WO2023001880A1

WO2023001880A1 - Bilayer tablet comprising telmisartan and indapamide

Info

Publication number: WO2023001880A1
Application number: PCT/EP2022/070332
Authority: WO
Inventors: Špela KASTELIC; Jernej Zadnik; Irena HROVAT; Janika Slanc Vovk; Gregor Ritlop
Original assignee: Krka, D. D., Novo Mesto
Priority date: 2021-07-22
Filing date: 2022-07-20
Publication date: 2023-01-26

Abstract

The invention relates to a bilayer tablet comprising telmisartan in combination with indapamide. Pref- erably, the bilayer tablet provides immediate release of telmisartan and prolonged release of indapamide. The invention also provides a method of producing said bilayer tablet.

Description

Bilayer tablet comprising telmisartan and indapamide

[0001] Priority is claimed of Slovenian patent application no. P-202100143 that was filed on July 22, 2021 and of European patent application no. 21200559.9 that was filed on October 1, 2021.

[0002] The invention relates to a bilayer tablet comprising telmisartan in combination with a inda- pamide. Preferably, the bilayer tablet provides immediate release of telmisartan and prolonged release of indapamide. The invention also provides a method of producing said bilayer tablet.

[0003] Telmisartan (4'-[2-n-propyl-4-methyl-6-(l-methylbenzimidazol-2-yl)-benzimidazol-l-ylme- thyl] -biphenyl-2 -carboxylic acid) is an angiotensin II receptor antagonist developed for the treatment of hypertension and other medical indications as disclosed e.g. in EP-A-502 314. Telmisartan is generally manufactured and supplied in the form of free acid. It is very poorly soluble in aqueous systems at the physiological pH range of the gastro-intestinal tract (pH 1 to 7). As disclosed in WO 00/43370, crystal line telmisartan exists in two polymorphic forms having different melting points. Under the influence of heat and humidity, the lower melting polymorph B transforms irreversibly into the higher melting polymorph A.

[0004] Indapamide (4-chloro-N-(2-methylindolyn-l-yl)-3-sulfamoyl-benzamide) is a thiazide diuretic indicated in the treatment of hypertension and edema. Indapamide is known from e.g. US 3,565,911. Various processes for the preparation of indapamide and for pharmaceutical compositions comprising indapamide are also known from the prior art. Indapamide in a prolonged release form already exists on the market as a mono-drug product.

[0005] Several approaches to produce dosage forms comprising an angiotensin II receptor antagonist in combination with a diuretic are known from the prior art.

[0006] EP-A 2260 833 discloses the preparation of separate fdm-coated tablets comprising telmisartan and a diuretic, respectively, in such a size and shape that they can be fdled into a capsule. By dividing the doses into two to four small tablets for telmisartan and into one or two small tablets for diuretic, a capsule of size 1 to 0 long can be fdled. Y et, with this approach the drug dissolution rate of telmisartan was reduced compared to the single entities due to a lag-time effect of the large capsule shells. Further more, with regard to patients' compliance a 0 long capsule is not deemed reliable.

[0007] WO 2011/149438 discloses a combination of antihypertensive active agents; a) indapamide (thi azide diuretic), b) amlodipine (calcium channel blocker) and c) telmisartan (angiotensin II receptor an tagonist). Indapamide is present in both the immediate release and prolonged release layer. The pro longed release layer is surrounded by the immediate release layer. No specific examples are presented. [0008] EP-B 2 252 273 discloses a solid pharmaceutical composition comprising at least two layers, wherein the first layer comprises a non-peptide angiotensin II receptor antagonist or a pharmaceutically acceptable salt thereof in a dissolving matrix, and the second layer comprises a diuretic or a pharmaceu tically acceptable salt thereof.

[0009] EP-A 2 582 361 relates to a multilayer pharmaceutical tablet comprising (a) at least one first tablet layer comprising 1 to 50 wt.-% telmisartan or a pharmaceutically acceptable salt thereof by weight of the first tablet layer and (b) at least one second tablet layer comprising 1 to 50 wt.-% of a diuretic and 50 to 99 wt.-% of at least one filler by weight of the second tablet layer, wherein the combined weight of the diuretic and the at least one filler is at least 87 wt.-% by weight of the second tablet layer.

[0010] WO 2009/058950 A2 discloses pharmaceutical tablets comprising a first layer formulated for immediate release of telmisartan from a dissolving matrix and a second layer formulated for immediate release of hydrochlorothiazide from a dissolving matrix, methods for producing tablets and methods of use for treating hypertension.

[0011] WO 03/059327 A1 relates to a bilayer pharmaceutical tablet which comprises a first layer for mulated for immediate release of the angiotensin II receptor antagonist telmisartan from a dissolving tablet matrix which contains telmisartan in substantially amorphous form, and a second layer formulated for immediate release of a diuretic like hydrochlorothiazide from a fast disintegrating tablet matrix.

[0012] N. Sharma et al., Int J Pharm Sci Res, 11(5), 2020, 2385-2395 discloses a bilayered immediate- release tablets of Telmisartan and Hydrochlorothiazide for the treatment of hypertension.

[0013] H. Khan et al., Research J Pharm and Tech, 10(4), 2017, 1985-1090 relates to formulation and in-vitro evaluation of FDC bilayer matrix tablets containing telmisartan as sustained release and hydro chlorothiazide as immediate release.

[0014] CN 102 579 382 A discloses a preparation method for a slow-release tablet of an indapamide- containing medicament. In the method, water is taken as a wetting agent for performing wet granulation, and the prepared HPMC particles are compact and regular, are porous on the surface and have high liquidity.

[0015] WO 2006/061502 Al relates to a tablet for the sustained release of indapamide, which can be used for the treatment of essential arterial hypertension. The tablet contains no polyvidone, but instead a mixture of at least two hydrophilic cellulosic polymers with different viscosities, such as hydroxypro- pyl methyl celluloses, which can be used to control the sustained release.

[0016] EP-B 1 467 712 discloses a method of producing a bilayer tablet comprising the angiotensin II receptor antagonist telmisartan in combination with the diuretic hydrochlorothiazide (HCTZ). The com bination drug displays an immediate drug release profile for both active ingredients. [0017] There is indication that combination therapy of telmisartan with indapamide, wherein inda- pamide is in a prolonged release form, shows synergistic therapeutic efficacy in the treatment of hyper tension. Fixed-dose combinations of telmisartan and indapamide allow for reducing administered dos ages and/or administration frequencies, especially upon oral administration. The advantages for the pa tients are improved convenience, better assurance of compliance, reduction of severity and frequency of side effects, because such combinations maintain substantially constant blood levels and avoid the fluctuations associated with conventional immediate formulations that are administered more than once a day.

[0018] It was an object of the invention to provide a fixed-dose combination comprising telmisartan and indapamide having advantages compared to the prior art. The fixed-dose combination should pro vide immediate release of telmisartan and prolonged release of indapamide. Further, the fixed-dose combination should display the same dissolution profile as mono-products of telmisartan and inda pamide.

[0019] This object has been achieved by the subject-matter of the patent claims.

[0020] A first aspect of the invention relates to a bilayer tablet comprising

(i) a first layer comprising telmisartan and

(ii) a second layer comprising indapamide, preferably in a prolonged release matrix.

[0021] Bilayer tablets are known to the skilled person. For details, reference is made to e.g. A. Abebe et ah, Review of bilayer tablet technology, Int J Pharm. 2014 Jan 30;461(l-2):549-58. doi: 10.1016/j.ijpharm.2013.12.028.

[0022] Generally, fixed-dose combinations of active ingredients providing immediate release are pre pared by either making a powder mixture or a co-granulate of the two active ingredients with the neces sary excipients, normally keeping the basic formulation of the corresponding mono-drug preparation and simply adding the second drug component. However, when the two active ingredients should be released in a different manner, i.e. one active ingredient according to an immediate release profile, the other active ingredient according to a prolonged release profile, this approach is not feasible.

[0023] It has now been found that a fixed-dose combination can be provided in form of a bilayer tablet that comprises a first layer comprising telmisartan, preferably providing immediate release of telmisar tan, and a second layer comprising a indapamide, preferably providing prolonged release of indapamide.

[0024] During the development phase, the inventors observed that the dissolution rate of telmisartan from dosage forms comprising indapamide in a prolonged release matrix and telmisartan in an immedi ate release formulation can be reduced due to interaction of the polymer present in the prolonged release matrix. It has been found that bilayer tablets can be provided wherein the contact time between the formulation providing prolonged release of indapamide and the formulation providing immediate re lease of telmisartan is reduced after the dosage form has been exposed to a dissolution medium. Thereby, a desired dissolution profile can be achieved that is similar or equal to the dissolution profile of the corresponding mono-drug preparations.

