LIQUID PHARMACEUTICAL COMPOSITIONS COMPRISING PERGOLIDE

Abstract

The invention relates to novel liquid pharmaceutical compositions comprising (8)-8-[(methylthio)methyl]-6-propylergoline (pergolide) as well as corresponding processes of manufacturing such liquid pharmaceutical compositions and their medical uses.

Claims

1. A liquid pharmaceutical composition comprising (8)-8-[(methylthio)methyl]-6-propylergoline (pergolide) according to formula (I): ##STR00002## wherein (8)-8-[(methylthio)methyl]-6-propylergoline (pergolide) comprises, preferably consists of, particles characterized through a particle size distribution D90 value of 300 m or less, more preferably 250 m or less, more preferably 200 m or less, more preferably 150 m or less, more preferably 100 m or less, even more preferably 90 m or less, even more preferably 80 m or less, even more preferably 70 m or less, even more preferably 60 m or less, even more preferably 50 m or less, most preferably 40 m or less.

2. The liquid pharmaceutical composition according to claim 1, wherein pergolide is micronized pergolide mesylate.

3. The liquid pharmaceutical composition according to claim 1, wherein the liquid pharmaceutical composition is a suspension.

4. The liquid pharmaceutical composition according to claim 3, wherein the suspension is an oily suspension, i.e. a suspension comprising one or more oil(s), such as mineral oil(s) and/or vegetable oil(s).

5. The liquid pharmaceutical composition according to claim 4, wherein the oily suspension is devoid of any water.

6. The liquid pharmaceutical composition according to claim 4, wherein the one or more oil(s) are selected form the group consisting of: refined soyabean oil, refined safflower oil, refined maize oil, virgin linseed oil, refined sunflower oil, refined rapeseed oil, and miglyol [mixture of medium-chain triglycerides (MCT), in particular of saturated fatty acids, such as caprylic acid and capric/caprinic acid], wherein preferably the miglyol is selected from the group consisting of: Miglyol 810, Miglyol, 812, Miglyol 829, Miglyol 840, more preferably Miglyol 812.

7. The liquid pharmaceutical composition according to claim 1, wherein the liquid pharmaceutical composition further comprises at least one antioxidant, preferably selected from the group consisting of: butylhydroxytoluene (BHT), ascorbyl palmitate (AP), butylhydroxyanisole (BHA), and alpha-tocopheryl acetate (AT), more preferably butylhydroxyanisole (BHA).

8. The liquid pharmaceutical composition according to claim 4, wherein the liquid pharmaceutical composition is substantially free of rapeseed oil and alpha-tocopheryl acetate (AT).

9. The liquid pharmaceutical composition according to claim 1, wherein the liquid pharmaceutical composition further comprises at least one flavour, preferably selected from the group consisting of: apple-carrot flavour, honey-carrot flavour, more preferably honey-carrot flavour.

10. The liquid pharmaceutical composition according to claim 1, wherein the liquid pharmaceutical composition further comprises at least one viscosity enhancer, preferably selected from the group consisting of: oleogel formers, such as silicium dioxide and/or ethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, zinc stearate, preferably silicium dioxide, wherein preferably the viscosity enhancer is present in a concentration of 0.1% (w/w) to 20% (w/w), more preferably 1% (w/w) to 10% (w/w), even more preferably 5% (w/w) to 10% (w/w), even more preferably 1% (w/w) to 4% (w/w), even more preferably 1% (w/w) to 2% (w/w), even more preferably 1.5% (w/w) to 2.5% (w/w), most preferably 1.5% (w/w) or 2.5% (w/w).

11. The liquid pharmaceutical composition according to claim 1, comprising (i) 0.1-1.0 g/L (0.01-0.1% w/w), preferably 0.1-0.65 g/L (0.01-0.065% w/w) pergolide; (ii) 750-995 g/L (75-99.5% w/w), preferably 850-995 g/L (85-99.5% w/w) oil; (iii) 0.05-1 g/L (0.005-0.1% w/w), preferably 0.05-0.1 g/L (0.005-0.01% w/w) antioxidant; (iv) 5-20 g/L (0.5-2.0% w/w), preferably 5-10 g/L (0.5-1% w/w) flavor.

