WO2008087399A1 - Nouveaux composés - Google Patents

Nouveaux composés Download PDF

Info

Publication number
WO2008087399A1
WO2008087399A1 PCT/GB2008/000134 GB2008000134W WO2008087399A1 WO 2008087399 A1 WO2008087399 A1 WO 2008087399A1 GB 2008000134 W GB2008000134 W GB 2008000134W WO 2008087399 A1 WO2008087399 A1 WO 2008087399A1
Authority
WO
WIPO (PCT)
Prior art keywords
irbesartan
mesylate
mesylate salt
crystalline
compounds
Prior art date
Application number
PCT/GB2008/000134
Other languages
English (en)
Inventor
Victor Jacewicz
Original Assignee
Rainbow Engineering Services
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 Rainbow Engineering Services filed Critical Rainbow Engineering Services
Publication of WO2008087399A1 publication Critical patent/WO2008087399A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

  • the present invention relates to novel salts of irbesartan and to their use in medical therapy, in particular to their use in the treatment and/or prophylaxis of disorders associated with hypertension, chronic renal failure, and diabetic neuropathy.
  • the present invention also relates to processes for preparing these novel salts of irbesartan.
  • Irbesartan i.e. 2-butyl-3-[p-(o-l H-tetrazol-5-ylphenyl)benzyl]- 1 ,3-diazaspiro[4,4]non- 1 -en-4- one otherwise, 2-butyl-3-[[2'-(lH-tetrazol-5-yl)[l,l'-bi ⁇ henyl]-4-yl]methyl]-l,3- diazaspiro[4,4]non- 1 -ene-4-one, otherwise 2-n-butyl-4-spirocyclopentane- 1 -[(2'-(tetrazol-5- yl)biphenyl-4-yl)methyl]- 2-imidazolin-5-one may be prepared by the methods described in U.S.
  • Example 5 describes a procedure for the preparation of irbesartan in unsalted form as a white crystalline solid melting at 180-181 0 C. The same example describes the preparation of a potassium salt monohydrate melting at 142-144°C.
  • European Patent Application 708103 discloses the existence and methods for the preparation of 2 crystalline forms of unsalted irbesartan, designated form A and form B. European Patent Application 708103 indicates that form A irbesartan comprises stable, non-hygroscopic needles of high electrostatic nature. The preparation of an amorphous form of irbesartan is described in PCT WO 2003 50110.
  • Irbesartan is one of many compounds described in US patent 5,270,317 and it is stated that these compounds are useful in the treatment of cardiovascular complaints such as hypertension and heart failure, as well as in the treatment of complaints of the central nervous system and in the treatment of glaucoma, diabetic retinopathy and renal insufficiency.
  • Irbesartan is the active ingredient in Aprovel® and Avapro® and one of the active ingredients in Coaprovel® which have been approved for use in the treatment of hypertension and diabetic neuropathy with an elevated serum creatinine and proteinuria.
  • the choice of a form of a pharmaceutical agent having an acidic functional group is not a matter of routine.
  • Sanofi/BMS the originator companies
  • only market the unsalted compound could lead one skilled in the art to believe that other forms were less preferred.
  • the choice of salts and forms of irbesartan other than the prior art forms is not therefore prima facie obvious in view of this technical prejudice and other concerns about the formation and properties of such salts and forms.
  • the irbesartan mesylate salts of this invention have appreciably higher aqueous solubility than the prior art crystalline unsalted compound.
  • the aqueous solubility of the crystalline irbesartan mesylate of example 1 is approximately 1% weight/weight at 11°C, and rises with temperature to greater than 4% weight/weight at 100 0 C.
  • wetting is the ability of liquids to form boundary surfaces with solid materials, and is determined by measuring the contact angle which a liquid forms in contact with a solid. The smaller the contact angle the larger the wetting tendency. Wetting phenomena are described in Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA on pages 278-9. In order for immersion of a solid to occur, the liquid must displace air and spread over the surface of the solid.
  • the yield is established by comparison of the weights of cost-critical starting material and product making allowance for molecular weights and purities. Purities are established by hplc, gc or other conventional analytical methods by means of a validated procedure and comparison with a reference standard. See for example Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA, ISBN 0-683-306472, page 597.