[0025] Further, it has been found that bilayer tablets overcome stability problems that are otherwise caused by the incompatibility of indapamide with basic constituents that are advantageously contained in the formulation providing immediate release of telmisartan.

[0026] Unless expressly stated otherwise, all percentages are expressed as weight percent. Unless ex pressly stated otherwise, all percentages are based on the total weight of the corresponding layer of the bilayer tablet according to the invention.

[0027] As used herein, the term " substantially amorphous " refers to a product comprising amorphous constituents in a proportion of at least 90 wt.-%, preferably at least 95 wt.-%, as determined by X-ray powder diffraction measurement.

[0028] According to The Council of Europe, Standard Terms, Introduction and Guidance for Use, ver sion 2.1.3, 16 November 2018, release characteristics describe the timing by which an active ingredient is made available in the body after administration of the pharmaceutical product, in comparison with a conventional, direct release of the active ingredient. Examples of release characteristics include " de layed ", " prolonged " and "conventional'' .

[0029] The term "immediate release" (sometimes also referred to as "conventional release") refers to fast dissolution characteristics such that the active ingredient telmisartan readily dissolves in a physio logical aqueous medium. The term " immediate release" has a well-acknowledged meaning in the art. Preferably, "immediate release" means that in an in vitro dissolution test according to Ph. Eur., basket method (20 mesh), 100 rpm, in 900 mL pH 6.8 phosphate buffer and at 37°C after 30 minutes at least 70 wt.-% of the active ingredient have been dissolved (released), relative to the total amount of this active ingredient that was originally contained in the dosage form (bilayer tablet).

[0030] The term "prolonged release" refers to release characteristics such that that the active ingredient indapamide is gradually released over time, allowing for a sustained effect. Preferably, "prolonged re lease" means that in an in vitro dissolution test according to Ph. Eur., paddle method, 100 rpm (tablets in Japanese sinkers (JS)), in 900 mL pH 6.8 phosphate buffer and at 37°C after 60 minutes not more than 50 wt.-% of the active ingredient have been dissolved (released), relative to the total amount of this active ingredient that was originally contained in the dosage form (bilayer tablet).

[0031] The term "prolonged release matrix" refers to a formulation where the active ingredient is em bedded in a material that causes prolonged release (sustained release) of this active ingredient from the formulation. [0032] The term “ water soluble diluent ” means an excipient, which is substantially soluble in water at room temperature.

[0033] The term “ water insoluble diluent ” means an excipient that is insoluble or very poorly soluble in an aqueous environment.

[0034] The bilayer tablet according to the invention comprises a first layer comprising telmisartan, preferably in a substantially amorphous form, preferably providing immediate release, and a second layer comprising a indapamide, preferably providing prolonged release.

[0035] According to the specification, "telmisartan" refers to the free acid of telmisartan or any physi ologically acceptable salt thereof. For the purpose of the specification, unless expressly stated otherwise, all amounts and percentages refer to the equivalent weight of the free acid of telmisartan.

[0036] Preferably, the bilayer tablet according to the invention comprises the free acid or physiologi cally acceptable salt of telmisartan. Preferably, the bilayer tablet according to the invention comprises physiologically acceptable salt of telmisartan formed in situ with one or more of the other constituents that are contained in the first layer of the bilayer tablet according to the invention, e.g. basic agents.

[0037] Preferably, the bilayer tablet according to the invention comprises telmisartan in substantially amorphous form. Substantially amorphous telmisartan may be produced by any suitable method known to those skilled in the art, for instance, fluid bed granulation, by freeze drying of aqueous solutions, coating of carrier particles in a fluidized bed, spray drying of telmisartan solution, by hot melt techniques and solution deposition on sugar pellets or other carriers.

[0038] Preferably, the first layer of the bilayer tablet according to the invention provides immediate release of telmisartan. In preferred embodiments, the first layer comprises telmisartan in substantially amorphous form dispersed in a disintegrating matrix having immediate release (fast dissolution) char acteristics. The disintegrating matrix may have acidic, neutral or basic properties. Preferably, the disin tegrating matrix has basic properties that are preferably based upon the presence of one or more basic agents.

[0039] In a particular preferred embodiment, the first layer comprises an intragranular phase and an extragranular phase. Preferably, telmisartan is incorporated intragranularly.

[0040] Preferably, the first layer of the bilayer tablet according to the invention comprises essentially the total amount of telmisartan that is contained in the bilayer tablet, i.e. the second layer of the bilayer tablet according to the invention preferably comprises no telmisartan.

[0041] Preferably, the first layer comprises 3 to 35 wt.-%, preferably 5 to 25 wt.-% of telmisartan, relative to the total weight of the first layer. [0042] The second layer of the bilayer tablet according to the invention comprises indapamide.

[0043] According to the specification, " indapamide " refers to the non-salt form or any physiologically acceptable salt thereof. For the purpose of the specification, unless expressly stated otherwise, all amounts and percentages refer to the equivalent weight of the non-salt form of the indapamide.

[0044] Preferably, the bilayer tablet according to the invention comprises the non-salt form of inda pamide. Preferably, the bilayer tablet according to the invention comprises no physiologically accepta ble salt of indapamide. However, it is contemplated that indapamide may form a salt with one or more of the other constituents that are contained in the second layer of the bilayer tablet according to the invention.

[0045] The indapamide, is preferably employed as a fine-crystalline powder, optionally in fine-milled, peg-milled or micronized form. For instance, the particle size distribution of indapamide, as determined by laser diffraction is preferably as follows: dlO: < 20 pm, preferably 1 to 10 pm; d50: < 50 pm, preferably 5 to 30 pm; and d90: < 100 pm, preferably 15 to 80 pm.

[0046] Preferably, the second layer of the bilayer tablet according to the invention comprises essentially the total amount of indapamide, that is contained in the bilayer tablet, i.e. the first layer of the bilayer tablet according to the invention preferably comprises no thiazide diuretic, preferably no indapamide.

[0047] In preferred embodiments, the bilayer tablet according to the invention comprises one or more additional active ingredients, i.e. besides telmisartan and indapamide. Said one or more additional active ingredients may independently of one another be contained in the first layer or the second layer. When an additional active ingredient is contained in the first layer, it is preferably dissolved according to an immediate release. When an additional active ingredient is contained in the second layer, it is preferably dissolved according to a prolonged release.

[0048] In other preferred embodiments, telmisartan and indapamide, are the only active ingredients that are contained in the bilayer tablet according to the invention.

[0049] Preferably, besides telmisartan, the first layer comprises one or more excipients. Pharmaceutical excipients (adjuvants) that are suitable for the preparation of immediate release formulations are known to the skilled person. Preferably, the one or more excipients are independently of one another selected from disintegrants, basic agents, binders, carriers, diluents such as water-soluble diluents and water- insoluble diluents, lubricants, flow control agents, crystallization retarders, solubilizers, coloring agents, pH control agents, surfactants and emulsifiers. [0050] In particularly preferred embodiments, the first layer of the bilayer tablet according to the in vention comprises at least one basic agent, at least one diluent, at least one disintegrant and optionally, other excipients.

[0051] Preferred other excipients and their preferred weight contents are as follows

- binders such as cellulose derivatives like hydroxymethylcellulose, hydroxyethylcellulose, hydroxy- propylcellulose and hydroxypropylmethylcellulose (hypromellose), polyvinyl pyrrolidone (pov idone); preferably at a weight content of from 0.5 to 10 wt.-% , more preferably 1 to 7 wt.-%, relative to the total weight of the first layer;

- lubricants such as stearic acid, magnesium stearate, sodium stearylfumarate, glycerol tribehenate, etc.; preferably at a weight content of from 0.1 to 5 wt.-%, more preferably 0.5 to 3 wt.-%, relative to the total weight of the first layer;

- flow control agents such as colloidal silica, talc, etc..; preferably at a weight content of from 0.1 to 5 wt.-%, more preferably 0.3 to 2 wt.-%, relative to the total weight of the first layer;

- crystallization retarders (crystallization inhibitors) such as povidone, etc.; preferably at a weight con tent of from 1 to 10 wt.-%, more preferably 2 to 8 wt.-%, relative to the total weight of the first layer;

- solubilizers such as pluronic, povidone, etc.; preferably at a weight content of from 1 to 10 wt.-%, more preferably 2 to 8 wt.-%, relative to the total weight of the first layer;

- coloring agents, including dyes and pigments such as iron oxide red, yellow, brown or black, titanium dioxide, calcium based pigments, etc.; preferably at a weight content of from 0.05 to 1.5 wt.-%, more preferably 0.1 to 0.8 wt.-%, relative to the total weight of the first layer;

- pH control agents such as sodium citrate, dibasic calcium phosphate, dibasic sodium phosphate, tert- butylamine, ethanolamine, etc.; preferably at a weight content of from 0.5 to 10 wt.-%, more prefer ably 2 to 8 wt.-%, relative to the total weight of the first layer;

- surfactants and emulsifiers such as pluronic, polyethylene glycols, sodium carboxymethyl cellulose, polyethoxylated and hydrogenated castor oil, etc.; preferably at a weight content of from 0.01 to 5 wt.-%, more preferably 0.05 to 1 wt.-%, relative to the total weight of the first layer; and mixtures of two or more of these excipients.

