WO2006034902A1

WO2006034902A1 - Pharmaceutical compositions of alpha-dihydroergocryptine for transdermal and/or transmucosal use

Info

Publication number: WO2006034902A1
Application number: PCT/EP2005/053630
Authority: WO
Inventors: Daniela Monti; Luigi Saccomani; Marco Fabrizio Saettone; Patrizia Chetoni; Susi Burgalassi; Federico Mailland
Original assignee: Polichem SA
Current assignee: Polichem SA
Priority date: 2004-09-29
Filing date: 2005-07-26
Publication date: 2006-04-06
Anticipated expiration: 2007-03-29
Also published as: ITMI20041855A1

Abstract

The present invention relates to novel pharmaceutical compositions of alpha-dihydroergocryptine, capable of allowing transdermal and/or transmucosal absorption of the active ingredient, and to the use thereof as formulations in transdermal preparations, patches, gels, creams, ointments, solutions, buccal preparations or vaginal preparations, for the treatment of diseases of the nervous system or endocrine diseases.

Description

TITLE

PHARMACEUTICAL COMPOSITIONS OF ALPHA-

DIHYDROERGOCRYPTINE FOR TRANSDERMAL AND/OR

TRANSMUCOSAL USE

The present invention relates to novel pharmaceutical compositions of alpha- dihydroergocryptine, capable of allowing the absorption of the active ingredient through the patient's skin. These formulations may be used in the form of transdermal systems, patches, gels, creams, ointments, solutions, buccal preparations, vaginal preparations, for the treatment of diseases of the nervous system or of endocrine diseases.

Alpha-dihydroergocryptine, or dihydroergocryptine, or ergotaman-3',6',18-trione- 9, 10-dihydro- 12'-hydroxy-2'(l -methylethyl)-5 '-(2-methylpropyl)-(5α', 1 Oa), is a known compound derived by hydrogenation of the double bond in the 9,10 position of the natural alkaloid alpha-ergocryptine. Alpha-dihydroergocryptine is a known prior art drug, and is used for the treatment of degenerative diseases of the central nervous system (US 4673681, EP 505608), with consequent disorders of cerebral neurotransmitters, or also of diseases of the endocrine system, connected with excessive secretion of hormones by the pituitary gland, with consequent modification of fertility in both men and women. In order to be effective, the drug must provide sufficient and enduring levels at the site of action in the brain or in the pituitary gland, and, since it has a half- life of the slow phase of approx. 10-15 hours in humans (Zanotti A., Proc. 2nd Eur. Winter Conference in Gynaecol. Obst., Madonna di Campiglio, 1989), it is usually administered orally in doses which are repeated 2-3 times daily. Since it has a high molecular weight, 578 g/M, alpha-dihydroergocryptine has little ability to pass through tissues, such as the intestinal mucosa, and has a low oral bioavailability of less than 3% of the administered dose. Accordingly, only a small proportion of the drug reaches the systemic circulation. For the same reason, percutaneous administration, which has already been proposed in EP 505608, does not allow substantial absorption of dihydroergocryptine. Moreover, parenteral use of the product, which would make it possible to overcome its poor absorption properties, is not suitable since alpha-dihydroergocryptine is intended for long-term use, for years or for the remainder of the patient's life. It has now surprisingly been discovered that when it is associated with lauric acid, or with essential oils of the Melaleuca or Tarchonanthus type, with terpenes such as eucalyptol, menthol, or with Tween 80, alpha-dihydroergocryptine is capable of passing through animal skin, and thus of being available to the systemic circulation and, ultimately, of being active when applied onto the patient's skin or mucous membranes.

The present invention accordingly provides pharmaceutical formulations of alpha- dihydroergocryptine for topical application, exhibiting high capability of the active ingredient to pass through skin and mucous membranes, which may readily be formulated in transdermal systems, patches, gels, creams, ointments, solutions, buccal preparations and/or vaginal preparations, and which may readily be used in long-term treatment by patients suffering from degenerative diseases of the central nervous system, or of the pituitary gland, with consequent fertility impairment.

DESCRIPTION OF THE INVENTION

The object of the present invention is to provide a novel pharmaceutical composition comprising: a. alpha-dihydroergocryptine, or ergotaman-3',6',18-trione-9,10-dihydro-12'- hydroxy-2'(l-methylethyl)-5'-(2-methylpropyl)-(5α',10α) or one of the salts thereof b. at least one component selected from among DMSO, low molecular weight solvents (< 100 g/M), emollients, surfactants, emulsifiers, plasticisers, terpenes, keratolytics, sulfide donors, cyclodextrins, plant extracts or essential oils.

