(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`Document FP9
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`Appl. No.: 11/273,575
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`1
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`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) Intemau'onal Publication Date
`1 September 2005 (01.09.2005)
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`(10) International Publication Number
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`WO 2005/079762 A1
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`(51) International Patent Classification7:
`31/4184, 31/403
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`A61K 9/24,
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`(21) International Application Number:
`PCT/EP2005/001498
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`(22) International Filing Date: 15 February 2005 (15.02.2005)
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`(25) Filing Language:
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`(26) Publication Language:
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`English
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`English
`
`(30) Priority Data:
`10 2004 008 804.7
`20 February 2004 (20.02.2004)
`
`DE
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): KOHLRAUSCH,
`Anja [DE/DE]; Ftinf Linden 31, 88400 Bibcrach (DE).
`
`(74) Cormnon Representative: BOEHRINGER INGEL-
`HEIM INTERNATIONAL GMBH; Binger Strasse 173,
`55216 lngelhcim (DE).
`
`(81) Designated Stath (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TI‘, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`ZW.
`
`(71) Applicant (for AE, AG, AL, AM, AT, AU, AZ, BA, BB, BE,
`BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CY, CZ,
`DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM,
`IIR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ. LC, LK,
`LR, LS, L7: LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ,
`NA. NI, NO, NZ, OM, PG, PH, PL, PT, R0, RU, SC, SD,
`SE, SG, SK, SL, 51’, S2, Tl, TM, TN, TR, T1: ’12, UA, UG,
`UZ, VC, VN, YU, ZA, ZM, ZW only): BOEHRINGER
`INGELHEIM lNTERNATIONAL GMBH [DE/DE];
`Binger Strasse 173, 55216 lngelheim (DE).
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, Tl, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, MC, NL, PL, PT, RO,
`SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN,
`GQ, GW, ML, MR, NE, SN, TD, TG).
`Published:
`— with international search report
`
`(71) Applicant (for DE only): BOEHRINGER INGELHEIM
`PHARMA GMBH & C0. KG [DE/DE]; Binger Stmsse
`173, 55216 lngelheim (DE).
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations " appearing at the begin-
`ning of each regular issue of the PCT Gazette.
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`(54) Title: MULTILAYER TABLET
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`005/079762A1||||l|||l|||||||Illlllllllllllll||||||I||||||||||||||||||||||||||||||||l|||||||||||||||ll|||||l
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`N (57) Abstract: A multilayer tablet comprises a first layer formulated for instant release of the angiotensin II receptor antagonist
`telmisartan from a dissolving tablet matrix, a second layer formulated for instant release of the angiotensin converting enzyme in-
`hibitor ramipril and optionally a diuretic from a disintegrating tablet matrix, and, optionally, a third layer formulated for instant
`release of a diuretic like hydrochlomthiazide from a fast disintegrating tablet matrix.
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`WO 2005/079762
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`PCT/EP2005/001498
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`Multilayer Tablet
`
`
`The present invention relates to a pharmaceutical tablet comprising a first layer of the
`angiotensin ll receptor antagonist telmisartan in a dissolving tablet matrix, a second
`layer of the angiotensin converting enzyme (AC E) inhibitor ramipril alone or together
`with a diuretic in a disintegrating tablet matrix, and optionally a third layer of a diuretic
`like hydrochlorothiazide in a fast disintegrating tablet matrix.
`‘
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`1O
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`Background of the invention '
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`I
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`Telmisartan is an angiotensin ll receptor antagonist develbped for the treatment of
`
`‘- hypertension and other medical indications as disclosedIn EP-A-502314. Its
`chemical name is 4'---[2-npropyl--4--methyl--6--(1- methylbenzimidazol-2-yl)-
`benzimidazol—1-y|methyl}biphenyt—Z-carboxylic acid having the following structure:
`
`
`
`Hooc O
`
`'Telmisartan is manufactured and supplied in the free acid form. It is characterized by.
