EP3886817A1 - Composition pharmaceutique comprenant du ramipril et de l'indapamide - Google Patents
Composition pharmaceutique comprenant du ramipril et de l'indapamideInfo
- Publication number
- EP3886817A1 EP3886817A1 EP19806009.7A EP19806009A EP3886817A1 EP 3886817 A1 EP3886817 A1 EP 3886817A1 EP 19806009 A EP19806009 A EP 19806009A EP 3886817 A1 EP3886817 A1 EP 3886817A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- layer
- ramipril
- indapamide
- weight
- compound
- 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
Links
- 229960003401 ramipril Drugs 0.000 title claims abstract description 111
- 229960004569 indapamide Drugs 0.000 title claims abstract description 81
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- NDDAHWYSQHTHNT-UHFFFAOYSA-N indapamide Chemical compound CC1CC2=CC=CC=C2N1NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 NDDAHWYSQHTHNT-UHFFFAOYSA-N 0.000 title claims description 56
- 239000008194 pharmaceutical composition Substances 0.000 title description 7
- -1 indapamide compound Chemical class 0.000 claims abstract description 65
- 239000012535 impurity Substances 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 29
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- 238000004704 ultra performance liquid chromatography Methods 0.000 claims abstract description 24
- 239000003381 stabilizer Substances 0.000 claims abstract description 21
- KEDYTOTWMPBSLG-HILJTLORSA-N ramiprilat Chemical compound C([C@H](N[C@@H](C)C(=O)N1[C@@H](C[C@@H]2CCC[C@@H]21)C(O)=O)C(O)=O)CC1=CC=CC=C1 KEDYTOTWMPBSLG-HILJTLORSA-N 0.000 claims abstract description 18
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- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 1
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- 229940068968 polysorbate 80 Drugs 0.000 description 1
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- 229920001592 potato starch Polymers 0.000 description 1
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- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
- KOVMAAYRBJCASY-JBDAPHQKSA-N ramipril diketopiperazine Chemical compound C([C@@H](C(=O)OCC)N1C([C@@H]2C[C@@H]3CCC[C@@H]3N2C(=O)[C@@H]1C)=O)CC1=CC=CC=C1 KOVMAAYRBJCASY-JBDAPHQKSA-N 0.000 description 1
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- 239000000377 silicon dioxide Substances 0.000 description 1
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
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- 239000000600 sorbitol Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
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- 230000009747 swallowing Effects 0.000 description 1
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- 230000002195 synergetic effect Effects 0.000 description 1
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- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- 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
- A61K31/40—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
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- composition comprising ramipril and indapamide
- the present invention relates to a pharmaceutical composition for oral administration in the form of a multilayer tablet comprising ramipril, or a pharmaceutically acceptable salt or a stereoisomer thereof, and indapamide, or a pharmaceutically acceptable salt thereof. It also relates to a process for the preparation of the pharmaceutical composition and to its medical uses, in particular in the treatment of hypertension.
- Ramipril is the generic name of compound (2S,3aS,6aS)-1-[(2S)-2- ⁇ [(2S)-1-ethoxy-1- oxo-4-phenylbutan-2-yl]amino ⁇ propanoyl]octahydrocyclo-penta[b]-pyrrole-2- carboxylic acid, the chemical structure of which is the following:
- Ramipril is a prodrug belonging to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is metabolized to ramiprilat in the liver and, to a lesser extent, kidneys. Ramiprilat is a potent, competitive inhibitor of ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATI I). Ramipril may be used in the treatment of hypertension, congestive heart failure, nephropathy, and to reduce the rate of death, myocardial infarction and stroke in individuals at high risk of cardiovascular events.
- ACE angiotensin-converting enzyme
- ramiprilat (ramipril diacid) is (2S,3aS,6aS)-1-[(S)- 2-[[(S)-1-carboxy-3-phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2- carboxylic acid, and its chemical structure, the following: Ramipril exhibits a strong sensitivity to heat and moisture and decomposes easily.
- WO2013/121233 discloses that excipients having high specific surface area and acidic character such as colloidal silicon dioxide are incompatible with ramipril and that their use during the formulation should be avoided.
- ramipril is also susceptible to degradation caused by the mechanical compression used in the manufacturing process for the preparation of prior art tablets. Hence, the hydrolysis of the ester groups of ramipril results in the impurity corresponding to the active metabolite, ramiprilat, which is identified as Impurity E.
