EP3727344A1 - Compositions pharmaceutiques à doses fixes comprenant de l'amlodipine, du ramipril et de l'atorvastatine - Google Patents

Compositions pharmaceutiques à doses fixes comprenant de l'amlodipine, du ramipril et de l'atorvastatine

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Publication number
EP3727344A1
EP3727344A1 EP18826316.4A EP18826316A EP3727344A1 EP 3727344 A1 EP3727344 A1 EP 3727344A1 EP 18826316 A EP18826316 A EP 18826316A EP 3727344 A1 EP3727344 A1 EP 3727344A1
Authority
EP
European Patent Office
Prior art keywords
ramipril
pharmaceutically acceptable
atorvastatin
amlodipine
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP18826316.4A
Other languages
German (de)
English (en)
Inventor
Andreas Kahm
Daniel Jünemann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Midas Pharma GmbH
Original Assignee
Midas Pharma GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Midas Pharma GmbH filed Critical Midas Pharma GmbH
Publication of EP3727344A1 publication Critical patent/EP3727344A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to fixed dosed pharmaceutical compositions comprising the three active pharmaceutical ingredients (APIs) Amlodipine, Atorvastatin and Ramipril, or their pharmaceutically acceptable salts or esters, with improved stability for the treatment of hypertension and related diseases.
  • APIs active pharmaceutical ingredients
  • Amlodipine is the international nonproprietary name (INN) of (F?S)-3-ethyl-5-methyl-2-[(2- aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1 ,4-dihydropyridine-3,5-dicarboxylate with the following chemical structure:
  • compositions of the calcium channel blocker (COB) Amlodipine in the modification of its benzene sulfonate (“besilate”) salt are registered and marketed under the trade name NORVASC ® for the treatment of, inter alia, hypertension.
  • Atorvastatin is the INN of (3F?,5/ : ?)-7-[2-(4-fluoro-phenyl)-3-phenyl-4-(phenylcarbamoyl)-5- propan-2-ylpyrrol-1 -yl]-3,5-dihydroxyheptanoic acid with the following chemical structure:
  • compositions of the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor Atorvastatin are registered and marketed under the trade names SORTIS ® and LIPITOR ® for the treatment of hypercholesterolemia and the prevention of cardiovascular diseases.
  • Ramipril is the INN of (2S,3aS,6aS)-1 -[(2S)-2-[[(2S)-1 -ethoxy-1 -oxo-4-phenylbutan-2- yl]amino]-propanoyl]-3,3a,4,5,6,6a-hexahydro-2H-cyclopenta-[b]pyrrole-2-carboxylic acid which has the following chemical structure:
  • compositions of the Angiotensin converting enzyme (ACE) inhibitor Ramipril are registered and marketed under the trade name DELIX ® for the treatment of, inter alia, cardiovascular disorders and hypertension.
  • TRINOMIA ® Fixed-dosed pharmaceutical compositions comprising Atorvastatin, Ramipril and Acetylsalicylic acid are registered and marketed under the trade name TRINOMIA ® .
  • TRINOMIA ® is not a uniform pharmaceutical dosage form, but a capsule which contains, depending on the strengths, three or even more film-coated immediate release tablets.
  • one active ingredient may be incompatible with another API or the stability of one active ingredient may be affected due to its incompatibility with an excipient that is commonly used in order to stabilize another API.
  • Amlodipine is known to be incompatible with the excipient lactose, rendering the composition of SORTIS ® unsuitable to serve as a basis for a fixed dose combination of Atorvastatin and Amlodipine.
  • Amlodipine besilate being weakly basic, is highly hygroscopic and sensitive to hydrolysis and the exposure to light. It exhibits physical properties as low bulk densities, poor flow or uniformity of dosage units. It is also susceptible to static electricity and highly cohesive. Amlodipine besilate is slightly soluble in water and has an absolute bioavailability of 64-90%. The formation of its main degradant is enhanced at low pH-values.
