EP1937220A2 - Preparation de ramipril presentant une stabilite accrue - Google Patents

Preparation de ramipril presentant une stabilite accrue

Info

Publication number
EP1937220A2
EP1937220A2 EP06794863A EP06794863A EP1937220A2 EP 1937220 A2 EP1937220 A2 EP 1937220A2 EP 06794863 A EP06794863 A EP 06794863A EP 06794863 A EP06794863 A EP 06794863A EP 1937220 A2 EP1937220 A2 EP 1937220A2
Authority
EP
European Patent Office
Prior art keywords
ramipril
salt
solid dosage
formulation
dosage form
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.)
Ceased
Application number
EP06794863A
Other languages
German (de)
English (en)
Inventor
Paul Jonathan Harrison
Anna Marie Elizabeth Power
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.)
Selamine Ltd
Original Assignee
Selamine Ltd
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
Priority claimed from GB0521529A external-priority patent/GB0521529D0/en
Priority claimed from GB0522047A external-priority patent/GB2431579A/en
Priority claimed from US11/508,916 external-priority patent/US20070098782A1/en
Application filed by Selamine Ltd filed Critical Selamine Ltd
Publication of EP1937220A2 publication Critical patent/EP1937220A2/fr
Ceased 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a dosage form of Ramipril and also to its manufacture and use.
  • the present invention relates to stability of formulations for treating or preventing various disease states involving the administration of Ramipril.
  • Ramipril has been used for the treatment of hypertension, heart failure, stroke, myocardial infarction, diabetes and cardiovascular disease. Ramipril may also reduce the risk of further strokes, heart attacks and cognitive impairment among stroke patients. It is commercially available at 1.25mg, 2.5mg, 5mg and lOmg strengths.
  • Ramipril is defined in official monographs in both the United States Pharmacopeia and the European Pharmacopoeia.
  • impurities A-N In the European Pharmacopoeia 14 impurities are categorised and labelled as impurities A-N.
  • Impurities A, B, C and D are defined as qualif ⁇ ed impurities with impurities E to N being classed as 'other detectable impurities'. Different limits have been applied to the two sets of impurities. To fulfil the United States standard, only impurities A, B, C and D require quantification. Of the 14 impurities that are named in the European Pharmacopoeia only two are identified as potential degradation products: impurities D and E.
  • Impurity D ramipril diketopiperazine
  • impurity E ramipril diacid or ramiprilat
  • Ramipril is converted in vivo to ramiprilat and can therefore be considered to be a prodrug of ramiprilat.
  • Ramiprilat is formed in vivo by ester hydrolysis to this active diacid from ramipril.
  • ester hydrolysis By the very nature of the compound it is therefore inherently designed to be sensitive to hydrolysis. It is important, when considering the formulation of such a compound that the potential hydrolysis is minimised by design, so that an adequate potency of the active ingredient in the formulation is maintained over the shelf life of the product.
  • Integral mixing of the components of a solid dosage form can be carried out on dry components, and hence direct compression has become a standard for tablet formulation.
  • Wet granulation methods and spray granulation methods are also known and offer additional options for mixing of tablet components. However, such methods are to be avoided if there is risk of damage to or degradation of components due to contact with solvents, especially water, used in the granulation.
  • a commercially viable shelf life of a formulated product would be considered to be 2 years or greater, and an acceptable potency over this shelf life would be 95 to 105%. This potency limit is applied in most European Pharmacopoeias, except where a compound is subject to substantial degradation such as Amoxycillin where a 90% potency lower limit applies.
  • the major degradation product identified in the British Pharmacopoeia is the diketopiperazine derivative (impurity D).
  • impurity D the major degradation product identified in the British Pharmacopoeia
  • the limits imposed by the British Pharmacopoeia on the diketopiperazine derivative infer that the loss in potency over the shelf life of the product would be expected to be due to the conversion of ramipril to the diketopiperazine degradation product.
  • a limit of 8% and 6% for this degradant is applied to the capsule and tablet formulation respectively, and therefore by simple mass balance, the potency could fall below the standard lower limit of 95%.
