AU2005313262A1 - Tablets for the sustained release of indapamide and preparation method thereof - Google Patents

Description

IN THE MATTER OF International Patent Application No. PCT/FR2005/003043 and IN THE MATTER OF an Application for a Patent in Australia. I, ADRIAN PAUL BROWN, M.A., M.C.I.L., M.I.T.I., employed as a translator by Abel & Imray, Chartered Patent Attorneys, of 20 Red Lion Street, London WC1 R 4PQ, do solemnly and sincerely declare that I am conversant with the English and French languages and am a competent translator thereof and that the following is a true translation to the best of my knowledge and belief of the specification as filed of International Patent Application No. PCT/FR2005/003043. DECLARED THIS 131h DAY OF APRIL 2007 A P BROWN - 1 FORMULA FOR TABLETS MAKING SUSTAINED RELEASE OF INDAPAMIDE POSSIBLE AFTER ADMINISTRATION BY THE ORAL ROUTE, AND PREPARATION PROCESS The present invention relates to the area of the formulation of medicaments. 5 More specifically, the invention relates to the formulation of tablets that comprise indapamide as active ingredient and that are intended for administration by the oral route. The present invention is accordingly directed at a tablet making sustained release of 10 indapamide possible, for use especially in the treatment of essential arterial hypertension. Said tablet does not contain polyvidone but a mixture of at least two hydrophilic cellulosic polymers of different viscosities, such as hydroxypropyl methylcelluloses, which make it possible to control that sustained release. This tablet optionally is film-coated. 15 Indapamide is known for its diuretic properties. This active ingredient is commonly prescribed as an antihypertensive agent, especially for treating essential arterial hypertension. The documents EP 519 820 and WO 2004/002475 describe formulae for matrix 20 tablets which are intended for oral administration and which make sustained release of indapamide possible, and also processes for their preparation. According to European Patent EP 519 820 (published on 6th December 1995 in the name of Adir et Compagnie), the sustained release of the active ingredient is controlled by 25 the association, in the tablets, of hydroxypropyl methylcellulose (HPMC) and polyvidone in amounts of from 30 to 50 % and from 2 to 10 %, respectively, of the total mass of a tablet. Release of indapamide that is linear for more than 8 hours is accordingly observed. In addition, 50 % of the total amount of indapamide is released between 5 and 14 hours. The blood levels in humans are from 20 to 80 ng/ml, 24 hours at most after administration 30 of the tablet by the oral route.

-2 The patent EP 519 820 also discloses a process for the preparation of such matrix tablets, using both moist granulation and direct compression. In accordance with that process, the indapamide, the polyvidone and lactose are first mixed and then moistened with an aqueous-alcoholic solution to yield a moist mass which is then granulated, dried 5 and subsequently classified. The granulate thereby obtained is mixed with HPMC and then lubricated with colloidal silica and magnesium stearate. Finally, the lubricated mixture is compressed on a rotary tablet press so that the tablets have a hardness, measured by diametral crushing, of approximately from 60 to 75 N. 10 The International Patent Application WO 2004/002475 (published on 8th January 2004 in the name of Pliva Krakow, Zaklady Farmaceutyczne S.A.) describes a tablet containing from 1.5 to 2.5 % by weight of indapamide, from 30 to 80 % by weight of lactose monohydrate, from 2 to 10 % by weight of copovidone, from 20 to 65 % by weight of hypromellose and from 0.1 to 5 % by weight of lubricants (for example, magnesium 15 stearate and/or anhydrous colloidal silica). The viscosity of the hypromellose is from 1000 to 20000 cP. The process for the preparation of the tablets in accordance with the Patent Application WO 2004/002475 comprises, firstly, mixing the indapamide with the lactose 20 monohydrate and the copovidone. The mixture is then moistened with purified water and then granulated. The granulate thereby obtained is dried, cooled, mixed with the hypromellose and with the lubricants and then compressed on a tablet press. The Applicant has found, surprisingly, contrary to the teaching of the patent 25 EP 519 820, that the association of two polymers from different chemical families, namely HPMC of high viscosity and a polyvidone, is not necessary in order to obtain perfectly controlled release of the active ingredient. The Applicant has in fact established that the association of two hydrophilic 30 cellulosic polymers, such as HPMCs, of different viscosities makes it possible to control the release of indapamide in an entirely satisfactory manner.