  • Ramipril is weakly acidic in nature and its main degradant ramipril- diketopiperazine (“DKP”, also referred to as “impurity D”) is formed at high pH-values. Besides exhibiting certain undesirable flow characteristics such as stickiness, it is very sensitive to degradation under oxidative conditions and wherein moisture is present. In addition, the formation of DKP is increased by mechanical stress during the formulation of Ramipril.
  • DKP main degradant ramipril- diketopiperazine
  • CN 101612403 discloses medicinal combinations of calcium channel blockers, ACE inhibitors and HMG-CoA reductase inhibitor and a pharmaceutically acceptable carrier.
  • ODT orally disintegrating tablets
  • Levamlodipine besilate, Ramipril and Atorvastatin are disclosed.
  • ODT formulations should be considered as solid oral preparations that disintegrate rapidly in the oral cavity, with an in- vitro disintegration time of approximately 30 seconds or less, when based on the United States Pharmacopeia (USP) disintegration test method or alternative.
  • USP United States Pharmacopeia
  • ODTs disintegrate within 3min in water.
  • Figure 1 shows the dissolution of formulations of 10mg Amlodipine, 10mg Ramipril and 40mg Atorvastatin prepared according to example 1 compared to DELIX ® and NORVASC ® and SORTIS ®
  • Figure 2 shows the dissolution of formulations of 5mg Amlodipine, 10mg Ramipril and 20mg Atorvastatin prepared according to example 1 compared to DELIX ® and NORVASC ® and SORTIS ®
  • Figure 3 shows the dissolution of formulations of 10mg Amlodipine, 10mg Ramipril and 40mg Atorvastatin prepared according to example 2 compared to DELIX ® and NORVASC ® and SORTIS ®
  • Figure 4 shows a flow chart of the manufacturing process of formulations according to example 1 .
  • Figure 5 shows a flow chart of the manufacturing process of formulations according to example 2.
  • the present invention relates to fixed dosed immediate release pharmaceutical compositions comprising the active substances Amlodipine, Ramipril and Atorvastatin, or their pharmaceutically acceptable salts or esters.
  • immediate release pharmaceutical compositions according to the present invention are characterized by the fact that they disintegrate in not less than 3 minutes, preferably within from 4 to 10 minutes under standard conditions as set in 2.9.1 of PharmEur (version 9.3).
  • the fixed dosed immediate release pharmaceutical compositions are in form of a capsule or a tablet, preferably a bilayer tablet.
  • Amlodipine is utilized in the form of its benzenesulfonate (besilate) salt and Atorvastatin is utilized in the form of its calcium salt.
  • Amlodipine besilate may be manufactured according to processes known in the art, e.g. as disclosed in patent application EP 0 244 944 A2.
  • Ramipril may be manufactured according to processes known in the art, e.g. as disclosed in patent application EP 0 079 022 A2.
  • a process for the preparation of Atorvastatin calcium is disclosed in WO 1997/003959 A1.
  • compositions of the present invention may comprise excipients such as filler(s), binder(s), lubricant(s), stabilizer(s), solubilizer(s), disintegrant(s), glidant(s) etc.
  • filler(s), binder(s), lubricant(s), stabilizer(s), solubilizer(s), disintegrant(s), glidant(s) etc. shall be understood as including a single compound but also multiple compounds.
  • compositions of the present invention comprise one or more pharmaceutically acceptable filler(s).
  • Pharmaceutically acceptable fillers according to the present invention are microcrystalline cellulose (MCC), calcium phosphates, calcium carbonate, magnesium carbonate, starch, powder cellulose, calcium silicate, sorbitol, dextrin, kaolin, magnesium oxide, calcium sulfate, xylitol, lactose and mixtures thereof.
  • the total amount of filler(s) is in the range from 30wt.-% to 90wt.-%, based on the total weight of the composition.
