PROCESS FOR THE PREPARATION OF DRUG DELIVERY SYSTEMS HAVING A TESTOSTERONE COMPOUND PRESENT IN AN OUTER LAYER OR PART, AS WELL AS SUCH DRUG DELIVERY SYSTEMS

Abstract

The invention relates to a process for preparing a time controlled, immediate release drug delivery system for oral administration of a first active ingredient to a subject in need thereof. The invention additionally relates to a dual drug delivery device, comprising the time controlled, immediate release drug delivery system according to the invention, further comprising a spray coating comprising a testosterone.

Claims

1. A process for preparing dual drug delivery devices for oral administration of a second and first active ingredient to a subject in need thereof, said process comprising the steps of (i) providing a time controlled, immediate release drug delivery system comprising a core and a first coating surrounding said core, wherein the core comprises cellulose, a filler selected from an organic and/or an inorganic salt, and the first active ingredient, being an active ingredient for treatment male or female sexual dysfunction, decreased/absence of sexual desire, sexual arousal problems, or erectile dysfunction, and wherein said first coating comprises a hydrophobic polymer and a hydrophilic substance; and (ii) spray coating testosterone or a functional analogue or derivative thereof onto said time controlled, immediate drug delivery systems in amounts in the spray coated layer within 10% of the desired pharmaceutical amounts, wherein the spray coating of step (ii) inclusive of its inherent drying step is carried out at a temperature of maximum 55° C.

2. A process according to claim 1, wherein the spray coating of step (ii) is carried out a temperature of 35-40° C.

3. A process according to claim 1 or 2, wherein step (i) comprises applying said first coating around the core at a temperature of 60° C. or higher.

4. A process according to any of claims 1-3, wherein step (i) comprises subjecting the time controlled, immediate release drug delivery system to a heating step after application of the first coating layer and before said step (ii).

5. A process for preparing dual drug delivery devices for oral administration of a second and first active ingredient to a subject in need thereof, said process comprising the steps of (i) providing a time controlled, immediate release drug delivery system comprising a core comprising cellulose, a filler selected from an organic and/or an inorganic salt, and the first active ingredient, being an active ingredient for treatment male or female sexual dysfunction, decreased/absence of sexual desire, sexual arousal problems, or erectile dysfunction, and preferably for the treatment of Hypoactive Sexual Desire Disorder in men, or Female Sexual Interest/Arousal Disorder, and a first coating surrounding said core, said first coating comprising a hydrophobic polymer and a hydrophilic substance; and (ii) spray coating said time controlled, immediate drug delivery systems with testosterone or a functional analogue or derivative thereof in amounts in the spray coated layer within 10% and preferably 7,5%, more preferably within 5%, most preferably within 4% of the desired pharmaceutical amounts.

6. The process according to claim 1, wherein testosterone or the functional analogue thereof is spray coated using a solution comprising a film forming polymer and a solvent system based on ethanol and water.

7. The process according to claim 6, wherein the film forming polymer is hydroxypropylmethylcellulose.

8. The process according to claim 2 or 7, wherein the weight ratio ethanol/water is 6/4-8/2.

9. The process according to any one of the preceding claims, wherein testosterone or the functional analogue thereof is spray coated using a solution further comprising a cyclodextrin, or a derivative or polymer thereof.

10. The process according to any one of the preceding claims, wherein testosterone or the functional analogue thereof is spray coated using a solution further comprises a flavouring compound and/or a sweetener.

11. The process according to any one of the preceding claims, wherein the first coating of step (i) is also applied using spray coating step.

12. The process according to any of claims 4-11, wherein the spray coating step ii) and/or in the embodiment of claim 11, the spray coating step in step (i) inclusive of its inherent drying step is carried out at temperatures up to maximally 55° C., preferably up to maximally 50° C., and more preferably at temperatures in the range of 35° C. to 45° C.

13. The process according to any one of the preceding claims, wherein the first coating around the core in step i) comprises ethylcellulose.

14. The process according to claim 9, wherein the first coating is applied at a temperature of 60° C. or higher; or wherein the provided time controlled, immediate release drug delivery system of step i) is subjected to a curing step.

15. The process according to any one of the preceding claims, wherein the first active ingredient is Sildenafil or Buspirone.

16. The process according to any one of the preceding claims wherein the spray coating step or steps is/are carried out in a perforated pan coater or fluid bed coater.

17. The process according to any of the preceding claims for preparing a batch of the dual drug delivery devices, wherein in step (ii) testosterone or a functional analogue or derivative thereof is included in the spray coated layer in at least 99% of the individual tablet in an amount thereof within 4% of the average amount of that compound in the batch.