  • the limit imposed on other impurities including ramiprilat (impurity E) is set at levels below 0.5% and, therefore, such impurities as degradation products are considered to be undesirable.
  • ACE inhibitor formulations are known in the art. Such formulations can be found in, for example, US 4,727,160, US 4,743,450, US 4,830,853, US 5,151,433, US 5,256,687, US 5,686,451, US2003/0027837, US2003/0049314, US 6,555,551, US 6,576,256, US2003/0215526, US2003/0225124, US2004/0157911, US2004/0157928, US2004/0171669, US2005/0009806, US 6,844,361, US 6,869,963, US 2005/0069586, US2005/0106237, US2005/0118259, US2005/0142196, US 2005/0169981, US2005/0186274, US2005/0202081, US2006/0034937, US2006/0134213, US2006/0159742, WO96/31197, WO98/10753, WO02/011709, WO 03/059388, WO03/0758
  • Degradation of pharmaceutically active compounds is of concern to both medical practitioners and to the community at large. If significant degradation takes place between manufacture and administration of an active then suboptimal dosing is highly likely. For actives used in the treatment of hypertension and cardiovascular disease dosing accuracy is of tantamount importance as ineffective treatment is likely to result in life-threatening complications.
  • the present invention provides a solid dosage form comprising ramipril and a pharmaceutically acceptable carrier, wherein the ramipril is in the form of a ramipril salt.
  • At least 50% of the ramipril is in the form of a ramipril salt.
  • a solid dosage form comprising ramipril and a pharmaceutically acceptable carrier, wherein at least 50% of the ramipril is in the form of a sodium or potassium ramipril salt and the pharmaceutical carrier is selected from the group consisting of calcium sulphate, calcium carbonate and a mixture thereof.
  • the present invention provides a solid dosage form comprising ramipril and a pharmaceutically acceptable carrier, wherein the pH of the dosage form is alkaline so as to maintain ramipril in the form of a salt during storage.
  • This pH is typically measured as pH of a 1% solution in water.
  • forumulations of the invention combine both first and second aspects.
  • preferred solid dosage forms both are prepared so as to have the % levels of ramipril salt recited and also are formulated with pH as specified so as to promote maintenance of ramipril in salt form.
  • the invention also provides a solid dosage form, comprising ramipril and a pharmaceutically acceptable carier, wherein: -
  • a 1% solution of the solid dosage form in water has a pH of 8 or greater; and (c) degradation of ramipril to the ramipril diketopiperazine during storage at
  • 25°C and 60% RH is less than 1% over 3 months.
  • the invention further provides a solid dosage from, comprising ramipril and a pharmaceutically acceptable carrier, wherein:-
  • a 1% solution of the solid dosage form in water has a pH of 7.5 or greater;
  • Stability is increased by having more of the ramipril in salt form.
  • the ramipril salt is selected from a salt of an alkali metal and a salt of an alkali earth metal.
  • the salt is selected from the lithium, calcium and potassium salts.
  • the salt is the sodium salt.
  • the solid dosage form is in the form of a tablet and tablets of different strengths are set out in the examples below.
  • the solid dosage form is in the form of a capsule.
  • the present invention provides a method of making a ramipril formulation, comprising obtaining a ramipril salt and incorporating the ramipril salt into the formulation.
  • At least 50% by weight of the ramipril is in the form of a ramipril salt.
  • a method of making a ramipril formulation comprising obtaining a ramipril salt and incorporating the ramipril salt into the formulation, wherein at least 50% by weight of the ramipril is in the form of a sodium or potassium ramipril salt and wherein the formulation comprises a pharmaceutical carrier selected from the group consisting of calcium sulphate, calcium carbonate and a mixture thereof.
  • the formulation is in solid dosage form, further preferably a tablet.
  • the solid dosage form is a capsule.
  • At least 70%, more preferably at least 80%, more preferably at least 85%, further preferably at least 90%, more preferably at least 95%, further preferably at least 98% by weight of the ramipril is in the form of a ramipril salt.
  • the method comprises:- adding ramipril to an aqueous solvent; converting the ramipril into a salt of ramipril; dissolving the salt of ramipril in the aqueous solvent; and removing the solvent, to yield dried ramipril salt.
  • the aqueous solvent consists essentially of water.