  • Preferred filler(s) are microcrystalline cellulose, calcium hydrogen phosphate and mixtures thereof. Lactose may be used in pharmaceutical compositions in form of a bilayer tablet wherein lactose is not comprised in the Amlodipine containing layer.
  • compositions of the present invention comprise one or more pharmaceutically acceptable binder(s).
  • Pharmaceutically acceptable binders according to the present invention are hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), dihydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, polymethacrylates, sodium alginate, polyvinylpyrrolidone, pregelatinized starch, vinylpyrrolidone/vinylacetate copolymers (copovidone) and mixtures thereof.
  • the total amount of binder(s) is in the range from 0.5wt.-% to 4%wt.-%, preferably in the range of from 1wt.-% to 3%wt.-%, based on the total weight of the composition.
  • Preferred binders are hydroxypropyl methylcellulose, and hydroxypropyl cellulose.
  • compositions of the present invention comprise one or more pharmaceutically acceptable disintegrant(s).
  • Suitable disintegrant(s) according to the present invention are carboxymethyl cellulose, crospovidone, sodium starch glycolate, croscarmellose, sodium carboxymethyl starch and mixtures thereof.
  • the total amount of disintegrant(s) is in the range from 0.25wt.-% to 4wt.-%, preferably in the range from 0.5wt.-% to 2wt.-%, based on the total weight of the composition.
  • Preferred disintegrant(s) are croscarmellose sodium, sodium starch glycolate and mixtures thereof.
  • the pharmaceutical compositions of the present invention comprise one or more pharmaceutically acceptable lubricant(s).
  • Suitable lubricants according to the present invention are sodium stearyl fumarate, magnesium stearate, calcium stearate, sodium stearate, stearic acid, hexanedioic acid, hydrogenated vegetable oil, glycerol fumarate and mixtures thereof.
  • the total amount of lubricant(s) is in the range from 0.25wt.-% to 2wt.-%, preferably in the range from 0.5wt.-% to 1wt.-%, based on the total weight of the composition.
  • the preferred lubricant is sodium stearyl fumarate.
  • compositions of the present invention may comprise a pharmaceutically acceptable stabilizer for Ramipril.
  • the ratio of Ramipril and the Ramipril stabilizer is in the range from 1 :0.5 to 1 :2 by weight, preferably in the range from 1 :1 to 1 :1.5 by weight.
  • the preferred stabilizer for Ramipril is glyceryl behenate.
  • compositions of the present invention may comprise a pharmaceutically acceptable stabilizer for Atorvastatin.
  • the ratio of Atorvastatin and the Atorvastatin stabilizer is in the range from 1 :1 to 1 :5 by weight, preferably in the range from 1 :2 to 1 :4 by weight.
  • the preferred stabilizer for Atorvastatin is calcium carbonate.
  • compositions of the present invention may comprise a pharmaceutically acceptable solubilizer for Atorvastatin.
  • the ratio of Atorvastatin and the Atorvastatin solubilizer is in the range from 5:1 to 40:1 by weight, preferably in the range from 10:1 to 25:1 by weight.
  • the preferred solubilizer is polysorbate 80.
  • compositions according to the present invention may optionally comprise pharmaceutically acceptable glidant(s) such as colloidal silicon dioxide, talcum, magnesium carbonate and mixtures thereof.
  • glidant(s) such as colloidal silicon dioxide, talcum, magnesium carbonate and mixtures thereof.
  • the amount of glidant(s) is preferably in the range from 0.1wt.-% to 1.5wt.-%, relative to the total weight of the composition.
  • the present invention relates to fixed dosed immediate release pharmaceutical compositions comprising the active substances Amlodipine, Ramipril, Atorvastatin, or their pharmaceutically acceptable salts or esters, and one or more pharmaceutically acceptable binder(s), one or more pharmaceutically acceptable filler(s), one or more pharmaceutically acceptable stabilizer(s), one or more pharmaceutically acceptable disintegrant(s), one or more pharmaceutically acceptable lubricant(s) and optionally one or more pharmaceutically acceptable solubilizer(s).