-3 Advantageously, the association of two polymers belonging to one and the same chemical family makes the preparation of the tablets simpler and less costly. Accordingly, in a first aspect the present invention relates to an indapamide tablet, 5 especially for the treatment of essential arterial hypertension, wherein the indapamide is associated with excipients making it possible to control its sustained release. Said excipients comprise, in the absence of polyvidone, a mixture of at least two hydrophilic cellulosic polymers of different viscosities, in amounts of approximately from 20 to 50 % by weight of a medium-viscosity or high-viscosity polymer and approximately from 0.5 to 10 10 % by weight of a low-viscosity polymer. In the formula, the low-viscosity polymer has the function of binding the various components whereas the medium-viscosity or high-viscosity polymer serves to form the matrix. 15 Release of the active ingredient takes place both by diffusion and by erosion of the matrix. In accordance with an embodiment, the mixture of at least two hydrophilic 20 cellulosic polymers comprises approximately from 25 to 45 %, preferably approximately from 30 to 35 %, more preferably approximately 31.51 %, by weight of the medium viscosity or high-viscosity polymer. Within the framework of the present invention, a medium-viscosity polymer will 25 preferably be used. In accordance with another embodiment, the mixture of at least two hydrophilic cellulosic polymers comprises approximately from 0.5 to 5 %, preferably approximately from I to 5 %, more preferably approximately 1.66 %, by weight of the low-viscosity 30 polymer.

-4 As understood by the invention, the hydrophilic cellulosic polymers are independently selected from the group comprising hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses and hydroxypropyl methylcelluloses. 5 Nevertheless it will be advantageous to use only hydroxypropyl methylcelluloses (HPMCs). HPMCs are commercially available polymers perfectly known to the skilled person and commonly used in the area of medicament formulation. By way of information, it is 10 mentioned that such polymers are marketed especially under the Trade Mark MethocelTM (distributed by companies such as Dow Chemical Co. and Colorcon). A high-viscosity HPMC can be selected from Methocel K15MTM and Methocel TM KOOM , the 2 % by weight aqueous solutions of which have viscosities of 15000 and 15 100000 cP, respectively. A medium-viscosity HPMC can be selected from Methocel E4MTM, Methocel K4MTM and Methocel K4MCR M, the 2 % by weight aqueous solutions of which have a viscosity of 4000 cP. Methocel K4MCRTM will preferably be used. 20 A low-viscosity HPMC can be selected from Methocel E5TM, Methocel E5 LVTM, Methocel E15 LVTM, Methocel E50 LVTM, Methocel K100 LVTM and Methocel F50 LVTM, the 2 % by weight aqueous solutions of which have viscosities of 5, 5, 15, 50, 100 and 50 cP, respectively. There will preferably be selected Methocel E5TM or Methocel 25 E5 LVTNI, more preferably Methocel E5 LVTM, the viscosity of a 2 % by weight aqueous solution of which is 5 cP. In accordance with another embodiment, the tablet to which the invention relates comprises, in addition to the active ingredient and the excipients already described, 30 - at least one filler such as lactose monohydrate; and/or - at least one lubricant such as magnesium stearate; and/or - at least one flow agent such as anhydrous colloidal silica.

-5 More especially, a tablet according to the invention has the following unitary formula (in mg/tablet): 5 Active ingredient: - indapamide 1.5 Excipients : - lactose monohydrate 129.00 10 - low-viscosity HPMC (e.g. Methocel E5 LVTM) 3.42 - medium-viscosity HPMC (e.g. Methocel K4MCR M) 65.00 - magnesium stearate 0.95 - anhydrous colloidal silica 0.41 15 According to another embodiment, the tablet to which the present invention relates is film-coated. In particular, the film coating a film-coated tablet according to the invention comprises: 20 - at least one binder such as a low-viscosity hydrophilic cellulosic polymer; and/or - at least one colouring agent such as titanium dioxide; and/or - at least one plasticiser such as polyethylene glycol. A particular embodiment of the film for coating a film-coated tablet in accordance 25 with the invention comprises (in mg/tablet): - low-viscosity HPMC (e.g. Methocel E5 LVTM) 4.701 - titanium dioxide 0.925 - polyethylene glycol (such as PEG 4000) 0.383 30 A preferred example of a film-coated tablet according to the invention has the following unitary formula (in mg/tablet): -6 Active ingredient: - indapamide 1.5 5 Excipients : - lactose monohydrate 129.00 - low-viscosity HPMC (e.g. Methocel E5 LV ) 3.42 - medium-viscosity HPMC (e.g. Methocel K4MCR M) 65.00 - magnesium stearate 0.95 10 - anhydrous colloidal silica 0.41 Coating : - low-viscosity HPMC (e.g. Methocel E5 LVT) 4.701 - titanium dioxide 0.925 15 - polyethylene glycol (such as PEG 4000) 0.383 A second aspect of the present invention relates to a process for the preparation of an indapamide tablet such as that described hereinbefore, which comprises at least the following steps: 20 a) mixing the indapamide and the low-viscosity hydrophilic cellulosic polymer; b) mixing the lactose and the medium-viscosity or high-viscosity hydrophilic cellulosic polymer, then moistening with the solution produced in step a), the wet mass thereby obtained then being granulated, dried and subsequently classified; c) lubrication of the granulate obtained in step b), using colloidal silica and 25 magnesium stearate; and d) compression of the lubricated mixture. At the end of the process there are preferably obtained tablets the hardness of which, measured by diametral crushing, ranges approximately from 60 to 75 N. 30 In accordance with an embodiment, the above process additionally comprises a step e) of coating the tablets produced in step d), so as to form film-coated tablets.