12. The liquid pharmaceutical composition according to claim 10 further comprising (v) 1-200 g/L (0.1-20% w/w), preferably 10-40 g/L (1-4% w/w) viscosity enhancer.

13. The liquid pharmaceutical composition according to claim 1, wherein the liquid pharmaceutical composition is suitable for direct administration to a subject, preferably an animal, more preferably a mammal, most preferably a horse.

14. The liquid pharmaceutical composition according to claim 1, wherein such liquid pharmaceutical composition is for oral administration, preferably for administration onto horse food.

15. Method for treating and/or preventing one or more medicinal indications in a subject in need of such treatment and/or prevention, preferably an animal, more preferably a mammal, most preferably a horse, selected from among the medicinal indications: Pituitary Pars Intermedia Dysfunction (PPID; Equine Cushing's Disease), comprising administering the liquid pharmaceutical composition according to claim 1.

16. A process for producing the liquid pharmaceutical composition according to claim 1 comprising the steps: (i) dispersing pergolide in one or more oil(s) to yield a pergolide suspension; (ii) preparing an antioxidant solution in one or more oil(s) containing at least one antioxidant; (iii) preparing a second suspension by mixing the pergolide suspension obtained in step (i) with the antioxidant solution obtained in step (ii); (iv) adding at least one flavor to the second suspension obtained in step (iii); and (v) homogenizing the suspension obtained in step (iv).

17. A process for producing the liquid pharmaceutical composition according to claim 1 comprising the steps: (i) preparing an antioxidant solution in one or more oil(s) containing at least one antioxidant; (ii) adding the at least one viscosity enhancer to the solution obtained in step (i) followed by homogenization; (iii) dispersing pergolide in one or more oil(s) to yield a pergolide suspension; (iv) preparing a suspension by mixing the pergolide suspension obtained in step (iii) with the antioxidant+viscosity enhancer containing suspension obtained in step (ii); (v) homogenizing the suspension obtained in step (iv); (vi) adding at least one flavor to the suspension obtained in step (v); and (vii) homogenizing the suspension obtained in step (vi).

18. A kit comprising: (a) a liquid pharmaceutical composition according to claim 1 and (b) a package leaflet including the information that the liquid pharmaceutical composition is to be used for the prevention and/or treatment of one or more medicinal indications in a subject in need of such prevention and/or treatment, which are selected from among the medicinal indications: Pituitary Pars Intermedia Dysfunction (PPID; Equine Cushing's Disease), wherein preferably such kit-of-parts further comprises a plasticified glass bottle for storage of the liquid pharmaceutical composition.

19. The kit according to claim 18 wherein the plasticified glass bottle is a 100 mL plasticified glass bottle.

20. The kit according to claim 19 further comprising a plug-in that functions as an interface for the plasticified glass bottle and a syringe sufficient to deliver the liquid pharmaceutical composition.

21. The kit of claim 20 wherein the syringe is a dial-a-dose-type syringe.

22. The kit of claim 21 wherein the dial-a-dose-type syringe comprises six dosing steps between 0.25 mg pergolide and 1.5 mg pergolide.

23. The kit of claim 18 wherein the plasticified glass bottle comprises a child-proof cap.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0079] FIG. 1: shows the certificate of analysis for micronized pergolide mesylate with a particle size distribution D90 value of 40 m or less (39.4 m) and a median particle size of equal to or more than 13 m (13.3 m).

EXAMPLES

[0080] The following examples serve to further illustrate the present invention; but the same should not be construed as a limitation of the scope of the invention disclosed herein.

Example 1Micronization of Pergolide Mesylate

[0081] Micronization of pergolide mesylate was performed according to the state-of-the-art using a spiral jet-mill as described below. The principles of jet-mills is for instance described in Vauck, Wilhelm R. A. Grundoperationen chemischer Verfahrenstechnik by Vauck, Wilhelm R. A. and Mller, Hermann A., 9.sup.th edition 1992, pages 329 to 332.