  • V max modelling is based on the theory that there is some maximum volume of a fluid which will pass a filter at a given pressure. At that point, the flow across the filter will be zero and therefore the resistance of the pad to flow infinite. On the basis of this model the rate of flow of filtrate is proportional to the driving force and the cross-sectional area of the filter bed. Measurements of flow rates and timing of standardised operations may be used to demonstrate advantage.
  • Quantification is achievable by measurement of the length of time and temperature in a specific drying apparatus to achieve a standardised reduction in the solvent level in a standardised quantity of product.
  • Other relevant factors which may give rise to an advantage include the need for agitation, and the need for or suitability for use in efficient apparatus such as filter driers.
  • Colour may be defined as the perception or subjective response of an observer to the objective stimulus of radiant energy in the visible spectrum extending over a range
  • colour 400nm to 700nm in wavelength.
  • Three attributes are commonly used to identify a colour: 1) hue, or the quality by which one colour family is distinguished from another, such as red, yellow, blue, green and intermediate terms; 2) value, or the quality that distinguishes a light colour from a dark one; and 3) chroma, or the quality that distinguishes a strong colour from a weak one, or the extent to which a colour differs from a grey of the same value.
  • the perception of colour and colour matches is dependent on conditions of viewing and illumination. Determinations should be made using diffuse, uniform illumination under conditions that reduce shadows and nonspectral reflectance to a minimum.
  • the surfaces of powders should be smoothed under gentle pressure so that a planar surface free from irregularities is presented.
  • Liquids should be compared in matched colour-comparison tubes, against a white background. If results are found to vary with illumination, those obtained in natural or artificial daylight are to be considered correct. Colours of standards should be as close as possible to those of the test specimens for quantifying colour differences. Instrumental methods for measurement of colour provide more objective data than the subjective viewing of colours by a small number of individuals.
  • the extent to which a product is associated with chemical impurities arising from earlier stages of synthesis is essentially unpredictable and depends both on the synthetic process, the nature of reagents used in the process, and on the physical, chemical, and surface properties of the product.
  • a novel salt, polymorph, or pseudopolymorph will have a different and unpredictable profile of trace impurities than a comparator salt.
  • the crystalline _ irbesartan mesylate salt of this invention forms fine crystals and is of value in the purification of irbesartan products. Once formed, the mesylate can be converted to unsalted irbesartan of high purity by neutralisation in either aqueous or alcoholic or mixed solvents.
  • Quantification of purity may be achieved by measurement and characterisation of impurity profiles, for example by GC-MS or LC-MS analysis and comparison with a reference material. Identification of all impurities is not essential providing sufficient characterisation is obtained from the analytical methodology, though it is of course desirable.
  • the European Pharmacopoeia describes definitions and methods by which bulk density of a powder may be measured. Apart from the inherent density of a material which depends on factors such as crystal structure which is unpredictable, there is also the contribution of interparticulate void volume which is equally unpredictable.
  • the bulk density is determined by measuring the volume of a known mass of powder, which has been passed through a screen, into a graduated cylinder. The tapped density is achieved by mechanically tapping a measuring cylinder containing a powder sample. After observing the initial volume, the cylinder is mechanically tapped, and volume readings are taken until little further volume change is observed.
  • Alternative forms of a drug substance may have unpredictably different chemical stabilities and so produce a quantifiable advantage for one form over the other.
