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`
`Patentanmeldung Nr.
`
`Patent application No.
`
`Demande de brevet n°
`
`12181465.1/EP12181465
`
`The organization code and number of your priority application, to be used for filing abroad under the Paris
`Convention, is EP12181465.
`
`Der Prasident des Europaischen Patentamts;
`lm Auftrag
`For the President of the European Patent Office
`Le President de I‘Office européen des brevets
`p.o.
`
`file
`
`U. lngmann
`
`gawk
`
`EPA/EPO/OEB Form 1014
`
`05.12
`
`

`

`
`
`Anmeldung Nr:
`Application no.:
`Demande no :
`
`121814651
`
`Anmelder / Applicant(s) / Demandeur(s):
`
`Cardiolynx AG
`Hochbergerstrasse 600
`4057 Basel/CH
`
`Anmeldetag:
`Date of filing:
`Date de depot :
`
`23.08.12
`
`Bezeichnung der Erfindung [Title of the invention / Titre de l‘invention:
`(Falls die Bezeichnung der Erfindung nicht angegeben ist, oder falls die Anmeldung in einer Nicht-Amtssprache des EPA eingereicht
`wurde, siehe Beschreibung bezt'iglich ursprl'inglicher Bezeichnung.
`If no title is shown, or if the application has been filed in a non-EPO language, please refer to the description for the original title.
`Si aucun titre n'est indiqué, ou si la demande a été déposée dans une langue autre qu'une langue officielle de l'OEB, se référer a la
`description pour le titre original.)
`
`Extended release compositions of an amino-C2-06-alkyl nitrate
`
`ln Anspruch genommene Prioritat(en) / Priority(Priorities) claimed / Priorité(s) revendiquée(s)
`Staat/Tag/Aktenzeichen / State/Date/File no. / Pays/Date/Numéro de dépét:
`
`Am Anmeldetag benannte Veitragstaaten / Contracting States designated at date of filing / Etats contractants désignées lors
`du dépét:
`
`AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MG MK MT NL NO PL
`PT RO RS SE SI SK SM TR
`
`EPA/EPO/OEB Form 1014
`
`05.12
`
`2
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`

`

`Extended release compositions of an amino-Cz-Cs-alkyl nitrate
`
`Field of the invention
`
`The present invention relates to extended release compositions of an amino-Cg-Cs-alkyl
`
`nitrate and of pharmaceutically acceptable salt thereof, and to fixed dose combinations
`
`with further pharmaceutically active drug substances.
`
`Background of the invention
`
`Nitrates have a long history of pharmaceutical use, causing vasodilatation and thereby
`
`increasing and improving blood flow. The main indications of nitrates are coronary heart
`
`disease, angina pectoris (chest pain), pulmonary hypertension, and congestive heart
`
`failure. There are several pharmaceutical compounds which are marketed and used in
`
`these indications. Examples are nitroglycerol, isosorbide dinitrate, and isosorbide
`
`mononitrate.
`
`All of the presently marketed nitrates show a distinct disadvantage. Whereas initially the
`
`proposed dose efficiently provokes a vasodilatation, the patient will develop tolerance
`
`(nitrate tolerance) after a certain time, and the dose has to be increased continuously. At
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`certain increased levels, toxic side effects will show up, preventing further safe use of the
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`drug.
`
`So far only one nitrate is known which does not provoke tolerance, AEN (2-aminoethyl
`
`nitrate). The corresponding drug product, Nilati|®, was marketed by Pharmacia AB, but
`
`later again withdrawn from the market. Whereas AEN shows an excellent pharmacological
`
`profile, in particular no development of nitrate tolerance, the short half-live of approx.
`
`2 hours requires frequent dosing and causes high peak—to—trough ratios, which is not
`
`desirable since it compromises appropriate patient compliance.
`
`AEN was protected under SE 168 308, its use under US 3,065,136.