[0082] EQUIPMENT USED FOR MICRONIZATION: Glove box on a MC50 spiral jet-mill with a bottom discharge of the product and using nitrogen as micronization and inertization gas.

[0083] PARTICLE-SIZE DISTRIBUTION (PSD) ANALYTICAL METHOD: Equipment Malvern Mastersizer 3000 equipped with Hydro MV dispersion unit

[0084] Dispersant Preparation1. Fill the dispersion unit with hexane2. Check that the channel 1 of background signal is less than 80 and no anomalous spikes are present3. Check the background signal: it has to be stable and complying with the following limits: Channel 1<100, Channel 20<60.

[0085] Sample PreparationRandomize the sample by manually tumbling and rolling for 30 seconds, weigh approximately 15 mg of powder in a 100 mL Erlenmeyer flask, add 2 mL of Span 85 (Sorbitane trioleate; 5% w/w water solution). A homogeneous mixture, using the tip of a small stainless steel spatula, has to be obtained.

[0086] Using a Pasteur pipette add 1 mL of water and homogenize the suspension. Repeat this operation until a volume of 8-10 mL is reached. Sonicate the sample for 5 seconds in an ultrasonic bath (25 kHz).

[0087] Parameters:

[0088] Optical ModelFraunhofer

[0089] Background measurement duration (red)30

[0090] Sample measurement duration (red)30

[0091] Number of measurements3

[0092] Averaging enabled?No

[0093] Pre-alignment delay0

[0094] Delay between measurements0

[0095] Pre-measurement delay30.00 s

[0096] Auto start measurementno

[0097] Obscuration low limit15%

[0098] Obscuration high limit25%

[0099] Background Check Limits[1:100]; [20;60]

[0100] Stirrer speed3000 rpm

[0101] Ultrasonication duration0.00 s

[0102] Analysis modelgeneral purpose

[0103] Analysis sensitivityenhanced

[0104] Procedure1. Once a stable background signal is obtained, proceed with the SOP2. Add the sample until the obscuration target is reached. Avoid droplets to fall directly into the liquid when adding the sample suspension putting the pipette tip under water3. Initiate the measurement4. The particle size distribution values (D10, D50 and D90) are taken directly from the Malvern screen. All three values determined for a sample are average and rounded to obtain the final values.

Example 2Preparation of a Liquid Pharmaceutical Composition According to the Present Invention

[0105] Without Nitrogen Purge:

[0106] The oily suspension is manufactured in an ointment processing vessel, equipped with stirrer, homogenizer, heating-/cooling jacket and vacuum pump, e.g. a Becomix, type Beco mini Lab.

[0107] In a first step, the antioxidant (0.010%/0.340 g) is dissolved separately utilizing sufficient volumes (5%/170 g) of Miglyol 812.

[0108] Second, the micronized API pergolide mesylate (0.069%/2.337 g; D90=39.4 m) is predispersed rapidly in a low amount of Miglyol 812 (5%/170 g) and added to the processing vessel. The micronized pergolide mesylate gets dispersed in the Miglyol-antioxidant-solution while stirring (5-10 min) and homogenization (rotor/stator principle, 8-12 m/s). If temperature increases above 25 C., the cooling jacket is turned on (below 25 C.). Honey carrot- or/and apple-carrot flavor is added (1%/34 g), followed by a homogenization step (rotor/stator principle, 8-12 m/s, 2-4 min). During the whole process, suitable process parameters (stirring time and speed, homogenization time and speed) are mandatory. The final suspension gets discharged via the homogenization element and filled into bottles and stored in a dark place.

[0109] With Nitrogen Purge:

[0110] The oily suspension is manufactured in an ointment processing vessel, equipped with stirrer, homogenizer, heating-/cooling jacket and vacuum pump, e.g. a Becomix, type Beco mini Lab. The process is run in nitrogen atmosphere.