`its very poor solubility in aqueous systems at the physiological pH'range of the
`gastro-intestinal tract of between pH i to 7. As disclosed in WO 00/43370, crystalline ’
`telmisartan exists in two polymorphic. forms having different melting points.- Under the
`influenceof heat and humidity, the-lower meltingpolymorph B transforms irreversibly
`into the higher melting polymorph A.
`
`‘
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`Ramipril disclosed in EP-A—079022 is a long-acting ACE inhibitor with the chemical
`
`name (28,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl]-octahydro-
`
`cyclopenta[b]pyrrole-2-carboxylic acid, 1-ethyl ester having the following structure:
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`WO 2005/079762
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`PCT/EP2005/001498
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`o
`
`‘oVCHa'
`
`NH
`
`\“
`
`H30 [\K
`
`0
`
`N .imCOOH
`
`H
`
`it inhibits the conversionvof angiotensin l'into angiotensin ll as well as the breakdown
`of the active vasodilator bradykinin. Both of these activities lead to vasodilation. it is
`being used in the treatment of hypertension and congestive heart failure and its
`
`active metabolite'is the free acid ramiprilat, which'Is obtained'in vivo upon
`administration of ramipril. Additionally ramipril has been suggested to effect a
`pronounced inhibition of ACEin tissues resultingin organ protective effects such as
`the heart,_lung, and kidney
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`1O
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`Diuretics are therapeutic agents used in the treatment of edema and hypertension.
`
`Occasionally they are combined with anti—hypertensive agents acting on the basis of
`
`a different mode of action to achieve synergistic therapeutic efficacy in the treatment
`- of hypertension. A preferred-diuretic is hydrochlorothiazide (HCTZ). The chemical
`name of HCTZ is 6-chloro-3,4-dihydro-2H-1,2,4—benzothiadiazine—7—sulfonamide-1 ,1-
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`dioxide having the following structure
`
`Obiect of the invention
`
`The mechanisms of action of telmisartan and ramipril are considered to cooperate
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`favourably in the treatment or prevention of conditions such as stroke, myocardial
`infarction, transient ischaemic attack, cardiovascular disease, diabetes, cognitive
`decline and dementia. As this assumptiongets supported by an increasing amount of
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`. clinical data, there is an increasing desirefor a fixed dose combination drug
`comprising the active ingredients telmisartan, ramiprii and‘o‘ptionally a diuretic sUch
`
`as hydrochlorothiazide. However, both telmisartan and ramiprii are chemical
`'compounds difficult to handle. Therefore, an oral fixed dose combination drug which
`combines the features of pharmacologic efficaCy, adequate drug stability and a
`reliable and robust method of manufaéture has to overcome a number of technical
`problems. it"Is an object of the present invention to provide such a fixed dose
`, combination drug.
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`10'
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`There are various types of fixed dose dosage forms conceivable but it cannot be
`predicted which” of these dosage forms combines product stability, pharmacological
`efficacy and reliable manufacture best. Examples of such dosage forms are oral
`
`osmotic systems (OROS), coated tablets, matrix tablets, press-coated tablets,
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`multilayer tablets and the'likeuThe present invention is based on the recognition, that
`the dosage form, which combines adequate drug stability, optimum drug release of
`both activeingredients, pharmacological efficacy and reliable manufacture for a
`combination of telmisartan and ramiprii best is a multilayer tablet.
`
`Generally, a fixed-dose combination of drugs intended for instant release is prepared
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`20
`
`by either making a powder mixture or a co—granulate of the two active ingredients
`
`_ with the necessary excipients, normally "keeping the basic formulation of the
`
`correspondingmono-drug preparation and simply adding the second drug
`component. 9
`I
`‘
`With a combination of telmisartan and ramipril, this approach does not appear
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`feasible .due to the incompatibility of ramiprii with components of the conventional
`
`telmisartan formulations. When including the diuretic HCTZ or the ACE inhibitor.