`
`Pharmaceutical formulations useful for sustained drug release became an important part
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`of medication in terms of improved treatment effect, reduction of side effects and patients’
`
`convenience. Extended release of an active drug provides many therapeutic advantages,
`
`the most important of which is that the drug blood levels are maintained for a long time
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`with minimal fluctuation. The problem with each dose of a standard immediate release
`
`drug is that the concentration of drug available to the body immediately peaks and then
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`declines rapidly. When the drug concentration reaches very high levels it contributes to
`
`adverse side effects, while when it remains at lower levels it does not provide any
`
`therapeutic benefit. Thus, it is desirable to release drugs at a constant rate, thereby
`
`maintaining drug concentration within the therapeutic range and eliminating the need for
`
`frequent dosages. Other advantages of extended release devices include: delivery to the
`
`required site, reduced risk of overdose with side effects, and economic advantage by
`
`virtue of a more efficient dosage.
`
`There are several designations found in literature to describe formulations that do not
`
`release the active drug substance immediately following oral administration. The term
`
`used in a document by the Center for Drug Evaluation and Research (Guidance for
`
`Industry, Extended Release Oral Dosage Forms: Development, Evaluation, and
`
`Application of In Vitro/ln Vivo Correlations; Food and Drug Administration, Center for Drug
`
`Evaluation and Research (CDER), September 1997) is “extended release dosage form”.
`
`Other designations are “sustained release formulation”, “controlled release formulation” or
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`“prolonged action formulation”.
`
`Modified-release preparations can be administered orally in single or multiple-unit dosage
`
`forms. Single-unit formulations contain the active ingredient within the single tablet or
`
`capsule, whereas multiple-unit dosage forms comprise a number of discrete particles that
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`are combined into one dosage unit, so as to form a multiple-unit system. Multiparticulates
`
`may not only be presented as capsule formulations, but as well as tablets.
`
`In matrix devices, the active agent appears as a dispersion within the polymer matrix and
`
`is typically formed by simple compression or wet granulation followed by compression of a
`
`polymer/drug mixture. Matrix formulations are probably the most common devices used
`
`for controlling the release of drugs.
`
`Among the various technologies used to control the systemic delivery of drugs, osmotic
`
`drug delivery is one of the most interesting and widely applicable. Osmotic drug delivery
`
`uses the osmotic pressure of drugs or other solutes for controlled delivery of drugs.
`
`Osmotic drug delivery systems offer distinct advantages which have contributed to the
`
`popularity of these systems (Verma RK et al., Drug Dev Ind Pharm 2000; 26:695-708).
`
`The best known systems are those originally developed by ALZA Corp. under the trade
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`name OROS®. Specifically, ODDS systems were as well used for nitrates, e.g. for
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`isosorbide mononitrate (Verma RK et al., Intl J of Pharmaceutics 2003; 263:9-24).
`
`Prolonged gastric retention systems have been studied to improve the in vivo behavior of
`
`extended-release dosage forms. The basic concept is that, being exposed to a more or
`
`less constant environment in the stomach, the in vivo release of the dosage forms will be
`
`more controllable. These forms are based on a range of totally different concepts, recently
`
`reviewed by Streubel A et al., Expert Opin Drug Deliv 2006; 3:217-233.
`
`Skin is the largest organ of the body and forms a protective barrier to the entry of foreign
`
`molecules. It is especially impermeable to water-soluble compounds, even in small
`
`quantities. However, moderately lipophilic drugs have been delivered through the skin for
`
`several years. Since the early 19703, there has been a significant effort to develop
`
`commercially viable transdermal formulations. Transdermal patch formulations of
`
`nitroglycerin, isosorbide dinitrate, clonidine, fentanyl, piroxicam, ketoprofen, nicotine,
`
`scopolamine, estradiol, norethisterone, levonorgestrel, and testosterone have been
`
`developed and commercialized in the cardiovascular, pain management, smoking
`
`cessation, hormone replacement therapy, and motion sickness markets.