[0052] The above excipients can be incorporated intragranularly or extragranularly. The excipients for the first layer are preferably chosen such that a non-acidic, fast disintegrating tablet matrix is obtained.

[0053] Preferably, the first layer comprises a disintegrant. Preferred disintegrants are selected from crospovidone, starch, maize starch, pregelatinized starch, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose, sodium and/or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose (e.g. croscarmellose sodium and/or croscarmellose calcium), polacrilin potas sium, low substituted hydroxypropylcellulose, sodium and/or calcium alginate, docusate sodium, methylcellulose, agar, guar gum, chitosan, alginic acid or mixtures thereof. More preferred disintegrants are selected from sodium starch glycolate, crospovidone, carboxymethylcellulose sodium, and croscar mellose sodium. Particularly preferred disintegrants are selected from croscarmellose sodium and cro spovidone.

[0054] Preferably, the disintegrant is incorporated extragranularly.

[0055] Preferably, the weight content of the disintegrant is within the range of from 1 to 20 wt.-%, preferably 2 to 15 wt.-%, relative to the total weight of the first layer.

[0056] Preferably, the first layer comprises a basic agent. Preferably, the basic agent is selected from alkali metal hydroxides, basic amino acids and amino sugar such as meglumine. Specific examples of suitable basic agents are alkali metal hydroxides such as NaOH and KOH; basic amino acids such as arginine and lysine; and meglumine (N-methyl-D-glucamine), NaOH and meglumine being preferred. It is particularly preferred that the basic agent comprises a mixture of an alkali metal hydroxide such as NaOH or KOH and an amino sugar such as meglumine in a weight ratio of 1 : 1 to 1:10, more particularly 1:2 to 1:5, more preferably 1:3 to 1:4.

[0057] Preferably, the basic agent is incorporated intragranularly.

[0058] Preferably, the weight content of the basic agent is within the range of from 0.25 to 20 wt.-%, preferably 0.40 to 15 wt.-%, relative to the total weight of the first layer.

[0059] Diluent in the first layer comprising telmisartan can be selected from water soluble and/or water insoluble diluents. Preferably the diluent is incorporated intragranularly and extragranularly. Preferably, the water-soluble diluent is selected from

(a) carbohydrates; preferably monosaccharides; more preferably glucose;

(b) oligosaccharides; preferably sucrose, lactose, or mixtures thereof; and

(c) sugar alcohols; preferably sorbitol, mannitol, dulcitol, ribitol, xylitol, or mixtures thereof.

[0060] The water-soluble diluent is preferably selected from anhydrous lactose, spray-dried lactose and lactose monohydrate, or a mixture thereof.

[0061] The water-insoluble diluent can be selected from the group consisting of water-insoluble poly saccharides, salts of alkaline or earth alkaline metals or mixture thereof, preferably it is selected from cellulose, starch and calcium, sodium or potassium salts of phosphoric acid, carbonic acid or sulphuric acid. The polysaccharide is preferably a polysaccharide comprising from 200 to 10,000 monosaccharide residues, preferably 500 to 10,000 monosaccharide residues, preferably glucose residues. The polysac- charide is preferably cellulose and/or starch. Cellulose may be selected from powdered cellulose, mi crocrystalline cellulose, silicified microcrystalline cellulose, most preferably microcrystalline cellulose is used. Starch may be selected from com starch, potato starch, rice starch, wheat starch, cassava starch, potato starch, pregelatinized starch. The water insoluble diluent is preferably selected from microcrys- talline cellulose.

[0062] The weight content of the diluent is within the range of from 35 to 90 wt.-%, preferably 50 to 85 wt.-%, relative to the total weight of the first layer.

[0063] Preferably, the first layer comprising telmisartan comprises a mixture of water-soluble diluent and water-insoluble diluent. Preferably, the weight content of the water-soluble diluent is within the range of from 5 to 40 wt.-%, preferably 7 to 30 wt.-%, relative to the total weight of the first layer. Preferably, the weight content of the water-insoluble diluent is within the range of from 30 to 80 wt.-%, preferably 40 to 75 wt.-%, relative to the total weight of the first layer. Preferably, the water-soluble diluent is incorporated intragranularly and the water insoluble excipient is incorporated extragranularly.

[0064] In preferred embodiments, the first layer comprises an intragranular phase and an extragranular phase.

[0065] Preferably, essentially the total amount of telmisartan that is contained in the first layer is con tained in the intragranular phase of the first layer.

[0066] Preferably, the extragranular phase of the first layer comprises a disintegrant; wherein the dis- integrant is preferably selected from crospovidone, starch, maize starch, pregelatinized starch, sodium starch glycolate, hydroxypropyl starch, sodium and/or calcium salts of carboxymethyl cellulose, cross- linked carboxymethylcellulose, polacrilin potassium, low substituted hydroxypropylcellulose, sodium and/or calcium alginate, docusate sodium, methylcellulose, agar, guar gum, chitosan, alginic acid and mixtures thereof; preferably from crospovidone, carboxymethylcellulose sodium, croscarmellose so dium, and mixtures thereof.

[0067] In particularly preferred embodiments, the extragranular phase of the first layer comprises croscarmellose sodium.

[0068] In further particularly preferred embodiments, the extragranular phase of the first layer com prises crospovidone.

[0069] Preferably, the weight content of the disintegrant, preferably croscarmellose sodium or cro spovidone, is within the range of from 1 to 20 wt.-%, preferably 2 to 15 wt.-%, relative to the total weight of the first layer.

[0070] In preferred embodiments, the extragranular phase of the first layer comprises a diluent, prefer ably a water-insoluble diluent. [0071] Preferably, the diluent is selected from the group consisting of water-insoluble polysaccharides, salts of alkaline or earth alkaline metals or mixture thereof; preferably from cellulose, starch and cal cium, sodium or potassium salts of phosphoric acid, carbonic acid or sulphuric acid; more preferably from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose; most prefera bly microcrystalline cellulose.

[0072] Preferably, the weight content of the diluent, preferably microcrystalline cellulose, is within the range of from 15 to 60 wt.-%, preferably 20 to 50 wt.-%, relative to the total weight of the first layer.

[0073] In particularly preferred embodiments, the first layer comprises

- 3 to 35 wt.-%, preferably 5 to 25 wt.-% of telmisartan;

- 0.25 to 20 wt.-%, preferably 0.40 to 15 wt.-% of basic agent;

- 35 to 90 wt.-%, preferably 50 to 85 wt.-% of diluent; and

- 1 to 20 wt.-%, preferably 2 to 15 wt.-% of disintegrant in each case relative to the total weight of the first layer.

[0074] In particularly preferred embodiments, the first layer comprises

- 3 to 35 wt.-%, preferably 5 to 25 wt.-% of telmisartan;

- 0.25 to 20 wt.-%, preferably 0.40 to 15 wt.-% of basic agent;

- 5 to 40 wt.-%, preferably 7 to 30 wt.-% of water-soluble diluent;

- 30 to 80 wt.-%, preferably 40 to 75 wt.-% of water-insoluble diluent; and

[0075] The second layer of the bilayer tablet according to the invention comprises indapamide, in a prolonged release tablet matrix. Preferably, indapamide in embedded in the prolonged release tablet matrix.

[0076] Preferably, the second layer comprises one or more excipients are independently of one another selected from diluents, gel-forming polymers, antioxidants, glidants, and lubricants.

