Solid oral pharmaceutical compositions including a nitrosamine inhibitor including mannitol

Abstract

The present invention relates to a solid oral pharmaceutical composition that includes: (a) an active pharmaceutical ingredient; (b) a nitrosamine inhibitor comprising mannitol; and (c) a pharmaceutically acceptable excipient. With the solid oral pharmaceutical compositions, at least one of: (i) the active pharmaceutical ingredient includes at least one covalently bonded amine group that is subject to conversion to nitrosamine; or (ii) the solid oral pharmaceutical composition includes at least one amine, that is other than the amine group covalently bonded to / within the active pharmaceutical ingredient, and which is subject to conversion to nitrosamine. The nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamine formed in the solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of the nitrosamine inhibitor.

Description

SOLID ORAL PHARMACEUTICAL COMPOSITIONS INCLUDING A NITROSAMINE INHIBITOR INCLUDING MANNITOLCROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims priority to United States Provisional Patent Application No. 63 / 607,812 entitled “Solid Oral Pharmaceutical Compositions Including a Nitrosamine Inhibitor Including Mannitol” filed December 8, 2023, the disclosure of which is hereby incorporated by reference in its entirety.TECHNICAL FIELD

[0002] The present invention relates to solid oral pharmaceutical compositions that include an active pharmaceutical ingredient, a nitrosamine inhibitor that includes mannitol, and a pharmaceutically acceptable excipient, where the nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamine formed in the solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of the nitrosamine inhibitor.BACKGROUND

[0003] Solid oral pharmaceutical compositions can be subject to the formation of nitrosamines over time, such as during storage and / or shipment thereof. Nitrosamines are considered to be undesirable contaminants due to the potential mutagenic effects associated therewith. Nitrosamines typically form from secondary aliphatic amines, and in some instances at slower rates from tertiary aliphatic amines. Sources of nitrosamine formation include, active pharmaceutical agents that have at least one amine group covalently bonded thereto / therein that is subject to conversion to nitrosamine, and / or at least one amine present within the solid oral pharmaceutical composition, that is not covalently bonded to / within the active pharmaceutical agent, and which is subject to conversion to nitrosamine. Formation of nitrosamines also typically involves the presence of a nitrosating agent, such as, but not limited to, nitrite (NO2') and / or dinitrogen trioxide (N2O3).

[0004] It would be desirable to develop new solid oral pharmaceutical compositions that have reduced levels of nitrosamine formation. It would be further desirable that such newlydeveloped solid oral pharmaceutical compositions include additives that meet regulatory requirements, such as, but not limited to, maximum daily exposure requirements.SUMMARY

[0005] In accordance with the present invention, there is provided a solid oral pharmaceutical composition comprising: (a) an active pharmaceutical ingredient; (b) a nitrosamine inhibitor comprising mannitol; and (c) a pharmaceutically acceptable excipient. With the solid oral pharmaceutical compositions, at least one of: (i) the active pharmaceutical ingredient comprises at least one covalently bonded amine group that is subject to conversion to nitrosamine; or (ii) the solid oral pharmaceutical composition comprises at least one amine, that is other than the amine group covalently bonded to / within the active pharmaceutical ingredient, and which is subject to conversion to nitrosamine. The nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamine formed in the solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of the nitrosamine inhibitor.

[0006] In further accordance with the present invention, there is also provided a method of forming a solid oral pharmaceutical composition comprising: (a) forming an intragranular dry blend comprising, (i) a first pharmaceutically acceptable excipient, and (ii) optionally a first nitrosamine inhibitor comprising mannitol; (b) forming a granulation solution comprising, (i) an active pharmaceutical ingredient, (ii) optionally a first nitrosamine inhibitor comprising mannitol, and (iii) a solvent; (c) combining together the granulation solution and the intragranular dry blend to form an intermediate composition; (d) forming a granulated composition from said intermediate composition; and (e) optionally combining together said granulated composition and an extragranular composition to form a final blend, wherein said extragranular composition comprises a second pharmaceutically acceptable excipient. It is provided that at least one of the first nitrosamine inhibitor and the second nitrosamine inhibitor is present. With the present method, at least one of, (A) the active pharmaceutical ingredient comprises at least one covalently bonded amine group that is subject to conversion to nitrosamine; or (B) the solid oral pharmaceutical composition comprises at least one amine that is subject to conversion to nitrosamine. In addition with the present method, the resulting solid oral pharmaceutical composition comprises nitrosamine inhibitor in an amount at least sufficient to reduce the amount of nitrosamine formed in the solid oral pharmaceuticalcomposition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of nitrosamine inhibitor.

[0007] The features that characterize the present invention are pointed out with particularity in the claims, which are annexed to and form a part of this disclosure. These and other features of the invention, its operating advantages and the specific objects obtained by its use will be more fully understood from the following detailed description in which non-limiting embodiments of the invention are illustrated and described.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 is a graphical representation of a plot of nitroso-betahistine (NBTH) formed at different stages during preparation of solid oral pharmaceutical compositions that include different levels of mannitol, and after tablets have been subjected to accelerated testing for 3 days at 70°C;

[0009] FIG. 2 is a graphical representation of a plot of nitroso-betahistine (NBTH) formed at different stages during preparation of solid oral pharmaceutical compositions that include different levels of mannitol, where the mannitol has been added at different stages during processing, and after tablets have been subjected to accelerated testing for 3 days at 70°C; and

[0010] FIG. 3 is a graphical representation of a plot of nitroso-betahistine (NBTH) formed as a function of time with liquid test samples to which different amounts of NO2 has been added.

[0011] In FIG’s 1 through 3 like characters and headings refer to the same components and / or have the same meanings, as the case may be, unless otherwise stated.DETAILED DESCRIPTION

[0012] As used herein, the articles "a," "an," and "the" include plural referents unless otherwise expressly and unequivocally limited to one referent.

[0013] Unless otherwise indicated, all ranges or ratios disclosed herein are to be understood to encompass any and all values, and subranges or subratios subsumed therein. For example, a stated range or ratio of "1 to 10" should be considered to include: any and all values therebetween, including the stated terminal values (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10); and subranges between (and inclusive of) the minimum value of 1 and the maximum value of 10, that is, all subranges or subratios beginning with a minimum value of 1 or more and endingwith a maximum value of 10 or less, such as but not limited to, 1 to 6.1, 3.5 to 7.8, and 5.5 to 10.