  • the present invention relates to fixed dosed immediate release pharmaceutical compositions
  • the active substances Amlodipine besilate, Ramipril, Atorvastatin calcium, from 0.5wt.-% to 4%wt.-% of one or more pharmaceutically acceptable binder(s), from 30wt.-% to 90 wt.-% one or more pharmaceutically acceptable filler(s), one or more pharmaceutically acceptable stabilizer(s), from 0.25wt.-% to 4wt.-% of one or more pharmaceutically acceptable disintegrant(s), from 0.25wt.-% to 2wt.-% of one or more pharmaceutically acceptable lubricant(s) and optionally one or more pharmaceutically acceptable solubilizer(s), all wt.-% being based on the total weight of the composition.
  • the fixed dosed immediate release pharmaceutical compositions further comprise calcium carbonate as a stabilizer for Atorvastatin wherein the ratio of Atorvastatin and calcium carbonate is in the range from 1 :1 to 1 :5 by weight, and glyceryl behenate as a stabilizer for Ramipril wherein the ratio of Ramipril and glyceryl behenate is in the range from 1 :0.5 to 1 :2 by weight.
  • the fixed dosed pharmaceutical compositions of the present invention exhibit excellent stability.
  • the content of impurity D of Ramipril after 3 months storage at 40 q C/75%RH is less than 5.0% w/w, preferably less than 3.50% w/w.
  • the fixed dosed pharmaceutical compositions of the present invention also exhibit very similar dissolution profiles compared to their respective brand products as regards all three active substances.
  • the fixed dosed pharmaceutical compositions of the present invention also exhibit excellent bioequivalence as compared to their respective brand products of the free combination as regards all three active substances.
  • the fixed dosed immediate release pharmaceutical compositions according to the present invention may be used in the treatment of hypertension and related diseases.
  • compositions in the form of bilayer tablets comprising 5mg/5mg or 5mg/10mg or 10mg/10mg of Ramipril/Amlodipine in a first layer and 10mg or 20mg or 40mg of Atorvastatin in a second layer.
  • two different layers may, in principal, be considered independent from each other. If the total weight of one layer is 285mg or more, the relative amount of Amlodipine besilate in the 10mg strength remains below 5wt.-% compared to the total weight of the layer. Provided this, there is no need to perform additional bioequivalence studies for a lower strength, e.g. the 5mg strength, if Amlodipine besilate is solely replaced by a filler so that the total weight of the layer remains constant.
  • the total weight of the layer should not exceed 345mg because then the 5mg strength would contain less than 2wt.-% Amlodipine besilate compared to the total weight of the layer. Accordingly, the product would be considered as a “non-standard” product, resulting in the need of costly and thus undesirable re-validation if the batch size is changed.
  • compositions with only 2.5mg of Amlodipine are not preferred embodiments of the present invention.
  • the minimum weight of the layer of 285mg as set out above results in a Ramipril content of 3.5wt.-% compared to the total weight of the layer for the 10mg strength.
  • Atorvastatin containing layer three different strengths (10mg, 20mg and 40mg) may be manufactured from a single pre-mix, i.e. only the total amount of the pre-mix is adapted between 100mg (for the 10mg strength), 200mg (for the 20mg strength) or 400mg (for the 40mg strength), i.e. the different strengths are weight-proportional.
  • this“single pre-mix” approach renders the manufacturing process much more cost efficient.
  • this approach does not suit for compositions comprising 80mg Atorvastatin since the corresponding Atorvastatin layer with a total weight of 800mg would result in tablets that are too heavy and too big.
