AU2007242062A1

AU2007242062A1 - Pharmaceutical compositions of oxcarbazepine with a median particle size of 15 to 30 microns

Info

Publication number: AU2007242062A1
Application number: AU2007242062A
Authority: AU
Inventors: Panagiotis Keramidas; Brett Antony Mooney
Original assignee: Alphapharm Pty Ltd
Current assignee: Alphapharm Pty Ltd
Priority date: 2006-04-21
Filing date: 2007-04-20
Publication date: 2007-11-01
Also published as: WO2007121523A1; EP2010499A4; EP2010499A1

Description

WO 2007/121523 PCT/AU2007/000522 Pharmaceutical compositions of oxcarbazepine with a median particle size of 15 to 30 microns Technical Field This invention relates to pharmaceutical compounds 5 and compositions comprising oxcarbazepine. Background Art Pharmaceutically active substances are commonly formulated into dosage forms to aid the delivery of small 10 amounts thereof. The amount of pharmaceutically active substance that will be present in oral dosage forms can vary from a very small amount such as about 0.125mg up to larger amounts such as about 1000mg, depending on the pharmaceutically active substance being used and the 15 pharmaceutical effective amount thereof. In order to be able to accurately administer these amounts of pharma ceutically active substances, the oral dosage form is often constituted of other pharmaceutically acceptable excipients that perform various functions depending on the 20 dosage form and the mode of action required. These excipients have an effect on the method and rate of delivery of the pharmaceutically active substance to the patient. Another aspect of pharmaceutical formulations that 25 affects the rate of delivery or the bioavailability of the pharmaceutically active substance is the particle size thereof. This relationship between particle size and bioavailability is well known in the pharmaceutical industry and across a range of pharmaceutical products. 30 In 1979, studies into the effect of crystal size on the bioavailability of Benoxaprofen were conducted (Biomed Mass Spectrom., 1979 Apr, 6(4), pp 173-8, Wolen RL et al; J. Pharm. Sci., 1979 Jul, 68(7), pp 850-2, Ridolfo AS et al). J. Pharm. Sci., 1980 Apr, 69(4), pp 391-4, Schoenwald 35 RD & Stewart P disclose the effect of particle size on the ophthalmic bioavailability of dexamethasone stating that "A statistically significant rank-order correlation was WO 2007/121523 PCT/AU2007/000522 -2 observed between increasing drug levels and decreasing particle size." Other examples include American Journal of Veterinary Research, 1980 Dec, 41(12), pp 2095-2101, Shastri S et al; Clinical Pharmacokinetics, 1998 Feb, 5 34(2), pp 155-62, Miller DB & Spence JD; Current Med Res Opin, 2000, 16(2), pp 134-8, Guichard JP et al; J. Microencapsul., 2001 May-June, 18(3), pp 359-71, Demirel M et al; and Pharmaceutical Dev Technol, 2004, 9(1), pp 1 13, Rasenick N & Muller BW. Also refer to US 2002035119 10 Al Rajiv, M et al; US 2003175338 Al Manoj, KP et al; WO 03/082241 A3 Kumar, PM et al; WO 03/080056 A2 (Teva Pharmaceutical Industries Ltd); and US RE37516 E Grebow, PE et al that discuss the relationship between particle size and bioavailability of the pharmaceutically active 15 substance. WO 98/35681 (Novartis) further illustrates the effect of reducing the particle size of a drug with poor aqueous solubility. The formulations disclosed therein comprise micronised oxcarbazepine particles with a median particle 20 size of between 2 to 12 microns (pm) . Such particle size enhances the dissolution rate and consequently the bioavailability. The problem with micronised particles of such a small size is that the particles can agglomerate into larger particles, thereby reducing the solubility and 25 consequently the bioavailability of the drug. Also micronising to a small particle size can also lead to stability and/or discolouration problems. Additionally, micronisation to such a small particle size requires greater energy input, more time and greater controls on 30 the micronisation process to achieve the required range whilst reducing the amount of rejected material. There is also potential for a stability problem associated with formulations of oxcarbazepine. The compound produces a faint orange discolouration attrib 35 utable to the formation of the oxidation product diketoiminodibenzyl: 10, 11-dihydro-10-oxo-5H-dibenzo [b, fI azepine-10,11-dione. This oxidation product is not WO 2007/121523 PCT/AU2007/000522 -3 considered to be pharmacologically harmful, however discolouration of the tablet is not desirable. US5472714 (Ciba-Geigy) discloses double-layered tab lets with pigmented hydrophilic, permeable inner and outer 5 coatings. The pigments generally include amounts of iron oxide for colouration, so each coating layer may include iron oxide. The Food and Drug Administration (US) has set limits for the maximum ingestion of iron oxide pigment to 5mg/day. Therefore, the amount of coating able to be used 10 may be limited by the allowable amount of iron oxide that can be ingested per day to an amount which may be below that required to overcome any discolouration problem. The above references are incorporated by reference herein where appropriate for appropriate teachings of 15 additional or alternative details, features and/or tech nical background. Bioavailability can also be increased with the use of a surfactant or wetting agent. This helps to increase the solubility of the pharmaceutically active substance and 20 thus bioavailability. However, there can be an undesired interaction between the pharmaceutically active substance and the wetting agent. Therefore, it is not always bene ficial to use a wetting agent to increase the solubility and/or bioavailability of a pharmaceutically active 25 substance. Thus there is always a need to provide improved formulations that overcome the problems of the prior art such as agglomeration and/or discolouration and to provide improved or alternative formulations that keep the bene 30 ficial properties of micronised particles, such as increase in aqueous solubility, leading to an increase in bioavailability. Summary of the Invention The inventors have found that surprisingly, a pharma 35 ceutical composition comprising oxcarbazepine of a defined particle size overcomes the above problems with prior art.