`
`Transdermal drug delivery circumvents first pass metabolism associated with the oral
`
`delivery of drugs, therefore delivery of certain compounds from the skin can require
`
`significantly smaller amounts of drugs than the corresponding oral dosage, potentially
`
`reducing dosage-related side-effects.
`
`Traditionally, low dose drugs with first pass metabolism problem after oral administration
`
`have been the ideal candidates for transdermal delivery. Increasing skin permeation rates
`
`for drugs therefore is a challenge that must be overcome for achieving target flux rates for
`
`therapeutic efficacy. The research over the past two decades has identified hundreds of
`
`novel technologies for overcoming skin barrier properties. Almost all of these technologies
`
`breach the top impervious barrier, stratum corneum, using chemicals, sound, light, heat,
`
`micro needles and electrical current.
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`Summary of the invention
`
`The present invention relates to extended release compositions of an amino-CZ-Ce-alkyl
`
`nitrate, in particular of 2-aminoethyl nitrate, and of pharmaceutically acceptable salts
`
`thereof.
`
`The invention further relates to a fixed dose combination of an amino-Cz-Ce-alkyl nitrate,
`
`in particular of 2—aminoethyl nitrate, and of pharmaceutically acceptable salts thereof with
`
`further pharmaceutically active drug substances.
`
`Detailed description of the invention
`
`The present invention relates to extended release compositions of an amino-CZ-Ce-alkyl
`
`nitrate in form of the free base or of a pharmaceutically acceptable salt.
`
`Cz-Ce-alkyl is an alkyl group of consisting of 2 to 6 carbon atoms, in particular ethyl,
`
`propyl, butyl, pentyl and hexyl. The alkyl group may be linear, as in n-propyl, n-butyl,
`
`n-pentyl and n-hexyl, or branched, as for example in iso-propyl, iso-butyl, sec-butyl,
`
`tert-butyl, iso-pentyl, 1-or 2-methylbutyl, 1-ethylpropyl, 1,2—dimethylpropyl, tert-pentyl, and
`
`corresponding branched hexyl groups, e.g. iso-hexyl and 1, 2, and 3-methyl-pentyl.
`
`A Cz-Ce-alkyl nitrate is sometimes also called Cz-Ce-alkanol nitrate, indicating more clearly
`
`that a nitrate is an ester of nitric acid with the corresponding alkanol, or also a nitro-
`
`oxyalkane. In the context of the present invention it is understood that in an alkyl nitrate
`
`the nitrate function is covalently bonded to the alkyl residue by an oxygen atom.
`
`In amino-Cg-Cs-alkyl nitrate, the amino group and/or the nitrate function may be in a
`
`primary, secondary or tertiary position, if possible at all. Preferably, the amino group is not
`
`bound to the same carbon atom as the nitrate function. More preferably, both amino group
`
`and nitrate function are in a primary position, for example as in 2—aminoethyl nitrate,
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`3—amino—propyl nitrate, 4—aminobutyl nitrate, 5—aminopentyl nitrate, 6—aminohexyl nitrate,
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`3-amino-2-methylpropyl nitrate, and 3-amino-2,2—dimethylpropyl nitrate. However, other
`
`substitution patterns are also considered, for example as in 2—amino-1-methylethyl nitrate,
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`3—amino—1—methylpropyl nitrate, 2—amino—1,1—dimethylethyl nitrate, 2—aminopropyl nitrate,
`
`2-aminobutyl nitrate, and 2-amino-3-methylbutyl nitrate.
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`Preferred amino-CZ-Cs-alkyl nitrates are 4-aminobutyl nitrate, 3-aminopropyl nitrate,
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`2—amino-1-methylethyl nitrate, and 2—aminoethyl nitrate, in particolar 4-aminobutyl nitrate
`
`and 2-aminoethyl nitrate. Most preferred is 2—aminoethyl nitrate (AEN), also known under
`
`the name itramine.