[0014] As used herein, unless otherwise indicated, left-to-right representations of linking groups, such as divalent linking groups, are inclusive of other appropriate orientations, such as, but not limited to, right-to-left orientations. For purposes of non-limiting illustration, theOleft-to-right representation of the divalent linking groupor equivalently -C(O)O-, is inclusive of the right-to-left representation thereof,r equivalently -O(O)C- or -OC(O)-.

[0015] Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as modified in all instances by the term “about.”

[0016] As used herein, “at least one of’ is synonymous with “one or more of,” whether the elements are listed conjunctively or disjunctively. For example, the phrases “at least one of A, B, and C” and “at least one of A, B, or C” each mean any one of A, B, or C, or any combination of any two or more of A, B, or C. For example, A alone; or B alone; or C alone; or A and B; or A and C; or B and C; or all of A, B, and C.

[0017] As used herein, “selected from” is synonymous with “chosen from” whether the elements are listed conjunctively or disjunctively. Further, the phrases “selected from A, B, and C” and “selected from A, B, or C” each mean any one of A, B, or C, or any combination of any two or more of A, B, or C. For example, A alone; or B alone; or C alone; or A and B; or A and C; or B and C; or all of A, B, and C.

[0018] All documents, such as but not limited to issued patents and patent applications, referred to herein, and unless otherwise indicated, are to be considered to be "incorporated by reference" in their entirety.

[0019] As used herein, the term “aliphatic group” and similar terms, such as “aliphatic substituent” means linear or branched aliphatic groups and / or cycloaliphatic groups, which are not aromatic, and which optionally include at least one carbon-carbon unsaturated linkage, such as at least one alkene linkage (-C=C-) and / or at least one alkyne linkage (-C=C-). With someembodiments, linear or branched aliphatic groups herein include 1 to 10 carbon atoms, and cycloaliphatic groups include 3 to 10 carbon atoms.

[0020] As used herein, recitations of “linear or branched” groups, such as linear or branched alkyl, are herein understood to include: a methylene group or a methyl group; groups that are linear, such as linear C2-C10 alkyl groups; and groups that are appropriately branched, such as branched C3-C10 alkyl groups.

[0021] The term “alkyl” as used herein means linear or branched, cyclic or acyclic C1-C10 alkyl. Linear or branched alkyl can include C1-C10 alkyl, such as C1-C5 alkyl, such as C2-C5 alkyl, such as C2-C4 alkyl. Examples of alkyl groups from which the various alkyl groups of the present invention can be selected from, include, but are not limited to, those recited further herein. Alkyl groups can include “cycloalkyl” groups. The term “cycloalkyl” as used herein means groups that are appropriately cyclic, such as, but not limited to, C3-C10 cycloalkyl (including, but not limited to, cyclic C3-C8 alkyl, or cyclic C5-C7 alkyl) groups.

[0022] Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. Representative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.

[0023] As used herein, the term “nitrosamine” and similar terms such as “nitrosamines,” “nitrosamine group,” and “nitrosamine groups” are inclusive of and interchangeable with “N-nitrosamine,” “N-nitrosamines,” “N-nitrosamine group,” and “N-nitrosamine groups.”

[0024] In accordance with some embodiments of the present invention, nitrosamines, the formation of which is reduced with the present solid oral pharmaceutical compositions, are represented by the following Formula (A).Formula (A)

[0025] With reference to Formula (A), R1and R2are each independently an aliphatic group, such as a linear or branched aliphatic group, such as an alkyl group, such as a linear or branched C1-C10 alkyl group, or a cycloaliphatic group, such as a C3-C10 cycloalkyl group. With some embodiments, R1and R2together form a cyclic group, such as a cycloaliphatic group includingfrom 2 to 10 carbon atoms, such as 2 to 10 methylene groups (-CH2-). In accordance with some further embodiments: R1is a linear or branched C1-C10 alkyl group, or a C3-C10 cycloalkyl group; and R2is an active pharmaceutical ingredient, in which case the nitrosamine group is part of the active pharmaceutical ingredient, which with some embodiments is referred to as an N-nitrosamine active pharmaceutical ingredient (or an N-nitroso pharmaceutical ingredient). In accordance with some additional embodiments, R1and R2together form a cyclic group, such as a cycloaliphatic group, including from 2 to 10 carbon atoms, such as 2 to 10 methylene groups (-CH2-), in which the cyclic ring thereof is fused to and / or bonded (e.g., by a single bond) to at least one other ring (not shown), such as a cycloaliphatic ring and / or an aromatic ring, of the active pharmaceutical ingredient, which with some embodiments is referred to as an N-nitrosamine active pharmaceutical ingredient (or an N-nitroso pharmaceutical ingredient).

[0026] The solid oral pharmaceutical compositions of the present invention include an active pharmaceutical ingredient. With some embodiments, the active pharmaceutical ingredient includes at least one covalently bonded amine group that is subject to conversion to nitrosamine. The covalently bonded amine groups of the active pharmaceutical ingredient, with some embodiments, are each independently a secondary aliphatic amine. With some further embodiments, the covalently bonded amine groups of the active pharmaceutical ingredient are each independently selected from amine groups represented by the following Formulas (B) and (C).Formula (B)

[0027] With reference to Formula (B), R3is an aliphatic group, such as a linear or branched aliphatic group, such as an alkyl group, such as a linear or branched C1-C10 alkyl group, or a cycloaliphatic group, such as a C3-C10 cycloalkyl group. The amine group represented by Formula (B) is covalently bonded to and extends from the active pharmaceutical ingredient.Formula (C)

[0028] With reference to Formula (C), Ring A is a cycloaliphatic ring, such as a C3-C10 cycloalkyl ring, which is typically fused to and / or covalently bonded (e.g., by a single bond) to at least one other ring (not shown), such as a cycloaliphatic ring and / or an aromatic ring, of the active pharmaceutical ingredient.

