Applicator system for applying a viscous liquid to the human skin

Abstract

The application relates to an applicator system (1) for applying a viscous liquid, in particular a transdermal pharmaceutical formulation, to the human skin comprising a metering dispenser (2) in turn comprising a container holding the viscous liquid and a pump (5) for metering the liquid and an applicator (3) detachably connected to the dispenser (2) and comprising an application surface (6) for receiving a metered amount of the liquid from the dispenser (2). The application surface (6) is convex.

Claims

1. An applicator system for applying a transdermal pharmaceutical formulation, comprising: a metering dispenser comprising a container for holding a supply of the formulation and a pump for dispensing a metered amount of the formulation, wherein the formulation is in a form of a viscous liquid; an applicator detachably connected to and enveloping the dispenser, wherein the applicator comprises a convex application surface for receiving a metered amount of the formulation from the dispenser, and the application surface is devoid of any aperture and porous region for metering the liquid to the application surface from the supply within; and a hygiene cap configured to cover the application surface.

2. The applicator system according to claim 1, wherein the application surface is rigid.

3. The applicator system according to claim 2, wherein the material forming the application surface has a Young's modulus of at least 1.5 GPa.

4. The applicator system according to claim 2, wherein the application surface is smooth.

5. The applicator system according to claim 1, wherein the dispenser has a metering accuracy of +/−15%, the dispenser dispenses the formulation in a range from 0.5 ml to 2.5 ml for each actuation, or both.

6. The applicator system according to claim 1, wherein the applicator doubles as a cap for the metering dispenser.

7. The applicator system according to claim 6, wherein the applicator comprises a sleeve to receive and secure the metering dispenser.

8. The applicator system according to claim 6, wherein the applicator has a total length of at least 6.5 centimeters, the applicator has at least 50% of the total length as a grip, or both.

9. The applicator system according to claim 1, wherein the application surface comprises a symbol, wherein the symbol marks an optimum location for placing the metered amount of the formulation onto the application surface.

10. The applicator system according to claim 1, wherein the viscous liquid has a viscosity of at least 3000 centipoise at 25 C.

11. The applicator system according to claim 1, wherein the formulation comprises at least one active agent and a solvent system present in an amount sufficient to solubilize the at least one active agent.

12. The applicator system according to claim 11, wherein the active agent is an androgen steroid hormone.

13. The applicator system according to claim 12, wherein the androgen steroid hormone is chosen from testosterone and a testosterone derivative.

14. The applicator system according to claim 13, wherein the testosterone is chosen from (8R,9S,10R,13S,14S,17S)-17-hydroxy-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17 dodecahydrocyclopentaphenanthren-3-one, testosterone enanthate, testosterone propionate, testosterone cypionate, testosterone phenylacetate, testosterone acetate, testosterone isobutyrate, testosterone buciclate, testosterone heptanoate, testosterone decanoate, testosterone undecanoate, testosterone caprate, testosterone isocaprate, 4-dihydrotestosterone, and combinations thereof.

15. The applicator system according to claim 13, wherein the testosterone derivative is chosen from methyl testosterone, testolactone, oxymetholone, and fluoxymesterone.

16. The applicator system according to claim 11, wherein the formulation comprises a C.sub.2 to C.sub.4 alkanol in an amount from about 5-50% wt, a polyalcohol in an amount from about 1-30% wt, a permeation enhancer in an amount from about 0.2-25% wt, a gelling agent in an amount from about 0.05-4% wt, a neutralizing agent in an amount from about 0.05-1% wt, and a chelating agent in an amount from about 0.001-5.0% wt.

17. The applicator system according to claim 16, wherein the C.sub.2 to C.sub.4 alkanol is ethanol and the polyalcohol is propylene glycol.

18. The applicator system according to claim 16, wherein the formulation further comprises 1%-2% wt testosterone, and a monoalkyl ether of diethylene glycol, wherein the formulation is substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters.

19. The applicator system according to claim 18, wherein the monoalkyl ether of diethylene glycol is diethylene glycol monoethyl ether.

