WO2007121523A1

WO2007121523A1 - Pharmaceutical compositions of oxcarbazepine with a median particle size of 15 to 30 microns

Info

Publication number: WO2007121523A1
Application number: PCT/AU2007/000522
Authority: WO
Inventors: Brett Antony Mooney; Panagiotis Keramidas
Original assignee: Alphapharm Pty Ltd
Priority date: 2006-04-21
Filing date: 2007-04-20
Publication date: 2007-11-01
Also published as: AU2007242062A1; EP2010499A4; EP2010499A1

Abstract

Oxcarbazepine having a D[v,0.5] value of between about 15 microns to about 30 microns and a D[v,0.9] value of less than or equal to 90 microns.

Description

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

Technical Field

This invention relates to pharmaceutical compounds and compositions comprising oxcarbazepine.

Background Art

Pharmaceutically active substances are commonly formulated into dosage forms to aid the delivery of small 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 lOOOmg, depending on the pharmaceutically active substance being used and the pharmaceutical effective amount thereof. In order to be able to accurately administer these amounts of pharmaceutically active substances/ the oral dosage form is often constituted of other pharmaceutically acceptable excipients that perform various functions depending on the 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 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. 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 efc al ; J. Pharm. Sci . , 1979 JuI, 68(7), pp 850-2, Ridolfo AS et al) . J. Pharm. Sci., 1980 Apr, 69(4), pp 391-4, Schoenwald RD & Stewart P disclose the effect of particle size on the ophthalmic bioavailability of dexamethasone stating that

«^ΛA3 statistically significant rank-order correlation was 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, 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 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 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 size of between 2 to 12 microns (μm) . 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 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 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- utable to the formation of the oxidation product diketoiminodibenzyl : 10, ll-dihydro-10-oxo-5H-dibenzo [b, f] azepine-10, 11-dione. This oxidation product is not considered to be pharmacologically harmful, however discolouration of the tablet is not desirable.

US5472714 (Ciba-Geigy) discloses double-layered tablets with pigmented hydrophilic, permeable inner and outer 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 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 additional or alternative details, features and/or technical 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 thus bioavailability. However, there can be an undesired interaction between the pharmaceutically active substance and the wetting agent. Therefore, it is not always beneficial to use a wetting agent to increase the solubility and/or bioavailability of a pharmaceutically active 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- 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- ceutical composition comprising oxcarbazepine of a defined particle size overcomes the above problems with prior art. According to one aspect of the invention there is provided oxcarbazepine having a D_tV/0.₅] value of between about 15 microns to about 30 microns and a D_tV/0._9] value of less than or equal to 90 microns. According to a further aspect there is provided a pharmaceutical composition comprising oxcarbazepine wherein said oxcarbazepine has a particle size with a D_[V/0.₅₁ 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. 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- 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 D[_V,o.₅] of between about 18 microns and about 30 microns . In an embodiment, there is provided a tablet according to the invention comprising between about lOOmg to lOOOmg oxcarbazepine, typically lOOmg to 700mg. Preferably the tablet comprises 150mg or alternatively 300mg or 600mg of oxcarbazepine. 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_[v,₀.₅] value of between about 15 and 30 microns and a D[_V,₀.₉] value of less than or 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 10%, microcrystalline cellulose, preferably between about 0 to 20%, colloidal anhydrous silica, preferably between 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 lOOmg to 700mg oxcarbazepine wherein said oxcarbazepine has a D_[v,₀._5] value of between about 15 microns and about 30 microns and a Div,o.9] value of less than or equal to 90 microns and further comprising pharmaceutically acceptable excipients selected from crospovidone, preferably between about lOmg - 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 lOmg - lOOmg, and more preferably 0 to 40mg colloidal anhydrous silica, preferably between about 0 to llmg and magnesium stearate preferably between about 0 to llmg.

