DMEU ENHANCER

Abstract

The present invention relates to a dosage form for transdermal administration of at least one active pharmaceutical ingredient with a logP≥3, comprising at least one penetration accelerator, wherein the at least one penetration accelerator comprises dimethylethylene urea, the use of such a dosage form as a medicament, and the use of dimethylethylene urea as penetration accelerator to increase the skin penetration of active pharmaceutical ingredients with a logP≥3.

Claims

1. A dosage form for transdermal administration of at least one active pharmaceutical ingredient, comprising at least one active pharmaceutical ingredient with a logP≥3 and at least one penetration accelerator, characterised in that the at least one penetration accelerator comprises dimethylethylene urea.

2. The dosage form according to claim 1, characterised in that the dosage form comprises a transdermal therapeutic system, a gel, a lotion, an ointment and/or a cream.

3. The dosage form according to claim 1, characterised in that the at least one active pharmaceutical ingredient with a logP≥3 has a water solubility of less than 0.01 mg/ml (at 20° C.).

4. The dosage form according to claim 1, characterised in that the at least one active pharmaceutical ingredient is selected from the group consisting of hypnotics, sedatives, antiepileptics, analeptics, psychoneurotropic drugs, neuroleptics, neuro muscle blockers, antispasmodics, antihistamines, antiallergics, cardiotonics, antiarrhythmics, diuretics, hypotensives, vasopressors, antitussives, expectorants, analgesics, thyroid, hormones, sexual hormones, glucocorticoid hormones, antidiabetics, antitumour drugs, antibiotics, chemotherapeutics, narcotics, anti Parkinson drugs, anti Alzheimer drugs and/or triptans.

5. The dosage form according to claim 1, characterised in that the dosage form represents a transdermal therapeutic system, characterised in that the transdermal therapeutic system has a backing and a matrix layer containing the at least one active pharmaceutical ingredient with a logP≥3.

6. The dosage form according to claim 5, characterised in that the at least one active penetration accelerator dimethylethylene urea is provided in the matrix layer in an amount of from 10 to 30 wt. % in relation to the active ingredient containing matrix layer.

7. The dosage form according to claim 5, characterised in that the matrix layer comprises at least one polymer selected from the group consisting of polyacrylates and/or polymethacrylates, natural and/or synthetic rubbers, polysiloxanes, styrene butadiene block copolymers, isobutylene and/or ethylene vinyl acetate copolymers.

8. The dosage form according to claim 5, characterised in that the dosage form represents a transdermal therapeutic system which is formed as membrane systems, wherein the at least one active pharmaceutical ingredient is present in the matrix layer in a reservoir, from which the at least one active pharmaceutical ingredient can be dispensed through a porous control membrane covering the reservoir.

9. The dosage form according to claim 8, characterised in that the control membrane comprises a polymer film, wherein the polymer forming the basis of the polymer film is selected from polyethylene, polypropylene, polyurethane, silicone and/or copolymers of ethylene and vinyl acetate.

10. The dosage form according to claim 5, characterised in that the matrix layer comprises further excipients selected from the group consisting of plasticisers, crystallisation inhibitors, stabilisers, antioxidants and/or neutralisers.

11. The dosage form according to claim 5, characterised in that the at least one active pharmaceutical ingredient is present in the matrix layer in an amount of from 0.1 to 50 wt. %, in relation to the weight of the matrix layer.

12. The dosage form according to claim 5, characterised in that the transdermal therapeutic system has a loading with the at least one active pharmaceutical ingredient of greater than 6 mg/cm2.

13. The dosage form according to claim 5, characterised in that exclusively dimethylethylene urea is contained as penetration accelerator in the dosage form.

14. The dosage form according to claim 1, for use as a medicament.

15. A method for the administration of at least one active pharmaceutical ingredient with a logP≥3 in combination with at least one penetration accelerator, wherein the penetration accelerator comprises dimethylethylene urea.

16. The dosage form according to claim 5, characterised in that the at least one active penetration accelerator dimethylethylene urea is provided in the matrix layer in an amount of from 12 to 25 wt. in relation to the active-ingredient-containing matrix layer.

17. The dosage form according to claim 5, characterised in that the at least one active penetration accelerator dimethylethylene urea is provided in the matrix layer in an amount of from 15 to 18 wt. % in relation to the active-ingredient-containing matrix layer.

Description

DESCRIPTION OF THE DRAWINGS

[0101] FIG. 1: Comparison of in vitro permeation profiles of progesterone in various transdermal enhancer systems.

[0102] FIG. 2: Comparison of in vitro permeation profiles of felodipine in various transdermal enhancer systems.

[0103] FIG. 3: Comparison of in vitro permeation profiles of curcumin in various transdermal enhancer systems.

[0104] FIG. 4: Comparison of in vitro permeation profiles of olanzapine in various transdermal enhancer systems.