-7 Under those conditions, in accordance with an embodiment, the coating step e) is carried out using a film comprising: - at least one binder such as a low-viscosity hydrophilic cellulosic polymer; and/or 5 - at least one colouring agent such as titanium dioxide; and/or - at least one plasticiser such as polyethylene glycol. Preference is given to the coating film comprising at least one low-viscosity hydrophilic cellulosic polymer, polyethylene glycol and titanium dioxide. 10 Further preference is given to the low-viscosity polymer used in the coating step e) being the same as that used in step a) of the process hereinbefore. In a particular embodiment, the polyethylene glycol used in the coating step e) is 1s PEG 400 or PEG 4000. Preference will be given to PEG 4000 because of its better plasticiser properties. In order to illustrate the present invention reference may be made to the accompanying Figures. 20 The experiments, the results of which are illustrated in the accompanying Figures, were carried out using: - a film-coated tablet in accordance with Example I hereinbelow ("tablet according to the invention"); and, 25 - for reference purposes, a tablet marketed in France under the Trade Mark Fludex* 1.5 mg (SR film-coated tablet) by the company Eutherapie. The composition of the matrix tablet is that described in the above-mentioned European Patent EP 519 820 ("reference tablet"). Figure I: dissolution kinetics of tablets in an 0.01M HCl medium. 30 Figure 2 : dissolution kinetics of tablets in an 0.01M HCl medium from 0 to 2 hours and subsequently in a phosphate buffer solution at pH 6.8.

-8 Figure 3 blood concentrations of indapamide - fasting study - single administration of a tablet. Figure 4 blood concentrations of indapamide - study in the course of a meal - single administration of a tablet. 5 Figure 5 : blood concentrations of indapamide - repeated dose (1 tablet per day for 7 days). The Examples hereinbelow relate to particular embodiments, making it possible to illustrate the general description of the present invention. It is perfectly evident that the invention is in no way limited to said Examples. 10 EXAMPLES Example 1 : Example of a unitary formula for a film-coated tablet according to the 15 invention Table 1 hereinbelow provides the unitary formula for a 1.5 mg film-coated indapamide tablet (in mg/tablet). 20 Table 1 Active ingredient: Indapamide 1.5 Excipients Lactose monohydrate 129.00 HPMC (Methocel E5 LVTM 3.42 HPMC (Methocel K4MCR ) 65.00 Magnesium stearate 0.95 Anhydrous colloidal silica 0.41 Coating : HPMC (Methocel E5 LVTM) 4.701 Titanium dioxide 0.925 Macrogol (PEG 4000) 0.383 TOTAL 206.29 -9 Example 2 : Example of a process for the preparation of a tablet according to the invention 5 A. Mixing of indapamide and low-viscosity hydrophilic cellulosic polymer A. 1. Preparation of the binder solution : The HPMC Methocel E5 LVTM is dissolved in water. to A.2. Preparation of the indapamide suspension : In a stainless steel vessel provided with a stirrer, indapamide is suspended in a portion (about 80 %) of the binder solution and mixing is carried out for 10 minutes. B. Preparation of the granulate 15 B.l. Preparation of the powder mixture (lactose and HPMC K4MCRTM): Lactose monohydrate and the HPMC K4MCRTM are placed in a granulator and are mixed for 5 minutes. 20 B.2. Preparation of the granulate: The powder mixture is moistened in the granulator in the presence of the indapamide solution prepared in step A.2. The vessel containing the indapamide suspension is rinsed using the rest of the binder solution. The wet mass is then passed through a 1000-micron mesh screen. At the end of that operation, the granulate obtained is transferred to a turbine 25 to dry it. Drying time: 14 hours. After drying, the granulate is passed through a 1200-micron mesh screen.