18. The dual drug delivery device obtainable by the process of any one of claims 1-17.

19. A batch of dual drug delivery devices according to claim 18, having an intra batch variation in the amount of testosterone or a functional analogue or derivative thereof in the spray coating layer around the first coating layer of within 10%, and preferably 7,5%, more preferably within 5%, most preferably within 4%.

Description

EXAMPLE 1

[0095] 4.6 kg sildenafil citrate, 6.7 kg dicalcium phosphate, 6.7 kg microcrystalline cellulose and 0.8 kg croscarmellose sodium were passed through a 600 micrometer sieve in a blending container and blended until a uniform mass was obtained. Then, 0.8 kg magnesium stearate was passed through a 600 micrometer sieve and added to the blend. The blend was lubricated by tumbling the blending container for 5 minutes. The blend was transferred to a tableting machine and compressed to tablets having a core weight of 300 mg, containing about 70 mg sildenafil citrate equivalent to 50 mg sildenafil per tablet.

[0096] In 14.4 liters ethanol (96%, denaturated), 432 g ethylcellulose (20 mPa.Math.s) and 864 g microcrystalline cellulose (Avicel PH105) were dispersed. The 7.2 kg sildenafil core tablets were loaded in a perforated drum film coater. The ethylcellulose and microcrystalline cellulose dispersion was subsequently sprayed on the sildenafil tablets and the solvent was removed by heating, while maintaining the exhaust temperature at about 40° C.

[0097] The coated tablets were gradually cooled.

[0098] During drug product stability testing, it was determined that the properties of the polymer barrier coating surrounding the sildenafil core changed upon storage. This resulted in a delayed dissolution profile of sildenafil from the original target of 2 to 3 hours to a time greater than 3 hours.

[0099] This effect was not observed in the tablets prepared in the working examples of WO 2012/158030.

[0100] It has been determined that the delayed release of sildenafil was attributable to an ageing phenomenon of the ethylcellulose-containing polymer coating. More specifically, in an effort to understand the cause of the delayed sildenafil core tablet rupture time on stability, it became apparent that the nature of the ethylcellulose polymer coating changed during storage, which, in turn, changed its swelling properties over time. This change was due to an ageing effect—rearrangement of the polymer chains increases the density of the coating, thereby reducing the speed of water uptake.

[0101] It was realized that in WO 2012/158030 the coat layers were applied on small-scale laboratory equipment and the drying temperature was uncontrolled (estimated to be between 60° C. and 80° C.).

[0102] Therefore, the effects of Additional Heat Treatment on Initial Rupture Time were checked.

[0103] Specifically, core tablets containing 50 mg sildenafil of the type made in Example 1 were coated with approximately 34 mg per tablet of barrier coating comprised of ethylcellulose and microcrystalline cellulose. After spraying of the barrier coating, samples were taken for analysis of core rupture time. The tablets were further processed in the film-coating equipment by applying heat (supply air 70° C. to 80° C., resulting in exhaust air >60° C.) for 3 hours. Samples were taken after 1, 2 and 3 hours of additional heat treatment to investigate the polymer coat curing effect.

[0104] The data, presented in Table 1 herein-below, demonstrated that this additional heating step shifted the average rupture time of the sildenafil core tablets from 90 minutes to an average of about 120 minutes. No clear differences in rupture time were observed among heat treatments of 1, 2 or 3 hours.

TABLE-US-00001 TABLE 1 Effect of Additional Heat Treatment on Sildenafil Core Rupture Time Additional Drying Time With End of Supply Air at 70° C. to 80° C. Parameter Spraying 1 hour 2 hours 3 hours Weight of 20 tablets (g) 6.6461 6.6040 6.6353 6.5968 (Initial testing at time zero) Rupture time (minutes) 105 110 121 117 (n = 6) 95 119 133 105 81 129 106 124 86 119 129 127 83 118 127 129 91 113 110 137 Average 90.2 118.0 121.0 123.2 Minimum 81 110 106 105 Maximum 105 129 133 137 Standard deviation 8.91 6.51 10.86 11.03

[0105] Stability of Experimental Batch With Additional Heat Treatment

[0106] Samples from the batch of Example 1 with the additional heat treatment for 1 hour and for 3 hours were stored up to 32 days under the conditions listed below. Stability data on the batch of Example 1 (i.e., coating without the additional heat treatment) served as the control for this experiment.