- ramipril diketopiperazine DKP, chemical name ethyl (2S)-2-[(3S,5aS,8aS,9aS)-3-methyl-1 ,4- dioxodecahydro-2/-/-cyclopenta[4,5]pyrrolo-[1 ,2-a]pyrazin-2-yl]-4-phenylbutanoate
- Impurities D and E are cited in the ramipril monograph of the European Pharmacopoeia (see for example, European
- compositions containing ramipril are disclosed for example in W02007/120930 and WO2013/121233.
- W02007/120930 discloses that an increase in the stability of the ramipril formulations (by reduction of the DKP impurity) is achieved by relatively decreasing the amount of inactive ingredients and increasing the amount of active ingredient in the formulation.
- This document specifically discloses capsules of ramipril containing pregelatinized starch, lactose anhydrous and sodium stearyl fumarate as excipients.
- WO2013/121233 discloses ramipril formulations, in particular in the form of capsules, which contain a disintegrant directly granulated with a binder. It also discloses a comparative example which is a tablet as disclosed in W02007/120930 with the modification that it is supplemented with sodium hydrogen carbonate. Specifically, the comparative tablet contains as excipients: sodium hydrogen carbonate, lactose, croscarmellose sodium, pregelatinized starch, and sodium stearyl fumarate.
- the tablet is prepared by mixing lactose, ramipril, sodium hydrogen carbonate, croscarmellose sodium and starch and granulating the mixture with 1 :1 (v/v) mixture of 96% (v/v) ethanol and water. The granules are sieved and dried and then mixed with sodium stearyl fumarate and tabletted. According to this document, this tablet shows a concentration of the impurity E (which corresponds to ramipril diacid) of 3.42% at 25°C/60% r.h., and 6.0 at 40°C/75% r.h after stability of 6 months.
- impurity E which corresponds to ramipril diacid
- Indapamide is an oral antihypertensive/diuretic. Its chemical name is 4-chloro-N-(2- methyl-2, 3-dihydroindol-1-yl)-3-sulfamoyl-benzamide, and its chemical structure, the following:
- impurity B (4-chloro-N-(2-methyl-1 H-indol-1- yl]-3-sulphamoyl-benzamide) and is cited in the indapamide monograph of the European Pharmacopoeia (see for example, European Pharmacopoeia 5.0).
- the inventors have developed a pharmaceutical composition for oral adminitration in the form of a multilayer tablet which comprises a first layer comprising indapamide, and a second layer comprising ramipril, wherein the second layer has an impurity level of (2S,3aS,6aS)-1 -[(S)-2-[[(S)-1 -carboxy-3- phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2-carboxylic acid (impurity E) equal to or lower than 1.0% after 6 months at 40 °C / 75% RH as measured by ultra performance liquid chromatography (UPLC).
- impurity E impurity E
- This oral multilayer tablet is stable, showing particularly low levels of impurities.
- the examples of the multilayer tablet of the invention show very reduced levels of the ramipril impurity E in comparison to the ramipril tablet of the prior art (see comparative example in WO2013/121233).
- the oral multilayer tablets of the invention have the advantage that they allow the administration of both ramipril and indapamide in a single dosage form. Further, they avoid any chemical incompatibilities between the active ingredients and/or accompanying pharmaceutically excipients by physical separation.
- the oral multilayer tablets of the invention also enable the development of different drug release profiles, such as immediate release for ramipril and sustained release for indapamide.
- the oral multilayer tablet of the invention has the advantage that it shows better patient convenience and compliance compared to the capsules.
- the oral multilayer tablet of the invention is easier to swallow and shows less tendency for hang-up (sticking to the mucosa) when swallowed.
- the manufacture of capsules requires more manufacture steps in comparison to the preparation of an oral multilayer tablet.
- the multilayer tablet of the invention is more cost/energy effective.
- an aspect of the invention relates to an oral multilayer tablet according to claim 1 comprising:
- a second layer comprising a ramipril compound and a stabilizing agent; wherein the ramipril compound is selected from ramipril, a pharmaceutically acceptable salt thereof, and a stereoisomer either of ramipril or of a pharmaceutically acceptable salt thereof; and the indapamide compound is selected from indapamide, a pharmaceutically acceptable salt thereof, and a stereoisomer either of indapamide or of a pharmaceutically acceptable salt thereof; and
- the second layer has an impurity level of (2S,3aS,6aS)-1-[(S)-2-[[(S)-1- carboxy-3-phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2-carboxylic acid (impurity E) equal to or lower than 1.0% after 6 months at 40 °C / 75% RH as measured by ultra performance liquid chromatography (UPLC).
- impurity E impurity E
- the oral multilayer tablets of the invention have the further advantage that they can be prepared by a process comprising fewer steps in comparison to the process for preparing the prior art capsules.