[0105] FIG. 5: TTS as a single-layer matrix system with a self-adhesive polymer matrix based on acrylate type Durotak™ 2054 (Henkel, Düsseldorf) and the non-adhesive polymer type Eudragit™ E100 (Röhm, Darmstadt), as is preferably used for the administration of olanzapine according to Example 4. [0106] (1) Carrier film, for example made of polyethylene terephthalate [0107] (2) Single-layer adhesive matrix polymer; contains the active ingredient, enhancer, and polymer excipient. [0108] (3) Protective film, for example made of polyethylene; is removed before application.

[0109] FIG. 6: Schematic representation of a transdermal application system for saturated active ingredient enhancer solutions with occlusion effect, as preferably used for Examples 1 to 3 for the administration of progesterone, felodipine and curcumin. [0110] (4) Backing, for example PET film coated with silicone bio PSA # 4302 (Dow Corning) [0111] (5) Self-adhesive adhesive ring (=adhesive eye) for example made of polyethylene foam and synthetic rubber as adhesive, for fixing the backing (for example Duplocoll® 5009 from Lohmann, Neuwied, (Germany)). [0112] (6) Textile and needled non-woven fabric, preferably with a weight of up to 150 g/m.sup.2, with regard to absorption behaviour suitable for the absorption of the active ingredient preparation (solution, gel, ointment) for example made of polyester or viscose, such as Paramoll® N260/150 (Lohmann, Neuwied (Germany)) or TWE non-woven 120 (TWE, Dierdorf (Germany)). The application area is, for example, 1.165 cm.sup.2. [0113] (7) Self-adhesive polyurethane film as control membrane and for fixing the system to the skin, for example Suprasorb® (Lohmann & Rauscher, Neuwied (Germany)). [0114] (8) Diffusion membrane, here preferably native human skin.

[0115] FIG. 7:

[0116] Comparison of in vitro permeation profiles of olanzapine in various transdermal enhancer systems.

[0117] FIG. 8:

[0118] TTS as a single-layer matrix system with a self-adhesive polymer matrix based on a silicone adhesive of the type Bio-PSA™ 7-4301 (Dow Corning Corp., Midland, Mich., USA), as preferably used for the administration of olanzapine according to Example 5. [0119] (1) Carrier film, for example made of polyethylene terephthalate. [0120] (2) Single-layer adhesive matrix polymer; contains the active ingredient, enhancer, and polymer excipient. [0121] (3) Protective film, for example made of polyethylene; is removed before application.

[0122] The invention will be described in greater detail hereinafter on the basis of non-limiting examples.

EXAMPLES

[0123] The following test series with the various penetration accelerators and for the selected active ingredients were carried out in the context of a typical in vitro permeation using Franz diffusion cells. The used acceptor medium was replaced completely for a new one at predetermined replacement times, and the content of permeated active ingredient amount in these acceptor solutions was determined by means of HPLC. As a comparison, the best penetration accelerators from each test series were used, applied as saturated active ingredient penetration accelerator solutions in Examples 1 to 3 and in Example 4 as a transdermal therapeutic system.

Example 1

[0124] Active ingredient: Progesterone (logP 3.87)

[0125] Skin model: Human skin; dermatomised at 500 μm, (female abdomen, date of birth 1968).

[0126] Acceptor: Phosphate buffer pH 5.5+0.1% NaN.sub.3+3% gamma-cyclodextrin as solubiliser, which is needed because progesterone is very lipophilic and therefore almost insoluble in water.

[0127] Loading: saturated solution of progesterone in DMEU, donor volume 150 μl as direct application to the epidermal skin surface (corresponds to a loading concentration of c=27.7 mg/cm.sup.2, which is quite high compared to other penetration accelerators, for example only 6.4 mg/cm.sup.2 for dimethyl isosorbide and 2.1 mg/cm.sup.2 for dipropylene glycol).

[0128] The cumulative amount of permeated progesterone at the predetermined exchange times is shown in FIG. 1.

[0129] The penetration acceleration of DMEU is clearly superior to that of the comparative compounds. In relation to the 52 h value or the flux rate in steady state, the effect of DMEU is greater by a factor of about 10 (dimethyl isosorbide) or 13 (dipropylene glycol).

Example 2

[0130] Active ingredient: Felodipine (logP 3.86)

[0131] Skin model: Human skin; dermatomised at 500 μm, (female abdomen, date of birth 1985).

[0132] Acceptor: Phosphate buffer pH 5.5+0.1% NaN.sub.3+2 wt. % Tween® 20 as solubiliser, which is needed because felodipine is very lipophilic and therefore almost insoluble in water.

[0133] Loading: Saturated solution of felodipine in DMEU, donor volume 150 μl as direct application to the epidermal skin surface (corresponds to a loading concentration of c=6.0 mg/cm.sup.2, which is quite high compared to others).

[0134] The cumulative amount of permeated felodipine at the predetermined replacement times is shown in FIG. 2.

[0135] The penetration acceleration of DMEU is clearly superior to that of the comparative compounds. In relation to the 24h value or the flux rate in steady state, the effect of DMEU is greater by a factor of about 10 (dimethyl isosorbide) or 4 (dipropylene glycol).

Example 3

[0136] Active ingredient: Curcumin (test active ingredient; logP 3.62)

[0137] Skin model: Human skin; dermatomised at 500 μm, (female abdomen, date of birth 1979).