[0107] Samples heat-treated for 1 additional hour were stored in the open at 40° C./75% RH for 32 days.

[0108] Samples heat-treated for 3 additional hours were stored as follows: [0109] in the open at 40° C./75% RH; [0110] packed in high-density polyethylene (HDPE) bottles and stored at 40° C./75% RH; and [0111] packed in HDPE bottles and stored at 4° C. to 8° C. The results for average rupture time are presented in Table 2.

TABLE-US-00002 TABLE 2 Average Rupture Time After Storage of Experimental Batch 2112/004 Rupture Time (minutes) Additional Drying Time With Supply Air at 70° C. to 80° C. 1 hour 3 hours 3 hours 3 hours Storage Open Open HDPE HDPE Conditions 40° C./ 40° C./ Bottle Bottle 75% RH 75% RH 40° C./ 4° C.-8° C. 75% RH Storage Time (days) 0 118 123 123 123 7 121 124 nd nd 20 130 115 115 124 32 117 114 125 122 Note: nd = not determined

[0112] The results indicated that, despite the expected intrinsic variability in the rupture time of the tablets, curing was obtained by applying an additional heat treatment to the ethylcellulose polymer coat. With the curing step, no aging which might influence the swelling and water-penetration properties of the polymer coating was observed.

[0113] When these tablets prepared according to this present example 1 were cured in a perforated drum film coater for 60 min at a tablet bed temperature of 67-69° C., the undesired product stability effects did not occur.

EXAMPLE 2

[0114] 0.3 kg buspirone HC1, 4.1 kg calcium sulphate dihydrate, 4.1 kg microcrystalline cellulose and 0.36 kg croscarmellose sodium were passed through a 600 micrometer sieve in a blending container and blended until a uniform mass was obtained. Then, 0.12 kg magnesium stearate was passed through a 600 micrometer sieve and added to the blend. The blend was lubricated by tumbling the blending container for 5 minutes. The blend was transferred to a tableting machine and compressed to tablets having a core weight of 300 mg, containing about 10 mg Buspirone hydrochloride per tablet. In 14.4 liters ethanol (96%, denaturated), 432 g ethylcellulose (20 mPa.Math.s) and 864 g microcrystalline cellulose (Avicel PH105) were dispersed. The 7.2 kg buspirone core tablets were loaded in a perforated drum film coater. The ethylcellulose and microcrystalline cellulose dispersion was subsequently sprayed on the Buspirone tablets and the solvent was removed by heating, while maintaining the exhaust temperature at about 40° C.

[0115] The coated tablets were gradually cooled. Afterwards the tablets were cured in a perforated drum film coater for 60 min at a tablet bed temperature of 67-69° C.

EXAMPLE 3

[0116] In 10.1 liters of a 70:30 mixture of ethanol (96%, denatured):purified water, 18 g testosterone, 48 g of hypromellose (5 mPa.Math.s), 96 g hydroxypropyl β-cyclodextrin, 36 g aspartame and 22 g menthol were added. More specifically, the cyclodextrin was dispersed in an aliquot of purified water; all ethanol was added; the testosterone and menthol were dissolved upon stirring. Hypromellose was added to the remainder of the water and stirred until dispersed. Both liquid phases were combined. Subsequently, the aspartame was added ant stirred until dissolved. A visibly clear solution was obtained.

[0117] 7.2 kg of barrier coated tablets as prepared in Example 2 were added in a 50 cm coating pan and placed in a coating machine equipped with a Schlick model 930/7-1 S35 (1.2 mm nozzle). Using a pan speed of 19 rpm, approximately 15 cm distance from spray gun to tablets and a 300 m.sup.3/hr supply air volume, atomizing air pressure of 0.7 bar and 1.0 bar pattern air pressure and an exhaust air temperature of 40-42° C. the tablets were coated at a target spray rate of 18-22 g/min.

[0118] In this way, it was found that on an industrial scale tablets were obtained wherein testosterone was present in the spray coating layer of each individual tablet within 3.6% of the average amount. Table 3 lists the individual data, the mean, the (relative) standard deviation and the acceptance value (AV) as the USP and Ph. Eur quality standard in content uniformity testing.

TABLE-US-00003 TABLE 3 Content uniformity of testosterone in the individual tablets (in % of theoretical 0.50 mg) CU Result % 1 104.088 2 98.793 3 101.730 4 101.755 5 99.579 6 98.601 7 99.717 8 101.936 9 100.638 10 98.237 Mean 100.5 Min 98.2 Max 104.1 SD 1.860 RSD 1.9 AV 4.5