[0029] The solid oral pharmaceutical composition, with some embodiments, includes at least one amine, that is other than the covalently bonded amine of the active pharmaceutical ingredient, and which is subject to conversion to nitrosamine, and which is referred to herein and with some embodiments as a free amine. The free amine of the solid oral pharmaceutical composition, with some embodiments, is present in / with the pharmaceutically acceptable excipient and / or the active pharmaceutical ingredient. The free amine, with some embodiments, is an aliphatic amine, such as a linear or branched aliphatic amine, and / or a cycloaliphatic amine. With some further embodiments, the free amine is a secondary aliphatic amine. The free amine, with some embodiments, is represented by the following Formula (D).Formula (D)

[0030] With reference to Formula (D), R4and R5are each independently an aliphatic group, such as a linear or branched aliphatic group, such as an alkyl group, such as a linear or branched C1-C10 alkyl group, or a cycloaliphatic group, such as a C3-C10 cycloalkyl group. With some embodiments, R4and R5together form a cyclic group, such as a cycloaliphatic group including from 2 to 10 carbon atoms, such as 2 to 10 methylene groups (-CH2-).

[0031] The active pharmaceutical ingredient, of the solid oral pharmaceutical compositions of the present invention, includes synthetic and / or natural active pharmaceutical ingredients, and / or pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of the active pharmaceutical ingredient, include but are not limited to HC1 salts thereof. Generalclasses of active pharmaceutical ingredients include, but are not limited to: analgesics; hypertension drugs, such as angiotensin II receptor blockers (ARBs), such as sartans, such as azilsartan, candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, and eprosartan; further hypertension drugs, such as beta blockers, such as propranolol, sotalol, acebutalol, metoprolol, atenolol, and labetolol; histamine H2-receptor antagonists (or histamine-2 blockers), such as cimetidine, ranitidine, nizatidine, and famotidine; histamine H3-receptor antagonists, such as betahistine, clobenpropit, and ciproxifan; antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), such sertraline, citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, and vortioxetine.

[0032] With some embodiments, the active pharmaceutical ingredient includes at least one of an angiotensin II receptor blocker, a beta-blocker, a histamine H2-receptor antagonist, a histamine H3-receptor antagonist, a selective serotonin reuptake inhibitor, and / or pharmaceutically acceptable salts of one or more thereof.

[0033] The active pharmaceutical ingredient, with some embodiments of the present invention, includes at least one covalently bonded amine group that is subject to conversion to nitro s amine.

[0034] In accordance with some embodiments, the active pharmaceutical ingredient includes at least one of betahistine, a pharmaceutically acceptable salt of betahistine, sertraline, a pharmaceutically acceptable salt of sertraline, propranolol, and / or a pharmaceutically acceptable salt of propranolol.

[0035] In accordance with some further embodiments, the active pharmaceutical ingredient includes at least one of betahistine, and / or a pharmaceutically acceptable salt of betahistine.

[0036] Betahistine can be represented by the following Formula (la),Formula (la)

[0037] A chemical name for betahistine, as represented by Formula (la), is N-methyl-2- (pyridin-2-yl)ethan-l -amine, or 2-[2-(methylamino)ethyl]pyridine.

[0038] The following Formula (lb) is a representative structure for N-nitroso betahistine (also referred to herein as nitroso-betahistine),Formula (lb)

[0039] A chemical name for N-nitroso betahistidine, as represented by Formula (lb), is N- methyl-N-(2-(pyridin-2-yl)ethyl)nitrous amide, which is abbreviated as NBTH herein.

[0040] Sertraline can be represented by the following Formula (Ila),Formula (Ila)

[0041] A chemical name for sertraline, as represented by Formula (Ila), is (lS,4S)-4-(3,4- dichlorophenyl)-N-methyl-l,2,3,4-tetrahydronaphthalen-l-amine.

[0042] The following Formula (lib) is a representative structure for N-nitroso sertraline (also referred to herein as nitroso-sertraline),Formula (lib)

[0043] A chemical name for the N-nitroso sertraline, as represented by Formula (lib), is N- ((lS,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydronaphthalen-l-yl)-N-methylnitrous amide.

[0044] Propranolol can be represented by the following Formula (Illa),Formula (Illa)

[0045] A chemical name for propranolol, as represented by Formula (Illa), is 1-(isopropylamino)-3-(naphthalen-l-yloxy)propan-2-ol.

[0046] The following Formula (Illb) is a representative structure for N-nitroso propranolol (also referred to herein as nitroso-propranolol),Formula (Illb)

[0047] A chemical name for the N-nitroso propranolol, as represented by Formula (Illb), is N-(2-hydroxy-3-(naphthalen-l-yloxy)propyl)-N-isopropylnitrous amide.

[0048] The active pharmaceutical ingredient is present in the solid oral pharmaceutical composition, in any suitable amount, such as a pharmaceutically effective amount. With some embodiments, the active pharmaceutical ingredient is present in the solid oral pharmaceutical composition in an amount of from 2 to 60 percent by weight, or 5 to 60 percent by weight, or from 10 to 60 percent by weight, or from 20 to 50 percent by weight, or from 30 to 40 percentby weight, the percent weights in each case being based on the total weight of the solid oral pharmaceutical composition.

[0049] The solid oral pharmaceutical compositions of the present invention include a nitrosamine inhibitor including mannitol. Mannitol can be represented by the following Formula (IV).Formula (IV)

[0050] A chemical name for mannitol, as represented by Formula (IV), is (2R,3R,4R,5R)- hexane-l,2,3,4,5,6-hexaol.

[0051] In accordance with some embodiments of the present invention, mannitol includes D-mannitol. In accordance with some further embodiments of the present invention, mannitol is D-mannitol.

[0052] While not intending to be bound by any theory, it is believed that, in some instances, at least some of the hydroxyl groups of mannitol are converted to nitrite (or nitrile) groups (- ONO), in the presence of a nitrosating agent, such as, but not limited to, nitrite (NO2') and / or dinitrogen trioxide (N2O3).

[0053] With some embodiments of the present invention, the nitrosamine inhibitor consists essentially of mannitol. With some further embodiments of the present invention, the nitrosamine inhibitor consists of mannitol.

[0054] In accordance with the present invention, the nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamine formed in the solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of the nitrosamine inhibitor.

[0055] As used herein, the recitation of “a comparative solid oral pharmaceutical composition that is free of the nitrosamine inhibitor” means a comparative composition that includes the same active pharmaceutical ingredient, the same pharmaceutically acceptable excipient, does not include the nitrosamine inhibitor, and which is prepared and evaluatedunder the same conditions, as the solid oral pharmaceutical composition according to the present invention. With some embodiments, the “comparative solid oral pharmaceutical composition that is free of the nitrosamine inhibitor” includes an amount by weight of pharmaceutically acceptable excipient (such as microcrystalline cellulose) that is increased by an amount by weight that is equivalent to the weight of nitrosamine inhibitor that is not present (or which has been removed).