`
`.Ramipril in a combination a reduced dissolution rate of HCTZ from a dissolving matrix
`
`as compared with dissolution from a disintegrating tablet is observed. Coating HCTZ
`
`or Ramipril particles in a fluidized—bed granulator with a polymer solution containing .
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`water soluble polymers like hydroxypropylcellulose, hydroxypropylmethylcellulose or
`polyvinylpyrrolidone, to reduce the contact surface area of HCTZ particles with the
`
`telmisartan or ramiprii formulation during mixing and compressing does not reduce
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`the contact area of HCTZ with the telmisartan or ramipril formulation in a compressed
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`tablet to a degree sufficient to achieve the desired prolonged shelf life. Furthermore,
`the dissolution rate of HCTZ from tablets comprising coated HCTZ ap‘pears further .
`
`reduced due to the gel-forming properties of the polymer.
`Another approach is to produce separate film-coated tablets for telmisartan, ramipril
`and, optionally, HCTZ in such a size and shape that these can be filled into a
`capsule. By dividing the doses into small tablets for telmisartan, ramipril and, '
`optionally, HCTZ, a the drug dissolution rate of telmisartan and ramiprilIs found to be
`reduced compared to the single entities due to a lag-time effect of the large capsule
`shells. Furthermore, with regard to patients' compliance, a zero long capsule'Is not
`deemed reliable.
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`10_
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`Summary. of the invention
`
`in accordance with the present invention problems associated with the preparation of
`a fixed dose combination drug comprising telmisartan, ramipril and, optionally,a
`diuretic can best be handled by means of a multilayer pharmaceutical tablet
`
`comprising a first layer of telmisartan, preferablyIn substantially amorphous form, in
`a dissolving tablet matrix and a second layer of ramipril alone or ra’mipril together with l
`a diuretic such as HCTZ in a disintegrating tablet matrix. Alternatively, the tablet may
`
`contain a third layer comprising the diuretic in a disintegrating tablet matrix. _
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`‘
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`The tablet according to the present invention provides a largely pH-independent
`dissolution of the poorly water-soluble telmisartan, thereby facilitating dissolution of
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`the drug at a physiological pH level, and adequate stability and drug release of
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`ramipril. In combination with a diuretic it provides for instant release of the diuretic
`from a fast disintegrating matrix. The tablet structure also overcomes the stability
`problem caused by the incompatibility of diuretics like HCTZ with basic constituents
`
`of telmisartan formulations and the stability problem caused by the-incompatibility of
`
`Ramipril with basic constituents of telmisartan.
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`Definitions
`
`As used herein, the term “substantially amorghous" refers to a product comprising
`amorphous constituents in a proportion of at least 90%, preferably at least 95%, as
`determined by X--ray powder diffraction measurement.
`,
`.
`The term “dissolving tablet matrix” refers to a pharmaceutical tablet base formulation
`
`having instant release (fast dissolution) characteristics that readily dissolvesIn a
`
`physiological aqueous medium.
`The term “Mg” refers to thiazide and thiazide-analogue diuretics like
`hydrochlorothiazide (l-lCTZ), clopamide, xipamide or chlorotalidone, and any other
`I diuretic suitable in the treatment of hypertension like furosemide and piretanide, and
`
`combinations thereof with amiloride and triamteren.
`
`’ refers to a pharmaceutical tablet base
`The term “disintegrating tablet matri
`' formulation having instant release charaCteristics that readily disintegrates in a '
`physiological aqueous‘medium.
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`10
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`15
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`Descrigtion of the invention
`A fixed dose combination according to the present invention represents a
`
`pharmaceutical multilayer tablet comprising a first layer of telmisartanIn substantially
`amorphous form, a second layer of ramipril alone or ramipril together With a diUretic
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`20
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`in a disintegrating tablet matrix, or optionally a third layer or a diureticIn a
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`disintegrating tablet matrix.