`
`Pharmaceutically acceptable salts of Cz—CB—alkyl nitrates are acid addition salts of
`
`pharmaceutically acceptable non-toxic inorganic and organic acids. Preferred
`
`pharmaceutically acceptable salts are acetate, benzoate, besylate (benzenesulfonate),
`
`bromide, chloride, camphorsulfonate, chlortheophyllinate, citrate, ethenedisulfonate,
`
`fumarate, gluconate, glutamate, hippurate, 2—hydroxyethanesulfonate, 2-hydroxy-2—
`
`phenylacetate, iodide, lactate, laurylsulfate, malate, maleate, mesylate (methane-
`
`sulfonate), methylsulfate, napsylate (2—naphthalenesulfonate), nitrate, octadecanoate,
`
`oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, tartrate, and tosylate
`
`(p-toluenesulfonate).
`
`Most preferred pharmaceutically acceptable salts are sulfate, phosphate, acetate and
`
`tosylate, in particular tosylate.
`
`Accordingly, it is an object of the present invention to provide an extended release
`
`composition of an amino-Cz-Cs-alkyl nitrate and pharmaceutically acceptable salts thereof
`
`allowing once or twice daily administration of the drug product.
`
`The term “extended release” as used herein in relation to the composition according to the
`
`invention or a coating or coating material or used in any other context means release
`
`which is not immediate release, but release over a pre—defined, longer time period of up to
`
`24 hours, such as 6-24 hours, preferably 12-24 hours.
`
`The extended—release characteristics for the release of amino—Cz—Ca—alkyl nitrate and
`
`pharmaceutically acceptable salts thereof may be varied by modifying the composition of
`
`each formulation component, including modifying any of the excipients and coatings or
`
`also transdermal patch layers which may be present. In particular the release of the active
`
`ingredient may be controlled by changing the composition and/or the amount of the
`
`extended-release coating, if such a coating is present. If more than one extended-release
`
`component is present, the coating or matrix former for each of these components may be
`
`the same or different. Similarly, when extended-release is governed by an extended-
`
`release matrix material, release of the active ingredient may be controlled by the choice
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`and amount of extended-release matrix material utilized. However, the use of ion
`
`exchange resin as the extended-release matrix material is excluded from the present
`
`invenfion.
`
`When the extended-release component comprises a modified release matrix material, any
`
`suitable extended—release matrix material or suitable combination of extended—release
`
`matrix materials except ion exchange resin may be used. Such materials are known to
`
`those skilled in the art. The term “extended-release matrix material” as used herein
`
`includes hydrophilic polymers, hydrophobic polymers and mixtures thereof which are
`
`capable of modifying the release of an active ingredient dispersed therein in vitro and in
`
`vivo.
`
`In a preferred embodiment, the extended-release composition according to the present
`
`invention will provide more or less constant plasma levels of amino-CZ-CB-alkyl nitrate and
`
`pharmaceutically acceptable salts thereof over 12 hours, more preferably over 24 hours.
`
`In case of a fixed-dose combination product, such a plasma profile produced from the
`
`administration of a single dosage unit is especially advantageous without the need for
`
`administration of two dosage units.
`
`One of the objects of this invention is to provide an extended release oral dosage form.
`
`For oral dosage forms, any coating material which modifies the release of the active
`
`ingredient in the desired manner may be used. In particular, coating materials suitable for
`
`use in the practice of the invention include but are not limited to polymer coating materials,
`
`such as cellulose acetate phthalate, cellulose acetate trimeIIitate, hydroxy propyI
`
`methylcellulose phthalate, polyvinyl acetate phthalate, ammonio methacrylate copolymers
`
`such as those sold under the trademark Eudragit® RS and RL, polyacrylic acid and
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`polyacrylate and methacrylate copolymers such as those sold under the trademark
`
`Eudragit® S and L, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose
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`acetate succinate, shellac; hydrogels and gel-forming materials, such as carboxyvinyl
`
`polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxy—
`
`methyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch,
`
`and cellulose based cross-linked polymers in which the degree of crosslinking is low so as
`
`to facilitate adsorption of water and expansion of the polymer matrix, hydoxypropyl
`
`cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, crosslinked starch,
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`microcrystalline cellulose, chitin, aminoacryl-methacrylate copolymer (Eudragit® RS-PM),
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`pullulan, collagen, casein, agar, gum arabic, and sodium carboxymethyl cellulose.