WO 2007/121523 PCT/AU2007/000522 -4 According to one aspect of the invention there is provided oxcarbazepine having a D[,O.5] value of between about 15 microns to about 30 microns and a Dry,o.

9 3 value of less than or equal to 90 microns. 5 According to a further aspect there is provided a pharmaceutical composition comprising oxcarbazepine where in said oxcarbazepine has a particle size with a DEV,o.,5 value of between about 15 microns and about 30 microns and a Dc,,o.

9 3 value of less than or equal to 90 microns. 10 Preferably the composition is in the form of an oral dosage formulation, more preferably the oral dosage formulation is a tablet and in a particularly preferred embodiment the tablet is film-coated. Alternatively, the formulation is a capsule. Another advantage of a formu 15 lation according to the invention is that it need not be taken with food. In an embodiment said oxcarbazepine has a particle size with a DfV,o..5 of between about 18 microns and about 30 microns. 20 In an embodiment, there is provided a tablet according to the invention comprising between about 100mg to 1000mg oxcarbazepine, typically 100mg to 700mg. Preferably the tablet comprises 150mg or alternatively 300mg or 600mg of oxcarbazepine. 25 According to further aspect of the invention there is provided a film-coated tablet composition comprising a core comprising between about 60 and 80% oxcarbazepine wherein said oxcarbazepine has a D[,o.

3 value of between about 15 and 30 microns and a Drv,o.