`
`The active ingredient telmisartan is generally supplied in its free acid form, although
`
`pharmaceutically acceptable salts such as the sodium salt may also be used. Since
`during subsequent processing telmisartan'IS normally dissolved and transformed into
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`a substantially amorphous form, its initial crystal morphology and particle size are of
`little importance for the physical and biopharmaceutical properties of the multilayer
`
`tablet formulation obtained. It is, however, preferred to remove agglomerates from
`
`the starting material," eg. by sieving, in order tofacilitate wetting and dissolution
`during further processing.
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`- s
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`Substantially amorphous telmisartan may be produced by any suitable method
`known to those skilled in .the. art, for instance, by freeze drying. of aqueous solutions,
`coating of carrier particles in a fluidized bed, and solvent deposition on sugar pellets
`or other carriers. Preferably, however, the substantially amorphous telmisartan is
`prepared by the specific spray-drying methOd described in WOO3/059327.
`.
`
`Ramiprilis supplied as a free ester or stabilized with a polymeric coating as
`described in EP-A-317878. Examples of polymers suitable for the protective coating
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`are cellulose derivatives such as hydroxyproplycellulose, hydroxypropylmethyl-
`cellulose, hydroxypropylmethylcellulose phthalate, hydroxyethylcellulose,
`ethylcellulose, cellulose acetate phthalate, cellulose acetate, polyvinyl acetate
`
`phthalate, polyvinylpyrrolidone, cationic and anionic polymers, copolymer with neutral,
`
`character based on poly(meth)acrylic esters (Eudragit(R) E, Eudragit(Fl) E 30 D),
`
`anionic polymer of methacrylic acid and methyl methacrylate (Eudragit(R) L or S,
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`Eudragit(R) L 30 D) and gelatin.
`
`The diuretic is usually employed as a fine-crystalline powder, optionally in fine-milled,
`peg—milled or micronized form. For instanCe, the particle size distribution of
`hydrochlorothiazide, as determined by the method oflasler light scatteringin a dry
`dispersion system (Sympatec Helos/Rodos, focal length 100 mm) is preferably as
`follows:
`
`dm:
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`5 20 um, preferably 2 to 10 pm
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`5 to. 50 um, preferably 10 to 30 um
`. dso :
`d90 :,- 20 to 100 um, preferably 40 to 80 pm
`
`A multilayer tablet according to the present invention generally contains
`10 to 160 mg, preferably 20 to 80 mg or 40 to 80 mg, of telmisartan;
`1 to 20 mg, preferably 5m 10 ~mg, of ramipril; and
`6.25 to 50 mg, preferably 12.5 to 25 mg, of a diuretic such as HCTZ.
`
`Presently preferred forms are multilayer tablets comprising 20/10 mg, 40/10 mg,
`
`80/10 mg, 20/5 mg, 40/5 mg, 80/5 mg, 20/2.5 mg, 40/2.5 mg and 80/2.5 mg of
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`telmisartanand ramipril,’ respectively. The preferred amounts of diuretic are 12.5 mg
`
`or 25 mg.
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`‘
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`The first tablet layer contains telmisartan in substantially amorphous form dispersed
`in a dissolving tablet matrix having instant release (fast dissolution) characteristics.
`The. dissolving tablet matrix may have neutral or basic properties, although a basic
`
`tablet matrix is preferred.
`
`In such a preferred embodiment, the dissolving matrix of the Telmisartan layer
`
`comprises a basic agent, a water-soluble diluent and, optionally, other excipients and
`adjuvants.
`.
`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.
`'
`V
`Specific examples of suitable water-soluble diluents are carbohydrates 'such as
`
`monosaccharides like glucose; oligosaccharides like sucrose, anhydrous lactose and
`lactose monohydrate; and sugar alcohols like sorbitol, mannitol, erythrol and xylitol.
`SorbitolIs a preferred diluent
`The other excipients and/or adjuvants are, for instance, selected from binders, j
`carriers,fillers, lubricants, flowcontrol agents, crystallization retarders, solubilizers,
`
`coloring agents, pH control agents, surfactants and emulsifiers, specific examples of
`which are given below in connection with the second tablet layer composition. The
`
`excipients and/or adjuvants for the first tablet layer composition are preferably
`chosen such that a non-acidic, fast dissolving tablet matrixIs obtained.
