HK1018200A - Transdermal therapeutic system for administering testosterone - Google Patents

Description

Transdermal therapeutic system for testosterone

According to the current state of the art, testosterone and testosterone derivatives are mainly used for hormone replacement therapy in men. In addition to primary and secondary sexual hypofunction, other indications are spermatorrhea, dyspareunia and premature ejaculation. Its trials for osteoporosis in men are also currently progressing; see, e.g., Rapads et al, Trends in Osteoporosis, 1(1989) 1-9.

Since the first-pass effect (first-pass effect) of testosterone is high, when it is orally administered, the efficacy is greatly reduced. Thus, in alternative therapies, administration is either in orally effective esters, such as testosterone undecanoate, or in injectable depot formulations, such as testosterone enanthate and testosterone propionate.

Those results have led to several significant starting points for the development of Transdermal Therapeutic Systems (TTS). With this system, high doses of active ingredient in oral administration can be avoided, painful injections are prevented and the blood levels can be well regulated and well matched to the circadian rhythm of about one day.

For example, US-A-4704282 describes A transdermal therapeutic system having A carrier film (reinforcing means), an active ingredient reservoir and A removable cover film (release liner). The active ingredient reservoir may be in the form of an aqueous or non-aqueous gel or polymer material in which the active ingredient is dissolved at a concentration which is not higher than the saturation concentration of the active ingredient in the matrix material. The matrix may include a permeation enhancer. The active ingredient to be administered may be, for example, testosterone. Of course, if testosterone is present in A less than saturated solution in A transdermal therapeutic system, the presence of A permeation enhancer is inevitable to obtain satisfactory blood levels, see WO-A-9210231, page 11, line 33.

US-A-4849224 proposes A transdermal therapeutic system whose active ingredient reservoir is formed by A carrier film (support foil) and A porous membrane. The active ingredient may be testosterone or testosterone esters. In addition to the active ingredient, a penetration enhancer may be provided. The usefulness of the known system is, of course, primarily taken into account within the limits of the active ingredient reservoir, which is formed by the laminate of the carrier film and the membrane, which is adhered to the skin by means of the adhesive ring. Since the adhesive is provided in a ring-like form, it is practical to provide a window through which the active ingredient and the permeation enhancer can permeate through the membrane to the skin without the permeation enhancer making unnecessary contact with the adhesive, since an additional ring-like sealing member is also provided for protecting the adhesive. The size of the known area is limited since only limited adhesion can be obtained in the annular adhesive area.

WO-A-9210231-EP-A-0562041 is based on the prior art of US-A-4849224, according to which an adhesive ring is provided on the skin for the adhesion of A transdermal therapeutic system; see WO-A-9210231, page 13, line 18/19. Alternatively, a bottom adhesive layer below the reservoir (a bottom adhesive layer unconnected below the reservoir) and also a reservoir adhesive coating (an adhesive skin of the reservoir) are recommended. However, since the use of A penetration enhancer is essential to the administration of testosterone according to the prior art, it is not clear how WO-A-9210231 prevents unwanted penetration of the penetration enhancer if the adhesive is not provided in A ring form.

WO-A-9503764, WO-A-9423707 and US-A-5152997 also describe transdermal therapeutic systems for the administration of testosterone, those systems being reservoir systems in which the active ingredient is present in A less than saturated form and in which penetration accelerators are also provided. Those known teachings correspond to the prior art as discussed in WO-A-9210231 (page 11, line 33).

The problem underlying the present invention is to provide a transdermal therapeutic system for the administration of testosterone or testosterone derivatives which does not require the use of permeation enhancers and which ensures satisfactory levels of active ingredients in the blood.

For this purpose, the invention proposes a Transdermal Therapeutic System (TTS) for administering testosterone or testosterone derivatives as an active ingredient, having

A carrier film (support foil),

-a reservoir for storing the liquid to be dispensed,

-an alcohol carrier for the active ingredient,

an adhesive layer for contacting the system with the skin, and

a removable cover film (release liner), wherein

-the system does not comprise a penetration enhancer,

the active ingredient is present in saturated form in the carrier of the active ingredient, and

-providing a film between the reservoir and the adhesive layer

The film does not control the release of the active ingredient, but the adhesive layer controls the release of the active ingredient.