  • a“dose-proportional” approach for the Amlodipine besilate and Ramipril containing layer and a“weight-proportional” approach for the Atorvastatin containing layer is advantageous from a regulatory perspective because, for the reasons set out above, up to nine different combinations of strengths may be registered with only one bioequivalence study. In addition, all nine different combinations of strengths may be produced from only three pre-mixes (two pre-mixes of Amlodipine/Ramipril and one pre-mix of Atorvastatin), which renders both the product development and the manufacturing very cost efficient.
  • a preferred embodiment of the present invention relates to a set of fixed dosed pharmaceutical compositions in the form of bilayer tablets, comprising 5mg/5mg, 5mg/10mg or 10mg/10mg of Amlodipine/Ramipril and 10mg, 20mg or 40mg of Atorvastatin.
  • it relates to 5mg/5mg/10mg, 5mg/5mg/20mg, 5mg/5mg/40mg, 5mg/10mg/10mg,
  • the actives should be combined in a way so that either all actives are incorporated in relatively low strengths or all actives are incorporated in relatively high strengths.
  • the ratio of Amlodipine to Atorvastatin and Ramipril to Atorvastatin shall remain in the range from 1 :2 to 1 :4.
  • a particular preferred set of fixed dosed pharmaceutical compositions according to the present invention comprise 5mg/5mg/10mg, 5mg/5mg/20mg, 5mg/10mg/20mg, 10mg/10mg/20mg and 10mg/10mg/40mg of Amlodipine/Ramipril/Atorvastatin.
  • An overview of the preferred strengths is provided in table 4.
  • the present invention also relates to fixed dosed immediate release pharmaceutical compositions in form of bilayer tablets for the treatment of hypertension, wherein the first layer comprises 5mg or 10mg Ramipril, 5mg or 10mg Amlodipine as Amlodipine besilate and one or more pharmaceutically acceptable binder(s), one or more pharmaceutically acceptable filler(s), one or more pharmaceutically acceptable stabilizer(s) and one or more pharmaceutically acceptable lubricant(s), and the second layer comprises 10mg, 20mg or 40mg Atorvastatin as Atorvastatin calcium, one or more pharmaceutically acceptable binder(s), one or more pharmaceutically acceptable filler(s), one or more pharmaceutically acceptable stabilizer(s), one or more pharmaceutically acceptable disintegrant(s), one or more pharmaceutically acceptable lubricant(s).
  • the first layer comprises 5mg or 10mg Ramipril, 5mg or 10mg Amlodipine as Amlodipine besilate and one or more pharmaceutically acceptable binder(s
  • the invention also relates to processes for the manufacture of uniform, stable pharmaceutical compositions comprising Amlodipine, Ramipril and Atorvastatin, or their pharmaceutically acceptable salts or esters.
  • compositions according to the present invention may be manufactured by a process comprising the steps of: a) preparing a first mixture comprising Ramipril and Amlodipine besilate and a first set of excipients by means of wet granulation or dry mixing;
  • step c) combining the mixture of step a) and the granules of step b), optionally with a third set of excipients;
  • step d) filling the product of step c) into capsules or compressing it into tablets, preferably into bilayer tablets.
  • Example 1 Pharmaceutical compositions a) Preparation of the Ramipril and Amlodipine layer by wet granulation
  • a first part (10%) of microcrystalline cellulose is passed through 0.8mm sieve of Quadro comill at 1700RPM, followed by a premix of Amlodipine besilate and Ramipril with 50% of the pregelatinized starch and 50% of the glyceryl behenate.
  • the mill is then rinsed by passing a second part (10%) of microcrystalline cellulose (step 1 ).
  • a high sheer mixer is saturated with the remaining third part (80%) of microcrystalline cellulose and the combined materials of step 1 are added and mixed (step 2).
  • the binder solution containing hydroxypropyl methyl cellulose is added and granules are formed (step 3).
  • the granules are then dried in a fluid bed dryer (step 4) and milled (step 5).