  • Standard test methods are described in the major pharmacopoeias and are also referenced on the US Food and Drug Administation Web site.
  • accelerated storage tests are performed by storage for a period of 1 year or more at elevated temperature (e.g. 40°C) and at standard humidity conditions (e.g. 75% RH), with samples being taken at regular intervals of approximately 1 month and assayed for overall purity, specific impurities, and a general impurity screen.
  • Stability to irradiation, especially visible and ultra-violet light is of increasing importance in pharmaceutical science and represents another area in which alternative forms of a drug substance may have significantly and unpredictably different properties. Testing details, such as-light source, flux-density r and duration are describedin Federal RegisteFNotices Volume 62, Number 95, pages 27115-27122, together with recommendations for analytical methodology and assessment of results.
  • melting points and glass transition temperatures will differ greatly for different salts, polymorphs, pseudopolymorphs, or other forms of a drug and are in essence unpredictable.
  • Methods for measuring melting points are well-described in the European Pharmacopoeia 4 th edition 2001, and United States Pharmacopeia 24 rd edition 1999-2003.
  • Various methods are acceptable but differ in detail, for example the melting point determined by the capillary method is the temperature at which the last solid particle of a compact column of a substance in a tube passes into the liquid phase.
  • Suitable apparatus is described in the above mentioned publications and may be calibrated using melting point reference substances such as those of the World Health Organisation or other appropriate substances.
  • Some materials have a tendency to change their physical form during storage, which can be a disadvantage in pharmaceutical manufacture. For example materials can settle and compact and lose their ability to flow freely.
  • One polymorphic form may wholly or partially convert to another over an uncertain time-frame, or solvates and hydrates may lose their solvent or water, and the resultant change in the physical properties of the drug substance can lead to a formulation with uncertain, unreliable, and unpredictable characteristics.
  • Clearly a polymorphic conversion can only occur from a less stable to a' more stable form, so there are advantages associated with thermodynamic stability, and the relative stability of a novel form is a priori unpredictable.
  • hygroscopicity is used to describe both the rate and the extent of water uptake. It is well established that hygroscopic products are difficult to handle and hence more expensive to formulate. Hygroscopicity is not a priori predictable, and an alternative salt may well be advantageous in this respect.
  • Apparatus for measurement of moisture contents of samples under controlled humidity conditions is available commercially, e.g from I Holland Ltd., Nottingham, U.K. Simple measurements may be made by monitoring the appearance and weight of samples exposed to atmospheres of known constant humidity and temperature, as described in, for example, The Merck Index 12 th edition, Merck and Co Inc.
  • compositions / delivery range of technologies are very important and will differ in a non- predictable manner depending on the specific properties of the drug form.
  • Pharmaceutical excipients are substances, other than the active pharmaceutical ingredient, that are used in the finished dosage form. There are very many widely differing excipients each with particular characteristics which form the basis of many widely differing formulations. Excipients and their properties are described in detail in the pharmaceutical literature, for example in Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA.
  • They serve many functions, for example they stabilise the drug substance by providing antioxidant, heavy-metal chelating, or light-protection properties. They also may be used to enhance bioavailability and to control the release of drug substance from dosage forms. For solid dosage forms, they provide suitable characteristics for dispensing the drug substance in accurate dosage units that have reproducible release properties. Diluents provide a flowable bulk, binders hold powders together after wet granulation, lubricants provide punch-releasing properties, and disintegrants help to disperse dosage forms in the gastrointestinal tract. There is a risk, which may be avoided by careful selection of the form of the drug, of incompatibilities between drug substance and excipients.