The present invention is based on the surprising observation that satisfactory levels of active ingredient in the blood can be or are particularly achieved when the active ingredient is present in A saturated form in A carrier for the active ingredient, whereas WO-A-9210231 requires that the active ingredient is in an unsaturated state.

According to the invention, testosterone esters, in particular testosterone enanthate, testosterone cypionate, testosterone propionate or testosterone undecanoate, or lower alkyl testosterone, in particular methyltestosterone, can be used as testosterone derivatives.

The active ingredient may be present in the form of a complex with a cyclodextrin or a cyclodextrin derivative, in particular β -cyclodextrin.

The film may be a polyethylene or polypropylene film.

According to a preferred embodiment, the reservoir is formed by a carrier film and a membrane.

According to the invention, the alcoholic carrier for the active ingredient may be ethanol or a low molecular weight monohydric alcohol, such as isopropanol, or a low molecular weight polyol, such as propylene glycol, or a mixture thereof.

For the adhesive layer according to the invention, pressure-sensitive, alcohol-resistant adhesives based on, for example, polyurethanes, isobutenes, polyvinyl ethers, silicones or acrylates can be used.

The silicone-based adhesive may be a silicone adhesive based on two main components: a polymer or binder, especially a polysiloxane, and a tackifying resin. Silicone adhesives are generally formulated with a cross-linking agent for the adhesive, typically a high molecular weight polydiorganosiloxane, and a suitable organic solvent is employed to create a three-dimensional silicate structure with the resin. The mixture of the resin and the polymer is the most important factor for changing the physical properties of the polysiloxane adhesive; see, for example, Sobieski et al, "Silicone Pressure Sensitive Adhesives," Handbook of Pressure Sensitive Adhesive Technology, 2nd ed., pp.508-517(D.Satas, ed.), Van Nostrand Reinhold, New York (1989).

Suitable pressure sensitive silicone adhesives are commercially available under the trademark BIO-PSA X7.

A further example of a silicone-based pressure-sensitive adhesive is trimethylated silica which has been treated with a polydimethylsiloxane having terminal trimethylsiloxy groups.

The acrylate-based adhesive may be a homopolymer, copolymer or terpolymer composed of various acrylic acid derivatives.

For example, the acrylate polymer may be a polymer of one or more monomers of acrylic acid and other copolymerizable monomers. The acrylate polymer may also comprise copolymers of acrylic acid and/or methacrylic acid alkyl esters and/or copolymerizable secondary monomers or monomers having functional groups. The adhesion of the resulting acrylate polymer can be varied by varying the amount of each of the typical monomers added as monomers. Typically, the acrylate polymer is comprised of at least 50% by weight of an acrylate, methacrylate, alkyl acrylate or methacrylate, 0-20% of a functional monomer copolymerizable with the acrylate, and 0-40% of a different monomer.

Given below are acrylate monomers that may be used with acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecyl methacrylate.

For example, functional monomers copolymerizable with the above acrylates, methacrylates, alkyl acrylates or alkyl methacrylates are useful, such as acrylic acid, methacrylic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, t-butylaminoethyl acrylate and methacrylate, methoxyethyl acrylate and methacrylate.

Additional details and examples of Pressure Sensitive acrylates suitable for use in the present invention are described in Satas handbook of Pressure Sensitive Adhesive Technology "Acrylic Adhesive" (Satas Pressure Sensitive Adhesive technical Manual "Acrylic Adhesive"), 2nd ed., pp.396-456(D.Satas, ed.), Van Nostrand Reinhold, New York (1989).

Suitable pressure sensitive acrylates are commercially available.

The transdermal therapeutic system of the present invention may additionally comprise alpha-tocopherol or alpha-tocopherol derivatives and/or viscosity increasing agents, such as hydroxypropylcellulose.

The invention is explained in more detail below with reference to the figures and examples.