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`The first tablet layer composition generally comprises 3 to 50 wt.%, preferably 5 to 35
`wt.%, of active ingredient; 0.25 to 20 wt.%, preferably 0.40 to 15 wt.%, of basic
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`agent; and 30 to 95 wt.%, preferably 60 to 80 wt.% of water-solublediluent (filler).
`
`Other (optional) constituents may, for instance, be chosen from one or more of the
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`folloWing excipients and/or adjuvants in the amounts indicated:
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`I 10 to 30 wt.%, preferably 15 to 25 wt.%, of binders,‘carriers and fillers, thereby
`replacing the water-soluble diluent;
`.
`0.1 to 5 wt.%, preferably 0.5 to 3 wt.%, of lubricants;
`0.1 to 5 wt.%, preferably 0.3 to 2 wt.%, of flow control agents;
`1 to 10 wt.%, preferably 2 to 8 wt.%, of crystallization retarders;
`1 to 10 wt.%, preferably 2 to 8 wt.%, of solubilizersf
`_
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`'
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`0.05 to 1.5 wt.%, preferably mm 0.8 wt.%, of coloring agents;
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`- 0.5 to 10 wt.%, preferably 2 to 8 wt.%, of pH control agents;
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`0.01. to 5 wt.%, preferably 0.05 to 1"wt.%, of surfactants and emulsifiers.
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`The second tablet layer composition comprises ramipril dispersed in a disintegrating
`
`tablet matrix having instant release (fast dissolution) characteristics. It optionally
`comprises ramipril together with a diuretic. The disintegrating tablet matrix may have
`weakly acidic, neutral or weakly basic properties, a neutral tablet matrix being
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`preferred.
`
`,
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`In a preferred embodiment, the disintegrating matrix comprises one or more fillers, a '
`binder or polymer, a disintegrant, a iubriCant and, optionally, other excipients and
`
`adjuvants.
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`Preferred fillers are selected from the group consisting of pregelatinized starch,
`microcristalline cellulose, low-substituted hydroxypropylcellulose, cellulose, mannitol,
`
`. erythritol, lactose, saccharose, claciumhydrogenphosphate, sorbitol, and xylitol.
`
`Particularly preferred are pregelatinized starch, microcristalline cellulose, mannitol
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`and lactose monohydrate.
`‘
`Preferred disintegrants are selected from the group consisting of croscarmellose sodium
`salt (cellulose carboxymethylether sodium salt, crosslinked), sodium starch glycolate,
`
`crosslinked polyvinylpyrrolidone' (crospovidone), corn starch and low-substituted
`hydroxypropylcellulose. Particularly preferred are sodium starch glycolate and
`croscarmellose sodium salt.
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`Preferred binders are selected from the group consisting of polyvinyl pyrrolidone.
`
`(Povidone), copolymers of vinylpyrrolidone with other vinyderivatives (Copovidone),
`hydroxypropylmethylcellulose, methylcellulose, hydroxypropyl-cellulose and low-
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`I substituted hydroxypropyl-cellulosei .ParticUlarly preferred are hydroxypropyl-
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`methylcellulose and Copovidone.
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`'
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`Preferred lubricants are sodium stearylfumarate and magnesium stearate.
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`The second tablet layer composition generally comprises 0.5 to 25 wt.%, preferably 1
`
`to 15 wt.% of ramipril and 50 to 95wt.%, preferably 75 to 90 wt.% of fillers. The
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`optional content. of diuretic amounts to 2 to 15 wt.%. .