[0077] Preferably, the second layer and/or the prolonged release matrix comprises a diluent. Preferred diluents include but are not limited to cellulose powder, microcrystalline cellulose, dibasic calcium phosphate, com starch, pregelatinized starch, carbohydrates such as monosaccharides like glucose; oli gosaccharides like sucrose, anhydrous lactose and lactose monohydrate; and sugar alcohols like sorbitol, mannitol, dulcitol, ribitol and xylitol. [0078] Preferably, the second layer and/or the prolonged release matrix comprises other excipients. Preferred other excipients are selected from

- binders such as polyvinyl pyrrolidone (povidone) etc.;

- disintegrants such as sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethyl- cellulose and dried com starch;

- lubricants such as stearic acid, magnesium stearate, sodium stearylfumarate, glycerol tribehenate, etc.;

- flow control agents such as colloidal silica, talc, etc.;

- solubilizers such as Pluronic, Povidone, etc.;

- antioxidants such as butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbic acid, sodium ascorbate, propyl gallate, cysteine, alpha-tocopherol or a mixture thereof;

- coloring agents, including dyes and pigments such as iron oxide red, yellow, brown or black, titanium dioxide, etc.;

- pH control agents such as citric acid, tartaric acid, fumaric acid, sodium citrate, dibasic calcium phos phate, dibasic sodium phosphate, etc.;

- surfactants and emulsifiers such as pluronic, polyethylene glycols, sodium carboxymethyl cellulose, polyethoxylated and hydrogenated castor oil, etc.; and mixtures of two or more of these excipients.

[0079] Preferably, the prolonged release matrix of the second layer comprises a gel-forming polymer.

[0080] In preferred embodiments, the prolonged release matrix of the second layer comprises an ani onic gel-forming polymer. Preferred anionic gel-forming polymers include but are not limited to acrylic acid polymerizate, methacrylic acid copolymers, alginates, carrageenans, acacia, xanthan gum, chitin derivates such as chitosan, carmellose sodium, carmellose calcium; preferably acrylic acid polymerizate, such as a carbomer (Carbopol^® copolymer).

[0081] Preferably, the anionic gel-forming polymer is selected from the group consisting of sodium carboxymethylcellulose, carboxymethyl cellulose, anionic polysaccharides, anionic gums, polymers of acrylic acid, carbomers (Carbopol^® copolymers), crosslinked copolymers of acrylic acid and a hydro- phobic Cl 0-30 alkyl acrylate co-monomers (Pemulen^® polymers), and polycarbophils.

[0082] The anionic gel-forming polymer(s) is (are) preferably incorporated extragranularly.

[0083] In preferred embodiments, the prolonged release matrix of the second layer comprises a non ionic gel-forming polymer. [0084] Preferred non-ionic gel-forming polymers according to the invention include but are not limited to

- alkylcelluloses, such as, methylcellulose;

- hydroxyalkylcelluloses, for example, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypro- pylcellulose or hydroxybutylcellulose;

- hydroxyalkyl alkylcelluloses, such as, hydroxyethyl methylcellulose and hydroxypropyl methyl- cellulose;

- carboxyalkylcellulose esters;

- other natural, semi- synthetic, or synthetic di-, oligo- and polysaccharides such as galactomannans, tragacanth, agar, guar gum, and polyfructans;

- methacrylate copolymers;

- polyvinylalcohol;

- polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate;

- combinations of polyvinylalcohol and polyvinylpyrrolidone; and

- polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide.

[0085] Particularly preferred non-ionic gel-forming polymers are cellulose ether derivatives such as hydroxypropyl methylcellulose and hydroxypropyl cellulose, most preferably hydroxypropyl methyl cellulose.

[0086] Different viscosity grades of hydroxypropyl cellulose and hydroxypropyl methylcellulose are commercially available. Hydroxypropyl methylcellulose (HPMC) preferably used in the invention has a viscosity grade ranging from about 100 mPa to about 100,000 mPa.

[0087] Hydroxypropyl methylcellulose polymers are preferably selected from the group consisting of HPMC K100 LV, HPMC K15M, HPMC K100M and HPMC K4M, more preferably selected from HPMC K4M and HPMC K100M, most preferably selected from HPMC K4M.

[0088] Preferably, the nonionic gel-forming polymer is hydroxypropyl methylcellulose (HPMC, hypro- mellose), preferably selected from the group consisting of HPMC K100 LV, HPMC K15M, HPMC K100M and HPMC K4M. These polymers are commercially available. Representative properties of the HPMC grades K100 LV, HPMC K100M and HPMC K4M according to the invention are compiled in the following table:

[0089] The non-ionic gel-forming polymer(s) is (are) preferably incorporated intragranularly and ex- tragranularly.

[0090] In preferred embodiments, HPMC K4M is contained in the prolonged release matrix both, in tragranularly and extragranularly. The weight ratio of the intragranular HPMC K4M and the extragran- ular HPMC K4M is preferably in the range from 100:0 to 50:50, more preferably 90: 10 to 80:20, most preferably about 84:16.

[0091] Preferably, the prolonged release matrix of the second layer comprises two gel-forming poly mers.

[0092] In a preferred embodiment, the prolonged tablet matrix comprises at least one, preferably at least two gel-forming polymers, preferably together with a diluent, and, optionally, other excipients.

[0093] In preferred embodiments, the at least two gel-forming polymers comprise at least one non ionic gel-forming polymer and at least one anionic gel-forming polymer. Preferably, the prolonged re lease tablet matrix comprises at least one non-ionic gel-forming polymer and one anionic gel-forming polymer. More preferably the prolonged release tablet matrix comprises one non-ionic gel-forming pol ymer and one anionic gel-forming polymer.

[0094] The prolonged release matrix preferably comprises at least one anionic gel-forming polymer, preferably a carbomer (Carbopol^® copolymer), and at least one non-ionic polymer, preferably selected from HPMC K100M and HPMC K4M.

[0095] In preferred embodiments, the prolonged release matrix of the second layer comprises a non ionic gel-forming polymer and an anionic gel-forming polymer. Preferably, the anionic gel-forming polymer is selected from the group consisting of sodium carboxymethylcellulose, carboxymethyl cellu lose, anionic polysaccharides, anionic gums, polymers of acrylic acid, carbomers (Carbopol^® copoly mers), crosslinked copolymers of acrylic acid and a hydrophobic Cl 0-30 alkyl acrylate co-monomers (Pemulen^® polymers), and polycarbophils. Preferably, the anionic gel-forming polymer is a carbomer (Carbopol^® copolymer) and the non-ionic gel-forming polymer is HPMC K100M or HPMC K4M.

[0096] In preferred embodiments, the at least two gel-forming polymers comprise two non-ionic gel forming polymers. The two non-ionic gel-forming polymers can have the same chemistry, i.e. can be derived from the same monomers, wherein said polymers differ in at least one parameter selected from the group consisting of solubility, viscosity and molecular weight. [0097] When the prolonged release matrix comprises more than one non-ionic gel-forming polymer, the preferred combination of non-ionic gel-forming polymers is a mixture of HPMC K100M and HPMC K4M.

[0098] When the prolonged release matrix comprises two non-ionic gel-forming polymers, like a mix ture of HPMC K4M and HPMC K100M, the relative weight ratio is preferably within the range of 40:60 to 80:20.

[0099] In preferred embodiments, the prolonged release matrix of the second layer comprises a first non-ionic gel-forming polymer and a second non-ionic gel-forming polymer which is different from the first non-ionic gel-forming polymer. Preferably, the first non-ionic gel-forming polymer and the second non-ionic gel-forming polymer are derived from the same monomers but differ in at least one parameter selected from the group consisting of solubility, viscosity and molecular weight. Preferably, the first non-ionic gel-forming polymer and the second non-ionic gel-forming polymer are selected from the group consisting of HPMC K100 LV, HPMC K100M and HPMC K4M. Preferably, the first non-ionic gel-forming polymer is HPMC K100M and the second non-ionic gel-forming polymer is HPMC K4M.

[0100] Preferably, the prolonged release matrix of the second layer comprises three gel-forming poly mers.

[0101] Preferably, the prolonged release matrix of the second layer comprises an anionic gel-forming polymer, a first non-ionic gel-forming polymer, and a second non-ionic gel-forming polymer which is different from the first non-ionic gel-forming polymer.

[0102] Preferably the anionic gel-forming polymer is a carbomer (Carbopol^®) copolymer, the first non ionic gel-forming polymer is HPMC K100M, and the second non-ionic gel-forming polymer is HPMC K4M.