  • Atorvastatin calcium is co-sifted with calcium carbonate and dry-mixed (step i). Lactose monohydrate, microcrystalline cellulose and croscarmellose sodium are added and dry-mixed (step ii). A binder solution prepared by addition of dispensed polysorbate 80 into a solution of hydroxypropyl cellulose and purified water is added to the mixture obtained in step ii and wet granulated (step iii).
  • the granules are then dried in a fluid bed dryer (step iv), sifted and milled (step v).
  • the dried Atorvastatin granules are then blended with microcrystalline cellulose and croscarmellose sodium (step vi) and finally lubricated with sodium stearyl fumarate (step vii).
  • the Ramipril-Amlodipine part and the Atorvastatin part are compressed into a bilayer tablet (step 8), optionally film coated (step 8a) and packed into Alu-Alu blisters (step 9).
  • the respective quantities are displayed in table 7.
  • Table 7 Table 7
  • uBR Rapril tabs
  • ICH Q 3 B USP (Atorvastatin + Amlodipine tabs)
  • Exemplary batches of tablets containing 10mg Amlodipine, 10mg Ramipril and 40mg Atorvastatin and 5mg Amlodipine, 10mg Ramipril and 20mg Atorvastatin are submitted to dissolution studies under standard conditions as displayed in table 9.
  • Tables 10 and 1 1 , figs. 1 and 2 indicate that the in-vitro-dissolution profiles for all actives are not only similar to the respective branded product, but also do not change significantly after having been submitted to stability testing.
  • table 12 additional data such as disintegration time, hardness and friability of an exemplary batch of tablets are displayed.
  • a first premix (premix I) is prepared by saturating a blender with a first part of the microcrystalline cellulose (55% w/w) (step 1 a), followed by addition of Ramipril, glyceryl behenate, calcium hydrogen phosphate, pregelatinized starch and HPMC (step 2a) and mixing (step 3a).
  • a second premix (premix II) is prepared by saturating a blender with a second part of the microcrystalline cellulose (45% w/w) (step 1 b), followed by addition of Amlodipine besilate and sodium starch glycolate (step 2b) and mixing (step 3b).
  • Premix I and premix II are then blended and dry mixed (step 4a). Finally, the blend is submitted to lubrication (step 5a).
  • the Atorvastatin layer is prepared as described in example 1 b.
  • the bilayer tablet is prepared as described in example 1 c.
  • BP Rapril tabs
  • Table 16 and fig. 3 indicate that the in-vitro-dissolution profiles for all actives are not only similar to the respective branded product, but also do not change significantly after having been submitted to stability testing.

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Abstract

La présente invention concerne des compositions pharmaceutiques à libération immédiate à doses fixes comprenant les trois substances actives Amlodipine, Atorvastatine et Ramipril, ou leurs sels ou esters pharmaceutiquement acceptables, pour le traitement de l'hypertension et de maladies associées.
EP18826316.4A 2017-12-20 2018-12-19 Compositions pharmaceutiques à doses fixes comprenant de l'amlodipine, du ramipril et de l'atorvastatine Pending EP3727344A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP17208852.8A EP3501502A1 (fr) 2017-12-20 2017-12-20 Compositions pharmaceutiques dosées fixes comprenant de l'amlodipine, du ramipril et de l'atorvastatine
PCT/EP2018/085746 WO2019121857A1 (fr) 2017-12-20 2018-12-19 Compositions pharmaceutiques à doses fixes comprenant de l'amlodipine, du ramipril et de l'atorvastatine

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EP3727344A1 true EP3727344A1 (fr) 2020-10-28

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EP18826316.4A Pending EP3727344A1 (fr) 2017-12-20 2018-12-19 Compositions pharmaceutiques à doses fixes comprenant de l'amlodipine, du ramipril et de l'atorvastatine

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EP4052695A1 (fr) * 2021-03-05 2022-09-07 Midas Pharma GmbH Compositions pharmaceutiques orales stables à libération immédiate à dose fixe comprenant de l'amlodipine, de l'atorvastatine et du candésartan cilexétil

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