  • the present invention provides novel amorphous and crystalline and liquid irbesartan methanesulfonate (mesylate).
  • novel forms of irbesartan mesylate are crystalline forms.
  • a preferred crystalline form is the colourless, crystalline salt described below in example 1.
  • more than one novel crystalline form may be possible and such polymorphs and pseudopolymorphs including hydrates and solvates also form an aspect of this invention.
  • irbesartan mesylate may be in the form of amorphous oils, gums or solids.
  • amorphous irbesartan mesylate may be used as an ingredient for inclusion in a range of formulations such as conventional tablets and capsules, or may be prepared in a form in which the salt' is absorbed in a carrier, for example an excipient or a mixture of excipients for tabletting or other formulation, or as a solution in a wax or similar pharmaceutically acceptable polymer, such as PEG or PVA.
  • the novel irbesartan mesylate may be in liquid form.
  • Such liquids may be prepared by conventional methods such as dissolving a crystalline or amorphous material in a suitable solvent. If aqueous solutions are prepared a small amount of methanesulfonic acid may be added to the aqueous medium to prevent disproportionation.
  • novel irbesartan mesylate examples include:
  • Examples of carriers which are suitable for use with the salts of this invention and which are capable of supporting a high salt loading are magnesium aluminometasilicate e.g. Neusilin® US2 and N-Zorbit® food grade starch. It will be appreciated that other carriers may also be used with the irbesartan mesylate salts of this invention and their capacity and the stability of the resulting product may be determined by routine experiment.
  • Examples of other carriers include, but are not limited to starch, microcrystalline cellulose, sodium carboxymethylcellulose, trehalose, laevulose, lactilol, xylitol, maltodextrin, sorbitol, methyl cellulose, ethyl cellulose, hydroxypropylcellulose, pregelatinised starch, calcium hydrogenphosphate, maltose, lactose, cellulose, talc, Amberlite ® XAD-4, Amberlite ® XAD-7, Amberlite ® XAD-16, AMBERSORB ® 348F, AMBERSORB ® 563,
  • AMBERSORB ® 572 Activated carbon, Activated carbon Darco ®, Activated carbon Darco ® G-60, Activated carbon Darco ® KB, Activated carbon Darco ® KB-B Activated carbon Norit ®, silica gel high purity grades with high pore volume e.g. 0.75 cc/g, and average pore diameter 6 ⁇ A. It will be appreciated that mixtures of more than one carrier may be used.
  • Solutions of the irbesartan mesylate salts of this invention may be prepared by contacting a suitable source of irbesartan with a suitable source of methanesulfonic acid.
  • a suitable source of irbesartan Most conveniently irbesartan is in unsalted form and the methanesulfonic acid is in its pure form of a low melting solid or liquid or as the commercially available aqueous solution.
  • the irbesartan source may initially be in solid form or in solution, which solution may be either an aqueous solution or a solution in an organic solvent or a solution in a mixed aqueous/organic solvent.
  • irbesartan In addition to unsalted irbesartan, other salts of irbesartan may be used, such as for example the prior art potassium salt or other salts with organic or inorganic bases. In addition the irbesartan may be generated in situ from a chemical precursor. Suitable solutions of irbesartan have been described in above-quoted references.
  • irbesartan itself may be dissolved in hot absolute ethanol at a concentration of 1 gramme in 10 ml, or in propan-2-ol at a concentration of 1 gramme in 20 ml, or in a mixture of water and ethanol (1 :3 by volume) at a concentration of 1 gramme in 11 ml, or with greater solubility in pure ethanol or ethanol containing a smaller proportion of water at greater concentration, with ultrasonication and heating.
  • irbesartan may be dissolved in a mixture of propan-2-ol and methanol (1 :;1 by volume) at a concentration of 1 gramme in 40 ml at ambient temperature, or at greater concentration at elevated temperature. Crystalline and non-crystalline irbesartan will also dissolve in methanesulfonic acid solutions such as aqueous, or mixed aqueous alcoholic solutions.