[0103] In preferred embodiments, the second layer (indapamide layer) has a total content of gel-form ing polymers, preferably one or more non-ionic gel-forming polymers and/or one or more anionic gel forming polymers of the prolonged release matrix, amounting to at least 25 wt.-%, preferably at least 30 wt.-%, more preferably at least 35 wt.-%, still more preferably at least 40 wt.-%, yet more preferably at least 45 wt.-%, most preferably at least 50 wt.-%, in each case relative to the total weight of the second layer (indapamide layer).

[0104] In preferred embodiments, the second layer (indapamide layer) has an intragranular phase and an extragranular phase, wherein essentially the total amount of indapamide that is contained in the sec ond layer (indapamide layer) is contained in the intragranular phase, and wherein the intragranular phase has a total content of gel-forming polymers, preferably one or more non-ionic gel-forming polymers and/or one or more anionic gel-forming polymers of the prolonged release matrix, amounting to at least 25 wt.-%, preferably at least 30 wt.-%, more preferably at least 35 wt.-%, still more preferably at least 40 wt.-%, yet more preferably at least 45 wt.-%, most preferably at least 50 wt.-%, and in particular at least 55 wt.-%, in each case relative to the total weight of the intragranular phase.

[0105] In particularly preferred embodiments, the prolonged release matrix comprises

- 30 to 60 wt.-%, preferably 40 to 55 wt.-% of non-ionic gel-forming polymer(s), and

- 1 to 10 wt.-%, preferably 1 to 5 wt.-% of anionic gel-forming polymer(s), in each case relative to the total weight of the second layer.

[0106] In preferred embodiments, the relative weight ratio between

- the total content of all non-ionic gel-forming polymers that are contained in the prolonged release matrix of the second layer and

- the total content of all anionic gel-forming polymers that are contained in the prolonged release ma trix of the second layer is within the range of from 30: 1 to 10:1, preferably 25:1 to 15: 1, more preferably 21: 1 to 19: 1; or 10:1 to 20:1.

[0107] In particularly preferred embodiments, the second layer and/or the prolonged release matrix comprises

- 0.1 to 10 wt.-%, preferably 0.2 to 5 wt.-%, most preferably 0.5 to 2 wt.-% of indapamide;

- 25 to 75 wt.-%, preferably 35 to 65 wt.-%, of diluent;

- 30 to 70 wt.-%, preferably 35 to 65 wt.-%, of gel-forming polymer, wherein the gel-forming polymer comprises 30 to 60 wt.-%, preferably 40 to 55 wt.-% of one or more non-ionic gel forming polymers, and 1 to 10 wt.-%, preferably 1 to 5 wt.-% of one or more anionic gel-forming polymers;

- 0 to 2 wt.-%, preferably 0 to 1.5 wt.-%, of antioxidant;

- 0.5 to 5 wt.-%, preferably 1 to 2 wt.-%, of glidant; and

- 0.1 to 3 wt.-%, preferably 0.5 to 2 wt.-% of lubricant; in each case relative to the total weight of the second layer and/or the prolonged release matrix.

[0108] The other excipients are generally employed in the same amount as in the telmisartan tablet layer composition.

[0109] In particularly preferred embodiments, the second layer and/or the prolonged release matrix comprises

- 0.5 to 2 wt.-% of indapamide;

35 to 65 wt.-%, of diluent; - 35 to 65 wt.-% of gel-forming polymer, wherein the gel-forming polymer comprises 40 to 55 wt.-%, preferably 50 wt.-%, of one or more non-ionic gel forming polymers and 1 to 5 wt.-%, preferably 2.5 wt.-%, of one or more anionic gel-forming polymers;

- 0 to 1.5 wt.-% of antioxidant;

- 1 to 2 wt.-% of glidant; and

- 0.5 to 2 wt.-% of lubricant; in each case relative to the total weight of the second layer and/or the prolonged release matrix.

[0110] In preferred embodiments, the bilayer tablet according to the invention is fdm-coated. In other preferred embodiments, the bilayer tablet according to the invention is not fdm-coated.

[0111] Preferably, the bilayer tablet according to the invention comprises 10 to 160 mg, more prefera bly 20 to 80 mg, of telmisartan and 0.1 to 10 mg, preferably 0.5 to 5 mg, more preferably 1.0 to 2.0 mg, most preferably 1.5 mg of indapamide. Particularly preferred bilayer tablets comprise 40 mg/1.5 mg or 80 mg/1.5 mg of telmisartan/indapamide, respectively.

[0112] The bilayer tablet according to the invention releases the telmisartan rapidly, with complete release preferably occurring within less than 30 min, and release of the major fraction preferably occur ring within less than 15 min. The dissolution kinetics of the bilayer tablet may be controlled in different ways. For instance, both layers may dissolve/disintegrate simultaneously or subsequently and independ ent from each other. Preferably, however, the first and second tablet layer dissolve/disintegrate inde pendently from each other. In a preferred way, the two layers separate from each other in a short time period which is demonstrated by separation times of 10 minutes or less, preferably of less than 6 minutes, more preferably less than 4 minutes, most preferably less than 3 minutes, and in particular 2 minutes or less, as determined by disintegration under static conditions in phosphate buffer medium having pH 6.8 or in acetate buffer medium having pH 4.5, preferably in phosphate buffer medium having pH 6.8. The specified separation time and dissolution release kinetics of telmisartan had significant impact on reach ing therapeutic telmisartan plasma concentration levels.

[0113] In preferred embodiments, the bilayer tablet according to the invention provides an in vitro dis solution profile using USP I method (basket apparatus, 20 mesh size) at 100 RPM in 900 mL phosphate buffer medium having pH 6.8, at a temperature of the dissolution medium of 37°C±0.5°C, such that after 5 minutes, relative to the total content of telmisartan that was initially contained in the bilayer tablet, at least 15 wt.-%, preferably at least 17.5 wt.-%, more preferably at least 20 wt.-%, still more preferably at least 22.5 wt.-%, yet more preferably at least 25 wt.-%, even more preferably at least 27.5 wt.-%, most preferably at least 30 wt.-%, and in particular at least 32.5 wt.-% of the telmisartan have been dissolved. [0114] In preferred embodiments, the bilayer tablet according to the invention provides an in vitro dis solution profde using USP I method (basket apparatus, 20 mesh size) at 100 RPM in 900 mL phosphate buffer medium having pH 6.8, at a temperature of the dissolution medium of 37°C±0.5°C, such that after 10 minutes, relative to the total content of telmisartan that was initially contained in the bilayer tablet, at least 57.5 wt.-%, preferably at least 60 wt.-%, more preferably at least 62.5 wt.-%, still more preferably at least 65 wt.-%, yet more preferably at least 67.5 wt.-%, even more preferably at least 70 wt.-%, most preferably at least 72.5 wt.-%, and in particular at least 75 wt.-% of the telmisartan have been dissolved.

[0115] Preferably, the bilayer tablet according to the invention is for use in the treatment of hyperten sion.

[0116] Preferably, the bilayer tablet according to the invention is for oral administration, preferably once daily or twice daily, more preferably once daily.

[0117] Another aspect of the invention relates to a packaging comprising a bilayer tablet according to the invention as described above packaged in a moisture proof packaging material; preferably selected from aluminum foil blister packs and HDPE containers.

[0118] The bilayer tablets of the invention may be packaged using a moisture-proof packaging material such as aluminum foil blister packs, or HDPE containers, which preferably comprise a desiccant.

[0119] To avoid oxidative degradation of active agents and other ingredients susceptible to such deg radation, the composition may be packaged into a primary packaging, such as a low gas permeable pri mary packaging, in an inert atmosphere such as nitrogen, argon or xenon, wherein nitrogen is especially preferred. This would provide for a decreased concentration of oxygen in the atmosphere surrounding the dosage form in the primary packaging such as for example a blister, strip, glass or plastic container.

[0120] As used herein, the term "decreased concentration of oxygen" means that the concentration of oxygen in the atmosphere surrounding the individual dosage form is below 10 vol.-%, preferably below 7.5 vol.-% and most preferably below 6 vol.-%.