The invention furthermore relates to the use of this composition for topical application, capable of providing sufficient and effective systemic bioavailability, in the form of transdermal systems, patches, gels, creams, ointments, solutions, buccal preparations or vaginal preparations.

The composition according to the present invention comprises alpha- dihydroergocryptine or a salt thereof as component a). The salt of alpha- dihydroergocryptine is preferably the methanesulfonate salt (mesylate). The quantity of component a) in the composition is between 0.01% and 50% by weight, more preferably between 0.1% and 10%, most preferably between 0.5% and 5%, relative to the total weight of the composition.

The composition furthermore contains as component b) at least one compound selected from among the following: dimethylsulfoxide (DMSO), low molecular weight solvents (< 100 g/M); emollients, such as mineral oils, isopropyl myristate, isopropyl palmitate, vegetable oils; gelling agents, such as stearyl alcohol, polyvinyl alcohol; surfactants, such as lauric acid, sodium lauryl sulfate, glyceryl monooleate, polyoxyethylene sorbitan monooleate; emulsifiers, such as lanolin, oleic acid, sesame oil; plasticisers, such as acetyltributyl citrate; terpenes, such as menthol, d-limonene, limonene oxide, carveol, carvone, pulegone, 1,8-cineole, eucalyptol; keratolytics, such as salicic acid, urea; sulfide donors, such as sulfurated amino acids, methionine, cystine, cysteine, taurine, methylsulfonylmethane; cyclodextrins, alpha, beta and mixtures; essential oils of Melaleuca alternifolia, Melaleuca viridiflora (niaouli), Tarchonanthus, geraniol, anethole, ascaridole, or also various combinations of the above -described permeation enhancers.

Particularly suitable compounds are those which do not have an irritant or sensitising action and which do not need to be carried in other substances with an irritant or sensitising action.

The quantity of component b) in the composition is between 0.1% and 50% by weight, more preferably between 1% and 30%, most preferably between 2.5% and 10% relative to the total weight of the composition.

The composition according to the present invention may furthermore contain one or more compatible and pharmacologically acceptable excipients as additional components, and may furthermore contain other associated active ingredients with a complementary or at least useful activity.

Compatible and pharmacologically acceptable excipients may comprise aqueous or organic solvent and cosolvents, carriers capable of modifying the organoleptic properties of the product to make it pharmaceutically acceptable, together with stabilisers, preservatives, retarding agents, chelating agents, antioxidants, silicates, flavourings, humectants, emollients, lanolin derivatives and agents with antimicrobial activity. Thermally thickening (thermosetting) agents and adhesives to allow effective and extended contact with the skin and mucous membranes may also be included.

The composition according to the present invention may be prepared using the typical methods normally used for formulating liquid preparations, such as solutions, suspensions, lotions or foams, or for semisolid preparations, such as pomades, creams, gels and ointments, or for solid preparations, such as buccal tablets, transdermal systems, patches, vaginal tablets, pessaries, suppositories. In the case of liquid formulations, components a) and b) may be brought into contact with a solvent or with a mixture of solvents and other components either simultaneously or separately using standard mixing methods. No particular order of mixing of the components is required. It is preferable to stir in order to ensure complete dissolution or fine suspension of the components. If one or more ingredients are in solid form, it is preferable to add the ingredient(s) gradually to the liquid part to avoid precipitation.

In the case of semisolid preparations, components a) and b) may be mixed with acceptable excipients, such as solvents, emulsifiers, surfactants, thickeners and/or gelling agents, either simultaneously or separately by means of standard mixing methods.

In the case of solid preparations, components a) and b) may be mixed dry or wet with acceptable excipients, such as binders, diluents, disintegrants, lubricants and/or adhesives, either simultaneously or separately by means of standard mixing, granulation or compression methods. In the case of preparations in transdermal systems or patches, components a) and b) may be mixed together with the adhesives and the other excipients by preparation of matrix systems, in which the drug is dispersed in the adhesive, or the drug is dispersed in a polymer, and the adhesive is applied subsequently. In other types of transdermal systems, of the "reservoir" type, components a) and b) may be prepared in liquid or semisolid preparations and applied to the systems and patches in special reservoirs.