[0111] In a first step, the antioxidant (0.010%/0.340 g) is dissolved separately utilizing sufficient volumes (5%/170 g) of Miglyol 812.

[0112] Second, the micronized API pergolide mesylate (0.069%/2.337 g; D90=39.4 m) is predispersed rapidly in a low amount of Miglyol 812 (5%/170 g) and added to the processing vessel. The micronized pergolide mesylate gets dispersed in the Miglyol-antioxidant-solution while stirring (5-10 min) and homogenization (rotor/stator principle, 8-12 m/s). If temperature increases above 25 C., the cooling jacket is turned on (below 25 C.). Honey carrot- or/and apple-carrot flavor is added (1%/34 g), followed by a homogenization step (rotor/stator principle, 8-12 m/s, 2-4 min). During the whole process, suitable process parameters (stirring time and speed, homogenization time and speed) are mandatory The final suspension gets discharged via the homogenization element and filled into bottles. The bottles are flooded with nitrogen and stored in a dark place.

[0113] Preferred parameter setup: API adding: Homogenizer speed 8 m/s; API adding: Homogenizer time: 5 min; API adding: Stirring speed: 1.0 m/s; Flavour adding: Homogenizer speed 8 m/s; Flavour adding: Homogenizer time: 4 min; Flavour adding: Stirring speed: 1.0 m/s

Example 3Preparation of a Liquid Pharmaceutical Composition According to the Present Invention

[0114] The antioxidant (butyl hydroxyl anisole; 0.34 g) is dissolved in Miglyol 812 (170.0 g) while stirring until the solution is clear and free of undissolved particles. 2,717.3 g Miglyol 812 are given into a Becomix; and the antioxidant containing solution is added slowly while stirring. The beaker of the antioxidant containing solution is rinsed with 85.0 g Miglyol 812 and given into the Becomix as well. The becomix is closed and flooded with nitrogen while stirring. The at least one viscosity enhancer (Aerosil 200 Pharma; 51.00 g or 85.00 g) is slowly given to the solution while stirring and homogenizing. The beaker of the resulting suspension is rinsed with 85.0 g Miglyol 812 and given into the Becomix as well. The becomix is closed and flooded with nitrogen while stirring until the suspension is clear and free of bigger lumps. Pergolide mesylate (2.3358 g) is dispersed in 170.0 g Miglyol 812 until it is completely dispersed and the dispersion is free of bigger lumps. Since pergolide mesylate is sensitive to oxygen, the contact to air should be avoided as much as possible. The resulting dispersion is added to the at least one viscosity enhancer containing suspension while stirring. The beaker of the dispersion is rinsed with 85.0 g Miglyol 812 and given into the Becomix as well. The becomix is closed and flooded with nitrogen while stirring until the suspension is clear and free of bigger lumps. The resulting combined suspension is homogenized until it is free of lumps. 34.0 g apple-carrot flavor are added slowly while stirring and given into the Becomix as well. The becomix is closed and flooded with nitrogen. The resulting final suspension is homogenized until it is homogenous and free of lumps. The suspension is filled immediately into bottles while stirring and homogenizing. The bottles are flooded with nitrogen and stored in a dark place.

REFERENCES

[0115] (1) Davis J et al., Journal of the American Veterinary Medical Association 2009, 234(3): 385-389 [0116] (2) EP 0 003 667 [0117] (3) EP 0 026 671 [0118] (4) EP 0 213 850 [0119] (5) Shank B et al., Journal of Pharmacy Practice 2010, 23(6): 570-574 [0120] (6) U.S. Pat. No. 3,901,894 [0121] (7) U.S. Pat. No. 4,166,182 [0122] (8) U.S. Pat. No. 4,246,265 [0123] (9) U.S. Pat. No. 4,782,152 [0124] (10) US 2008/260846 [0125] (11) Vauck, Wilhelm R. A. Grundoperationen chemischer Verfahrenstechnik by Vauck, Wilhelm R. A. and Mller, Hermann A., 9.sup.th edition 1992, pages 329 to 332. [0126] (12) WO 96/40139 [0127] (13) WO 02/11727