[0056] The amount of nitrosamine formed in the inventive and comparative solid oral pharmaceutical compositions can be determined in accordance with art-recognized analytical methods. With some embodiments, the amount of nitrosamine formed in the inventive and comparative solid oral pharmaceutical compositions is determined using liquid chromatography-mass spectrometry (LC-MS).

[0057] In accordance with some embodiments, shortly after preparation of the inventive and comparative solid oral pharmaceutical compositions, an initial (or to) amount (or level) of nitrosamine is determined. The inventive and comparative solid oral pharmaceutical compositions are then typically subjected to accelerated testing under controlled conditions of elevated temperature, such as 50°C or 70°C, and relative humidity (RH), such as 70% RH or 75% RH. Test samples are typically withdrawn and analyzed to determine the amount of nitrosamine formed, over a period of time, such as days (e.g., 3, 6, and / or 30 days).

[0058] In accordance with some embodiments, the reduction in the amount of nitrosamine formed in the inventive solid oral pharmaceutical compositions, over a period of time, is characterized as a percent reduction relative to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition, which is calculated using the following Equation-(l):Equation-(l)*(comparative amount of nitrosamine formed at tx) - (inventive amount of nitrosamine formed at tx)(comparative amount of nitrosamine formed at tx) ■■

[0059] With reference to Equation-(l), the “comparative amount of nitrosamine formed at tx” means the amount of nitrosamine formed in the comparative solid oral pharmaceutical composition at time tx. With further reference to Equation-(l), the “inventive amount of nitrosamine formed at tx” means the amount of nitrosamine formed in the solid oral pharmaceutical composition according to the present invention at time tx.

[0060] With some embodiments of the present invention, the amount of nitrosamine formed in the solid oral pharmaceutical composition according to the present invention is reduced by at least 10 percent by weight, or at least 20 percent by weight, or at least 30 percent by weight, or at least 40 percent by weight, or at least 50 percent by weight, in each case as compared to the amount of nitrosamine formed in the comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor, in each case under the same test and environmental conditions, and for the same period of time.

[0061] With some further embodiments of the present invention, the amount of nitrosamine formed in the solid oral pharmaceutical composition according to the present invention is reduced by at least 75 percent by weight, compared to the amount of nitrosamine formed in the comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor, in each case under the same test and environmental conditions, and for the same period of time.

[0062] With some further embodiments of the present invention, the amount of nitrosamine formed in the solid oral pharmaceutical composition according to the present invention is reduced by at least 80 percent by weight, or at least 85 percent by weight, or at least 90 percent by weight, or at least 95 percent by weight, in each case as compared to the amount of nitrosamine formed in the comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor, in each case under the same test and environmental conditions, and for the same period of time.

[0063] With some further embodiments of the present invention, the amount of nitrosamine formed in the solid oral pharmaceutical composition according to the present invention is reduced by from 92 percent by weight to less than or equal to 100 percent by weight, or by 93 percent by weight to less than or equal to 98 percent by weight, compared to the amount of nitrosamine formed in the comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor, in each case under the same test and environmental conditions, and for the same period of time.

[0064] The nitrosamine inhibitor can be present in the solid oral pharmaceutical composition according to the present invention in any amount, provided such amount is at least sufficient so as to reduce the amount of nitrosamine formed in the solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of the nitrosamine inhibitor.

[0065] With some embodiments, the nitrosamine inhibitor is present in an amount of at least 0.05 percent by weight, based on weight of the active pharmaceutical ingredient.

[0066] With some further embodiments, the nitrosamine inhibitor is present in an amount of from 0.05 percent by weight to 750.0 percent by weight, or from 0.05 percent by weight to 700 percent by weight, or from 0.05 percent by weight to 650.0 percent by weight, or from 0.05 percent by weigh to 625.0 percent by weight, based on weight of the active pharmaceutical ingredient, inclusive of the recited amounts.

[0067] With some further embodiments, the nitrosamine inhibitor is present in an amount of from 0.5 percent by weight to 750.0 percent by weight, or from 0.5 percent by weight to 700 percent by weight, or from 0.5 percent by weight to 650.0 percent by weight, or from 0.5 percent by weigh to 625.0 percent by weight, based on weight of the active pharmaceutical ingredient, inclusive of the recited amounts.

[0068] With some additional embodiments, the nitrosamine inhibitor is present in an amount of at least 0.05 percent by weight, or at least 0.5 percent by weight, or at least 50 percent by weight, or at least 100 percent by weight, or at least 125 percent by weight, or at least 150 percent by weight, or at least 200 percent by weight, or at least 300 percent by weight, based on weight of the active pharmaceutical ingredient. With some additional embodiments, the nitrosamine inhibitor is present in an amount of less than or equal to 750.0 percent by weight, or less than or equal to 650.0 percent by weight, or less than or equal to 625 percent by weight, based on weight of the active pharmaceutical ingredient. The nitrosamine inhibitor can be present, with some embodiments, in an amount ranging from any combination these recited lower and upper values, inclusive of the recited values, such as, 0.05 percent by weight to 750.0 percent by weight, or from 50 percent by weight to 650.0 percent by weight, or from 100.0 percent by weight to 625 percent by weight, or from 200 percent by weight to 650 percent by weight, or from 300 percent by weight to 650 percent by weight, based on weight of the active pharmaceutical ingredient.

[0069] With some embodiments, the nitrosamine inhibitor is introduced into the solid oral pharmaceutical composition at any point (or points) during preparation of the solid oral pharmaceutical composition.

[0070] The nitrosamine inhibitor, with some embodiments, is introduced into the solid oral pharmaceutical composition by at least one of an intra-granular (or intragranular) addition method and / or an extra-granular (or extragranular) addition method. Any art-recognizedintra-granular addition method, and any art-recognized extra-granular addition method can be used.

[0071] In accordance with some embodiments, at least a portion of the nitrosamine inhibitor is introduced into the solid oral pharmaceutical composition in (or as part of) a solution that includes the nitrosamine inhibitor and a solvent.