`The other excipients and/or adjuvants'are, for instance, selected from binders,
`
`carriers, fillers, lubricants, flow control agents, crystallization retarders, solubilizers,
`coloring agents, pH control agents, surfactants and emulsifiers, specific examples of
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`. which are given below in connection with the third tablet layer composition. The
`excipients and/or adjuvants for the second tablet layer composition are preferably
`
`chosen such that a neutral, disintegrating tablet matrix is obtained. Examples for
`
`such fillers are mannitol, pregelatinized starch, lactose monohydrate and cellulose
`derivatives like low substituted hydroxypropylcellulose.
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`The optional third tablet layer composition contains a diuretic in a fast disintegrating
`tablet matrix. In ‘a preferred embodiment, the disintegrating tablet matrix comprises a
`filler, a binder, a disintegrant and, optionally, other excipients and, adjuvants.
`The filler is preferably selected from anhydrous lactose, spray-dried lactose and ‘
`
`lactose monohydrate.
`The binder is selected from the group of dry binders and/or the group of wet
`granulation binders, depending on the manufacturing process chosen for the second
`tablet 'layer; Suitable dry binders are, e.g., cellulose powder and microcrystalline ‘
`cellulose-Specific examples of wet granulation binders are corn starch, polyvinyl
`pyrrolidone (Povidon), vinylpyrrolidone-vinylacetate copolymer (Copovidone) and
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`cellulose derivatives like hydroxymethylcellulose, hydroxyethylcellulose,
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`hydroxypropyI-cellulose and hydroxypropylmethylcellulose.
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`Suitable disintegrants are, e.g., sodium starch glycolate, Crospovidon,
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`Croscarmellose, sodium carboxymethylcellulose and dried 'corn starch, sodium starch
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`glycolate being preferred.
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`The other excipients and adjuvants, if used, are preferably selected from diluents and
`carriers such as cellulose powder, microcrystalline‘ cellulose, cellulose derivatives like
`hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and hydroxy?
`propylmethylcellulose, dibasic calcium phosphate, corn starch, pregelatinized starch,
`
`polyvinyl pyrrolidone (.Povidone) etc.; lubricants such as stearic acid, magnesium
`stearate, Sodium stearylfumarate, glycerol tribehenate, etc.; flow control agents such
`
`as colloidal silica, talc, etc.,- crystallization retarders such as Povidone, etc.;
`
`solubilizers such as Pluronic, Povldone, etc.; coloring agents, including dyes and
`pigments such as Iron Oxide Red or Yellow, titanium dioxide, talc, etc.; pH control
`
`agents such as citric acid, tartaric acid, fumaric acid, sodium citrate, dibasic calcium
`phosphate, 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 and/or
`
`adJuvants
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`In _a particularly preferred embodiment the third layer is positioned between the first
`' and second layer to avoid contact of telmisartan andramipril with each other. The
`layers can be differentiated by using different colors.
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`Such a third tablet layer composition generally comprises 1.5 to 35 wt.%, preferably 2
`to 15_wt.°/o, of active ingredient; 25 to 75 wt.%, preferably 55 to 65 wt.%, of filler; 10
`
`to 40 wt.%, preferably 15 to 35 wt.%, of dry binder; 0.5 to 5 wt.%, preferably 1 to 4
`wt.%, of wet granulation binder; and 1 to 10 wt.%, preferably 2 to 8‘wt.%, of
`
`disintegrant. The other excipients and adjuvants are generally employed in the same
`amount as in the first tablet layer composition.
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`For preparing a bilayer tablet according to the present invention, the first and second
`
`tablet layer compositions may be compressed in the usual manner in a bilayer tablet
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`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. 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
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`WO 2005/079762
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`PCT/EP2005/001498
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`'-11-_
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`‘ first'and second tablet layers is in therange of from 1:10 to 1:2. For instance, the first
`tablet layer may be compressed at moderate force of 4 to 8 kN, whereas the main
`
`compression of first plus second layer is performed at a force of 10 to 20 _kN.
`
`During bilayer tablet compression adequate bondformation between the two layers is
`achieved by virtue of distance attraction forces (intermolecular forces) and
`
`mechanical interlocking between the particles.