- the first and second layers can be in any order.
- Another aspect of the invention relates to a process for the preparation of the multilayer tablet as defined above which comprises the following steps:
- step ii) mixing the mixture of step i) with one or more pharmaceutically acceptable excipients in order to obtain a second mixture;
- step iii) granulating the mixture of step ii), optionally in the presence of an additional granulation liquid in order to obtain granules;
- step iv) milling and drying the granules obtained in step iii) in order to obtain a granulate
- step d) compressing the first and second layer compositions from step a) and b) and, optionally, the one or more additional layer compositions of step c), to form a multilayer tablet comprising a first layer comprising an indapamide compound and a second layer comprising a ramipril compound;
- steps a), b), and c) can be carried out in any order;
- the second layer has an impurity level of (2S,3aS,6aS)-1-[(S)-2-[[(S)-1- carboxy-3-phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2-carboxylic acid (impurity E) equal to or lower than 1.0% after 6 months at 40 °C / 75% RH as measured by ultra performance liquid chromatography (UPLC).
- impurity E impurity E
- a further advantage of the invention is that the ramipril granulates containing a stabilizing agent show good flowability properties.
- Another aspect of the invention relates the oral multilayer tablet comprising ramipril and indapamide as defined above, for use as a medicament.
- Another aspect of the invention relates to the oral multilayer tablet comprising ramipril and indapamide as defined above, for use in the treatment of hypertension, particularly of hypertension in patients whose blood pressure is not adequately controlled on ramipril alone, in patients whose blood pressure is not adequately controlled on indapamide alone, or in patients whose blood pressure is not adequately controlled with ramipril alone followed by indapamide alone or vice versa.
- this aspect relates to the use of ramipril and indapamide for the manufacture of an oral multilayer tablet as defined above for the treatment of hypertension, particularly of hypertension in patients whose blood pressure is not adequately controlled on ramipril alone, in patients whose blood pressure is not adequately controlled on indapamide alone, or in patients whose blood pressure is not adequately controlled with ramipril alone followed by indapamide alone or vice versa; and may also be formulated as a method for the treatment of hypertension, particularly of hypertension in patients whose blood pressure is not adequately controlled on ramipril alone, in patients whose blood pressure is not adequately controlled on indapamide alone, or in patients whose blood pressure is not adequately controlled with ramipril alone followed by indapamide alone or vice versa, which comprises administering a therapeutically effective amount of the oral multilayer tablet comprising ramipril and indapamide as defined above in a subject in need thereof, including a human.
- the invention refers to an oral multilayer tablet as defined above comprising a first layer containing an indapamide compound and a second layer containing a ramipril compound, and, optionally, one or more additional layers either comprising or not a further active ingredient.
- multilayer tablet refers to a tablet containing two or more layers that have been arranged in a stepwise manner and then compressed into a single dosage form.
- Each of the layers of the multilayer tablet of the invention comprises one active ingredient and pharmaceutically acceptable excipients.
- the multilayer tablet is a bilayer tablet.
- the multilayer tablets of the invention can be uncoated or film-coated.
- indapamide compound encompasses indapamide, as well as any pharmaceutically acceptable salt thereof, and any stereoisomer or mixtures thereof, either of indapamide or of any of its pharmaceutically acceptable salts.
- any solid forms of the indapamide compound such as anhydrates, solvates, hydrates, crystalline and amorphous forms, are also encompassed by the present invention.
- the second layer has an impurity level of impurity E equal to or lower than 0.1%, particularly equal to or lower than 0.05%, after 6 months at 40 °C / 75% RH as measured by ultra performance liquid chromatography (UPLC).
- the second layer does not comprise any binder.
- the indapamide compound is present in the first layer in an amount from 0.6 to 40%, more particularly from 0.7 to 10%, by weight with respect to the total weight of the first layer. More particularly, the indapamide compound is indapamide.
- ramipril compound encompasses ramipril, as well as any pharmaceutically acceptable salt thereof, and any stereoisomer or mixtures thereof, either of ramipril or of any of its pharmaceutically acceptable salts.
- any solid forms of the ramipril compound such as anhydrates, solvates, hydrates, crystalline and amorphous forms, are also encompassed by the present invention.
- the ramipril compound is present in the second layer in an amount from 1 to 20%, more particularly from 1 to 10%, and even more particularly, from 2 to 6% by weight with respect to the total weight of the second layer. More particularly, the ramipril compound is ramipril.
- pharmaceutically acceptable salt refers to any non-toxic salt which can be used for therapeutic purposes.