[0072] In accordance with some embodiments, at least a portion of the nitrosamine inhibitor is introduced into the solid oral pharmaceutical composition in (or as part of) a solution that includes the nitrosamine inhibitor and a solvent, where the solvent includes water. With some further embodiments, the solvent includes water and an organic solvent, where the organic solvent is selected from: an alcohol, such as a linear or branched Ci-Cio alcohol; an alkylene glycol, such as a linear or branched C2-C6 alkylene glycol; a polyalkylene glycol, where, for example, each alkylene glycol (or alkylene ether) unit is independently a linear or branched C2-C6 alkylene glycol unit (or linear or branched C2-C6 alkylene ether unit); a polyol having at least three hydroxyl groups, such as glycerine, trimethylolpropane, pentaerythritol, and / or bis- trimethylolpropane; and combinations thereof. With some embodiments, the solvent, (of the solution that includes the nitrosamine inhibitor and solvent) consists essentially of water, or consists of water, or is water.

[0073] In accordance with some embodiments, at least a portion of the nitrosamine inhibitor is introduced into the solid oral pharmaceutical composition in (or as part of) a solution that includes the nitrosamine inhibitor, the active pharmaceutical agent, and a solvent.

[0074] With some embodiments, at least a portion of the nitrosamine inhibitor is introduced into the solid oral pharmaceutical composition in (or as part of) a solution that includes the nitrosamine inhibitor, the active pharmaceutical agent, and a solvent, and where the solution is a granulation solution.

[0075] With some additional embodiments, at least a portion of the nitrosamine inhibitor is introduced into the solid oral pharmaceutical composition in (or as part of) a solution that includes the nitrosamine inhibitor, the active pharmaceutical agent, a solvent, and a compound including at least one carboxylic acid group, such as citric acid and / or citric acid monohydrate, and where the solution is a granulation solution.

[0076] At least 5 percent by weight of the nitrosamine inhibitor, with some embodiments, is introduced into the solid oral pharmaceutical composition in (or as part of) the solution including the nitrosamine inhibitor and the solvent, where the percent by weight of nitrosamineinhibitor is based on total weight of nitrosamine inhibitor present in the solid oral pharmaceutical composition.

[0077] In accordance with some further embodiments: from 5 percent by weight to 55 percent by weight (or from 5 percent by weight to 40 percent by weight, or from 5 percent by weight to 30 percent by weight) of the nitrosamine inhibitor is introduced into the solid oral pharmaceutical composition in the solution that includes the nitrosamine inhibitor and the solvent; and from 45 percent by weight to 95 percent by weight (or from 60 percent by weight to 95 percent by weight, or from 70 percent by weight to 95 percent by weight) of the nitrosamine inhibitor is introduced into the solid oral pharmaceutical composition in (or as part of) an intragranular composition, where the percent by weights of nitrosamine inhibitor are in each case based on total weight of nitrosamine inhibitor present in the solid oral pharmaceutical composition. With some embodiments, the intragranular composition that includes the nitrosamine inhibitor, is an intragranular dry-blended composition that is free of solvent.

[0078] The solid oral pharmaceutical compositions of the present invention include at least one pharmaceutically acceptable excipient. Classes of pharmaceutically acceptable excipients include, but are not limited to: diluents, such as sugar compounds, such as lactose, dextrin, glucose, sucrose, and sorbitol, and / or inorganic compounds, such as silicates, calcium salts, magnesium salts, sodium chloride, and potassium chloride; binders, compression aids, and granulating agents, such as natural and / or synthetic polymers, such as starches, polymeric sugars, sugar alcohol, and cellulose derivatives; disintegrants, such as starch, cellulose derivatives, alginates, and crospovidone (cross-linked polyvinylpyrrolidone); glidants, such as anhydrous silicon and other silica compounds; and lubricants, such as stearic acid and salts of stearic acid.

[0079] With some embodiments, the pharmaceutically acceptable excipient includes at least one of microcrystalline cellulose, sucrose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium starch glycolate, starch, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, magnesium stearate, oleic acid, stearic acid, stearyl alcohol, calcium carbonate, dextrose, lactose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, silica, titanium dioxide, gelatin, or triglycerides.

[0080] The pharmaceutically acceptable excipient(s) can be present in the solid oral pharmaceutical compositions of the present invention in any suitable amount. With some embodiments, the pharmaceutically acceptable excipient is present in an amount of from 0.05to 99.5 percent by weight, or from 5 to 95 percent by weight, or from 10 to 90 percent by weight, the percent weights in each case being based on the total weight of the solid oral pharmaceutical composition.

[0081] The solid oral pharmaceutical compositions of the present invention can be in any suitable form. With some embodiments, the solid oral pharmaceutical composition of the present invention is in a form selected from tablets, capsules, and free flowing granules. The solid oral pharmaceutical compositions of the present invention can be formed into tablets, capsules, and / or free flowing granules in accordance with art-recognized methods.

[0082] In accordance with some embodiments of the present invention, the solid oral pharmaceutical composition is prepared by a dry method (or dry-blend method). With some embodiments, each component of the solid oral pharmaceutical composition is individually subjected to size exclusion treatment, such as sieving, to remove larger agglomerates, which results in the formation of size exclusion treated ingredients. The size exclusion treated ingredients are then, with some embodiments, combined (or mixed) together to form a dry-blended composition. The dry-blended composition, with some embodiments, is subjected to tableting, which results in the formation of solid oral pharmaceutical compositions according to present invention, which are in the form of tablets.

[0083] There present invention also relates to a method of forming a solid oral pharmaceutical composition as described previously herein. With the method of the present invention, the first and second pharmaceutically acceptable excipients are each independently selected from those classes and examples of pharmaceutically acceptable excipients as described previously herein.

[0084] With some embodiments of the method of the present invention, the first nitrosamine inhibitor including mannitol and the second nitrosamine inhibitor including mannitol are each as described previously herein with regard to the nitrosamine inhibitor including mannitol. With some embodiments of the method of the present invention, the first nitrosamine inhibitor including mannitol and the second nitrosamine inhibitor including mannitol, are the same

[0085] In accordance with some embodiments of the method of the present invention: the intraganular composition includes the first nitrosamine inhibitor that includes mannitol; and the granulation solution includes the second nitrosamine inhibitor that includes mannitol, and the solvent includes water. The solvent of the granulation composition is as described previously herein.