The composition according to the present invention is applied in liquid, semisolid or solid form to skin and/or mucous membranes, and contains a quantity of active ingredient, alpha-dihydroergocryptine, which is capable of releasing for one or more days, and is thus applied from once daily to once weekly. The preferred component b) of the present invention exhibits a surprising effect of potentiating the transdermal or transmucosal absorption of alpha- dihydroergocryptine. This effect is particularly marked with lauric acid, essential oil of Melaleuca alternifolia, niaouli, eucalyptol, limonene, Tarchonanthus and/or polyoxyethylene sorbitan monooleate (preferably sold as Tween 80). The composition of the present invention and its ability to pass through skin/membranes is illustrated, but not limited, by the following Examples. All quantities stated in percent are percentages of total weight. EXAMPLE 1

A solution with the following composition by weight was prepared: l. ethanol 89.0%

2. lauric acid 10.0%

3. alpha-dihydroergocryptine mesylate 1.0%

The formulation was prepared by means of a suitable container equipped with a stirrer. The ethanol and lauric acid were placed in the container until dissolution was complete. Once a clear solution had been obtained, the alpha- dihydroergocryptine mesylate was added and the mixture stirred for 30 minutes. Once applied onto the skin, the solution neither burnt nor caused irritation at the site of application. EXAMPLE 2 A gel with the following composition by weight was prepared:

1. alpha-dihydroergocryptine mesylate 1.00%

2. M. alternifolia essential oil 10.00%

3. ethanol 63.00%

4. Carbopol® 1342 2.00%

5. sodium methylparaben 0.37%

6. sodium propylparaben 0.04%

7. imidazolidinyl urea 0.21%

8. purified water to make up to 100.00% N.B.: composition of Carbopol® 1342: carbomer, viscosity in aqueous solution

(1% wt./vol.): 9500-26000 mPas.

The formulation was prepared by means of a suitable turboemulsifier. The ethanol, alpha-dihydroergocryptine mesylate and essential oil of Melaleuca were placed in the container in order to obtain a solution. The water and all the other components were added to this solution and mixed in the turboemulsifier until completely dispersed.

A homogeneous, semitransparent whitish gel was obtained. Once applied onto the skin, the gel could be rubbed in easily without burning or causing irritation at the site of application.

EXAMPLE 3

A gel with the following composition by weight was prepared:

1. alpha-dihydroergocryptine mesylate 1.00%

2. T. camphoratus essential oil 5.00%

3. ethanol 64.38%

4. Carbopol® 941 4.00%

5. Transcutol® 25.00%

6. sodium methylparaben 0.37%

7. sodium propylparaben 0.04%

8. imidazolidinyl urea 0.21%

N.B.: composition of Carbopol® 941: carbomer, viscosity in aqueous solution

(0.5% wt./vol.): 4000-11000 mPas. Composition of Transcutol®: diethylene glycol monoethyl ether

The formulation was prepared as in Example 2.

EXAMPLE 4

A gel with the following composition by weight was prepared:

1. alpha-dihydroergocryptine mesylate 2.00%

2. eucalyptol 5.00% 3. ethanol 40.00%

4. Klucel® HF 1.50%

5. sodium methylparaben 0.37%

6. sodium propylparaben 0.04%

7. imidazolidinyl urea 0.21%

8. propylene glycol 50.88% N.B.: composition of Klucel: hydroxypropylcellulose

The formulation was prepared as in Example 2.

EXAMPLE 5

A gel with the following composition by weight was prepared:

1. alpha-dihydroergocryptine mesylate 1.00%

2. menthol 5.00%

3. Lutrol® F 127 15.00%

4. PEG 200 25.00%

5. sodium methylparaben 0.37%

6. sodium propylparaben 0.04%

7. imidazolidinyl urea 0.21%

8. water to make up to 100.00%

N.B.: composition of Lutrol® F 127: polyoxyethylene/polyoxypropylene copolymer composition of PEG 200: polyethylene glycol.

The formulation was prepared by means of a suitable turboemulsifier. The water and Lutrol were placed in the container and cooled to 4°C to obtain a solution.

While maintaining the same temperature, the alpha-dihydroergocryptine mesylate, the PEG 200 and all the other components were added to the solution and mixed in the turboemulsifier until completely dispersed. The resultant composition was left to stand at ambient temperature for 12 hours.