  • Solutions of irbesartan mesylate may also be prepared from crystalline or non-crystalline irbesartan mesylate by dissolving in a suitable solvent, for example in an aqueous, alcoholic or mixed aqueous alcoholic solvent.
  • a suitable solvent for example in an aqueous, alcoholic or mixed aqueous alcoholic solvent.
  • a particularly preferred solvent is ethanol. If aqueous solutions are prepared a small amount of methanesulfonic acid may be added to the aqueous medium to prevent disproportionation.
  • Suitable solution concentrations of reagents for the preparation of the irbesartan mesylate salts of this invention are between 1% to 30% by weight. Reactions of solids with solutions are allowed to proceed until substantially all the solid has reacted, which may require between 10 minutes and 10 hours or longer, but the time required may be shortened by use of elevated temperatures and ultrasonication. At least a stoichiometric quantity of methanesulfonic acid is advantageously used, but an excess, for example between 1.5 and 10 equivalents, is preferred.
  • the irbesartan mesylate solution may be combined at this stage with excipients, absorbants, carriers or dispersion matrix media, either as solids or in solution.
  • Amorphous forms of irbesartan mesylate may then be isolated by either vacuum evaporation, spray-drying, precipitation with an antisolvent, or freeze drying, however the aqueous solubility of irbesartan mesylate at low temperatures is not high enough to make freeze-drying a preferred method for routine isolation. If a vacuum evaporation technique is used to isolate amorphous forms of irbesartan mesylate, it should be carried out as rapidly as possible and under conditions which avoid the presence of seeds of the crystalline salt so as to minimise crystallisation of the salt. Alcoholic or mixed aqueous/alcoholic solvents are preferred to 100% aqueous solvent, and ethan ⁇ l is particularly advantageous.
  • a concentration of between 1% and 40% weight/volume may be used, comprising irbesartan mesylate in solution and any excipients and/or dispersion media and/or carriers in finely powdered form or in solution, optionally at elevated temperature, though a concentration of between 10 and 40% is preferred.
  • Stock mixtures containing organic solvents may be spray dried in a closed loop spray dryer. The apparatus parameters are adjusted to give an acceptable product by routine means, but control of outlet gas temperature and solvent content of the outlet gas is particularly important.
  • the outlet temperature is kept above 3O 0 C but below 7O 0 C, more preferably below 50 0 C, and the solvent content of the outlet gases is kept below 2 grammes per 100 grammes, more preferably below 1.2 grammes per 100 grammes. If a solid carrier or absorbant is used, outlet temperatures above 5O 0 C may be acceptable so long as the solid carrier or absorbant retains a free-flowing character at such temperatures.
  • spray drying is described in the following publications which are incorporated herein by reference: Spray-drying handbook 5th edition by K Masters, Longman Scientific &
  • Drying to the full extent that is desirable for a stable pharmaceutical product is not always practicable during efficient use of the isolation apparatus, particularly in the case of spray- drying, so in all the above procedures a final air or vacuum drying step may be necessary to reduce residual water and solvent to an acceptable level.
  • Crystalline irbesartan mesylate may be prepared by following the same procedures as have been described for the preparation of irbesartan mesylate solutions and then seeding with crystalline irbesartan mesylate, if necessary concentrating, cooling, or adding an anti-solvent - and then allowing sufficient time for crystallisation to take placeT
  • crystalline irbesartan mesylate may be prepared by trituration of the amorphous salt with a solvent s ⁇ ch as water, acetone, or an alcohol such as ethanol or propan-2-ol, or mixtures thereof.
  • solvents may also be used as determined by routine experimentation.