[0086] With some embodiments of the method of the present invention, the second nitrosamine inhibitor is present in an amount of from 5 percent by weight to 55 percent by weight (or from 5 percent by weight to 40 percent by weight, or from 5 percent by weight to 30 percent by weight), and the first nitrosamine inhibitor is present in an amount of from 45 percent by weight to 95 percent by weight (or from 60 percent by weight to 95 percent by weight, or from 70 percent by weight to 95 percent by weight), the percent weights in each case being based on the total weight of the first nitrosamine inhibitor and of the second nitrosamine inhibitor present in the resulting oral pharmaceutical composition.

[0087] With the method of the present invention the granulation solution and the intragranular dry blend are combined together to form an intermediate composition. Combining together the granulation solution and the intragranular dry blend can be achieved in accordance with art-recognized methods.

[0088] A granulated composition is formed from the intermediate composition, with the method of the present invention. The granulation process can be conducted in accordance with art-recognized methods, and includes, with some embodiments, high-shear granulation, followed sequentially by drying and milling.

[0089] In accordance with some embodiments of the method of the present invention, the granulated composition or the final blend, is subjected to tableting to form tablets. Tableting can be conducted in accordance with art-recognized methods.

[0090] The present invention can be further characterized by one or more of the following non-limiting clauses.

[0091] Clause 1: A solid oral pharmaceutical composition comprising:(a) an active pharmaceutical ingredient;(b) a nitrosamine inhibitor comprising mannitol; and(c) a pharmaceutically acceptable excipient, wherein at least one of, (i) said active pharmaceutical ingredient comprises at least one covalently bonded amine group that is subject to conversion to nitrosamine; or (ii) said solid oral pharmaceutical composition comprises at least one amine that is subject to conversion to nitrosamine, and wherein said nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamine formed in said solid oral pharmaceutical composition, compared tothe amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

[0092] Clause 2. The solid oral pharmaceutical composition of clause 1, wherein said active pharmaceutical ingredient comprises at least one of, an angiotensin II receptor blocker, a beta-blocker, a histamine H2-receptor antagonist, a histamine H3-receptor antagonist, a selective serotonin reuptake inhibitor, or pharmaceutically acceptable salts of one or more thereof.

[0093] Clause 3: The solid oral pharmaceutical composition of clause 1 or clause 2, wherein said active pharmaceutical ingredient comprises at least one covalently bonded amine group that is subject to conversion to nitrosamine.

[0094] Clause 4: The solid oral pharmaceutical composition of any one of clauses 1 to 3, wherein said active pharmaceutical ingredient comprises at least one of betahistine, or a pharmaceutically acceptable salt of betahistine.

[0095] Clause 5: The solid oral pharmaceutical composition of any one of clauses 1 to 4, wherein said amount of said nitrosamine inhibitor is at least 0.05 percent by weight, based on weight of said active pharmaceutical ingredient.

[0096] Clause 6: The solid oral pharmaceutical composition of any one of clauses 1 to 5, wherein said amount of said nitrosamine inhibitor is from 0.05 percent by weight to 750.0 percent by weight, based on weight of said active pharmaceutical ingredient.

[0097] Clause 7: The solid oral pharmaceutical composition of any one of clauses 1 to 6, wherein, said amount of said nitrosamine inhibitor is from 0.5 percent by weight to 650.0 percent by weight, or from or from 50 percent by weight to 650.0 percent by weight, the percent weights in each case are based on weight of said active pharmaceutical ingredient.

[0098] Clause 8: The solid oral pharmaceutical composition of any one of clauses 1 to 7, wherein the amount of nitrosamine formed in said solid oral pharmaceutical composition is reduced by at least 50 percent by weight, compared to the amount of nitrosamine formed in said comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

[0099] Clause 9: The solid oral pharmaceutical composition of any one of clauses 1 to 8, wherein the amount of nitrosamine formed in said solid oral pharmaceutical composition is reduced by at least 75 percent by weight, compared to the amount of nitrosamine formed insaid comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

[0100] Clause 10: The solid oral pharmaceutical composition of any one of clauses 1 to 9, wherein the amount of nitrosamine formed in said solid oral pharmaceutical composition is reduced by at least 80 percent by weight, compared to the amount of nitrosamine formed in said comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

[0101] Clause 11: The solid oral pharmaceutical composition of any one of clauses 1 to 10, wherein said nitrosamine inhibitor is introduced into said solid oral pharmaceutical composition by at least one of an intra-granular method or an extra-granular method.

[0102] Clause 12: The solid oral pharmaceutical composition of any one of clauses 1 to 11, wherein at least a portion of said nitrosamine inhibitor is introduced into said solid oral pharmaceutical composition in a solution comprising said nitrosamine inhibitor and a solvent.

[0103] Clause 13: The solid oral pharmaceutical composition of clause 12, wherein said solvent comprises water.

[0104] Clause 14: The solid oral pharmaceutical composition of clause 12 or clause 13, wherein said solution further comprises said active pharmaceutical agent.

[0105] Clause 15: The solid oral pharmaceutical composition of any one of clauses 12 to14, wherein said solution is a granulation solution.

[0106] Clause 16: The solid oral pharmaceutical composition of any one of clauses 12 to15, wherein at least 5 percent by weight of said nitrosamine inhibitor is introduced into said solid oral pharmaceutical composition in said solution comprising said nitrosamine inhibitor and said solvent, wherein the percent by weight of nitrosamine inhibitor is based on total weight of nitrosamine inhibitor present in said solid oral pharmaceutical composition.

[0107] Clause 17: The solid oral pharmaceutical composition of any one of clauses 12 to16, wherein from 5 percent by weight to 55 percent by weight of said nitrosamine inhibitor (or from 5 percent by weight to 40 percent by weight, or from 5 percent by weight to 30 percent by weight) is introduced into said solid oral pharmaceutical composition in said solution comprising said nitrosamine inhibitor and said solvent, and from 45 percent by weight to 95 percent by weight of said nitrosamine inhibitor (or from 60 percent by weight to 95 percent by weight, or from 70 percent by weight to 95 percent by weight) is introduced into said solid oralpharmaceutical composition in an intragranular composition, wherein the percent by weights of nitrosamine inhibitor are in each case based on total weight of nitrosamine inhibitor present in said solid oral pharmaceutical composition.