EXAMPLE 6

A vaginal tablet having the following composition by weight was prepared:

1. alpha-dihydroergocryptine mesylate 10 mg

2. sodium lauryl sulfate 10 mg

3. lactose monohydrate 290 mg

4. hydroxypropylmethylcellulose 2910 40 mg

5. magnesium stearate 10 mg

The formulation was prepared by initial granulation of the active ingredient, mixing and compressing using standard methods. The alpha-dihydroergocryptine mesylate and a proportion of the lactose were mixed for 10 minutes in mixer and wetted with a solution of hydroxypropylmethylcellulose in water and granulated for 10 minutes. After 12 hours' drying, the granules were finely screened. During screening, the remainder of the lactose and the magnesium stearate were added and the mixture was mixed for 10 minutes in a stainless steel container. The mixture was then compressed.

The resultant tablets are white and homogeneous in appearance even over an extended period. EXAMPLE 7 A matrix-type transdermal system with the following structure was prepared: a) external cover: Scotchpat Film no. 1009 (polyester film, 3M) b) polymer matrix, with the following composition:

1. alpha-dihydroergocryptine mesylate 3.0 mg

2. d-limonene 2.0 mg

3. propylene glycol 15.0 mg

4. PVP/VA-E-335 (50% wt./wt.) 80.0 mg c) acrylic type adhesive film (Pharmaceutical Grade transfer adhesive no. 9871, 3M)

N.B.: composition of PVP/V A-E-335: polyvinylpyrrolidone/vinyl acetate copolymer in a 30:70 ratio, K value = 25-35, nitrogen content 3.6% EXAMPLE 8 A reservoir type transdermal system having following structure was prepared: 1. impermeable support made from heat-sealable polyester laminate

2. drug reservoir, containing 200 mg of the composition of Example 4, sealed between layers 1 and 3

3. microporous polyethylene membrane, for controlled release of the drug

4. acrylic type adhesive film (Pharmaceutical Grade transfer adhesive no. 9871, 3M)

5. peelable protective layer

The system was prepared by heat sealing to form patches with an available area for release of 2.0 cm².

The transdermal system is shown in section in Figure 1.

EXAMPLE 9

2. Melaleuca alternifolia essential oil 10.0%

3. alpha-dihydroergocryptine mesylate 1.0%

The formulation was prepared as in Example 1. Once applied onto the skin, the solution neither burnt nor caused irritation at the site of application. EXAMPLE 10 A matrix-type transdermal system with the following structure was prepared: a) external cover: Scotchpat Film no. 1009 (polyester film, 3M) b) polymer matrix, with the following composition:

1. alpha-dihydroergocryptine mesylate 1.0 mg

2. eucalyptol 0.5 mg

3. acetyl tributyl citrate 2.5 mg

4. isopropyl alcohol 51.4 mg

5. acetone 34.6 mg

6. EUDRAGIT RS 100 10.0 mg c) acrylic type adhesive film (Pharmaceutical Grade transfer adhesive no. 9871, 3M)

N.B.: composition of EUDRAGIT RS 100: poly(ethyl acrylate, methyl methacrylate, trimethylammoniumethyl methacrylate chloride) in a ratio of 1:2- 0.1 COMPARATIVE EXAMPLE 1

An in vitro study of penetration through hairless mouse skin was performed. Horizontal diffusion cells made up of two symmetrical communicating half-cells of Pyrex glass with a capacity of 8.5 ml were used. Each half-cell (respectively the receiving and donor compartments) had an upper opening to allow filling and sampling with a Teflon closure to prevent evaporation of the solvent. The horizontal cell used for the study of the present Example is shown in Figure 2. Star-shaped magnetic stirrers at a constant speed of 600 revolutions/min were used to keep the solutions homogeneous within the compartments, the temperature was maintained at 37°C by circulating temperature-controlled water in the jacketed wall of the half-cells. A portion of hairless mouse skin was placed between the two half-cells. The surface area affected by permeation was on average 1.70 cm².

The donating phase consisted of the preparation of the Example 1 or of a reference solution of the following composition: l. ethanol 99.0%

2. alpha-dihydroergocryptine mesylate 1.0%

The receiving phase consisted of phosphate buffer at pH = 7.4 containing sodium azide as preservative (0.003% wt./vol.).