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`In a particular embodiment of the invention, non-ionic matrix material is used.
`
`As will be appreciated by the person skilled in the art, excipients such as plasticisers,
`
`lubricants, solvents and the like may be added to the coating. Suitable plasticisers include,
`
`for example, acetylated monoglycerides, butyl phthalyl butyl glycolate, dibutyl tartrate,
`
`diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethyl glycolate, glycerol, propylene
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`glycol, triacetin, citrate, tripropionin, diacetin, dibutyl phthalate, acetyl monoglyceride,
`
`polyethylene glycols, castor oil, triethyl citrate, polyhydric alcohols, acetyl triethyl citrate,
`
`dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, di—isononyl phthalate, butyl
`
`octyl phthalate, dioctyl azelate, epoxidized tallate, tri-isoctyl trimellitate, diethylhexyl
`
`phthalate, di-n-octyl phthalate, di-isooctyl phthalate, di-isodecyl phthalate, di-n-undecyl
`
`phthalate, di—n—tridecyl phthalate, tri—2—ethylhexyl trimellitate, di—2—ethylhexyl adipate,
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`di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, and dibutyl sebacate.
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`For oral dosage forms, extended release of the active ingredient in the desired manner
`
`may be obtained by embedding the drug in a matrix. In matrix devices, the active agent
`
`appears as a dispersion within the polymer matrix and is typically formed by the simple
`
`compression of a polymer/drug mixture, through its dissolution in a common solvent or
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`melt granulation. Matrix formulations are particularly preferred for controlling the release of
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`the active ingredient of the present invention, since they are relatively easy to
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`manufacture compared to other devices.
`
`Among the many oral dosage forms that can be used for extended drug release, matrix
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`tablets, as obtained by the direct compression of a polymer mixture, are preferred. Matrix
`
`materials considered are biocompatible natural polymers, e.g. HPMC, HEMC, EHEC,
`
`HMHEC, CMHEC, methylcellulose, guar, pectin, agar, algin, gellan gum, xanthan gum,
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`acacia, starch and modified starches, carrageenans, amylose starch, and the like. Ion
`
`exchange resins are excluded from the scope of the invention.
`
`Particular swellable hydrophilic polymers considered as matrix materials are
`
`poly(hydroxyalkanol methacrylate) (MW 5 kD — 5,000 kD), polyvinylpyrrolidone (MW 10 kD
`
`- 360 kD), anionic and cationic hydrogels, polyvinyl alcohol having a low acetate residual,
`
`a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride
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`and styrene, ethylene, propylene or isobutylene, pectin (MW 30 kD - 300 kD), poly-
`
`saccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides,
`
`Polyox® polyethylene oxides (MW 100 kD - 5,000 kD), AquaKeep® acrylate polymers,
`
`diesters of polyglucan, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, and
`
`sodium starch glucolate (e.g. Explotab®; Edward Mandell Co. Ltd.).
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`Further particular hydrophilic polymers considered are polysaccharides, methyl cellulose,
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`sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl
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`cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers,
`
`polyethylene oxides (e.g. Polyox®, Union Carbide), methyl ethyl cellulose, ethyl hydroxyl-
`
`ethylcellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, collagen,
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`starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate,
`
`glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of methacrylic acid
`
`or methacrylic acid (e.g. Eudragit®), other acrylic acid derivatives, sorbitan esters, natural
`
`gums, lecithins, pectin, alginates, ammonium alginate, sodium, calcium and/or potassium
`
`alginates, propylene glycol alginate, agar, and gums such as arabic, karaya, locust bean,
`
`tragacanth, carrageens, guar, xanthan, scleroglucan and mixtures and blends thereof.