[0108] Clause 18: The solid oral pharmaceutical composition of any one of clauses 1 to 17, wherein said pharmaceutically acceptable excipient comprises at least one of microcrystalline cellulose, sucrose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium starch glycolate, starch, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, magnesium stearate, oleic acid, stearic acid, stearyl alcohol, calcium carbonate, dextrose, lactose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, silica, titanium dioxide, gelatin, or triglycerides.

[0109] Clause 19: The solid oral pharmaceutical composition of any one of clauses 1 to 18, wherein said solid oral pharmaceutical composition is in a form selected from tablets, capsules, and free flowing granules.

[0110] Clause 20: A method of forming a solid oral pharmaceutical composition comprising:(a) forming an intragranular dry blend comprising,(i) a first pharmaceutically acceptable excipient, and(ii) optionally a first nitrosamine inhibitor comprising mannitol;(b) forming a granulation solution comprising,(i) an active pharmaceutical ingredient,(ii) optionally a second nitrosamine inhibitor comprising mannitol, and(iii) a solvent;(c) combining together said granulation solution and said intragranular dry blend to form an intermediate composition;(d) forming a granulated composition from said intermediate composition; and(e) optionally combining together said granulated composition and an extragranular composition to form a final blend, wherein said extragranular composition comprises a second pharmaceutically acceptable excipient, provided that at least one of said first nitrosamine inhibitor and said second nitrosamine inhibitor is present, wherein at least one of, (A) said active pharmaceutical ingredient comprises at least one covalently bonded amine group that is subject to conversion to nitrosamine; or (B) said solidoral pharmaceutical composition comprises at least one amine that is subject to conversion to nitrosamine, and wherein said solid oral pharmaceutical composition comprises nitrosamine inhibitor in an amount at least sufficient to reduce the amount of nitrosamine formed in said solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of nitrosamine inhibitor.

[0111] Clause 21: The method of clause 20, wherein said intraganular composition comprises said first nitrosamine inhibitor comprising mannitol; and said granulation solution comprises said second nitrosamine inhibitor comprising mannitol, and said solvent comprises water.

[0112] Clause 22: The method of clause 20 or clause 21, wherein said first nitrosamine inhibitor comprising mannitol and said second nitrosamine inhibitor comprising mannitol, are the same.

[0113] Clause 23: The method of any one of clauses 20 to 22, wherein said second nitrosamine inhibitor is present in an amount of from 5 percent by weight to 55 percent by weight (or from 5 percent by weight to 40 percent by weight, or from 5 percent by weight to 30 percent by weight); and said first nitrosamine inhibitor is present in an amount of from 45 percent by weight to 95 percent by weight (or from 60 percent by weight to 95 percent by weight, or from 70 percent by weight to 95 percent by weight), the percent weights in each case being based on the total weight of said first nitrosamine inhibitor and of said second nitrosamine inhibitor.

[0114] Clause 24: The method of any one of clause 20 to 23, wherein said granulated composition or said final blend, is subjected to tableting to form tablets.

[0115] The present invention is more particularly described in the following examples, which are intended to be illustrative only, since numerous modifications and variations therein will be apparent to those skilled in the art. Unless otherwise specified, all parts and all percentages are by weight.EXAMPLES

[0116] In Part 1 of the following examples, there is described the preparation and evaluation of comparative solid oral pharmaceutical compositions and those according to the presentinvention, which include different levels of nitrosamine inhibitor, and different addition sequences thereof. In Part 2, there is described the preparation and evaluation of test solutions to which were added different levels of NO2, with and without nitrosamine inhibitor.Part 1

[0117] In the following Table 1 there is provided a tabulation of ingredients used to prepare a comparative solid oral composition (CE-1) and those according to the present invention (Ex’s 1-4).Table 1(1)The betahistine dihydrochloride was obtained commercially from ZCL Chemical Ltd.(2)The mannitol was obtained commercially from Roquette under the tradename PEARLITOL 25C Mannitol.(3)The citric acid monohydrate was obtained commercially from Jungbunzlauer.(4)The purified water was generated in-house and met requirements for use in pharmaceutical compounding, and was added Q.S.(5)The microcrystalline cellulose was obtained commercially from JRS Pharma under the tradenames VIVAPUR 101 and VIVAPUR 102 microcrystalline cellulose.(6)The colloidal silicon dioxide was obtained commercially from Evonik Degussa under the tradename AEROSIL 200 VV PHARMA.(7)The talc was obtained commercially from Luzenac.

[0118] The solid oral pharmaceutical compositions of CE-1 and Ex’s 1-4 of Table 1 were in each case prepared under the same conditions and in accordance with the following description. The Part- II - Intra-granular ingredients were initially dry-blended (or dry-mixed). In the next step, the Part I - Granulation Solution and the dry-blend were combined together in a high- shear granulation unit, which resulted in the formation of wet granules. The wet granules were dried in a fluidized bed drier, which resulted in the formation of dried granules. The dried granules were milled using a FitzMill impact mill fitted with a 1.4 mm aperture screen. The Part III - Extra-granular ingredients were separately screened using a 1.0 mm aperture screen. The screened Part III - Extra-granular ingredients and the milled and screened dried granules were combined, which resulted in the formation of a final blend. The final blend was subjected to tableting, which resulted in the formation of tablets.

[0119] For CE-1 and Ex’s 1, 2, and 4, samples were obtained after drying, milling, the final blend, and tableting (Day 0 / to), and analyzed by LC-MS for the amount of nitroso-betahistine present. The tablets were then subjected to accelerated testing at 70°C and ambient relative humidity, for three days, followed by LC-MS analysis to determine the amount of nitroso-betahistine (NBTH) present. Ex-3 was analyzed by LC-MS for the amount of nitroso-betahistine present after drying, with the initial tablets (Day 0 / to), and after subjecting the tablets to accelerated tested at 70°C and ambient relative humidity, for three days. The analytical results are summarized in the following Table 2.Table 2

[0120] The results of CE-1, Ex-1, and Ex-3 are presented graphically in FIG. 1 of the drawings.