[0121] A further aspect of the invention relates to method for producing a bilayer tablet according to the invention as described above, the method comprising the steps of:

(i) providing a first composition for the first layer comprising telmisartan by fluid bed granulation a) preparing an aqueous solution of telmisartan, at least one basic agent, a binder and, optionally, a solubilizer; b) spraying said aqueous solution onto a premix of at least one diluent and at least one basic agent in a fluid-bed granulating machine to obtain a granulate; c) optionally, drying the granulate; d) mixing said granulate with at least one extragranular excipient, selected from a diluent, a dis- integrant, a colorant and, optionally, a lubricant, to obtain a premix; d') optionally, mixing said premix with at least one lubricant to obtain a final blend for the telmisartan tablet layer; e) optionally, adding other excipients in any of steps a) to d');

(ii) providing a second composition for the second layer comprising indapamide by f) mixing and/or granulating a indapamide, with the constituents of a prolonged release tablet matrix and, optionally, further excipients; g) admixing extragranular excipients and a lubricant to obtain a final blend for the indapamide tablet layer;

(iii) introducing either the first composition or the second composition in a tablet press;

(iv) compressing said composition to form a tablet layer;

(v) introducing the other of the first composition and the second composition into the tablet press; and

(vi) compressing both compositions to form the bilayer tablet.

[0122] For optimum dissolution/disintegration and drug release properties, a specific method of pro ducing the bilayer tablet according to the invention has been developed which method comprise

(i) providing a first composition for the first layer by a) preparing an aqueous solution of telmisartan, at least one basic agent, a binder and, optionally, a solubilizer; b) spraying said aqueous solution onto a premix of at least one water-soluble diluent and at least one basic agent in a fluid-bed granulating machine to obtain granulate; c) optionally drying the granulate d) mixing said granulate with at least one extragranular excipient, selected from a diluent, a dis- integrant, a colorant and, optionally, a lubricant, to obtain a premix; d') optionally mixing said premix with at least one lubricant to obtain a final blend for the telmisartan tablet layer; e) optionally, adding other excipients in any of steps a) to d');

(ii) providing a second composition for the second layer by f) mixing indapamide with at least one gel-forming polymer, at least one diluent and, optionally, further excipients, in high-shear granulator; g) spraying granulation liquid, preferably purified water, onto the mix obtained in step f) to obtain a granulate; h) drying the granulate in fluid-bed machine and sieving the granulate; i) mixing said granulate with extragranular excipients, including at least one diluent, a glidant, and, optionally, at least one gel-forming polymer, to obtain a premix; j) mixing said premix with at least one lubricant to obtain a final blend for the indapamide tablet layer; k) optionally, adding other excipients in any of steps f) to j);

(iv) compressing said composition at a compression force (tamping force) within the range of from 1.5 to 5 kN to form a tablet layer, preferably 1.8 to 4kN;

(vi) compressing both compositions to form the bilayer tablet, preferably at a compression force within the range of from 5 to 25 kN, preferably 8 to 20kN.

[0123] Since during subsequent processing telmisartan is normally dissolved and transformed into a substantially amorphous form, its initial crystal morphology and particle size are of little importance for the physical and biopharmaceutical properties of the bilayer tablet obtained. It is however preferred to remove agglomerates from the starting material, e.g. by sieving, in order to facilitate wetting and disso lution during further processing.

[0124] In a preferred embodiment of this method, an aqueous alkaline solution of telmisartan is pre pared by dissolving the active ingredient in purified water with the help of one or more basic agents like sodium hydroxide. A binder and, optionally, a solubilizer and/or a recrystallization inhibitor may be added. The dry matter content of the starting aqueous solution is preferably 10 to 40 wt.-%, more pref erably 15 to 35 wt.-%.

[0125] The aqueous solution is then sprayed onto premix of at least one diluent and at least one basic agent like meglumine, at room temperature or preferably at increased temperatures of inlet air, for in stance, between 45 and 100°C in a fluid-bed machine, at a spray pressure of, for instance, 1 to 4 bar. The outlet air temperature of the fluid-bed machine is preferably kept at a value of between about 20 and 40°C while the other process parameters such as spray pressure, spraying rate, inlet air temperature, etc. are adjusted accordingly.

[0126] After granulating, the active ingredient (telmisartan) as well as the excipients contained in the granulate are preferably in a substantially amorphous state with no crystallinity being detectable. [0127] Mixing is preferably carried out in two stages, i.e. in a first mixing step the granulate, at least one diluent, a disintegrant, at least one colorant and, optionally, a lubricant are admixed using, e.g., a high-shear mixer or a free-fall blender; and in a second mixing step at least one lubricant is blended with the premix, preferably also under conditions of high shear.

[0128] The method of the invention is however not limited to these mixing procedures and, generally, alternative mixing procedures may be employed in steps c), d), d'), and also in the subsequent steps f) and g), such as, e.g., container mixing with intermediate screening.

[0129] The second composition for the second layer is preferably prepared using a wet granulation technique. Indapamide is preferably mixed with at least one gel-forming polymer, at least one diluent and, optionally, further excipients. The granulation liquid is preferably sprayed onto a premix and sub sequently the wet granulate obtained is dried, e.g. in a fluidized-bed dryer or drying chamber. The dried mixture is preferably sieved and then other excipients, for example diluents, a glidant, and, at least one gel-forming polymer, are preferably admixed, e.g. using a tumbling mixer or free-fall blender. In a sec ond mixing step, a lubricant is preferably blended with the premix, whereafter the composition is ready for compression.

[0130] For production of the bilayer tablet according to the invention, the first composition and the second composition are compressed in a bilayer tablet press, e.g. a rotary press in the bilayer tableting mode, in the manner described above. In order to avoid any cross-contamination between the first com position and the second composition, any mixture residues should be carefully removed during tableting by intense suction of the die table within the tableting chamber.

[0131] The bilayer tablet according to the present invention is preferably prepared by compressing the first composition and the second composition in an usual manner in a bilayer tablet press, e.g. a high speed rotary press in a bilayer tableting mode. However, care should be taken not to employ an excessive compression force for the first tablet layer.

[0132] Preferably, the ratio of the compression force applied during compression of the first tablet layer to the compression force applied during compression of both the first and second tablet layers is in the range of from 1:50 to 1: 1, preferably 1: 10 to 1:2, more preferably 1:8 to 1:4.

[0133] For instance, the first tablet layer may be compressed at moderate force of 1.5 to 5 kN, prefera bly to 1.8 to 4 kN, whereas the main compression of first plus second layer is performed at a force of 5 to 25 kN, preferably 8 to 20 kN.

[0134] During bilayer tablet compression adequate bond formation between the two layers is achieved by virtue of distance attraction forces (intermolecular forces) and mechanical interlocking between the particles. [0135] Another aspect of the invention relates to a bilayer tablet that is obtainable by the method ac cording to the invention as described above.

[0136] The following examples further illustrate the invention but are not to be construed as limiting its scope.

mples T1-T13 - preparation of formulation for first layer comprising telmisartan:

37] Telmisartan, sodium hydroxide and povidone were dissolved in water. The obtained solution was sprayed by binary nozzle using compressed air for ization on a mixture of meglumine and lactose in a fluid bed dryer to prepare dry telmisartan granulate. Extragranular excipients were added to the dry granulate mixed in a stainless steel container to obtain telmisartan compression mixture.

xamples Il-Il 1 - preparation of formulation for second layer comprising indapamide:

intragranular, i.e. Hypromellose K4M + Hypromellose K100M; ² relative to mass of indapamide granulate (intragranular phase) intragranular + extragranular, i.e. Carbomer + Hypromellose K4M + Hypromellose K100M; ⁴ relative to mass of indapamide layer 138] Indapamide, part of microcrystalline cellulose, part of hypromellose, part of silica, colloidal anhydrous and lactose were granulated with water in a high- ear mixer. Wet granulate was dried in fluid bed dryer. The remaining part of microcrystalline cellulose, the remaining part of hypromellose, the remaining part f silica, colloidal anhydrous, carbomer, if present in formulation, optionally colorant(s) ferric oxide(s) and magnesium stearate were added to the dry granulate d mixed in a stainless steel container to obtain indapamide compression mixture.

Examples of 1 to 7 - preparation of bilaver tablets:

[0139] Methods:

[0140] Separation time : The separation time testing for bilayer tablet was carried out under static con ditions in phosphate buffer medium having pH 6.8, at a temperature of the dissolution medium of 37°C±0.5°C (especially 37°C).

[0141] Dissolution : Comparison of dissolution profiles of bilayer tablets was carried out using USP I method (basket apparatus, 20 mesh size) at 100 RPM in phosphate buffer medium having pH 6.8, at a temperature of the dissolution medium of 37°C±0.5°C.

[0142] Telmisartan compression mixture and indapamide compression mixture were compressed to bilayer tablets using bilayer tableting machine.

[0143] The following bilayer tablets were prepared:

* did not separate completely

[0144] Figure 1 shows a comparison of dissolution profdes of telmisartan.