- the preparation of pharmaceutically acceptable salts of the compounds of the invention can be carried out by methods known in the art. For instance, they can be prepared from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods.
- such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate pharmaceutically acceptable base or acid in water or in an organic solvent or in a mixture of them.
- the base compounds and their salts may differ in some physical properties but they are equivalent for the purposes of the present invention.
- stereoisomer refers to all isomers of individual compounds that differ only in the orientation of their atoms in space.
- stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), and isomers that are not mirror images of one another (diastereoisomers).
- the present invention relates to each of these stereoisomers and also mixtures thereof.
- the multilayer tablets of present invention are intended for oral administration and provide for immediate release of the ramipril compound and sustained release of the indapamide compund when administered.
- immediate release means that ramipril is released substantially immediately upon contact with gastric juices and results in substantially complete dissolution within about 45 minutes. In one embodiment, about equal or higher than 80% by weight of ramipril is completely dissolved after 45 minutes.
- sustained release means that indapamide is released over a prolonged period of time. In this case dissolved amount of inadapamide, using USP I method, meets acceptance criteria:
- the first layer comprises a sustained release-matrix former selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), ethyl cellulose (EC), methyl cellulose (MC), carboxymethyl cellulose (CMC), povidone, poly(meth)acrylates (such as Eudragit NE, Eudragit RS) or mixtures thereof.
- HPMC hydroxypropyl methylcellulose
- HPMC hydroxypropyl methylcellulose
- the sustained release-matrix former is in an amount from 10 to 60% by weight with respect to the total weight of the first layer, particularly from 20 to 50%, even particularly from 30 to 40%.
- the first layer i.e. the indapamide layer, does not comprise a carbomer.
- the oral multilayer tablet of the present disclosure does not present friability problems. Particularly, no delamination of the layers is produced.
- the second layer comprises a stabilizing agent.
- the stabilizing agent is present in the second layer in an amount from 1 to 20 wt%, more particularly from 1 to 10 wt%, such as of 1.25 wt%, 2.5 wt% or 5 wt%, with respect to the total weight of the second layer.
- the stabilizing agent is selected from the group consisting of metal oxides, disodium edetate, tocopherol, cyclodextrins and derivatives, alkali or alkaline earth metal (particularly sodium, magnesium, and calcium) bicarbonates, carbonates, citrates and phosphates, and mixtures thereof. More particularly, the stabilizing agent is selected from the group consisting of alkali or alkaline earth metal (particularly sodium, magnesium, and calcium) bicarbonates, carbonates, and mixtures thereof. Even more particularly, the stabilizing agent is an alkali or alkaline earth metal bicarbonate, such as sodium hydrogen carbonate.
- the first and the second layer contain one or more
- pharmaceutically acceptable excipients may be selected from the group consisting of diluents, disintegrants, glidants, surfactants, colorants, and lubricants.
- diluents include, without limitation, lactose; cellulose derivatives such as crystalline cellulose and powdered cellulose; carbonates and phosphates, such as calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate; sucrose; sugar alcohols such as mannitol, sorbitol, xylitol, and isomalt (Galen IQ (Beneo)); starches such as maize starch, potato starch, rice starch, wheat starch, pregelatinized starch; coprocessed lactose and cellularlose (Cellatose 80 (Meggle)), coprocessed lactose and microcrystalline cellulose (Microcelac (Meggle)), coprocessed starch and lactose (Starlac (Meggle)), coprocessed starch, lactose and microcrystalline cellulose (Combilac (Meggle)), coprocessed microcrystalline cellulose and silicon dioxide
- carboxymethylcellulose carboxymethylcellulose
- crospovidone crosslinked povidone
- low-substituted hydroxypropyl cellulose pregelatinized starch, sodium starch glycolate, colloidal silicon dioxide, dried corn starch, and the like.
- glidants include, without limitation, talc, silica derivatives, such as colloidal silicon dioxide, and the like.
- lubricants include, without limitation, magnesium stearate, stearic acid, sodium stearyl fumarate, zinc stearate, and the like.
- surfactants include, without limitation, sodium lauryl sulfate, polysorbate 80, poloxamers, and the like.
- the first and/or second layer contain one or more diluents, in particular in an amount from 10 to 95%, more particularly from 30 to 90%, by weight with respect to the total weight of the corresponding layer. More particularly, the diluents are selected from lactose, maize starch, starch pregelatinized, microcrystalline cellulose, and a mixture thereof.
- the second layer contains a disintegrant, in particular in an amount from 0.5 to 15%, more particularly from 1 to 8%, by weight with respect to the total weight of the second layer.