9 j value of less than or 30 equal to 90 microns, and pharmaceutically acceptable excipients. In an embodiment the excipients include crospovidone, preferably between about 2 to 10%, hypromellose (hydroxy propyl methylcellulose), preferably between about 2 to 35 10%, microcrystalline cellulose, preferably between about 0 to 20%, colloidal anhydrous silica, preferably between WO 2007/121523 PCT/AU2007/000522 -5 about 0 to 5% and magnesium stearate preferably between about 0 to 5%. In an embodiment the film-coated tablet composition comprises a core comprising about 100mg to 700mg 5 oxcarbazepine wherein said oxcarbazepine has a D[,,o.s] value of between about 15 microns and about 30 microns and a D[,,o.91 value of less than or equal to 90 microns and further comprising pharmaceutically acceptable excipients selected from crospovidone, preferably between about 10mg 10 - 80mg, and more preferably 4 to 21mg hypromellose, preferably between about 5 to 50mg, and more preferably 4 to 21mg microcrystalline cellulose, preferably between about 10mg - 100mg, and more preferably 0 to 40mg colloidal anhydrous silica, preferably between about 0 to 15 11mg and magnesium stearate preferably between about 0 to 11mg. In an embodiment the film-coated tablet composition comprises a core comprising about 150mg of oxcarbazepine, wherein said oxcarbazepine has a DrV,O.sJ value of between 20 about 15 to 30 microns and a Dty,o.

9 j value of less than or equal to 90 microns, and pharmaceutically acceptable excipients comprising 4 to 21mg of crospovidone, 4 to 21mg of hydroxypropyl methylcellulose, 0 to 42mg of microcrystalline cellulose, 0 to 11mg of colloidal 25 anhydrous silica and 0 to 11mg of magnesium stearate. In an embodiment the film-coated tablet composition comprises a core comprising about 300mg of oxcarbazepine, wherein said oxcarbazepine has a Drv,o.

5 value of between about 15 to 30 microns and a D[v,o.

9 3 value of less than or 30 equal to 90 microns, and pharmaceutically acceptable excipients comprising 8 to 42mg of crospovidone, 8 to 42mg of hydroxypropyl methylcellulose, 0 to 84mg of microcrystalline cellulose, 0 to 22mg of colloidal anhydrous silica and 0 to 22mg of magnesium stearate. 35 In an embodiment the film-coated tablet composition comprises a core comprising about 600mg of oxcarbazepine, wherein said oxcarbazepine has a DrE,O.5] value of between WO 2007/121523 PCT/AU2007/000522 -6 about 15 and microns and a DEv,O.

9 ] value of less than or equal to 90 microns, and pharmaceutically acceptable excipients comprising 16 to 84mg of crospovidone, 16 to 84mg of hydroxypropyl methylcellulose, 0 to 168mg of 5 microcrystalline cellulose, 0 to 44mg of colloidal anhydrous silica and 0 to 44mg of magnesium stearate. In another embodiment a film-coated tablet according to the invention comprises one or more coating polymers preferably the or each coating polymer is selected from 10 film-coating systems such as Opadryo or Opadry* II by Colorcon, preferably Opadry' II Buff OY-LS-37200 and Opadry® II White OY-LS-28908. In a particularly preferred embodiment, between about lmg to 20mg of the coating system is present. 15 In a further aspect the invention provides a method of treating partial seizures in patients with epilepsy comprising administering to a patient suffering from epilepsy an effective amount of oxcarbazepine or a pharmaceutical composition containing it, including a 20 film-coated tablet, as described herein. According to a further aspect the present invention provides the use of oxcarbazepine or a pharmaceutical composition containing it, including a film-coated tablet, as described herein in the treatment of partial seizures 25 in a patient with epilepsy. According to a further aspect the present invention provides the use of oxcarbazepine as described herein in the manufacture of a medicament for use in the treatment of partial seizures in a patient with epilepsy. 30 Brief Description of the Drawings Figure 1 is a flow chart illustrating a process of preparing a pharmaceutical composition in accordance with the present invention. 35 WO 2007/121523 PCT/AU2007/000522 -7 Detailed Description of the Preferred Embodiments Example 1 Manufacture of Tablet Granules 1. Weigh out the ingredients as per formula (see Table 5 1). 2. Dissolve a portion of the hypromellose in the purified water. 3. Screen the oxcarbazepine, a portion of the crospovidone and the remaining hypromellose through a 10 coarse screen, add to the granulator and mix. 4. Add solution from Step 2 to the granulator and mix to form granules. 5. Add extra water if necessary, to achieve a good granulate. 15 6. Screen the wet mass (typically through 0.5 inch screen). 7. Empty the granules into the drier and dry, such that the product and/or exhaust temperature is NMT 50 0 C. 8. Screen the granules to achieve a uniform granule 20 size. 9. Add the granules to the blender. 10. Screen the microcrystalline cellulose, the remaining crospovidone and colloidal anhydrous silica through a coarse screen, add to the contents of the blender and 25 blend. 11. Screen the magnesium stearate, add to the contents of the blender and blend. Compression of Tablets 30 1. Compress the granules to specification on a tablet press fitted with appropriate punches. Coating of Tablets 35 1. Add the Opadryo II Buff OY-LS-37200 to the purified water and mix.