[0145] The cluster of Examples with separation time of above 2.0 minutes under static conditions (Ex. 1, Ex. 2, Ex. 3a, Ex 4 and Ex. 7a) also showed low dissolution profiles, all under 90% at final dissolution time point of 15 minutes.

[0146] The cluster of Examples with separation time of 2.0 minutes or lower (Ex. 3, Ex. 4a, Ex. 5, Ex. 6, Ex. 7, Ex. 7b and Ex. 7c) shows faster dissolution profiles, all above 90% at final dissolution time point 15 minutes.

[0147] Example 1 in the low separation and dissolution cluster exhibited a significantly lower in vivo plasma profile in comparison to Example 5, which belongs to the fast layer separation and dissolution cluster (see pharmacokinetic screening below). [0148] Pharmacokinetic screening: Two in vivo single dose studies were conducted on 36 healthy male volunteers under fasting conditions to verify the impact of separation time and dissolution release kinet ics on telmisartan plasma concentrations. Bilayer tablets were compared to therapeutically established mono layer Micardis^® (telmisartan) tablet employing a crossover design. Blood samples were taken at predefined times up to 72 h to capture telmisartan concentrations in plasma. All plasma samples were analyzed by a validated LC/MS-MS method.

[0149] Figure 2 shows plasma profiles of Examples 1 and 5 versus monolayer Micardis^® (telmisartan) tablet (circles represent Example 1, whereas squares represent Example 5).

Claims

Patent claims:

1. A bilayer tablet comprising

(i) a first layer comprising telmisartan; and

(ii) a second layer comprising indapamide in a prolonged release matrix.

2. The bilayer tablet according to claim 1, wherein the first layer provides immediate release of telmisartan; preferably wherein in an in vitro dissolution test according to Ph. Eur., 100 rpm, in 900 mL pH 6.8 phosphate buffer and at 37°C after 30 minutes at least 70 wt.-% of telmisartan have been dissolved, relative to the total amount of telmisartan that was originally contained in the bilayer tablet.

3. The bilayer tablet according to claim 1 or 2, wherein the first layer comprises one or more excip ients.

4. The bilayer tablet according to claim 3, wherein the one or more excipients are independently of one another selected from disintegrants, basic agents, binders, carriers, diluents, water-soluble diluents, water-insoluble diluents, lubricants, flow control agents, crystallization retarders, solu bilizers, coloring agents, pH control agents, surfactants and emulsifiers.

5. The bilayer tablet according to any of the preceding claims, wherein the first layer comprises a basic agent.

6. The bilayer tablet according to claim 5, wherein the basic agent is selected from alkali metal hydroxides, basic amino acids and meglumine.

7. The bilayer tablet according to any of the preceding claims, wherein the first layer comprises a water-soluble diluent and or a water-insoluble diluent.

8. The bilayer tablet according to claim 7, wherein the water-soluble diluent is selected from

(a) carbohydrates; preferably monosaccharides; more preferably glucose;

(b) oligosaccharides; preferably sucrose, lactose, or mixtures thereof; and

(c) sugar alcohols; preferably sorbitol, mannitol, dulcitol, ribitol, xylitol, or mixtures thereof, and wherein the water insoluble diluent is selected from the group consisting of water-insol uble polysaccharides, salts of alkaline or earth alkaline metals or mixture thereof.

9. The bilayer tablet according to any of the preceding claims, wherein the first layer comprises an intragranular phase and an extragranular phase.

10. The bilayer tablet according to claim 9, wherein essentially the total amount of telmisartan that is contained in the first layer is contained in the intragranular phase of the first layer.

11. The bilayer tablet according to claim 9 or 10, wherein the extragranular phase of the first layer comprises a disintegrant.

12. The bilayer tablet according to claim 11, wherein the disintegrant is selected from crospovidone, starch, maize starch, pregelatinized starch, sodium starch glycolate, hydroxypropyl starch, sodium and/or calcium salts of carboxymethyl cellulose, cross-linked carboxymethylcellulose, polacrilin potassium, low substituted hydroxypropylcellulose, sodium and/or calcium alginate, docusate so dium, methylcellulose, agar, guar gum, chitosan, alginic acid and mixtures thereof; preferably from crospovidone, carboxymethylcellulose sodium, croscarmellose sodium, and mixtures thereof.

13. The bilayer tablet according to any of claims 9 to 12, wherein the extragranular phase of the first layer comprises croscarmellose sodium.

14. The bilayer tablet according to any of claims 9 to 12, wherein the extragranular phase of the first layer comprises crospovidone.

15. The bilayer tablet according to claim 13 or 14, wherein the weight content of croscarmellose sodium or crospovidone is within the range of from 1 to 20 wt.-%, preferably 2 to 15 wt.-%, relative to the total weight of the first layer.

16. The bilayer tablet according to any of claims 9 to 15, wherein the extragranular phase of the first layer comprises a diluent, preferably a water-insoluble diluent.

17. The bilayer tablet according to claim 16, wherein the diluent is selected from the group consisting of water-insoluble polysaccharides, salts of alkaline or earth alkaline metals or mixture thereof; preferably from cellulose, starch and calcium, sodium or potassium salts of phosphoric acid, car bonic acid or sulphuric acid; more preferably from powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose; most preferably microcrystalline cellulose.

18. The bilayer tablet according to claim 16 or 17, wherein the weight content of the diluent, prefer ably microcrystalline cellulose, is within the range of from 15 to 60 wt.-%, preferably 20 to 50 wt.-%, relative to the total weight of the first layer.

19. The bilayer tablet according to any of the preceding claims, wherein the first layer comprises

- 3 to 35 wt.-%, preferably 5 to 25 wt.-% of telmisartan;

- 0.25 to 20 wt.-%, preferably 0.40 to 15 wt.-% of basic agent; and

- 35 to 90 wt.-%, preferably 50 to 85 wt.-% of diluent; in each case relative to the total weight of the first layer.

20. The bilayer tablet according to any of the preceding claims, wherein the first layer comprises at least one basic agent, at least one diluent, at least one disintegrant and optionally, other excipients.

21. The bilayer tablet according to any of the preceding claims, wherein the second layer provides prolonged release of indapamide; preferably wherein indapamide is embedded in the prolonged release matrix and wherein the prolonged release matrix causes prolonged release of indapamide; preferably wherein in an in vitro dissolution test according to Ph. Eur., 100 rpm, in 900 mL pH 6.8 phosphate buffer and at 37°C after 60 minutes not more than 50 wt.-% of indapamide have been dissolved, relative to the total amount of indapamide that was originally contained in the bilayer tablet.

22. The bilayer tablet according to any of the preceding claims, wherein the second layer comprises one or more excipients are independently of one another selected from diluents, gel-forming pol ymers, antioxidants, glidants, and lubricants.

23. The bilayer tablet according to any of the preceding claims, wherein the prolonged release matrix of the second layer comprises a gel-forming polymer.

24. The bilayer tablet according to any of the preceding claims, wherein the prolonged release matrix of the second layer comprises an anionic gel-forming polymer.

25. The bilayer tablet according to claim 24, wherein the anionic gel-forming polymer is selected from the group consisting of sodium carboxymethylcellulose, carboxymethyl cellulose, anionic polysaccharides, anionic gums, polymers of acrylic acid, carbomers, crosslinked copolymers of acrylic acid and a hydrophobic Cl 0-30 alkyl acrylate co-monomers, and polycarbophils.

26. The bilayer tablet according to any of the preceding claims, wherein the prolonged release matrix of the second layer comprises a nonionic gel-forming polymer.

27. The bilayer tablet according to claim 26, wherein the nonionic gel-forming polymer is selected from the group consisting of HPMC K100 LV, HPMC K100M and HPMC K4M.

28. The bilayer tablet according to any of the preceding claims, wherein the prolonged release matrix of the second layer comprises two gel-forming polymers.

29. The bilayer tablet according to claim 28, wherein the prolonged release matrix of the second layer comprises a non-ionic gel-forming polymer and an anionic gel-forming polymer.

30. The bilayer tablet according to claim 29, wherein the anionic gel-forming polymer is selected from the group consisting of sodium carboxymethylcellulose, carboxymethyl cellulose, anionic polysaccharides, anionic gums, polymers of acrylic acid, carbomers, crosslinked copolymers of acrylic acid and a hydrophobic Cl 0-30 alkyl acrylate co-monomers, and polycarbophils.

