
    5. Applicator system (1) according to any of the preceding claims, characterized by the fact that the dispenser (2) has a dispensing accuracy of +/- 15%, preferably +/- 10%, and / or it is configured to deliver a metered amount per application in the range of 0.5 to 2.5 ml.
    [0006]
    6. Applicator system (1) according to any one of the preceding claims, characterized by the fact that the applicator (3) bends as a lid for the dispenser (2).
    [0007]
    7. Applicator system (1) according to claim 6, characterized in that the applicator (3) comprises a sleeve (8) for receiving and securing the dispenser (2).
    [0008]
    8. Applicator system (1) according to claim 7, characterized in that the applicator (3) has a total length of at least 6.5 centimeters, preferably at least 9 centimeters and / or at least 50% the length of the applicator (3) are suitable as a claw (10).
    [0009]
    9. Application system (1) according to any one of the preceding claims, characterized by the fact that the application surface (6) comprises a symbol (9) to mark the ideal location for dispensing the viscous liquid.
    [0010]
    10. Applicator system (1) according to any one of the preceding claims, characterized by the fact that the viscous liquid has a viscosity of at least 3000 centipoise (at 25 ° C), preferably in the range of 5000 to 50000 centipoise.
    [0011]
    11. Applicator system (1) according to any one of the preceding claims, characterized by the fact that the viscous liquid contains testosterone or a derivative thereof.
    [0012]
    12. Application system (1) according to any one of the preceding claims, characterized in that the pharmaceutical formulation comprises at least one active agent and a solvent system present in an amount sufficient to solubilize the at least one active agent.
    [0013]
    13. Applicator system (1), according to claim 12, characterized by the fact that the at least one active agent is testosterone or a derivative thereof.
    [0014]
    14. Applicator system (1) according to claim 12 or 13, characterized in that the formulation comprises alkanol in an amount between about 5 - 50% by weight, polyalcohol in an amount between about 1 - 30% by weight, permeation enhancer in an amount between about 0.2 - 25% by weight, gelling agent in an amount between about 0.05 - 4% by weight, neutralizing agent in an amount between about 0.05 - 1% by weight, and chelating agent in an amount between about 0.001 - 5.0% by weight.
    [0015]
    15. Applicator system (1), according to claim 14, characterized by the fact that the formulation comprises 1% by weight - 2% by weight of testosterone, C2 to C4 alkanol, polyalcohol, and diethylene glycol monoalkyl ether, in that said formulation is substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters.
    [0016]
    16. Applicator system (1), according to claim 15, characterized by the fact that the formulation comprises 1% by weight - 2% by weight of testosterone, 44.0% by weight of ethanol, 20.0% by weight of propylene glycol, and 5.0% by weight of diethylene glycol monoethyl ether, wherein said formulation is substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters.
    [0017]
    17. Applicator system (1), according to claim 16, characterized by the fact that the formulation comprises 1% by weight - 2% by weight of testosterone, 44.0% by weight of ethanol, 20.0% by weight propylene glycol, 5.0% by weight of diethylene glycol monoethyl ether, 1.20% by weight of carbomer, 0.35% by weight of triethanolamine, 0.06% by weight of disodium edetate and water (qs), wherein said formulation is substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters.
    [0018]
    18. Applicator system (1), according to claim 17, characterized by the fact that the formulation consists of 1% by weight - 2% by weight of testosterone, 44.0% by weight of ethanol, 20.0% by weight weight of propylene glycol, 5.0% by weight of diethylene glycol monoethyl ether, 1.20% by weight of carbomer, 0.35% by weight of triethanolamine, 0.06% by weight of disodium edetate and water (qs) .
    [0019]
    19. Application system (1) according to claims 15 to 18, characterized in that the formulation comprises 2% by weight of testosterone.
    [0020]
    20. Kit characterized by the fact that it comprises an applicator system (1), as defined in any of the preceding claims, and instructions for its use.
    [0021]
    21. Kit according to claim 20, characterized by the fact that it is adapted to dispense 1.25 ml by applying a formulation consisting of 2% by weight of testosterone, 44.0% by weight of ethanol, 20.0 % by weight of propylene glycol, 5.0% by weight of diethylene glycol monoethyl ether, 1.20% by weight of carbomer, 0.35% by weight of triethanolamine, 0.06% by weight of disodium edetate and water ( qs).
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    法律状态:
    2018-03-13| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-12-11| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-07-16| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2020-03-24| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-12-08| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-02-09| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 20/06/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201161501292P| true| 2011-06-27|2011-06-27|
    EP11171533.0|2011-06-27|
    EP11171533|2011-06-27|
    US61/501,292|2011-06-27|
    PCT/EP2012/061784|WO2013000778A1|2011-06-27|2012-06-20|Applicator system for applying a viscous liquid to the human skin|
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