`
`The multilayer tablets obtained release the active ingredients rapidly and in a largely
`pH-independent fashion, with complete release occurring within less than 60 min-and
`release of the major fraction occurring within less than 15 min. The dissolution/'-
`disintegration kinetics of the multilayer tablet may be controlled in different ways. For
`
`instance, the layers may dissolve/disintegrate simultaneously. Preferably, however,
`the second layer containing ramipril and the third tablet layer containing a diuretic
`disintegrate first whereas-the first layer containing telmisartan dissolves
`subsequently.
`4
`
`In accordance with the present invention, a substantially increased dissolution rate of
`
`the active ingredients and, in particular, of telmisartan is achieved. Normally, at least
`
`70% and typically at least 90% of the drug load are dissolved after 30 min.
`
`The multilayer tablets of the present invention tend to be slightly hygroscopic and are
`therefore preferably packaged using a moisture-proof packaging material such as
`
`aluminium foil blister packs, or polypropylene tubes and HDPE bottles which
`preferably contain a desiccant.
`
`A preferred method of producing the bilayer tablet according to the present invention
`
`comprises
`
`(i)
`
`providing a first tablet layer composition by
`a) preparing an aqueous solution of telmisartan, at least one basic agent
`' and, optionally, a solubilizer and/or a crystallization retarder;
`
`b)
`
`spray-drying said aqueous solution to obtain a spray-dried granulate;
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`WO 2005/079762
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`212'-
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`c) mixing said spray-dried granulate with a water-soluble_diluent to obtain a
`. premix;
`I
`.
`.
`‘
`.
`I
`I
`d) mixing said premix with a lubricant to obtain a final blend for the first layer;
`
`9) optionally, adding other excipients and/or adjuvants in any of steps a) to
`d);
`.
`,
`.
`providing a second tablet
`layer composition comprising ramipril alone or
`together with a diuretic
`V
`optionally providing a third tablet layer composition comprising a diuretic
`
`the first, second and third tablet layer composition to
`compressing each of
`form a tablet layer; and '
`.
`I
`
`(ii)
`
`-
`
`(iii)
`
`(iv)
`
`(v)
`
`compressing the separate tablet layers to form a multilayer tablet.
`
`To provide a first tablet layer composition-an aqueous alkaline solution of telmisartan
`’is prepared by dissolving the active ingredient in purified water withthe help of one or
`more basic agents like sodium hydroxide and meglumine. Optionally, a solubilizer
`
`and/or a recrystallization retarder may be added. The dry matter content of the
`starting aqueous solution is generally 10 to 40 wt.%, preferably 20 to 30 wt.%.
`The aqueous solution is then spray-dried at room temperature or preferably at
`increased temperatures of, for instance, between 50 and 100°C in a co—current or
`countercurrent spray-drier at a spray pressure of, for instance, 1 to 4 bar. Generally
`speaking, the spray-drying conditions are preferably chosen in such a manner that a
`spray-dried granulate having a residual humidity of s 5 wt-.%, preferably 5 3.5 wt.%, is
`obtained in the separation cyclone. To that end, the outlet air temperature of the
`spray-drier is preferably ‘kept at a value of between about 80 and 90°C while the
`other process parameters such as spray pressure, spraying rate, inlet air.
`temperature, etc. are adjusted accordingly.
`‘
`The spray-dried granulate obtained is preferably a fine powder having the following
`
`particle size distribution:
`
`d1o:
`
`dso :
`
`dgo :
`
`S 20 pm, preferably .'<. 10 pm
`
`s 80 pm, preferably 20 to 55 um
`
`S 350 pm, preferably 50 to 150 um
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`WO 2005/079762
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`PCT/EP2005/001498
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`-13-'
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`After spray-drying, the active ingredient telmisartan as well as the excipients
`
`containedIn the spray-dried granulate are in a substantially amorphous state with no
`crystallinity being detectable. From a physical point of view, the spray-d-ried granulate
`
`is a solidified solution or glass having a "glass transition temperature T9 of preferably
`
`> 50°C, more preferably > 80°C.