  • a preferred method of preparing crystalline irbesartan mesylate is to add methanesulfonic acid, either pure or in aqueous solution, to a vigorously stirred slurry of unsalted irbesartan in water, preferably at elevated temperature, for example at reflux, until a clear solution greater than 2% weight/volume of irbesartan is obtained. Cooling the solution results in crystallisation of irbesartan mesylate, though partial evaporation may also be used to increase the yield.
  • the irbesartan mesylate of this invention also has the potential to be prepared as solid or liquid solutions or dispersions in a liquid or polymeric carrier or matrix.
  • Such matrix dispersions may be prepared in a variety of ways; the irbesartan mesylate may be added to the matrix material either as a solid or in solution, and the matrix material itself may also be either in the form of a solid (or liquid, as appropriate) or in solution. If both materials are solids then heating and stirring of a melt may be utilised to form a homogenous mixture before the product is cooled, and either ground to a powder, or left as a liquid or semi-liquid suitable for further formulation.
  • Various techniques are known for the formation of suitable granules and platform products from melts, for example spray congealing techniques to produce pellets have been described by Kanig J.Pharm Sci 53, 188, 1964 and by Kreuschner et al.
  • a liquid matrix may be used to dissolve the solid irbesartan mesylate, or a solution of the matrix product may be formed by mixing a solution of the irbesartan mesylate with a solution of the matrix material, and the solvent subsequently removed by evaporation or spray-drying.
  • Suitable solvents for preparing solid or liquid solutions or dispersions include water, common alcohols, ketones, esters, and ethers. Preferred solvents are water, methanol, ethanol, propan-2-ol, and mixtures thereof.
  • the liquid or polymeric carrier or matrix material or solution thereof may form the solvent for the salt formation reaction.
  • the irbesartan and methanesulfonic acid components may be added separately to the carrier or matrix material or solution thereof, optionally with heating to produce a melt or otherwise ensure a homogenous mixture.
  • the product may then be cooled or evaporated and further treated to produce a form suitable for further formulation.
  • Suitable ratios of irbesartan mesylate to liquid or polymeric carrier or matrix material may vary from 1 : 100 to 10: 1 , preferably from 1 :20 to 3 : 1.
  • a volatile solvent used to form the matrix dispersion, it may be difficult to remove it all by evaporation. In the case of solvents such as water or ethanol this is not a problem and . substantial residues may be tolerated, indeed may improve the stability and properties of the product. However residues which decrease the viscosity to the extent that crystallisation may occur on storage are undesirable. Less desirable solvents must be removed sufficiently by extended, optionally elevated temperature evaporation to ensure a pharmaceutically acceptable product.
  • Suitable liquid or polymeric carrier or matrix materials include the following: animal, vegetable or mineral oils, fats, waxes, chocolate, chewing gum base, maize oil, lecithin, groundnut oil, sunflower oil, cottonseed oil, lauroylmonoglyceride, lanolin, gelatin, isinglass, agar, carnauba wax, beeswax, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyethylene glycol esters, ovalbumin, soybean proteins, gum arabic, starch, modified starch, crospovidone, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, chicle, polypropylene, dextrans, including dexran 40, dextran 70 and dextran 75, dextrins, alpha-
  • Preferred materials are PVP and PEG, which are available in various grades differing chiefly in their mean molecular weight. In the case of PVP this may be between 2,000 and 3,000,000, however material in the range 8,000 to 500,000 is more preferred e.g. PVP K-15, K-30, K-40, K-90. In the case of PEG products the mean molecular weight may be in the range 200 to 20,000, but 1,000 to 10,000 is more preferred e.g. PEG 2000, PEG 8000.
  • irbesartan mesylate salts of the present invention may be prepared on any suitable scale according to the procedures herein outlined and those procedures which are conventional to one skilled in the art of pharmaceutical chemistry, in particular in the preparation of salt forms. Techniques for scale-up are described in the literature for example Pharmaceutical Process Scale-Up by Michael Levin, Marcel Dekker, New York 2003, ISBN 0824706250, which publication is incorporated herein by reference.