- the disintegrant is croscarmellose sodium.
- the first layer contains one or more glidants, in particular in an amount from 0.1 to 10%, more particularly from 0.2 to 5%, by weight with respect to the total weight of the first layer.
- the glidants are selected from talc and colloidal silicon dioxide.
- the first and/or second layer contain a lubricant, in particular in an amount from 0.1 to 10%, more particularly from 0.2 to 5%, by weight with respect to the total weight of the corresponding layer.
- the lubricant is selected from magnesium stearate and sodium stearyl fumarate.
- the second layer i.e. the ramipril layer
- lactose monohydrate is spray dried lactose monohydrate, which provides a particularly good flowability.
- particle size of a granulate can be important to assure good mass uniformity and uniformity of the manufactured dosage form unit.
- the ramipril layer is made of a ramipril granulate having a particle size wherein from about 60% to 90% are below 250 micrometers, particularly from about 65% to about 75%, such as about 70% of the particles are below 150 micrometers.
- the oral multilayer tablet in particular an uncoated multilayer tablet, comprises or consists of:
- an indapamide compound in particular indapamide, in an amount from 0.6 to 40%, particularly from 1 to 10%, by weight with respect to the total weight of the first layer;
- a sustained release-matrix former in particular hydroxypropyl methyl cellulose (HPMC), in an amount from 10 to 60% by weight with respect to the total weight of the first layer;
- HPMC hydroxypropyl methyl cellulose
- a diluent in particular lactose, in an amount from 10 to 95%, particularly from 30 to 90%, by weight with respect to the total weight of the first layer;
- glidants in particular colloidal silicon dioxide, in an amount from 0.1 to 10%, particularly from 0.2 to 5%, by weight with respect to the total weight of the first layer;
- a lubricant in particular magnesium stearate, in an amount from 0.1 to 10%, particularly from 0.2 to 5%, by weight with respect to the total weight of the first layer;
- a ramipril compound particularly ramipril, in an amount from 1 to 20%, particularly from 1 to 10%, by weight with respect to the total weight of the second layer;
- a stabilizing agent in particular an alkali or alkaline earth metal
- bicarbonate in an amount from 1 to 20%, particularly from 1 to 10%, by weight with respect to the total weight of the second layer;
- diluents in particular lactose and maize starch, in an amount from 10 to 95%, particularly from 30 to 90%, by weight with respect to the total weight of the second layer;
- a disintegrant in particular croscarmellose sodium, in an amount from 0.5 to 15%, particularly from 1 to 8%, by weight with respect to the total weight of the second layer;
- a lubricant in particular sodium stearyl fumarate, in an amount from 0.1 to 10%, particularly from 0.2 to 5%, by weight with respect to the total weight of the second layer.
- the glidant is other than colloidal silicon dioxide.
- the second layer does not comprise any binder.
- the oral multilayer tablet in particular an uncoated oral multilayer tablet, consists of:
- an indapamide compound in particular indapamide, in an amount from 0.6 to 40%, particularly from 1 to 10%, by weight with respect to the total weight of the first layer;
- sustained release-matrix former in particular hydroxypropyl
- HPMC methylcellulose
- a diluent in particular lactose, in an amount from 10 to 95%, particularly from 30 to 90%, by weight with respect to the total weight of the first layer
- one or more glidants in particular talc and colloidal silicon dioxide, in an amount from 0.1 to 10%, particularly from 0.2 to 5%, by weight with respect to the total weight of the first layer
- a lubricant in particular magnesium stearate, in an amount from 0.1 to 10%, particularly from 0.2 to 5%, by weight with respect to the total weight of the first layer;
- a ramipril compound particularly ramipril, in an amount from 1 to 20%, particularly from 1 to 10%, by weight with respect to the total weight of the second layer;
- a stabilizing agent in particular an alkali or alkaline earth metal
- bicarbonate in an amount from 1 to 20%, particularly from 1 to 10%, by weight with respect to the total weight of the second layer;
- one or more diluents in particular lactose and maize starch, in an amount from 10 to 95%, particularly from 30 to 90%, by weight with respect to the total weight of the second layer;
- a disintegrant in particular croscarmellose sodium, in an amount from 0.5 to 15%, particularly from 1 to 8%, by weight with respect to the total weight of the second layer;
- a lubricant in particular sodium stearyl fumarate, in an amount from 0.1 to 10%, particularly from 0.2 to 5%, by weight with respect to the total weight of the second layer.
- the glidant is other than colloidal silicon dioxide.
- pharmaceutically acceptable excipients refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.