  • the solvent comprises a mixture of water and alcohol, more preferably a mixture of water and ethanol, the mixture containing preferably at least 40%, more preferably at least 60% water by weight.
  • Ramipril is relatively insoluble in aqueous solvents.
  • the methods hence typically comprise dispersing ramipril particles in the aqueous solvent.
  • the method comprises adding an alkali to the solvent to convert the ramipril into the ramipril salt.
  • the method comprises adding sodium hydrogen carbonate to the solvent to convert the ramipril into the ramipril salt.
  • the method comprises converting at least 50% of the ramipril into the ramipril salt, more preferably at least 70%, more preferably at least 80%, more preferably at least 85%, further preferably at least 90%, more preferably at least 95%, further preferably at least 98%.
  • the converting comprises maintaining the ramipril in the aqueous solvent in the presence of a metal compound for sufficient time that substantially all the ramipril is converted into ramipril salt.
  • a solid dosage formulation comprising ramipril obtained by making the formulation out of a ramipril preparation, wherein at least 50% of the ramipril in the ramipril preparation is in the form of a ramipril salt.
  • a solid dosage formulation comprising ramipril and a pharmaceutically acceptable carrier, obtained by making the formulation out of a ramipril preparation, wherein at least 50% of the ramipril in the ramipril preparation is in the form of a sodium or potassium ramipril salt and the pharmaceutical carrier is selected from the group consisting of calcium sulphate, calcium carbonate and a mixture thereof.
  • a solid dosage form comprising a sodium or potassium ramipril salt and a pharmaceutical carrier selected from the group consisting of calcium sulphate, calcium carbonate and a mixture thereof, obtained by the methods described herein.
  • the present invention preferably provides a ramipril formulation which is basic.
  • a basic ramipril formulation wherein the ramipril is in the form of a ramipril salt.
  • the ramipril is in the form of a ramipril salt.
  • at least 50% of the ramipril is in the form of a ramipril salt.
  • dosage forms that can be used for the oral administration of ramipril are anticipated.
  • dosage forms include suspensions, solutions, tablets (chewable, dispersible and conventional), capsule formulations, multiparticulate formulations and formulations adapted to control the release of the drug from the oral dosage form, a so called sustained release formulation.
  • Solid formulations according to the invention preferably give a pH of greater than 7 when made up as a 1% solution in water. Any formulations having this property are said to be basic. Liquid formulations according to the invention preferably have a pH greater than 7.
  • the altered degradation pathway is beneficial in the case of ramipril formulations because the product of the altered degradation pathway is an active metabolite of the drug. Degradation over time to other (inactive) products can thus be minimised.
  • the invention preferably provides ramipril formulations that display altered degradation pathway to the active metabolite ramiprilat, rather that the inactive diketopiperazine.
  • the "altered degradation pathway” may be obtained or promoted by the inclusion of stabilisers in the formulation that makes the pH of a 1% solution in water basic in pH, i.e. greater than pH 7.
  • Preferred formulations according to the invention give a pH of greater than 7.5, more preferably greater than pH 8.
  • Liquid formulations according to the invention preferably have a pH of greater than 7.5, more preferably greater than pH 8.
  • stabiliser means any material that by its inclusion will render the pH of a 1% solution of the formulation basic.
  • stabilisers include carbonate salts, amino acids with basic side chains, and amines, although many suitable “stabilisers” will be known to those of skill in the art.
  • Preferred formulations according to the invention include citrate, carbonate salts, arginine, and ethanolamine, ethanolamine being particularly useful for liquid formations.
  • Other examples of “stabilisers” include sodium lauryl sulphate, talc, magnesium stearate, sodium carbonate, sodium bicarbonate, calcium carbonate and salts.
  • the present invention also relates to a ramipril formulation that demonstrates substantially no degradation to ramipril diketopiperazine during storage.
  • substantially all degradation taking place during storage is to ramiprilat.
  • the formulations of the invention may contain any suitable pharmaceutical excipients such as binders, coatings, sweeteners, surfactants, lubricants, glidants, fillers, other active ingredients, colorants and any other excipients or additives known to those in the art.