In an embodiment the film-coated tablet composition comprises a core comprising about 150mg of oxcarbazepine, wherein said oxcarbazepine has a D[_V,0.5] value of between about 15 to 30 microns and a D[_V, o.s] 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 llmg of colloidal anhydrous silica and 0 to llmg of magnesium stearate.

In an embodiment the film-coated tablet composition comprises a core comprising about 300mg of oxcarbazepine, wherein said oxcarbazepine has a D[_V,o.₅] value of between about 15 to 30 microns and a D_[v, ₀.₉] value of less than or 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. In an embodiment the film-coated tablet composition comprises a core comprising about 600mg of oxcarbazepine, wherein said oxcarbazepine has a D[_V/0.₅] value of between about 15 and microns and a D[_V/0.9] 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 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 film-coating systems such as Opadry 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. 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 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 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.

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. Detailed Description of the Preferred Embodiments

Example 1

Manufacture of Tablet Granules

1. Weigh out the ingredients as per formula (see Table 1) .

2. Dissolve a portion of the hypromellose in the purified water.

3. Screen the oxσarbazepine, a portion of the crospovidone and the remaining hypromellose through a 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. 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 50⁰C.

8. Screen the granules to achieve a uniform granule 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 blend.

11. Screen the magnesium stearate, add to the contents of the blender and blend.

Compression of Tablets

1. Compress the granules to specification on a tablet press fitted with appropriate punches.

Coating of Tablets

1. Add the Opadry^® II Buff OY-LS-37200 to the purified water and mix. 2. Add the Opadry^® 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 for an average tablet weight gain of approximately

3%.

A flow diagram of the above process is presented in Figure 1.

Table 1 - shows tablet formulations according to the invention.

Formulations prepared as per Table 1 exhibited improved and acceptable bioavailability and stability- characteristics . 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 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 "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 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.

Claims

Claims :

1. Oxcarbazepine having a D[_V.o.₅] value of between about 15 microns to about 30 microns and a D_[V/0.₉] value of less than or equal to 90 microns.

2. Oxcarbazepine according to claim 1 having a D[_Vf0.s] value of between about 18 microns and about 30 microns .

3. A pharmaceutical composition comprising oxcarbazepine, wherein said oxcarbazepine has a D[_V, 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.

4. A composition according to claim 3 wherein said oxcarbazepine has a D[_V,o.s] value of between about 18 microns and 30 microns.

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.

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 is film-coated.

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

10. A composition according to claim 9 comprising 150mg oxcarbazepine .

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

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, wherein said oxcarbazepine has a D[_V,o.₅] value of between about 15 and 30 microns and a D_[v,₀.₉] value of less than or equal to 90 microns, and pharmaceutically acceptable excipients.

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 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 oxcarbazepine has a D[_V,₀.s] value of between about 15 to 30 microns and a D[_V,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 microcrystalline cellulose, 0 to llmg of colloidal anhydrous silica and 0 to llmg of magnesium stearate.

16. A tablet according to any one of claims 13 to 15 wherein the film coating comprises one or more coating polymers.

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

18. A film-coated tablet composition comprising a core comprising about 300mg of oxcarbazepine, wherein said oxcarbazepine has a D_[V/o.5] value of between about 15 and 30 microns and a D_[Vr0.9] value of less than or equal to 90 microns, and pharmaceutically acceptable excipients comprising 8 to 42mg of crospovidone, 8 to 42mg of hydroxypropyl methylσellulose, 0 to 84mg of microcrystalline cellulose, 0 to 22mg of colloidal anhydrous silica and 0 to 22mg of magnesium stearate.

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 Opadry II or mixtures thereof.

21. A film-coated tablet composition comprising a core comprising about 600mg of oxcarbazepine, wherein said oxcarbazepine has a D[_V,o.s] value of between about 15 and microns and a D_[v,₀.₉] 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 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.

23. A tablet according to claim 22 wherein the or each coating polymer is selected from Opadry II or mixtures thereof.

24. A method of treating partial seizures in patients with epilepsy comprising administering to a patient suffering from epilepsy an effective amount of either 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.

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 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.