20. The applicator system according to claim 18, wherein the formulation comprises 2% wt testosterone.

21. The applicator system according to claim 11, wherein the formulation comprises 1% wt-2% wt testosterone, 44.0% wt ethanol, 20.0% wt propylene glycol, and 5.0% wt diethylene glycol monoethyl ether, wherein the formulation is substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters.

22. The applicator system according to claim 11, wherein the formulation comprises 1 wt-2% wt testosterone, 44.0% wt ethanol, 20.0% wt propylene glycol, 5.0% wt diethylene glycol monoethyl ether, 1.20% wt carbomer, 0.35% wt triethanolamine, 0.06% wt edetate disodium and water (q.s.), wherein the formulation is substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters.

23. The applicator system according to claim 22, wherein the formulation consists of 1% wt-2% wt testosterone, 44.0% wt ethanol, 20.0% wt propylene glycol, 5.0% wt diethylene glycol monoethyl ether, 1.20% wt carbomer, 0.35% wt triethanolamine, 0.06% wt edetate disodium and water (q.s.).

24. A kit comprising: (A) the applicator system according to claim 1, and (B) instructions for use thereof.

25. The kit according to claim 24, wherein the applicator system dispenses 1.25 ml of the formulation for each actuation of the metered dispenser, and wherein the dispensed formulation consists of 2% wt testosterone, 44.0% wt ethanol, 20.0% wt propylene glycol, 5.0% wt diethylene glycol monoethyl ether, 1.20% wt carbomer, 0.35% wt triethanolamine, 0.06% wt edetate disodium and water (q.s.).

Description

(1) 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.

(2) FIG. 1 is a perspective view of an applicator and dispenser according to the present invention.

(3) FIG. 2 is an exploded view of the applicator shown in FIG. 1.

(4) FIGS. 3A to 3D illustrate steps of a method of applying a viscous liquid to the human skin.

(5) FIGS. 1 and 2 show an applicator system 1 for applying a transdermal pharmaceutical formulation to the human skin, in accordance with the present invention. The system comprises a metering dispenser 2 and an applicator 3 clamped onto the dispenser.

(6) The dispenser 2 is a so-called airless metering dispenser comprising a cylindrical housing 4 and a metering pump 5. The housing contains a pouch (not shown), e.g. made of an aluminium and polyethylene multilayer foil, to ensure protection of the liquid inside against oxygen and UV rays. The metering pump is actuated by pushing and delivers a constant and precise dose of, e.g. 1.25 ml+/−5% with each actuation. Suitable airless metering pumps are commercially available, e.g. from Lablabo.

(7) The applicator comprises a convex, continuous application surface 6 for receiving a metered amount of the viscous liquid from the dispenser 2. In this example, the surface is part of an insert 7 which is clamp fitted and/or welded into the distal end of a sleeve 8. The insert is made of a plastomer, e.g. acrylonitrile butadiene styrene (ABS), having a Young's modulus of e.g. 3 GPa. The application surface is smooth, with a texture of stage 21 (measured in accordance with VDI 3400 standard) or smoother.

(8) The surface 6 is provided with a symbol 9 to indicate the optimum location for metering the viscous liquid onto it. In this example, the symbol comprises a drop and a circle surrounding the drop to indicate the boundary of the optimum location.

(9) As shown in FIG. 1, the applicator doubles as a cap for the dispenser. To this end, the sleeve 8, with its proximal end, fits clampingly about the dispenser 2.

(10) 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 grip 10. The grip ends at some distance from the application surface to provide a barrier between the two.

(11) To prevent any residues from rubbing off on other surfaces, e.g. towels or persons, such as family members of the user of the applicator system, a hygiene cap 11, made of e.g. polycarbonate, is provided to cover the application surface after use.

(12) FIGS. 3A to 3D illustrate the typical steps of a method of applying a gel to the human skin with the present applicator. The hygiene cap is removed from the application surface (FIG. 3A) and the applicator is removed from the dispenser (FIG. 3B), in no specific order. A single dose of gel is metered onto the application surface (FIG. 3C) and the dose is applied onto the skin, preferably spreading the gel over a wider area (FIG. 3D) to facilitate uptake. If a double or triple amount is indicated, these latter two steps can be repeated accordingly.