  • suitable pharmaceutical excipients such as binders, coatings, sweeteners, surfactants, lubricants, glidants, fillers, other active ingredients, colorants and any other excipients or additives known to those in the art.
  • Formulations of the invention may contain buffers that keep the pH of the formulation within an alkaline range even in the presence of significant amounts of acid.
  • the formulations of the invention help to ensure that patients treated using said formulations receive the dose of ramipril (or ramiprilat) intended by the prescribing physician.
  • Formulations according to the invention also offer extended shelf lives. Because the efficacy of treatment does not decrease as the formulations of the invention age (or at least decreases at a vastly reduced rate when compared to known formulations) less wastage of expired medicaments occurs. There is, therefore, a concomitant reduction in unit cost for medicaments according to the invention over previously known formulations.
  • Preferred formulations according to the invention give degradation to ramipril diketopiperazine during storage at 25°C and 60% RH for 3 months of less than 1%, more preferably less than 0.5%.
  • the present invention also provides a method for treating or preventing a disease in a mammal selected from the group consisting of hypertension, heart failure, stroke, myocardial infarction, diabetes and cardiovascular disease or for reducing the risk of further strokes, heart attacks and cognitive impairment among stroke patients comprising administering to a mammal in need of such treatment a formulation according to the present invention.
  • the mammal is preferably human, but can also be a non-human animal.
  • the present invention also provides the use of a formulation according to the present invention in the manufacture of a medicament for the treatment of hypertension, heart failure, stroke, myocardial infarction, diabetes and cardiovascular disease or for reducing the risk of further strokes, heart attacks and cognitive impairment among stroke patients.
  • the medicament is in the form of a capsule or, in particular, a tablet.
  • liquid formulations such as suspensions and syrups.
  • this invention provides a therapeutic package suitable for commercial sale, comprising a container, a ramipril formulation according to the invention, and, associated with said container, notice advising of extended shelf life.
  • ramipril may be administered alone or in combination with other therapeutic agents.
  • ramipril is co-administered with a diuretic agent, preferably the diuretic is selected from hydrochlorothiazide or piretanide.
  • Ramipril is typically present in formulations according to the invention in an amount of from about 1.25 mg to about 10 mg. Other formulations may have 2.5 mg or 5 mg per tablet. The amount of active can be adjusted to be outside these limits depending, for example, on the size of the animal subject being treated (e.g., a horse).
  • the term 'Ramipril' includes all the pharmaceutically acceptable versions thereof, e.g. salts, esters, clathrates thereof, and also anhydrous as well as hydrated forms.
  • formulations herein may be varied, that is additions and replacement of ingredients with equivalents may be made, without departing from the scope of the invention as herein claimed.
  • the formulation mentioned may advantageously contain citrate salts in place of carbonates and bicarbonates whilst retaining the extended shelf life.
  • Table 1 Stability of starch/ramipril blend in a capsule
  • the impurity levels reported in the examples above are the levels of impurity when stored in bottles for 14 days at 40 0 C 75 % relative humidity, with the exception of formulation 4 which was stored for 1 month at the same conditions.
  • wet granulation is used to formulate basic formulations according to the invention to ensure that the principle degradation product is ramiprilat.
  • Samples of the granule produced were filled into 60ml HDPE bottles with 33mm necks and a screw caps and placed on stability at 4O 0 C 75% RH.
  • the ramipril raw material used was commercially sourced from Neuland.
  • the related substances were determined at the time points specified using the standard methods of analysis for this drug.
  • Capsule Data were manufactured as part of a development campaign at Cobalt Canada.
  • the formulation needs to be alkaline to ensure that the ramiprilat is formed in an aqueous environment.