31. The bilayer tablet according to claim 29 or 30, wherein the anionic gel-forming polymer is a carbomer and the non-ionic gel-forming polymer is HPMC K100M or HPMC K4M.

32. The bilayer tablet according to any of claims 28 to 31, wherein the prolonged release matrix of the second layer comprises a first non-ionic gel-forming polymer and a second non-ionic gel forming polymer which is different from the first non-ionic gel-forming polymer.

33. The bilayer tablet according to claim 32, wherein the first non-ionic gel-forming polymer and the second non-ionic gel-forming polymer are derived from the same monomers but differ in at least one parameter selected from the group consisting of solubility, viscosity and molecular weight.

34. The bilayer tablet according to claim 32 or 33, wherein the first non-ionic gel-forming polymer and the second non-ionic gel-forming polymer are selected from the group consisting of HPMC K100 LV, HPMC K100M and HPMC K4M.

35. The bilayer tablet according to claim 34, wherein the first non-ionic gel-forming polymer is HPMC K100M and the second non-ionic gel-forming polymer is HPMC K4M.

36. The bilayer tablet according to any of the preceding claims, wherein the prolonged release matrix of the second layer comprises three gel-forming polymers.

37. The bilayer tablet according to any of the preceding claims, wherein the prolonged release matrix of the second layer comprises an anionic gel-forming polymer, a first non-ionic gel-forming pol ymer, and a second non-ionic gel-forming polymer which is different from the first non-ionic gel forming polymer.

38. The bilayer tablet according to claim 37, wherein the anionic gel-forming polymer is a carbomer, the first non-ionic gel-forming polymer is HPMC K100M, and the second non-ionic gel-forming polymer is HPMC K4M.

39. The bilayer tablet according to any of claims 29 to 38, wherein the relative weight ratio between

- the total content of all anionic gel-forming polymers that are contained in the prolonged release matrix of the second layer is within the range of from 10: 1 to 20: 1.

40. The bilayer tablet according to any of the preceding claims, wherein the second layer has a total weight content of gel-forming polymers of at least 25 wt.-%, preferably at least 30 wt.-%, more preferably at least 35 wt.-%, still more preferably at least 40 wt.-%, yet more preferably at least 45 wt.-%, most preferably at least 50 wt.-%, in each case relative to the total weight of the second layer.

41. The bilayer tablet according to any of the preceding claims, wherein the second layer comprises an intragranular phase and an extragranular phase.

42. The bilayer tablet according to claim 41, wherein essentially the total amount of indapamide that is contained in the second layer is contained in the intragranular phase of the second layer.

43. The bilayer tablet according to claim 41 or 42, wherein the intragranular phase of the second layer has a total weight content of gel-forming polymers of at least 25 wt.-%, preferably at least 30 wt- %, more preferably at least 35 wt.-%, still more preferably at least 40 wt.-%, yet more preferably at least 45 wt.-%, most preferably at least 50 wt.-%, and in particular at least 55 wt.-%, in each case relative to the total weight of the intragranular phase of the second layer.

44. The bilayer tablet according to any of the preceding claims, wherein the second layer comprises

- 0.1 to 10 wt.-%, preferably 0.2 to 5 wt.-%, most preferably 0.5 to 2 wt.-% of indapamide; - 25 to 75 wt.-%, preferably 35 to 65 wt.-%, of diluent;

- 30 to 70 wt.-%, preferably 35 to 65 wt.-%, of gel-forming polymer, wherein the gel-forming polymer comprises

- 30 to 60 wt.-%, preferably 40 to 55 wt.-% of one or more non-ionic gel forming polymers, and

- 1 to 10 wt.-%, preferably 1 to 5 wt.-% of one or more anionic gel-forming polymers;

- 0 to 2 wt.-%, preferably 0.05 to 1.5 wt.-%, of antioxidant;

- 0.5 to 5 wt.-%, preferably 1 to 2 wt.-%, of glidant; and

- 0.1 to 3 wt.-%, preferably 0.5 to 2 wt.-% of lubricant; in each case relative to the total weight of the second layer.

45. The bilayer tablet according to any of the preceding claims, which comprises 10 to 160 mg of telmisartan and 0.1 to 10 mg of indapamide.

46. The bilayer tablet according to claim 45, which comprises 20 to 80 mg of telmisartan and 1.5 mg of indapamide.

47. The bilayer tablet according to any of the preceding claims, wherein the two layers separate from each other in separation time of 10 minutes or less, preferably of less than 6 minutes, more pref erably less than 4 minutes, most preferably less than 3 minutes, and in particular 2 minutes or less, as determined by disintegration under static conditions in phosphate buffer medium having pH 6.8.

48. The bilayer tablet according to any of the preceding claims, which provides an in vitro dissolution profile using USP I method (basket apparatus, 20 mesh size) at 100 RPM in 900 mL phosphate buffer medium having pH 6.8, at a temperature of the dissolution medium of 37°C±0.5°C, such that after 5 minutes, relative to the total content of telmisartan that was initially contained in the bilayer tablet, at least 15 wt.-%, preferably at least 17.5 wt.-%, more preferably at least 20 wt.-%, still more preferably at least 22.5 wt.-%, yet more preferably at least 25 wt.-%, even more prefer ably at least 27.5 wt.-%, most preferably at least 30 wt.-%, and in particular at least 32.5 wt.-% of the telmisartan have been dissolved.

49. The bilayer tablet according to any of the preceding claims, which provides an in vitro dissolution profile using USP I method (basket apparatus, 20 mesh size) at 100 RPM in 900 mL phosphate buffer medium having pH 6.8, at a temperature of the dissolution medium of 37°C±0.5°C, such that after 10 minutes, relative to the total content of telmisartan that was initially contained in the bilayer tablet, at least 57.5 wt.-%, preferably at least 60 wt.-%, more preferably at least 62.5 wt.- %, still more preferably at least 65 wt.-%, yet more preferably at least 67.5 wt.-%, even more preferably at least 70 wt.-%, most preferably at least 72.5 wt.-%, and in particular at least 75 wt.- % of the telmisartan have been dissolved.

50. The bilayer tablet according to any of the preceding claims for use in the treatment of hyperten sion.

51. A packaging comprising a bilayer tablet according to any of the preceding claims packaged in a moisture proof packaging material; preferably selected from aluminum foil blister packs, and HDPE containers.

52. A method for producing a bilayer tablet according to any of claims 1 to 50, the method comprising the steps of:

(i) providing a first composition for the first layer by a) preparing an aqueous solution of telmisartan, at least one basic agent, a binder and, op tionally, a solubilizer; b) spraying said aqueous solution onto a premix of at least one water-soluble diluent and at least one basic agent in a fluid-bed granulating machine to obtain a granulate; c) optionally, drying the granulate; d) mixing said granulate with at least one extragranular excipient, selected from a diluent, wherein at least one diluent is water-insoluble diluent, a disintegrant, a colorant and, op tionally, a lubricant, to obtain a premix; d') optionally, mixing said premix with at least one lubricant to obtain a final blend for the telmisartan tablet layer; e) optionally, adding other excipients in any of steps a) to d');

(ii) providing a second composition for the second layer by f) mixing and/or granulating indapamide, with the constituents of a prolonged release tablet matrix and, optionally, further excipients; g) admixing extragranular excipients and a lubricant to obtain a final blend for the inda pamide tablet layer;

(iv) compressing said composition to form a tablet layer;

(v) introducing the other of the first composition and the second composition into the tablet press; and (vi) compressing both compositions to form the bilayer tablet.

53. The method according to claim 52, wherein step (ii) comprises the substeps of f) mixing indapamide with at least one gel-forming polymer, at least one diluent and, optionally, further excipients, in high-shear granulator; g) spraying granulation liquid, preferably purified water, onto the mix obtained in step f) to obtain a granulate; h) drying the granulate in fluid-bed machine and sieving the granulate; i) mixing said granulate with extragranular excipients, including at least one diluent, a glidant, and, optionally, at least one gel-forming polymer, to obtain a premix; j) mixing said premix with at least one lubricant to obtain a final blend for the indapamide tablet layer; and k) optionally, adding other excipients in any of steps f) to j).

54. The method according to claim 52 or 53, wherein step (iv) is performed at a compression force within the range of from 1.5 to 5 kN, preferably 1.8 to 4 kN.

55. The method according to any of claims 52 to 54, wherein step (vi) is performed at a compression force within the range of from 5 to 25 kN, preferably 8 to 20 kN.

56. A bilayer tablet that is obtainable by the method according to any of claims 52 to 55.