`
`Based on 100 parts by weight of active ingredient telmisartan, the spray-dried
`granulate preferably contains 5 to 200 parts by weight of basic agent and, optionally,
`
`.
`
`solubilizer and/or crystallization retarder.
`The water-soluble diluent"Is generally employed"In an amount of 30 to 95 wt.%,
`preferably 60 to 80 wt.%,' based on the weight of the first tablet layer composition.
`
`The lubricant is generally added to the premix in 'an amount of 0.1 to 5 wt.%,
`
`preferably 0.3 to 2 wt. %, based on the weight of the first tablet layer composition.
`
`MixingIs carried out in two stages, i.e. in a first mixing step the spray-dried granulate
`and the diluent are admixed using, e. g., a high--shear mixer or a free-fall blender,
`
`and'In a Second mixing step the lubricantIs blended with the premix, preferably also .’
`under conditions of high shear. 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'), and also in the subsequent steps f) and 9), such as, e.g.,
`
`1O
`
`15:
`
`20
`
`' container mixing with intermediate screening.
`
`- To provide a second tablet layer composition comprising ramipril alone, ramipril is
`premixed and granulated with a binder solution using a fluid bed granulator.'Part of
`the excipients can be premixed and granulated together with ramipril in the fluid bed
`
`25
`
`granulator. Optionally ramipril can be dissolved or suspended in the binder solution in
`order to improve content uniformity of Ramipril in the final product. The dried.
`
`granules are sieved through an appropriate sieve. After addition of the other
`excipients the mixture is blended in a free fall blender. Alternative methods for
`
`'30
`
`granulation of ramipril and excipients with the binder solution are high shear
`
`granulation or one pot granulation, followed by wet sieving, drying and dry sieving of
`
`the granules.
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`WO 2005/079762
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`PCT/EP2005/001498
`
`-14-
`
`First 'and second'tablet layer compositions as described above can be-compressed
`into bilayer tablets of the target tablet weight with appropriate size and crushing
`strength, using an appropriate tablet press. Optional an appropriate external lubricant
`spray system for the dies and punches can be used during manufacturing of tablets
`
`in order to improve lubrication.
`
`To provide an alternative second tablet layer composition comprising ramipril
`together with a diuretic such as hydrochlorothiazide (HCTZ), ramipril and
`hydrochlorothiazide are premixed and granulated together with part of the excipients
`with a binder solution in a fluid bed granulator as described above. Optionally the
`
`active ingredients can be dissolved .or suspended in the binder solution in order to
`
`improve content uniformity in the final product. After addition 'of the other excipients
`
`the mixture is blended in a free fall blender.
`
`.
`
`1O
`
`15
`
`First and alternative second layer compositions as described above can be
`
`compressed into bilayer tablets with appropriate size and crushing strength, using an
`appropriate tablet press. Optional an appropriate external lubricant spray system for
`
`the dies and punches can be used during manufacturing of tablets in order to.
`
`20-
`
`improve lubrication.
`
`In a further embodiment a third tablet layer composition comprising a diuretic may be
`
`prepared by dry-mixing the constituent components, 9.9. by means of a high-intensity
`mixer or a free-fall blender. Alternatively and preferably, the third tablet layer,
`composition is prepared using a wet granulation techni‘que‘ wherein an aqueous
`
`solution of a wet granulation binder is added to a premix and subsequently the Wet
`
`granulate obtained is dried, 9.9. in a fluidized-bed dryer or drying chamber. The dried
`mixture is screened and then a lubricant is admixed, eg. using a tumbling mixer or'
`
`free-fall blender.
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`First, second and third layer compositions as described above can be compressed
`into 3-layer tablets with appropriate size and crushing strength, using an appropriate
`
`tablet press.
`
`For the production of bilayer tablets according to the present invention, the separate
`tablet layer compositions can be compressed in a bilayer tablet press, e.g. a rotary
`
`press in the bilaye