`
`Preferred modified release matrix materials suitable for the practice of the present
`
`invention are microcrystalline cellulose, sodium carboxymethylcellulose, hydoxyalkyl-
`
`celluloses such as hydroxypropylmethylcellulose and hydroxypropylcellulose, poly-
`
`ethylene oxide, alkylcelluloses such as methylcellulose and ethylcellulose, polyethylene
`
`glycol, polyvinylpyrrolidone, cellulose acteate, cellulose acetate butyrate, cellulose acteate
`
`phthalate, cellulose acteate trimellitate, polyvinylacetate phthalate, polyalkylmethacrylates,
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`polyvinyl acetate, and mixture thereof.
`
`Another object is to provide a multiparticulate extended release composition.
`
`The term “particulate” as used herein refers to a state of matter which is characterized by
`
`the presence of discrete particles, pellets, beads, granules, or small tablets (“mini-tablets”)
`
`irrespective of their shape or morphology.
`
`The term “multiparticulate” as used herein means a plurality of discrete, or aggregated,
`
`particles, pellets, beads, granules, small tablets or mixture thereof irrespective of their
`
`shape or morphology. The term “multiparticulate” includes every subunit of a size smaller
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`than 5 mm, e.g. pellets, granules, sugar seeds (non-pareil), minitablets, powders, and
`
`crystals, with drugs being entrapped in or layered around cores.
`
`Although similar in vitro drug release profiles can be obtained with single-unit and
`
`multiple-unit dosage forms, the latter offer several advantages over single-unit systems
`
`such as non—disintegrating tablets or non—disintegrating capsules, and represent a
`
`preferred embodiment of the invention.
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`Multiparticulates according to the invention are filled into capsule or compressed into
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`tablets. Tablets allow to insert a breaking score, making it possible to sub-divide the dose,
`
`and still maintaining the extended-release characteristics of the multiparticulate
`
`formulation. Multiparticulates provide many advantages over single—unit systems because
`
`of their small size. They are less dependable upon gastric emptying, resulting in less inter-
`
`and intra-subject variability in gastrointestinal transit time. They are also better distributed
`
`and less likely to cause local problems. Other advantages include adjustment of the
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`strength of a dosage unit by changing the number of multiparticulates in the unit,
`
`administration of incompatible drugs in a single dosage unit by separating them in
`
`different multiparticulates, and combination of multiparticulates with different drug release
`
`rates to obtain the desired overall release profile. In multiple unit systems, the total drug
`
`dose is divided over multiparticulates that make up that system. Failure of a few units may
`
`not be as consequential as failure of a single-unit system, where a failure may lead to
`
`dose-dumping of the drug.
`
`Still another object of the present invention is to provide a single-unit extended release
`
`tablet—, film coated tablet— or hard capsule formulation of an amino—Cz—CB—alkyl nitrate and
`
`pharmaceutically acceptable salts thereof. The term “hard capsules” includes any type of
`
`hard capsule made from gelatin or a different material, e.g. hypromellose and gellan gum
`
`(VcapsT'V') or pullulan and carrageenan (NPcapsT'V').
`
`Another object of the present invention is to provide an osmotically controlled oral dosage
`
`form of an amino—Cz—Ce—alkyl nitrate and pharmaceutically acceptable salts thereof. Drug
`
`delivery from an osmotic drug delivery system is not influenced by the different
`
`physiological factors within the gut. Osmotic drug delivery systems (ODDS), apart from
`
`maintaining plasma concentration within therapeutic range, also prevent sudden increase
`
`in plasma concentration that may produce side effects and sharp decrease in plasma
`
`concentrations that may reduce the efficacy of the drug. Considered are single-layer core
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`osmotic pumps using conventional tablets as a core. Elementary osmotic pump (EOP)
`
`and the controlled porosity (OP) are two different embodiments of this technology. Further
`
`preferred are dosage forms based on the so-called “push-pull system” using a bi-layer
`
`kernel (multi-layer core osmotic pumps).