  • Formulations with dibasic calcium phosphate are less stable than formulations that use alternative calcium salts, such as calcium sulphate & calcium carbonate
  • formulation C • The stability of the product is sensitive to increases in the bicarbonate levels rather than calcium carbonate levels as formulation C is more stable when compared with formulation B.
  • Formulation C has a higher percentage of sodium bicarbonate and a lower percentage levels with respect to ramipril.
  • Stabilising agents of choice were Sodium Bicarbonate, Arginine, and Sodium Carbonate.
  • Stabilising agents of choice were Sodium Bicarbonate, Arginine, and Sodium Carbonate.
  • ramiprilat is the principal degradant, with the exception of formulation M where arginine was low in concentration relative to ramipril and lactose was the diluent and formulation J where the product was wet granulated after 14 days with a high diketopiperazine value at granulation stage and lactose was the diluent.
  • Formulations were manufactured with the buffer sodium citrate, which buffers to a pH around 7.8 (see Table 8).
  • Table 8 Formulations of Ramipril tablets containing increasing concentration of Sodium Citrate.
  • Ramiprilat is not the principle degradant when the alkali is replaced by a buffer.
  • Ramiprilat is the principal degradant when alkaline substances are added, such as arginine, sodium bicarbonate and sodium carbonate.
  • the ratio of the alkaline substance used to stabilise ramipril is important with regard to degradation pathway, the total impurity levels detected on stability, and the extent of the suppression of the diketopiperazine impurity level: it is preferred to have an excess.
  • the diluents calcium sulphate and calcium carbonate are preferred to dibasic calcium phosphate and lactose.
  • ramipril reacts with the alkaline substances to form a salt in situ.
  • the sodium or arginate component of the salt prevents by steric hindrance the degradation pathway to the diketopiperazine.
  • the levels of alkali agents are preferably in excess of the molar concentration required to form a stoichiometric salt of ramipril.
  • Granulation process involves the mixing of a number of ingredients and some of these ingredients will dissolve in water used for granulation. The granulation solvent in the powder mix will therefore be a complex solution. Excess alkali is used to ensure that the salt is formed in situ. Separately from the manufacturing process, the end formulation preferably has excess alkali, to maintain ramipril in the salt form.
  • Calcium sulphate and calcium carbonate are preferred excipients, because the microenvironment of the granule, the surface of the material will be alkaline, whereas the microenvironment for lactose and surprisingly dibasic calcium phosphate is acidic.
  • the product utilises sodium bicarbonate as the stabilising agent and calcium sulphate as the major diluent.
  • Calcium sulphate has an advantage over other excipients in that it can absorb water into its structure through the formation of complex hydrates, reducing the amount of free water available for the hydrolysis reaction. Absolute low moisture content is not essential for achieving adequate stability for the product.
  • the preferred formulations are stable with up to 8% moisture being detected.
  • the invention thus provides conditions preferred for producing a tablet of ramipril that is stable over its shelf life and where the principal degradant is the "active" metabolite/ compound ramiprilat, and manufactures the product in such a way that a salt of ramipril is formed and/or maintained in situ, by reacting or combining the acid component of ramipril with a suitable alkaline.
  • the invention thus provides stable ramipril-containing formulations together with methods for the manufacture thereof.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une préparation pharmaceutique contenant du ramipril essentiellement sous la forme d'un sel de ramipril, cette préparation étant tamponnée à un pH basique. Le ramipril dans la préparation se dégrade de préférence en diacide ou en ramiprilate plutôt qu'en dicétopipérazine.
EP06794863A 2005-10-21 2006-10-23 Preparation de ramipril presentant une stabilite accrue Ceased EP1937220A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB0521529A GB0521529D0 (en) 2005-10-21 2005-10-21 Ramipril formulation
GB0522047A GB2431579A (en) 2005-10-28 2005-10-28 Ramipril formulations
US11/273,575 US20070259941A1 (en) 2005-10-28 2005-11-15 Ramipril formulation
US11/508,916 US20070098782A1 (en) 2005-10-28 2006-08-24 Ramipril Formulation
PCT/GB2006/003927 WO2007045907A2 (fr) 2005-10-21 2006-10-23 Preparation de ramipril presentant une stabilite accrue