- 10 C. Lubrication of the granulate (mixture ready for compression) The granulate is returned to the turbine. Magnesium stearate and anhydrous colloidal silica are added. All the ingredients are mixed in the turbine for 15 minutes. 5 D. Preparation of the tablets The mixture obtained in Step B. is transferred to the filling compartment of a rotary tablet press in order to produce the tablets. And, optionally: 10 E. Coating of the tablets E. 1. Coating suspension : Water is introduced into a stainless steel vessel provided with a stirrer and a homogeniser. 15 With stirring, the HPMC E5 LVTM is added and stirring is continued until dissolution is complete. When dissolution is complete, PEG 4000 is added, and then titanium dioxide, and stirring and homogenisation are carried out until a suspension is obtained. E.2. Coating of the tablets : 20 The coating film is applied to the tablets rotating in the turbine, with the aid of an automatic spraying device. At the end of this step, each tablet is coated with approximately 6 mg of film (theoretically 6.01 mg/tablet) so as to obtain an average weight of 206.29 + 5 %. Appearance: White, round, biconvex tablet. 25 Colour: White.

Claims (9)

1. Indapamide tablet, wherein the indapamide is associated with excipients making it possible to control its sustained release, characterised in that said excipients comprise, in 5 the absence of polyvidone, a mixture of at least two hydrophilic cellulosic polymers of different viscosities, in amounts of approximately from 20 to 50 % by weight of a medium viscosity or high-viscosity polymer and approximately from 0.5 to 10 % by weight of a low-viscosity polymer, it being possible for said tablet to be used especially for the treatment of essential arterial hypertension. 10

2. Tablet according to claim 1, characterised in that said mixture comprises approximately from 25 to 45 %, preferably approximately from 30 to 35 %, more preferably approximately 31.51 %, by weight of said medium-viscosity or high-viscosity polymer. 15

3. Tablet according to claim 1 or 2, characterised in that said medium-viscosity or high-viscosity polymer is a medium-viscosity polymer.

4. Tablet according to any one of claims 1 to 3, characterised in that said mixture 20 comprises approximately from 0.5 to 5 %, preferably approximately from I to 5 %, more preferably approximately 1.66 %, by weight of said low-viscosity polymer.

5. Tablet according to any one of claims 1 to 4, characterised in that said hydrophilic cellulosic polymers are independently selected from the group comprising hydroxymethyl 25 celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses and hydroxypropyl methylcelluloses.

6. Tablet according to claim 5, characterised in that said hydrophilic cellulosic polymers are hydroxypropyl methylcelluloses. 30

7. Tablet according to any one of claims I to 6, characterised in that it is film-coated. - 12

8. Tablet according to claim 7, characterised in that it has the unitary formula (in mg/tablet): Active ingredient 5 - indapamide 1.5 Excipients : - lactose monohydrate

129.00 - low-viscosity HPMC (e.g. Methocel E5 LV T) 3.42 10 - medium-viscosity HPMC (e.g. Methocel K4MCR M) 65.00 - magnesium stearate 0.95 - anhydrous colloidal silica 0.41 Coating 15 - low-viscosity HPMC (e.g. Methocel E5 LV T) 4.701 - titanium dioxide 0.925 - polyethylene glycol (such as PEG 4000) 0.383 9. Process for the preparation of an indapamide tablet according to any one of 20 claims 1 to 8, characterised in that it comprises at least the following steps: a) mixing the indapamide and the low-viscosity hydrophilic cellulosic polymer; b) mixing the lactose and the medium-viscosity or high-viscosity hydrophilic cellulosic polymer, then moistening with the solution produced in step a), the wet mass thereby obtained then being granulated, dried and subsequently classified; 25 c) lubrication of the granulate obtained in step b), using colloidal silica and magnesium stearate; and d) compression of the lubricated mixture. 10. Process according to claim 9, characterised in that it additionally comprises a 30 step e) of coating the tablets produced in step d).