(13) The applicator system according to the present invention allows use of standard metering pumps, made in large quantities and thus providing good accuracy at relatively low costs, and enables substantially complete transfer of the amount of viscous liquid metered onto the application surface from that surface to the skin.

EXPERIMENTS

(14) A phase 2, open-label, sequential dose escalation study in 18 adult hypogonadal males, i.e. males having a baseline morning serum testosterone concentration <300 ng/dL, was carried out to evaluate the pharmacokinetics of three volumes (1.25, 2.50 and 3.75 mL) of a testosterone gel formulation. The gel formulation consisted of 2% wt of testosterone, 44% wt of ethanol, 20.0% wt of propylene glycol, 5% wt of monoethyl ether of diethylene glycol, 1.20% wt of carbomer, 0.35% wt of triethanolamine, 0.06% wt of edetate disodium 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 hand application.

(15) Objectives of the study in adult hypogonadal males were to:

(16) 1. investigate the steady-state pharmacokinetics of total testosterone (and dihydrotestosterone (DHT)) after 7 days of treatment with each of 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;

(17) 2. investigate the steady-state pharmacokinetics of total testosterone (and DHT) after 7 days of treatment with one volume (2.50 mL) of the gel applied by hand to the shoulder/upper arm.

(18) The gel, when administered by an applicator of the invention, was delivered in aliquots of 1.25 mL (23 mg/pump actuation). A total of 1.25 mL (23 mg, 1 pump actuation), 2.50 mL (46 mg, 2 pump actuations) or 3.75 mL (70 mg, 3 pump actuations) were administered per application.

(19) Subjects applied 2.50 mL of the gel by hand for 7 days, followed by a 7-day washout period. After the washout, subjects applied three volumes of the gel (1.25, 2.50 and 3.75 mL) in a sequentially escalating fashion with an applicator of the invention, with no washout period between treatment phases (each seven days). Total testosterone and DHT blood levels were determined pre-application and at 2, 4, 6, 8, 10, 12 and 24 hours post-application on 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 AUCτ (Area Under the Curve), Cmax (maximum concentration), Cavg (average concentration), and Estimated Responder Rate (percentage of patients having a concentration of total testosterone in the therapeutic range, 300 to 1050 ng/dL). The patient was also asked to state his preference for a particular method of application.

(20) The duration of the treatment period for each subject from the screening visit to the last visit was approximately 70 days.

(21) The results are shown in Tables 1 and 2 below.

(22) TABLE-US-00001 TABLE 1 Different doses with applicator according to invention AUCτ C.sub.ave C.sub.max Treatment [ng .Math. h/dL] [ng/dL] [ng/dL] dose (Mean ± SD) (Mean ± SD) (Mean and range) 1.25 mL 5785 ± 1236 241 ± 52  398 225-690  2.50 mL 7714 ± 2664 321 ± 111 641 233-1410 3.75 mL 10353 ± 3820  431 ± 159 1025  215-3150

(23) TABLE-US-00002 TABLE 2 Comparison application with applicator and by hand AUCτ C.sub.avg C.sub.max Estimated [ng .Math. h/dL] [ng/dL] [ng/dL] Responder Treatment (Mean ± SD) (Mean ± SD) (Mean and range) Rate 2.50 mL 7714 ± 2664 321 ± 111 641 55.6 with 233-1410 applicator 2.50 mL 7829 ± 2759 326 ± 115 520 50.0 by hand 231-2020

(24) Table 1 shows a substantially proportional increase of AUCτ, Cmax, and Cavg with increased dosage, confirming that the applicator provides accurate transfer of the metered amounts of the gel from the application surface to the skin. This proportionality can be employed to relatively quickly establish the correct dosage for a particular patient.

(25) Table 2 shows a reduced variability of AUCτ, Cmax, and Cavg, when the gel is applied with the applicator instead of by hand. This too confirms more accurate transfer. Further, Table 2 shows a higher responder rate indicating an increased efficacy of the gel when it is applied with the applicator according to the present invention.

(26) Also, 15 of the 18 subjects preferred use of the applicator over application by hand, i.e. the applicator provides an incentive for correct and efficacious administration of the gel.

(27) The invention is not restricted to the above-described embodiments which can be varied in a number of ways within the scope of the claims.