Publications (1)

Publication Number Publication Date
EP1937220A2 true EP1937220A2 (fr) 2008-07-02

Family

ID=37909496

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06794863A Ceased EP1937220A2 (fr) 2005-10-21 2006-10-23 Preparation de ramipril presentant une stabilite accrue

Country Status (3)

Country Link
EP (1) EP1937220A2 (fr)
AU (1) AU2006303068A1 (fr)
WO (1) WO2007045907A2 (fr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030215526A1 (en) * 2002-03-08 2003-11-20 Scott Stofik Stable formulations of angiotensin converting enzyme (ACE) inhibitors
US6869963B2 (en) * 2003-07-11 2005-03-22 Sandoz Ag Stable pharmaceutical compositions containing an ACE inhibitor
EA011862B1 (ru) * 2004-03-24 2009-06-30 Актавис Груп Хф. Композиции рамиприла
GB2431579A (en) * 2005-10-28 2007-05-02 Arrow Int Ltd Ramipril formulations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007045907A3 *

Also Published As

Publication number Publication date
AU2006303068A1 (en) 2007-04-26
WO2007045907A2 (fr) 2007-04-26
WO2007045907A3 (fr) 2007-08-30

Similar Documents

Publication Publication Date Title
RU2260428C2 (ru) Фармацевтическая композиция, содержащая производное бензамида и обладающая повышенной растворимостью и поглощаемостью при оральном применении
EP2058010B1 (fr) Composition pharmaceutique
US20080108687A1 (en) Ramipril formulation
EP2180883B1 (fr) Composition pharmaceutique contenant un antagoniste des canaux calciques de type dihydropyridine et son procédé de préparation
US10653626B2 (en) Powder for oral suspension containing lamotrigine
US8187635B2 (en) Pharmaceutical composition containing a pyrrolidone anticonvulsant agent and method for the preparation thereof
HUP0103431A2 (hu) 5-HT4 receptor agonista vagy antagonista hatóanyagot tartalmazó, orális gyógyászati készítmény
US9572806B2 (en) Elution-stabilized preparation
JP4901966B2 (ja) 小型化塩酸サルポグレラート経口投与製剤
KR20150003726A (ko) 프라수그렐을 함유하는 안정한 즉시방출형 경구 약제학적 조성물
JP6027710B1 (ja) 糖尿病治療用固形製剤
RU2465900C2 (ru) Фармацевтические композиции, содержащие ирбесартан
US20070259941A1 (en) Ramipril formulation
US7160556B2 (en) Immediate release medicinal compositions for oral use
JP4567640B2 (ja) 小型化塩酸サルポグレラート経口投与製剤
JP2009533461A (ja) ２−アザ−ビシクロ［３．３．０］−オクタン−３−カルボン酸誘導体の安定な医薬組成物
JPH1121236A (ja) ロキソプロフェン・ナトリウム固形製剤
US20070053975A1 (en) Ramipril formulation
JP7571470B2 (ja) エドキサバンを含有する口腔内崩壊錠
JP6116847B2 (ja) シクロデキストリンとの混合体を含有する錠剤
EP1937220A2 (fr) Preparation de ramipril presentant une stabilite accrue
CA2626613A1 (fr) Preparation de ramipril presentant une stabilite accrue
JPH10226644A (ja) 医薬組成物
WO2024043842A1 (fr) Compositions pharmaceutiques comprenant de l'acide chénodésoxycholique (cdca) en tant que principe actif et d'autres excipients pertinents
HK1133817B (en) Pharmaceutical composition

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20080310

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20080925

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED

18R Application refused

Effective date: 20090515