WO 2007/121523 PCT/AU2007/000522 -8 2. Add the Opadryo II White OY-LS-28908 to the solution from Step 1 and mix until the Opadry' II colours have dispersed. 3. Coat the tablets using the coating solution, aiming 5 for an average tablet weight gain of approximately 3%. A flow diagram of the above process is presented in Figure 1.

WO 2007/121523 PCT/AU2007/000522 -9 Table 1 - shows tablet formulations according to the invention. Ingredients Function %/Total Active Ingredient Tablet Weight Oxcarbazepine (D [,o.

5 ] 15-30pm, D ,o.

9 3 9 90p m) Batch MMD (pm) 0307027 18.91 0405021 16.16 0406029 16.29 Active 70 0302011 24.67 0210023 Drum M2 15.38 0210023 Drum M3 17.68 0210023 Drum M1 22.52 0510052 22.52 0510053 24.71 Other tablet core ingredients Crospovidone Disintegrant 9.0 Hypromellose Binder 5.0 Water-purified Granulating Solvent q.s. Cellulose-microcrystalline Filler 11.0 Silica-colloidal anhydrous Glidant/Anticaking 1.0 agent Magnesium stearate Lubricant 1.0 Total (theoretical tablet 97.0 core weight) Film Coating Ingredients 1 Opadry II Buff OY-LS-37200 Coating 1.5 Opadry II White OY-LS-28908 Coating 1.5 Water-purified Coating solvent q.s. Total (theoretical tablet 100.00 weight) WO 2007/121523 PCT/AU2007/000522 - 10 Formulations prepared as per Table 1 exhibited improved and acceptable bioavailability and stability characteristics. 5 Of course it will be understood that the above examples are not intended to limit the scope if the invention. Various changes and modifications may be made by those skilled in the art without departing from the scope and spirit of the invention which is defined in the 10 claims below. In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprise" or variations such as 15 "comprises" or "comprising" is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention. It will be clearly understood that, although a number 20 of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country. 25

Claims

1. Oxcarbazepine having a Dtv,o. 5 s value of between about 15 microns to about 30 microns and a DEv,o. 9 ] value of less than or equal to 90 microns. 5

2. Oxcarbazepine according to claim 1 having a DEv,o.s1 value of between about 18 microns and about 30 microns. 10

3. A pharmaceutical composition comprising oxcarbazepine, wherein said oxcarbazepine has a D[,,o.s] value of between about 15 microns and about 30 microns and a D[V,O. 9 ] value of less than or equal to 90 microns, and pharmaceutically acceptable excipients. 15

4. A composition according to claim 3 wherein said oxcarbazepine has a D[v,o.

5 3 value of between about 18 microns and 30 microns. 20 5. A composition according to claim 3 or 4 in the form of an oral dosage formulation.