- terapéuticaally effective amount refers to the amount of ramipril and indapamide in the oral multilayer tablet as defined above that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed.
- the particular dose of ramipril and indapamide in the oral multilayer tablet as defined above administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the particular condition being treated, and other similar considerations.
- step ii) mixing the mixture of step i) with one or more pharmaceutically acceptable excipients in order to obtain a second mixture;
- step iii) granulating the mixture of step ii), optionally in the presence of an additional granulation liquid in order to obtain granules;
- step iv) milling and drying the granules obtained in step iii) in order to obtain a granulate
- step d) compressing the first and second layer compositions from step a) and b) and, optionally, the one or more additional layer compositions of step c), to form a multilayer tablet comprising a first layer comprising an indapamide compound and a second layer comprising a ramipril compound;
- steps a), b), and c) can be carried out in any order; and wherein the second layer has an impurity level of (2S,3aS,6aS)-1-[(S)-2-[[(S)-1- carboxy-3-phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2-carboxylic acid (impurity E) equal to or lower than 1.0%, 0.1%, or 0.05% after 6 months at 40 °C / 75% RH as measured by ultra performance liquid chromatography (UPLC).
- impurity E impurity E
- step d) the first and second layer compositions from step a) and step b) and, optionally, the one or more additional layer compositions of step c), can be compressed in any order.
- the ramipril layer tableted first and then tableting the indapamide layer on a bilayer machine it is possible to have the ramipril layer tableted first and then tableting the indapamide layer on a bilayer machine, or to have the indapamide layer tableted first and then tableting the ramipril layer on a bilayer machine.
- the water and the stabilizing agent can be in the form of an aqueous solution.
- drying in step iv) is performed untill loss on drying of the granulate is equal to or lower than 1.4%, particularly equal to or lower than 1.0, more particularly of 0.9, 0.8, 0.7, 0.6 or 0.5%.
- Loss on drying can be determined by drying the granulate, particularly by heating at 80°C, using a dryer with a precision balance.
- one or more pharmaceutically aceptable excipients are added.
- aceptable excipients diluents, disintegrants, glidants, surfactants, colorants, and lubricants.
- the one or more pharmarceutical aceptable excipients comprised in the second layer are one or more diluents and one or more disintegrants. More particularly, the one or more diluents are lactose and maize starch, particularly in an amount from 10 to 95%, more particularly from 30 to 90%, by weight with respect to the total weight of the second layer; and the one or more disintegrants is
- croscarmellose sodium particularly in an amount from 0.5 to 15%, more particularly from 1 to 8%, by weight with respect to the total weight of the second layer.
- the second layer does not comprise any binder.
- the first layer comprises a lubricant and step a) of the process above comprises the following steps:
- step i' blending an indapamide compound with one or more pharmaceutically acceptable excipients, except the lubricant in order to obtain a mixture; and ii’) blending the mixture obtained in step i') with the lubricant.
- the additional granulation liquid used for preparing the second layer is a (Ci-C4)alcohol, more particularly ethanol, particularly in a water:(Ci-C4)alcohol ratio of 1 :1 v/v or in a water:(Ci-C4)alcohol ratio of 2.1 :1 v/v.
- the second layer contains a lubricant and step b) of the process above comprises the following steps:
- step ii' mixing the mixture of step i) with one or more pharmaceutically acceptable excipients in order to obtain a second mixture
- iii’ granulating the second mixture of step ii’) by optionally adding a granulation liquid, preferably a (C1-C4) alcohol, in order to obtain granules; iv’) milling and drying the granules obtained in step iii’) in order to obtain a granulate; and
- a granulation liquid preferably a (C1-C4) alcohol
- step iv’ blending the granules obtained in step iv’) with the lubricant.
- Step d) may be carried out in a usual manner, e.g. a high-speed rotary press (i.e. Korsch XL400) in a multilayer tableting mode.
- a high-speed rotary press i.e. Korsch XL400
- the skilled expert will know how to determine them, in particular with respect to the suitable compression force to be applied, tableting speed, feeders speed, vaccum and the diameter punch.
- the first tablet layer may be compressed at a force of 0.1 to 5.0 kN
- precompression of first plus second layer may be performed at a force of 0.1 to 15.0 kN
- the main compression of first plus second layer may be performed at a force of 5.0 to 25.0 kN.
- the diameter punch may be from 7-1 1 mm, more particularly 9 mm.
- the ramipril-containing layer is placed onto the indapamide-containing layer).
- the multilayer tablet thickness is from 4.2 to 6.3 mm.