Each experiment lasted 5 hours. At 1 hour intervals, 5.0 ml of the solution were collected for analysis and immediately replaced with an identical volume of fresh buffer. Each experiment was repeated 6 times. The samples collected in this way were analysed for their content of alpha-dihydroergocryptine using the HPLC method. Figure 3 summarises the results of the alpha-dihydroergocryptine (DHE) permeation study with and without lauric acid through hairless mouse skin. While there was no permeation through the cutaneous membrane by the active ingredient present in the reference formulation, the formulation of Example 1, containing lauric acid, in contrast permitted permeation of alpha- dihydroergocryptine (DHE) in an amount of up to 2.5 μg/cm² after 5 hours. COMPARATIVE EXAMPLE 2

An in vitro study of penetration through hairless mouse skin was performed using a similar method to that stated in Comparative Example 1. The permeation study was performed using horizontal cells as in Comparative Example 1. The donating phase consisted of the preparation of Example 9, or of a reference solution with a composition identical to that stated in Comparative Example 1. Figure 4 summarises the results of the alpha-dihydroergocryptine (DHE) permeation study with and without Melaleuca alternifolia essential oil (tea tree oil) through hairless mouse skin.

While there was no permeation through the cutaneous membrane by the active ingredient present in the reference formulation, the formulation of Example 9, containing M. alternifolia essential oil, in contrast allowed permeation of alpha- dihydroergocryptine (DHE) in an amount of up to approx. 60 μg/cm² after 5 hours. EXAMPLE I l

An in vitro permeation study through hairless mouse skin has been performed by a method similar to that reported in Comparative Example 1. Horizontal cells have been used as in Comparative Example 1. Donor phase consisted of experimental solutions containing alpha-dihydroergocryptine mesylate (DHE - PoIi Industria Chimica, Milan, Italy) prepared by dissolving the drug in ethanol (EtOH) or propylene glycol (PG - Merck Darmstadt, Germany), with or without permeation enhancers. The following permeation enhancers were tested: lauric acid (LA - Sigma Chem. St Louis, USA) tea tree oil (essential oil of Melaleuca alternifolia)(TTO - Variati & Co., Milan Italy), essential oil of Niaouli (Melaluca viridans)(NIA - A.C.E.F., Piacenza Italy), Eucalyptol (1,8 cineol) (EUC - A.C.E.F.), essential oil of Tarconanthus camphoratus (TC - Di Schiena Holos, Milan, Italy), D-limonene (LIM - Sigma), tweenδO (TW80 - Sigma), terpinen-4- ol (TRO - Sigma). The percent compositions of the tested solutions are reported in the following tables 1 and 2.

Tab.1 - Percent composition (% w/w) of tested solutions of DHE mesylate in EIOH.

Tab.2 - Percent composition (% w/w) of tested solutions of DHE mesylate in PG.

For each tested vehicle the following parameters were calculated from the steady- state slopes of linear plots of the amount of drug in the receiving chamber (Q) vs. time (t): steady-state flux (J), i.e. amount of drug permeating a unit cross-section of the membrane in unit time; lag time, i.e. time required to reach membrane saturation and steady-state conditions; percent drug permeated at the end of the experiment. EtOH and PG were chosen as solvents on account of their capacity to dissolve DHE. However, no DHE transdermal flux from either solvent was detected.

A transdermal flux of 0.40 ± 0.11 μg/cm2h (Fig.5) was achieved by adding 10%

LA to a 1% DHE solution in EtOH (vehicle A5); the lag time was 1.50 ± 0.29 h.

The DHE flux increased up to 2 μg/cm2h by adding 10% NIA, EUC or LIM to the 1% solution of DHE in EtOH (vehicles Al, A2 and A3) without any statistical difference; at the same time, the lag time value decreased to 0.43 ± 0.18 in the case of vehicle A3. The percent drug permeated at end of the experiments (Q%5h) ranged between 0.47 and 0.78%.

Similar results, in terms of Q%5h, were observed for vehicle A4 (10% TW80,

Q%5h = 0.57 ± 0.13).

The best results were observed for vehicle A6 (10% TTO): DHE flux and lag time were 9.47 ± 1.69 μg/cm2h and 0.57 ± 0.19 h, respectively; Q%5h was 2.98 ± 0.47

(Fig.6).

An ethanol vehicle containing 10% TRO (A7), main constituent of the TTO essential oil (-50%), was then prepared and tested. The DHE flux from vehicle

A7 was 2.20 ± 0.40 μg/cm2h, not different from those observed for vehicles Al,

A2 and A3 (10% NIA, EUC and LIM, respectively, Fig.6).