6. A composition according to claim 5 wherein the oral dosage formulation is a tablet. 25

7. A composition according to claim 5 wherein the oral dosage formulation is a capsule.

8. A composition according to claim 6 wherein the tablet 30 is film-coated.

9. A composition according to claim 2 or 3 comprising between about 100mg to 700mg oxcarbazepine. 35

10. A composition according to claim 9 comprising 150mg oxcarbazepine. WO 2007/121523 PCT/AU2007/000522 - 12

11. A composition according to claim 9 comprising 300mg oxcarbazepine. 5

12. A composition according to claim 9 comprising 600mg oxcarbazepine.

13. A film-coated tablet composition comprising a core comprising between about 60 and 80% oxcarbazepine, 10 wherein said oxcarbazepine has a D[,o.5] value of between about 15 and 30 microns and a DEV,o.9) value of less than or equal to 90 microns, and pharmaceutically acceptable excipients. 15

14. A tablet composition according to claim 13 wherein the pharmaceutically acceptable excipients are selected from the group consisting of about 2 to 10% crospovidone, about 2 to 10% hydroxypropyl methylcellulose, about 0 to 20% microcrystalline 20 cellulose, about 0 to 5% colloidal anhydrous silica and about 0 to 5% magnesium stearate.

15. A film-coated tablet composition comprising a core comprising about 150mg of oxcarbazepine, wherein said 25 oxcarbazepine has a DEV,o.5] value of between about 15 to 30 microns and a Dc,o.9] value of less than or equal to 90 microns, and pharmaceutically acceptable excipients comprising 4 to 21mg of crospovidone, 4 to 21mg of hydroxypropyl methylcellulose, 0 to 42mg of 30 microcrystalline cellulose, 0 to 11mg of colloidal anhydrous silica and 0 to 11mg of magnesium stearate.

16. A tablet according to any one of claims 13 to 15 wherein the film coating comprises one or more 35 coating polymers. WO 2007/121523 PCT/AU2007/000522 - 13

17. A tablet according to claim 16 wherein the or each coating polymer is selected from Opadryo II or mixtures thereof. 5

18. A film-coated tablet composition comprising a core comprising about 300mg of oxcarbazepine, wherein said oxcarbazepine has a DIV,O.53 value of between about 15 and 30 microns and a Drf,o. 9 ] value of less than or equal to 90 microns, and pharmaceutically acceptable 10 excipients comprising 8 to 42mg of crospovidone, 8 to 42mg of hydroxypropyl methylcellulose, 0 to 84mg of microcrystalline cellulose, 0 to 22mg of colloidal anhydrous silica and 0 to 22mg of magnesium stearate. 15

19. A tablet according to claim 18 wherein the film coating comprises one or more coating polymers.

20. A tablet according to claim 19 wherein the or each coating polymer is selected from Opadryo II or 20 mixtures thereof.

21. A film-coated tablet composition comprising a core comprising about 600mg of oxcarbazepine, wherein said oxcarbazepine has a D[v,o.5] value of between about 15 25 and microns and a Drv,o.9] value of less than or equal to 90 microns, and pharmaceutically acceptable excipients comprising 16 to 84mg of crospovidone, 16 to 84mg of hydroxypropyl methylcellulose, 0 to 168mg of microcrystalline cellulose, 0 to 44mg of colloidal 30 anhydrous silica and 0 to 44mg of magnesium stearate.

22. A tablet according to claim 21 wherein the film coating comprises one or more coating polymers. 35

23. A tablet according to claim 22 wherein the or each coating polymer is selected from Opadry' II or mixtures thereof. WO 2007/121523 PCT/AU2007/000522 - 14

24. A method of treating partial seizures in patients with epilepsy comprising administering to a patient suffering from epilepsy an effective amount of either 5 oxcarbazepine as claimed in claim 1 or claim 2, a pharmaceutical composition as claimed in any one of claims 3 to 12 or a film-coated tablet as claimed in any one of claims 13 to 23. 10

25. Use of oxcarbazepine as claimed in claim 1 or 2 in the manufacture of a medicament for the treatment of partial seizures in a patient with epilepsy.

26. Use of oxcarbazepine as claimed in claim 1 or 2, a 15 pharmaceutical composition as claimed in any one of claims 3 to 12 or a film-coated tablet as claimed in any one of claims 13 to 23 in the treatment of partial seizures in a patient with epilepsy.