[0138] Acceptor: Phosphate buffer pH 5.5+0.1% NaN.sub.3+2 wt. % Tween® 20 as solubiliser, which is needed because curcumin is very lipophilic and therefore almost insoluble in water.

[0139] Loading: Saturated solution of curcumin in DMEU, donor volume 150 μl as direct application to the epidermal skin surface (corresponds to a loading concentration of 12.75 mg/cm.sup.2, which is very high compared to that of just 1.29 mg/cm.sup.2 for dimethyl isosorbide).

[0140] The cumulative amount of permeated curcumin at the predetermined replacement times is shown in FIG. 3.

[0141] The penetration acceleration of DMEU is clearly superior to that of the comparative compound. In relation to the 112h value or the flux rate in steady state, the effect of DMEU is greater than the effect of dimethyl isosorbide by a factor of about 5.

Example 4

[0142] Active ingredient: Olanzapine (logP 4.1)

[0143] Skin model: Human skin; non-dermatomised, full skin (female abdomen, date of birth 1967).

[0144] Acceptor: Phosphate buffer pH 5.5+0.1% NaN.sub.3+2 wt. % Tween® 20 as solubiliser, which is needed because olanzapine is very lipophilic and therefore almost insoluble in water.

[0145] Loading: Active ingredient loading 10 wt. % in the transdermal therapeutic system, corresponding to 6 mg/cm.sup.2 (At a wet-extraction line thickness of 3000 μm). This is very high compared to the transdermal therapeutic system with Eutanol G as penetration accelerator with only 0.26 mg/cm.sup.2 loading.

[0146] Loading system: Transdermal therapeutic system as a single-layer matrix system with a self-adhesive polymer matrix based on the acrylate type Durotak™ 2054 (Henkel, Düsseldorf) and the non-adhesive polymer type Eudragit™ E100 (Röhm, Darmstadt) in a ratio of 4:1 as excipient with 18 wt. % DMEU as penetration accelerator.

[0147] The cumulative amount of permeated curcumin at the predetermined replacement times is shown in FIG. 4.

[0148] The penetration acceleration of DMEU is clearly superior to that of the comparative compound. In relation to the 72 h value or the flux rate in steady state, the effect of DMEU is greater than the effect of Eutanol G by a factor of about 3.6.

Example 5

[0149] Active ingredient: Olanzapine (logP 4.1)

[0150] Skin model: Human skin; non-dermatomised, full skin (female abdomen, date of birth 1967).

[0151] Acceptor: Phosphate buffer pH 5.5+0.1% NaN.sub.3+2 wt. % Tween® 20 as solubiliser, which is needed because olanzapine is very lipophilic and therefore almost insoluble in water.

[0152] Loading: Active ingredient loading 10 wt. % in the transdermal therapeutic system, corresponding to 6.47 mg/cm.sup.2 (At a wet-extraction line thickness of 3000 μm). This is very high compared to the transdermal therapeutic system with Eutanol G as penetration accelerator with only 0.26 mg/cm.sup.2 loading.

[0153] Loading system: Transdermal therapeutic system as a single-layer matrix system with a self-adhesive polymer matrix based on silicone type BIO-PSA™ 7-4301 (Dow Corning Corp., Midland, Mich., USA) with 18 wt. % DMEU as penetration accelerator (see FIG. 8).

[0154] The cumulative amount of permeated olanzapine at the predetermined replacement times is shown in FIG. 7.

[0155] The penetration acceleration of DMEU is clearly superior to that of the comparative compound. In relation to the 72 h value or the flux rate in steady state, the effect of DMEU is greater than the effect of Eutanol G by a factor of about 2.8.

Example 6

[0156] Active ingredient: Olanzapine (logP 4.1)

[0157] Skin model: Human skin; non-dermatomised, full skin (female abdomen, date of birth 1985).

[0158] Acceptor: Phosphate buffer pH 5.5+0.1% NaN.sub.3+2 wt. % Tween® 20 as solubiliser, which is needed because olanzapine is very lipophilic and therefore almost insoluble in water.

[0159] Loading: Active ingredient loading 20 wt. % in the transdermal therapeutic system, corresponding to 8.5 mg/cm.sup.2 at a wet extraction line thickness of 1200 μm. This loading is very high compared to the transdermal therapeutic system with Eutanol G as penetration accelerator with only 0.26 mg/cm.sup.2 loading.

[0160] Loading system: Transdermal therapeutic system as a single-layer matrix system with a self-adhesive polymer matrix based on silicone type BIO-PSA™ 7-4301 (Dow Corning Corp., Midland, Mich., USA) with 30 wt. % DMEU as penetration accelerator (see FIG. 8).

[0161] The cumulative amount of permeated olanzapine at the predetermined replacement times is shown in FIG. 7.

[0162] The penetration acceleration of DMEU is clearly superior to that of the comparative compound. In relation to the 72 h value or the flux rate in steady state, the effect of DMEU is greater than the effect of Eutanol G by a factor of about 6.