Two 1% DHE solutions in PG containing 10% NIA and 10% EUC (vehicles Bl and B2, respectively) were then prepared and tested in vitro: the use of PG produced a significant increase of DHE transdermal permeation, if compared to the corresponding ethanol solutions Al (10% NIA, J = 2.03 ± 0.98 μg/cm2h) and

A2 (10% EUC, J = 2.00 ± 0.62 μg/cm2h): the flux values were 6.50 ± 1.56 and

2.77 ± 0.20 μg/cm2h for vehicle Bl (10% NIA, Fig.7) and B2 (10% EUC, Fig.8), respectively. No appreciable difference in lag times was observed with respect to solutions Al and A2.

A further increase of DHE transdermal flux was obtained with vehicle B3 (5%

NIA; J = 8.03 ± 0.64 μg/cm2h), even if not significantly different from vehicle

Bl (10% NIA, J = 6.50 ± 1.56 μg/cm2h); the lag time, on the other hand, increased significantly up to 1.37 ± 0.66 h.

Conversely, vehicle B4 (5% EUC) showed a reduced DHE flux (0.63 ± 0.48 μg/cm2h) if compared to vehicle B2 (10% EUC, J = 2.77 ± 0.20 μg/cm2h, Fig.8).

A further reduction of NIA content to 1% (vehicle B5) caused a drastic decrease of DHE flux (J = 1.30 ± 0.15 μg/cm2h, Fig.3).

No DHE permeation was detected by keeping the NIA concentration at 5% while reducing the drug content to 0.5% (vehicle B6).

In order to compare the enhancing activities of TC and NIA, vehicle B7 (5% TC) was prepared: Figure 9 shows the corresponding permeation plots. Both DHE flux and lag time for vehicle B7 (5% TC, J = 12.47 ± 1.61 μg/cm2h, It = 2.13 ± 0.09 h) were significantly higher if compared to those observed for vehicle B3 (5% NIA,

J = 8.03 ± 0.64 μg/cm2h, It =1.37 ± 0.66 h); no significant difference between

Q%5h values was observed (1.81 ± 0.38 vs. 2.37 ± 0.38% for vehicles B3 and B7, respectively).

Claims

1. A pharmaceutical composition for topical use comprising: a. alpha-dihydroergocryptine or one of the pharmaceutically acceptable salts thereof; b. at least one component selected from among DMSO, low molecular weight solvents (< 100 g/M), emollients, surfactants, emulsifiers, plasticisers, terpenes, keratolytics, sulfide donors, cyclodextrins, plant extracts or essential oils.

2. A composition according to claim 1, in which said solvents are selected from among low molecular weight alcohols; said emollients are selected from among: mineral oils, isopropyl myristate, isopropyl palmitate and vegetable oils; said gelling agents are selected from among: stearyl alcohol and polyvinyl alcohol; said surfactants are selected from among: lauric acid, sodium lauryl sulfate, polyoxyethylene sorbitan monooleate and glyceryl monooleate; said emulsifiers are selected from among: lanolin, oleic acid and sesame oil; said plasticiser is acetyltributyl citrate; said terpenes are selected from among: menthol, d-limonene, limonene oxide, carveol, carvone, pulegone, 1,8-cineole, and eucalyptol; said keratolytics are selected from among: salicic acid and urea; said sulfide donors are selected from among: sulfurated amino acids, methionine, cystine, cysteine, taurine, methylsulfonylmethane; said cyclodextrins are selected from among: alpha- and beta-cyclodextrins; said plant extracts or essential oils are selected from among: extracts or essential oils of Melaleuca, Tarchonanthus, geraniol, anethole, ascaridole.

3. A composition according to claim 2, in which the low molecular weight alcohols are selected from among ethanol and isopropanol.

4. A composition according to claim 2, in which the plant extracts are composed of plants or plant parts, juices, dry extracts, alcoholic extracts, aqueous- alcoholic extracts, glycol extracts or essential oils.

5. A composition according to claim 2, in which said Melaleuca is Melaleuca alternifolia or Melaleuca viridiflora.

6. A composition according to claim 2, in which the Melaleuca extract is niaouli.

7. A composition according to claim 2, in which said Tarchonanthus is Tarchonanthus camphoratus.

8. A composition according to any one of the preceding claims comprising at least one pharmacologically acceptable carrier.