`
`A further object of the present invention is to provide a transdermal drug delivery system
`
`of an amino-Cz-CG-alkyl nitrate and pharmaceutically acceptable salts thereof, releasing
`
`the active drug continuously over a time window of approximately 24 hours or more, e.g.
`
`up to 7 days.
`
`The skin permeation rate of amino-Cz-CB-alkyl nitrates are positively influenced by
`
`chemical enhancers, for example cosolvents such as ethanol, isopropanol, glycerol,
`
`polyethylene glycol, propylene glycol, pyrrolidones, dimethylsulfoxide, laurocapram
`
`(1-dodecylazepan-2-one) and the like, surfactants, fatty acid esters such as polyethylene
`
`glycol monolaurate, and terpenes such as menthol. Preferred dermal penetration
`
`enhancers are laurocapram and laurocapram derivatives, and oleic acid and its esters,
`
`such as methyl, ethyl, propyl, isopropyl, butyl, vinyl and glyceryl esters, dodecyl
`
`(N,N-dimethylamino)acetate and dodecyl (N,N-dimethylamino)propionate, and 2-n-nonyl-
`
`1-3-dioxolane. Most preferred dermal penetration enhancers are oleic acid and its esters,
`
`dodecyl (N,N-dimethylamino)—acetate and —propionate, and 2-n-nonyl-1-3-dioxolane. The
`
`penetration enhancers facilitate the delivery of drugs through the skin by temporarily
`
`altering the top skin barrier layer.
`
`A variety of transdermal technologies, including reservoir patches, matrix patches,
`
`poration devices and iontophoretic devices are considered. Preferred are drug—in—
`
`adhesive and reservoir patches. The drug-in-adhesive patches combine adhesive and the
`
`drug in a single layer making it less costly to manufacture. Such patches may be used for
`
`several days, e.g. up to 7 days, are light weight and thin, and can be rather small and
`
`translucent.
`
`Poration technologies and iontophoretic delivery are not of relevance for extended—release
`
`delivery of amino-Cz-Ce-alkyl nitrates and pharmaceutically acceptable salts thereof, but
`
`are of interest for fixed-dose combination therapy with further drugs which show a very
`
`low permeation through human skin.
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`Drug-in-adhesive systems incorporate amino-Cg-Cs-alkyl nitrates into a carrier such as a
`
`polymeric matrix and/or a pressure-sensitive adhesive, such as silicone adhesive, silicone
`
`rubber, acrylic adhesive, polyethylene, polyisobutylene, polyvinyl chloride, nylon, or the
`
`like formulation. The pressure-sensitive adhesive must adhere effectively to the skin and
`
`permit migration of the medicament from the carrier through the skin and into the
`
`bloodstream of the patient. The amino—Cz—CG—alkyl nitrate is directly incorporated into the
`
`adhesive in one single layer, or alternatively dissolved in the polymeric matrix until its
`
`saturation concentration is reached. Any additional drug remains dispersed within the
`
`matrix. When drug migrates through the skin and thereby is removed from the surface of
`
`the matrix, more of the drug diffuses out of the interior in response to the decreased
`
`concentration at the surface. The release rate is therefore not constant over time, but
`
`instead gradually decreases as the drug concentration decreases.
`
`Reservoir patches contain a reservoir or a pocket which holds the amino-Cz-Cs-alkyl
`
`nitrates, encapsulated in a gel. A protective seal covers the contents of the patch. A
`
`permeable film allows the nitrates to flow through at a controlled rate.
`
`In order to modify the rate of delivery from the transdermal device, a specific single-
`
`polymer matrix or a blend of soluble (miscible) polymers is considered. Polymers
`
`considered are those listed above for oral drug forms.