- the present invention also relates to an oral multilayer tablet comprising:
- a second layer comprising a ramipril compound and a stabilizing agent; and wherein the ramipril compound is selected from ramipril, a pharmaceutically acceptable salt thereof, and a stereoisomer either of ramipril or of a pharmaceutically acceptable salt thereof; and the indapamide compound is selected from indapamide, a pharmaceutically acceptable salt thereof, and a stereoisomer either of indapamide or of a pharmaceutically acceptable salt thereof; and wherein the second layer has an impurity level of (2S,3aS,6aS)-1-[(S)-2-[[(S)-1-carboxy-3- phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2-carboxylic acid (impurity E) equal to or lower than 1.0% after 6 months at 40 °C / 75% RH as measured by ultra performance liquid chromatography (UPLC); and wherein the multilayer
- the expression "obtainable by” is used herein for defining the oral multilayer tablet of the invention by its preparation process.
- it refers to the multilayer tablet that can be obtained through the preparation process which comprises the steps of: a) providing a first layer composition by:
- step ii) mixing the mixture of step i) with one or more pharmaceutically acceptable excipients in order to obtain a second mixture;
- step iii) granulating the second mixture of step ii), optionally in the presence of an additional granulation liquid in order to obtain granules;
- step iv) milling and drying the granules obtained in step iii) in order to obtain a granulate
- step d) compressing the first and second layer compositions from step a) and b) and, optionally, the one or more additional layer compositions of step c), to form a multilayer tablet comprising a first layer comprising an indapamide compound and a second layer comprising a ramipril compound;
- steps a), b), and c) can be carried out in any order.
- the second layer has an impurity level of (2S,3aS,6aS)-1-[(S)-2-[[(S)-1- carboxy-3-phenylpropyl]amino]propanoyl]octahydrocyclopenta-[b]pyrrole2-carboxylic acid (impurity E) equal to or lower than 1.0% after 6 months at 40 °C / 75% RH as measured by ultra performance liquid chromatography (UPLC).
- impurity E impurity E
- drying in step iv) is performed untill loss on drying is equal to or lower than 1.4%, particularly of 1.0, 0.9, 0.8, 0.7, 0.6 or 0.5%.
- the present disclosure also relates to a the multilayer tablet comprising ramipril and indapamide as defined above for use in the treatment of hypertension, particularly:
- the expresion "is not adequately controlled on" a pharmaceutically active ingredient means that blood pressure remains above 140/90 mmHg despite use of the pharmaceutically active ingredient.
- the expressions“obtainable”,“obtained” and similar equivalent expressions are used interchangeably and, in any case, the expression“obtainable” encompasses the expression“obtained”.
- Indapamide was mixed with all the excipients except magnesium stearate. After that, magnesium stearate was screened and mixed with the rest of components. A blend ready for the tabletting process was obtained.
- Ramipril, sodium hydrogen carbonate, lactose monohydrate, starch pregelatinised, croscarmellose sodium, and iron oxide yellow were weighed. All materials were screened apart from ramipril and sodium hydrogen carbonate.
- Purified water and sodium hydrogen carbonate were added to high-shear granulator and mixed. Then, ramipril was added to high-shear granulator and mixed. Lactose monohydrate, starch pregelatinised, croscarmellose sodium, iron oxide yellow were added to the high-shear granulator and mixed. Granulation is performed after adding ethanol anhydrous. Subsequently, wet milling was performed. The milled granulate was dried in a fluid bed dryer until loss on drying was less than 1.4%. The dry granulate was milled. Sodium stearyl fumarate was screened and added to the granulate and the whole mass was mixed. A mixture ready for the tabletting process was obtained.
- Example 1a 1.5 mg indapamide / 5 mg ramipril
- Example 1 b (1.5 mg indapamide / 10 mg ramipril)
- the ramipril-containg layer was obtained by wet granulation. Ramipril and all excipients (except stearyl fumarate) were placed into a high shear granulator. The mixture was granulated with water and dried in a fluid bed. After dry screening the blend, it was mixed with stearyl fumarate and croscarmellose sodium. A mixture ready for the tabletting process was obtained.
- Examples 2.1 and 2.4 are bilayer tablets made with compositions of Example 1c
- Examples 2.2 and 2.3 are bilayer tablets made with compositions of Example 1d
- Their stability was evaluated on samples placed in stability chambers. Results after 6 or 18 months at 25°C/60%RH and at 40°C/75%RH are summarized in Table 1 to 4 below.
- BLOQ below limit of quantification, namely below 0.05 %
- impurity E was below limit of quantification (BLOQ), namely below 0.05 %, even after 18 months. Additionally, after 6 months, or even after 18 months, at 25°C/60% RH, impurity D was maintained considerably low.