9. A composition according to claim 8, in which the pharmacologically acceptable carrier is selected from among the following: aqueous or organic solvent and cosolvents, stabilisers, preservatives, retarding agents, chelating agents, antioxidants, silicates, flavourings, humectants, emollients, lanolin derivatives and agents with antimicrobial activity, thermally thickening (thermosetting) agents and adhesives.

10. A composition according to any one of the preceding claims, in which component a) is alpha-dihydroergocryptine methanesulfonate

11. A composition according to any one of the preceding claims, in which the quantity of component a) is between 0.01% and 50% by weight, more preferably between 0.1% and 10%, most preferably between 0.5% and 5% relative to the total weight of the composition.

12. A composition according to any one of the preceding claims, in which component b) is present in an amount of between 0.1% and 50% by weight, more preferably between 1% and 30%, most preferably between 2.5% and 10% relative to the total weight of the composition.

13. A composition according to any one of the preceding claims, which contains one or more further active ingredients.

14. A composition according to any one of the preceding claims characterised in that it is selected from among: transdermal systems, patches, gels, creams, ointments, solutions, buccal preparations or vaginal preparations.

15. Use of (a) alpha-dihydroergocryptine or one of the pharmaceutically acceptable salts thereof together with (b) at least one component selected from among low molecular weight solvents (<100 g/M), emollients, surfactants, emulsifiers, plasticisers, terpenes, keratolytics, sulfide donors, cyclodextrins, plant extracts or essential oils, for the preparation of a pharmaceutical composition for topical use for the treatment of diseases of the nervous system or of endocrine diseases.

16. Use according to claim 15, in which said solvents are selected from among low molecular weight alcohols; said emollients are selected from among: mineral oils, isopropyl myristate, isopropyl palmitate and vegetable oils; said gelling agents are selected from among: stearyl alcohol and polyvinyl alcohol; said surfactants are selected from among: lauric acid, sodium lauryl sulfate, polyoxyethylene sorbitan monooleate and glyceryl monooleate; said emulsifiers are selected from among: lanolin, oleic acid and sesame oil; said plasticiser is acetyltributyl citrate; said terpenes are selected from among: menthol, d-limonene, limonene oxide, carveol, carvone, pulegone, 1,8- cineole, and eucalyptol; said keratolytics are selected from among: salicic acid and urea; said sulfide donors are selected from among: sulfurated amino acids, methionine, cystine, cysteine, taurine, methylsulfonylmethane; said cyclodextrins are selected from among: alpha- and beta-cyclodextrins; said plant extracts or essential oils are selected from among: extracts or essential oils of Melaleuca, Tarchonanthus, geraniol, anethole, ascaridole.

17. Use according to claim 16, in which the low molecular weight alcohols are selected from among ethanol and isopropanol.

18. Use according to claim 16, in which the plant extracts are composed of plants or plant parts, juices, dry extracts, alcoholic extracts, aqueous - alcoholic extracts, glycol extracts or essential oils.

19. Use according to claim 16, in which said Melaleuca is Melaleuca alternifolia or Melaleuca viridiflora.

20. A composition according to claim 16, in which the Melaleuca extract is niaouli.

21. Use according to claim 16, in which said Tarchonanthus is Tarchonanthus camphoratus.

22. Use according to any one of the preceding claims, comprising at least one pharmacologically acceptable carrier.

23. Use according to claim 22, in which the pharmacologically acceptable carrier is selected from among the following: aqueous or organic solvent based solvents and cosolvents, stabilisers, preservatives, retarding agents, chelating agents, antioxidants, silicates, flavourings, humectants, emollients, lanolin derivatives and agents with antimicrobial activity, thermally thickening (thermosetting) agents and adhesives.

24. Use according to any one of the preceding claims, in which component a) is alpha-dihydroergocryptine methanesulfonate.

25. Use according to any one of the preceding claims, in which the quantity of component a) is between 0.01% and 50% by weight, more preferably between 0.1% and 10%, most preferably between 0.5% and 5% relative to the total weight of the composition.

26. Use according to any one of the preceding claims, in which component b) is present in an amount of between 0.1% and 50% by weight, more preferably between 1% and 30%, most preferably between 2.5% and 10% relative to the total weight of the composition.

27. Use according to any one of the preceding claims, wherein one or more further active ingredients are used.

28. Use according to any one of the preceding claims characterised in that said composition is selected from among: transdermal systems, patches, gels, creams, ointments, solutions, buccal preparations or vaginal preparations.