  • amorphous and crystalline irbesartan mesylate, solid dispersions of irbesartan mesylate, irbesartan mesylate absorbed onto carriers, and liquid and solid solutions of irbesartan mesylate may be formulated into pharmaceutical compositions, according to procedures well known in the art. Suitable procedures include those provided in Remington: The Science and Practice of Pharmacy 20th edition, Alfonso R Gennaro editor, Lippincott, Williams, and Wilkins, Philadelphia USA, ISBN 0-683-306472; The art, science, and technology of pharmaceutical compounding by Loyd V Allen, American Pharmaceutical Association, 2001, ISBN 1582120358 - incorporated herein by reference.
  • these compositions are adapted for oral use such as tablets, capsules, zydis, gums, candies, chocolates, sachet and oral liquids, or are adapted for topical use such as gels, lotions, patches, or ointments, or are adapted for parenteral use such as intravenous, intramuscular, or subcutaneous injection, or are adapted for use as suppositories, or are adapted for inhalation therapy such as bronchial or nasal inhalation therapy.
  • oral use such as tablets, capsules, zydis, gums, candies, chocolates, sachet and oral liquids
  • topical use such as gels, lotions, patches, or ointments
  • parenteral use such as intravenous, intramuscular, or subcutaneous injection
  • inhalation therapy such as bronchial or nasal inhalation therapy.
  • a further feature of the invention is a method of treating a disease or condition associated with hypertension, chronic renal failure, and diabetic neuropathy which comprises administering to a warm-blooded mammal an effective amount of the compounds of this .
  • the invention also relates to the use of compounds of this invention in the manufacture of a medicament for use in a disease condition.
  • a process for the manufacture of a pharmaceutical composition containing one or more of the compounds of this invention which comprises admixing one or more of the compounds of this invention with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for use in the above-mentioned utilities which comprises a pharmaceutical composition containing one or more of the compounds of this invention.
  • Figure 1 represents an infra-red spectrum in the range 500-4000 wavenumbers measured by the nujol mull technique on a Perkin-Elmer Paragon 1000 infra-red spectrometer at 2 wavenumber resolution using 10 scans. Small quantities of the sample material were mixed with nujol mineral oil to form a paste and pressed between sodium chloride windows. Background subtraction was performed to limit signals due to atmospheric water vapour and carbon dioxide.
  • Figure 2 is the same spectrum in the range 550 to 2000 wavenumbers. It will be appreciated that whilst every effort was made to ensure that the spectrum was properly recorded, variation in individual technique, instrument, and apparatus may give rise to small differences when samples are analysed under different conditions. Varying residual signals due to atmospheric water and carbon dioxide and slight differences in peak intensities, position and resolution are normal in this analytical technique and the present invention is not limited to the exact details of the spectrum provided.
  • Example 1 is illustrative of the present invention and are not intended to limit it in any way:
  • the infra-red spectrum showed prominent absorption maxima at about 1770, 1635, 1516, 1232, 1041 , 940, and 842 wavenumbers.
  • Irbesartan mesylate from example 1 (0.12 g) was dissolved in absolute ethanol (10 ml) with warming and heated to reflux to destroy seeds of crystalline irbesartan mesylate. A clear solution was obtained and was evaporated under reduced pressure with the water bath set to 50 0 C to produce a clear oil.
  • the irbesartan mesylate from example 2 was dissolved in absolute ethanol (10 ml) to give a clear solution.
  • Neusilin® US2 magnesium aluminometasilicate (0.38 g) was added and the mixture stirred briefly and then left to stand for 1 hour.
  • the slurry was then evaporated under reduced pressure with the water bath set to 50 0 C to produce a free-flowing white solid comprising irbesartan mesylate absorbed in Neusilin® US2 magnesium aluminometasilicate. Yield after drying over phosphoric oxide under vacuum overnight was 0.45 g.