According to fig. 1, the transdermal therapeutic system of the invention may comprise a carrier film (support foil) (1), which may be slightly convex and forms a reservoir (2) together with a membrane (3), the membrane (3) not controlling the release of the active ingredient. According to fig. 1, applied to the membrane (3) is an adhesive layer (5), the adhesive layer (5) controlling the release of the active ingredient. The adhesive layer (5) is further covered with a cover film (release liner) (6), and the cover film is removed before administration. According to this figure, the carrier film (1) can be provided with an annular bead (4) in the peripheral region of the adhesive layer (5) and the film (3) can be sealed in the contact region.

Examples

For the adhesive layer, a silicone-based pressure-sensitive adhesive (trimethylated silica which has been treated with a polydimethylsiloxane having trimethylsiloxy groups as terminal groups; the thickness of the layer when dry is about 35 to 45 μm; the weight per unit surface area is about 50 to 60g/m²). A PET covering film (thickness: about 75 μm; weight per unit surface area: about 100 g/m) was coated with a coating apparatus²) Applied to a silicone adhesive. Then, a microporous polyethylene film or a microporous polypropylene film (heat-sealable; having a thickness of about 50 μm; a weight per unit surface area of about 10 g/m) was laminated on the coated covering film²) To form a laminate of cover film, adhesive and film. The laminate was then welded to a polyester carrier film (aluminium was vapourised with a polyolefin sealant layer (heat sealable) and a thickness of about 70 mu) using a sealer (with welding rings)m) are welded in such a way that gaps for the introduction of the active ingredient are retained. The loadable Transdermal Therapeutic System (TTS) is loaded, for example, with a Hamilton syringe or a tube pump (tube pump) equipped with a cannula, with the following active ingredient solutions:

composition of the active ingredient solution of each TTS:

mg/TTS Testosterone 60.5696% ethanol 157.18 propylene glycol 48.11 α -tocopherol 56.78 hydroxypropyl cellulose 5.98 the density of the active ingredient solution 0.91285g/cm in a fill volume of 360 μ l of the reservoir 328.61²The filling amount of the reservoir is 328.6mg

After filling, the filling gap is welded. The loaded transdermal therapeutic system is output by perforation with a perforator.

Claims (8)

1. A Transdermal Therapeutic System (TTS) for the administration of testosterone or a testosterone derivative as an active ingredient has

A carrier film (support foil),

-a reservoir for storing the liquid to be dispensed,

-an alcohol carrier for the active ingredient,

an adhesive layer for contacting the system with the skin, and

a removable cover film (release liner), wherein

-the system does not comprise a penetration enhancer,

the active ingredient is present in saturated form in the carrier of the active ingredient, and

-providing a film between the reservoir and the adhesive layer, which film does not control the release of the active ingredient, but the adhesive layer controls the release of the active ingredient.

2. System according to claim 1, characterized in that as testosterone derivative a testosterone ester, especially testosterone enanthate, testosterone cypionate, testosterone propionate or testosterone undecanoate, or a lower alkyl testosterone, especially methyltestosterone.

3. The system according to claim 1 or 2, characterized in that the active ingredient is present in the form of a complex with a cyclodextrin or a cyclodextrin derivative, in particular β -cyclodextrin.

4. A system as claimed in any preceding claim, wherein the reservoir is formed from a carrier film and a membrane.

5. A system according to any of the preceding claims, characterized in that ethanol or a low molecular weight mono-or polyol, especially propylene glycol, or a mixture thereof, is used as alcoholic carrier for the active ingredient.

6. A system according to any of the preceding claims, characterized in that the adhesive of the adhesive layer is a pressure-sensitive, alcohol-resistant, polyurethane-, isobutylene-, polyvinyl ether-, silicone-or acrylate-based adhesive.

7. A system according to any preceding claim characterised in that the carrier of the active ingredient further comprises alpha-tocopherol or an alpha-tocopherol derivative.

8. A system according to any preceding claim characterised in that the carrier for the active ingredient further comprises a viscosity increasing agent such as hydroxypropyl cellulose.