- the oral multilayer tablets above are stable, showing particularly low levels of impurities. More particularly, they show very reduced levels of the ramipril impurity E in comparison to the ramipril tablet of the prior art (see comparative example in WO2013/121233).
- Friability of the tablet of Example 1 c was assessed.
- Friability test was performed according to Ph. Eur. method. Friability is the % of weight loss of tablets caused by mechanical action during the test. Tablets are weighed before test and after testing. Friability is expressed as a percentage loss on pre test tablet weight.
- Flowability of the granulate is particularly important to ensure uniform filling of the matrices during compression in the process for the manufacture of a bilayer tablet.
- Two ramipril granulates were prepared using the following two types of lactose monohydrate as diluent:
- the ramipril granulate was manufactured as described in Example 1 d.
- Ramipril granules comprising spray dried lactose monohydrate were characterized with a much better flowability than ramipril granules comprising milled lactose monohydrate.
- Granulate composed of spray dried lactose contained less fine particles (having a particle size wherein about 30% of the particles were below 75 pm). Particularly, granulate comprising spray dried lactose monohydrate flew through a 10 mm nozzle during the test, whereas granulate comprising milled lactose monohydrate did not.
- Example 5 Particle size of ramipril granulate
- a ramipril granulate having a particle size wherein about 70% of the particles were below 150 micrometers was prepared accordinging to Example 4, granulate A. The details are shown in Table 8 below.
- the obtained granulate allowed providing a bilayer tablet with a ramipril layer having a good mass uniformity.
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Abstract
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EP18460069 | 2018-11-27 | ||
PCT/EP2019/082610 WO2020109319A1 (fr) | 2018-11-27 | 2019-11-26 | Composition pharmaceutique comprenant du ramipril et de l'indapamide |
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EP4103158B1 (fr) | 2020-02-10 | 2024-09-04 | Adamed Pharma S.A. | Composition comprenant du ramipril et de l'indapamide |
EP4389118A1 (fr) * | 2022-12-22 | 2024-06-26 | Zaklady Farmaceutyczne Polpharma S.A. | Composition pharmaceutique sous forme d'un melange de poudre seche, comprenant du ramipril et de l'indapamide |
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DE102004008804A1 (de) | 2004-02-20 | 2005-09-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Mehrschichttablette |
EP1901739A2 (fr) | 2006-04-19 | 2008-03-26 | Teva Pharmaceutical Industries Ltd | Compositions pharmaceutiques stables de derives de l'acide 2-aza-bicyclo[3.3.0]-octane-3-carboxylique |
PL204780B1 (pl) | 2006-06-02 | 2010-02-26 | Zak & Lstrok Ady Farmaceutyczn | Tabletka powlekana o przedłużonym uwalnianiu substancji aktywnej otrzymywana metodą bezpośredniego tabletkowania zawierająca indapamid albo jego farmaceutyczną sól oraz farmaceutycznie dopuszczalne wypełniacze, zastosowanie karbomeru do wytwarzania tabletki oraz sposób jej powlekania |
WO2008124611A1 (fr) | 2007-04-05 | 2008-10-16 | Dr. Reddy's Laboratories Ltd. | Compositions pharmaceutiques comportant du ramipril et de l'indapamide |
AU2008237177A1 (en) | 2007-04-05 | 2008-10-16 | Velomedix, Inc | Automated therapy system and method |
WO2008132756A1 (fr) | 2007-05-01 | 2008-11-06 | Lupin Limited | Compositions pharmaceutiques stables de ramipril |
RU2479310C2 (ru) | 2011-02-09 | 2013-04-20 | Открытое акционерное общество "Химико-фармацевтический комбинат "АКРИХИН" (ОАО "АКРИХИН") | Фармацевтическая композиция для лечения артериальной гипертензии и застойной сердечной недостаточности и способ ее получения |
GB201116993D0 (en) | 2011-10-03 | 2011-11-16 | Ems Sa | Pharmaceutical compositions of antihypertensives |
EP2814465B1 (fr) | 2012-02-17 | 2019-07-03 | Egis Gyógyszergyár Zrt. | Formule pharmaceutique à stabilité améliorée |
RU2618471C2 (ru) * | 2012-12-03 | 2017-05-03 | Закрытое Акционерное Общество "Вертекс" | Пероральная фармацевтическая композиция диуретика и ингибитора АПФ в микронизированной форме, лекарственное средство и его применение |
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2019
- 2019-11-26 WO PCT/EP2019/082610 patent/WO2020109319A1/fr unknown
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