Abstract

Nouveaux sels d'irbesartane et leur utilisation en thérapie médicale, en particulier dans le traitement et/ou la prévention de troubles associés à l'hypertension, l'insuffisance rénale chronique et la neuropathie diabétique.
PCT/GB2008/000134 2007-01-18 2008-01-16 Nouveaux composés WO2008087399A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0700992.1 2007-01-18
GBGB0700992.1A GB0700992D0 (en) 2007-01-18 2007-01-18 Novel compounds

Publications (1)

Publication Number Publication Date
WO2008087399A1 true WO2008087399A1 (fr) 2008-07-24

Family

ID=37846596

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/000134 WO2008087399A1 (fr) 2007-01-18 2008-01-16 Nouveaux composés

Country Status (2)

Country Link
GB (1) GB0700992D0 (fr)
WO (1) WO2008087399A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5270317A (en) * 1990-03-20 1993-12-14 Elf Sanofi N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present
US5541209A (en) * 1994-08-22 1996-07-30 Bristol-Myers Squibb Company Method of treating or preventing cardiac arrhythmia employing an N-substituted heterocyclic derivative
WO2006073376A2 (fr) * 2005-01-05 2006-07-13 Krka, Tovarna Zdravil, D.D., Novo Mesto Preparation d'un derive de tetrazole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5270317A (en) * 1990-03-20 1993-12-14 Elf Sanofi N-substituted heterocyclic derivatives, their preparation and the pharmaceutical compositions in which they are present
US5541209A (en) * 1994-08-22 1996-07-30 Bristol-Myers Squibb Company Method of treating or preventing cardiac arrhythmia employing an N-substituted heterocyclic derivative
WO2006073376A2 (fr) * 2005-01-05 2006-07-13 Krka, Tovarna Zdravil, D.D., Novo Mesto Preparation d'un derive de tetrazole

Also Published As

Publication number Publication date
GB0700992D0 (en) 2007-02-28

Similar Documents

Publication Publication Date Title
CN102448444B (zh) 包括硝基儿茶酚衍生物的药物制剂及其制备方法
JP6336420B2 (ja) ニトロカテコール誘導体を含む医薬製剤及びその製造方法
Bartolomei et al. Physico-chemical characterisation and intrinsic dissolution studies of a new hydrate form of diclofenac sodium: comparison with anhydrous form
KR101953270B1 (ko) 무정형 레터모비어 및 그의 경구 투여용 고체 제약 제제
Bonfilio et al. A discriminating dissolution method for glimepiride polymorphs
EP2988733B1 (fr) Composition pharmaceutique contenant du macitentan cristallin
EA028769B1 (ru) Фармацевтические композиции, содержащие рифаксимин и аминокислоты, способ их получения и их применение
JP6215238B2 (ja) Ｎ−エチル−ｎ−フェニル−１，２−ジヒドロ−４，５−ジ−ヒドロキシ−１−メチル−２−オキソ−３−キノリンカルボキサミド、その製剤、および使用
TWI715291B (zh) 包含parp抑制劑的藥物組合物
ES2377552T3 (es) Composiciones disueltas fácilmente y estables de candesartán cilexetilo preparadas con una granulación por vía húmeda
WO2014125352A1 (fr) Compositions pharmaceutiques contenant du tadalafil
WO2016097314A1 (fr) Formes amorphes et cristallines d'idélalisib et procédé pour les produire
AU2011334679B2 (en) Formulations comprising methylthioninium chloride
WO2008087399A1 (fr) Nouveaux composés
WO2008087397A1 (fr) Nouveaux composés
WO2008087401A1 (fr) Nouveaux composés
WO2018002673A1 (fr) Nouvelles formulations d'antagonistes du récepteur de l'angiotensine ii
CA2912733A1 (fr) Comprime d'agomelatine stable de type x et son procede de preparation
BRPI0621739A2 (pt) formulação estável que consiste em drogas sensìveis à umectação e seu procedimento de fabricação
US20150080435A1 (en) Pharmaceutical composition containing crystalline sorafenib tosylate
RU2774382C1 (ru) Способ получения аморфной формы n-[2-(диэтиламино)этил]-5-[(z)-(5-фтор-1,2-дигидро-2-оксо-3h-индол-3-илиден)метил]-2,4-диметил-1h-пиррол-3-карбоксамида малата, продукт и его применение для лечения онкологических и иммунологических заболеваний
CA2884731C (fr) Composition pharmaceutique a administrer par voie orale presentant une meilleure elution et/ou une meilleure capacite d'absorption
CN101426789A (zh) 2－n－{5－[[4－[2－(甲基－2－吡啶氨基)乙氧基]苯基]甲基]－2，4－噻唑烷二酮}丁二酸、其制备方法以及具有马来酸罗格列酮的组合物
US20230338338A1 (en) Pharmaceutical compositions comprising ionic liquids
Diño et al. Drug-Excipient Compatibility Testing of Cilostazol Using FTIR and DSC Analysis.

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08701812

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08701812

Country of ref document: EP

Kind code of ref document: A1