`
`The drug-in-adhesive patches are manufactured by following sequence: Appropriate
`
`amounts of adhesives are dissolved in a solvent in a vessel. The amino-Cz-Ce-alkyl nitrate
`
`or a pharmaceutically acceptable salt thereof is added and dissolved/dispersed in a
`
`polymer mixture, and optional co—solvents and enhancers are added. The solution is
`
`coated onto a protective release liner at a controlled specified thickness. Then the coated
`
`product is passed through an oven to drive off volatile solvents. The dried product on the
`
`release liner is combined with the backing material and wound into rolls for storage. The
`
`roll of film is then cut at the desired size and packaged.
`
`Another object of the present invention is to provide a fixed—dose combination of an
`
`amino-CZ-CG-alkyl nitrate and pharmaceutically acceptable salts thereof and further
`
`pharmacologically active drug substances, whereby the amino-CZ-Cs-alkyl nitrate and
`
`pharmaceutically acceptable salts thereof are provided in extended release form, and the
`
`further drug substances will be preferably in immediate release form.
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`Any pharmaceutically active compound for which a combination therapy with amino-
`
`Cz-Cs-alkyl nitrate is useful may be combined in a fixed-dose combination according to the
`
`invention. Compounds falling into this category are:
`
`Sartans (angiotensin receptor blockers, ARB’s), angiotensin enzyme inhibitors (ACE-l),
`
`renin antagonists and other classes of antihypertensive drugs (e.g. beta blocker, calcium
`
`channel blockers (CCB’s) for the treatment of arterial hypertension;
`
`endothelin antagonists such as bosentan, mazisentan and others for the treatment of
`
`pulmonary hypertension;
`
`statins and other drugs indicated for the treatment of dyslipidaemias, especially LDL
`
`cholesterol-lowering drugs;
`
`biguanides such as metformin, thiazolidinediones (glitazones) such as pioglitazone or
`
`aleglitazar, sulfonureas such as glibenclamide or glimepiride, SGLT2 antagonists such as
`
`dapagliflozin, canagliflozin, ipragliflozin, tofogliflozin and empagliflozin, dipeptidyl
`
`peptidase—(DPP)—4 inhibitors such as sitagliptin, vildagliptin, saxagliptin and linagliptin, and
`
`any other oral drug indicated for the treatment and prevention of diabetes and/or diabetic
`
`complications;
`
`antithrombotics, antiplatelets, anticoagulants and other drug indicated for the treatment or
`
`prevention of thrombosis or other coagulopathies;
`
`antianginal drugs such as betablockers, calcium channel antagonists (CCB’s), ranolazine,
`
`ivabradin and others;
`
`vasodilators such hydralazine, cilostazol and other phospodiesterase lll inhibitors (PDE
`
`lll) indicated for the treatment of peripheral artery disease or hypertension or acute or
`
`chronic heart failure (CHF) or vascular diseases; and
`
`aldosterone antagonists such as spironolactone, eplerenone and aldosterone synthase
`
`inhibitors (ASl’s) indicated for the treatment of chronic heart failure (CHF) or chronic
`
`kidney diseases or pulmonary hypertension.
`
`It is to be understood that this list is made only for the purpose of describing or providing
`
`various pharmaceutically active compounds which may be used in combination with
`
`amino—Cz—Ce—alkyl nitrate and pharmaceutically acceptable salts thereof. The list is not
`
`intended to limit the scope of the present invention. All such pharmaceutically active
`
`compounds for which it is clinically reasonable to be used in a combination therapy are
`
`thus within the scope of the present invention.
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`13
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`Preferred pharmaceutically active compounds for a fixed-dose combination with amino-
`
`Cz-Cs-alkyl nitrate and pharmaceutically acceptable salts thereof are valsartan, azilsartan,
`
`mazisentan, cilostazol, pioglitazone, sitagliptin and Iinagliptin, in particular valsartan,
`
`cilostazol and pioglitazone.
`
`Amino—CZ—Ca—alkyl nitrate and pharmaceutically acceptable salts thereof, calculated as
`
`free base, are preferably present in a composition in an amount of from 0.01 to 100 mg,
`
`preferably in th