[0121] The results of Ex-1, Ex-2, Ex-3, and Ex-4 are presented graphically in FIG. 2 of the drawings.Part 2

[0122] Liquid test samples were prepared from the ingredients listed in the following Table 3. The liquid test samples were prepared by first mixing the citric acid, betahistine, optionally mannitol, and water together, and then introducing NO2 thereto in the amounts indicated. The liquid test samples were each initially mixed by vortex agitation at 2500 RPM for one minute.Table 3

[0123] The liquid test samples of Table 3 were maintained at room temperature (approximately 25 °C) in sealed containers. Initial (to) samples and samples over subsequent hours were obtained and analyzed by LC-MS for the amount of nitroso-betahistine (NBTH formed), the results of which are summarized in the following Table 4.Table 4

[0124] The results of Table 4 are presented graphically in FIG. 3 of the drawings, where the amount of nitroso-betahistine (NBTH) formed is plotted as a function of time (hours).

[0125] The present invention has been described with reference to specific details of particular embodiments thereof. It is not intended that such details be regarded as limitations upon the scope of the invention except insofar as to the extent that they are included in the accompanying claims.

Claims

What is Claimed is:

1. A solid oral pharmaceutical composition comprising:(a) an active pharmaceutical ingredient;(b) a nitrosamine inhibitor comprising mannitol; and(c) a pharmaceutically acceptable excipient, wherein at least one of, (i) said active pharmaceutical ingredient comprises at least one covalently bonded amine group that is subject to conversion to nitrosamine; or (ii) said solid oral pharmaceutical composition comprises at least one amine that is subject to conversion to nitrosamine, and wherein said nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamine formed in said solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

2. The solid oral pharmaceutical composition of claim 1, wherein said active pharmaceutical ingredient comprises at least one of, an angiotensin II receptor blocker, a beta-blocker, a histamine H2-receptor antagonist, a histamine H3-receptor antagonist, a selective serotonin reuptake inhibitor, or pharmaceutically acceptable salts of one or more thereof.

3. The solid oral pharmaceutical composition of claim 1, wherein said active pharmaceutical ingredient comprises at least one covalently bonded amine group that is subject to conversion to nitrosamine.

4. The solid oral pharmaceutical composition of claim 3, wherein said active pharmaceutical ingredient comprises at least one of betahistine, or a pharmaceutically acceptable salt of betahistine.

5. The solid oral pharmaceutical composition of claim 1, wherein said amount of said nitrosamine inhibitor is at least 0.05 percent by weight, based on weight of said active pharmaceutical ingredient.

6. The solid oral pharmaceutical composition of claim 5, wherein said amount of said nitrosamine inhibitor is from 0.05 percent by weight to 750.0 percent by weight, based on weight of said active pharmaceutical ingredient.

7. The solid oral pharmaceutical composition of claim 6, wherein, said amount of said nitrosamine inhibitor is from 0.5 percent by weight to 650.0 percent by weight, based on weight of said active pharmaceutical ingredient.

8. The solid oral pharmaceutical composition of claim 1, wherein the amount of nitrosamine formed in said solid oral pharmaceutical composition is reduced by at least 50 percent by weight, compared to the amount of nitrosamine formed in said comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

9. The solid oral pharmaceutical composition of claim 1, wherein the amount of nitrosamine formed in said solid oral pharmaceutical composition is reduced by at least 75 percent by weight, compared to the amount of nitrosamine formed in said comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

10. The solid oral pharmaceutical composition of claim 1, wherein the amount of nitrosamine formed in said solid oral pharmaceutical composition is reduced by at least 80 percent by weight, compared to the amount of nitrosamine formed in said comparative solid oral pharmaceutical composition that is free of said nitrosamine inhibitor.

11. The solid oral pharmaceutical composition of claim 1, wherein said nitrosamine inhibitor is introduced into said solid oral pharmaceutical composition by at least one of an intra-granular method or an extra-granular method.

12. The solid oral pharmaceutical composition of claim 1, wherein at least a portion of said nitrosamine inhibitor is introduced into said solid oral pharmaceutical composition in a solution comprising said nitrosamine inhibitor and a solvent.

13. The solid oral pharmaceutical composition of claim 12, wherein said solvent comprises water.

14. The solid oral pharmaceutical composition of claim 13, wherein said solution further comprises said active pharmaceutical agent.

15. The solid oral pharmaceutical composition of claim 14, wherein said solution is a granulation solution.

16. The solid oral pharmaceutical composition of claim 12, wherein at least 5 percent by weight of said nitrosamine inhibitor is introduced into said solid oral pharmaceutical composition in said solution comprising said nitrosamine inhibitor and said solvent, wherein the percent by weight of nitrosamine inhibitor is based on total weight of nitrosamine inhibitor present in said solid oral pharmaceutical composition.

17. The solid oral pharmaceutical composition of claim 12, wherein from 5 percent by weight to 55 percent by weight of said nitrosamine inhibitor is introduced into said solid oral pharmaceutical composition in said solution comprising said nitrosamine inhibitor and said solvent, and from 45 percent by weight to 95 percent by weight of said nitrosamine inhibitor is introduced into said solid oral pharmaceutical composition in an intragranular composition, wherein the percent by weights of nitrosamine inhibitor are in each case based on total weight of nitrosamine inhibitor present in said solid oral pharmaceutical composition.

18. The solid oral pharmaceutical composition of claim 1, wherein said pharmaceutically acceptable excipient comprises at least one of microcrystalline cellulose, sucrose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium starch glycolate, starch, xylitol, fructose, sorbitol, calcium phosphate, calcium sulfate, magnesium stearate, oleic acid, stearic acid, stearyl alcohol, calcium carbonate, dextrose, lactose, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, silica, titanium dioxide, gelatin, or triglycerides.

19. The solid oral pharmaceutical composition of claim 1, wherein said solid oral pharmaceutical composition is in a form selected from tablets, capsules, and free flowing granules.

20. A method of forming a solid oral pharmaceutical composition comprising:(a) forming an intragranular dry blend comprising,(i) a first pharmaceutically acceptable excipient, and(ii) optionally a first nitrosamine inhibitor comprising mannitol;(b) forming a granulation solution comprising,(i) an active pharmaceutical ingredient,(ii) optionally a second nitrosamine inhibitor comprising mannitol, and(iii) a solvent;(c) combining together said granulation solution and said intragranular dry blend to form an intermediate composition;(d) forming a granulated composition from said intermediate composition; and(e) optionally combining together said granulated composition and an extragranular composition to form a final blend, wherein said extragranular composition comprises a second pharmaceutically acceptable excipient, provided that at least one of said first nitrosamine inhibitor and said second nitrosamine inhibitor is present, wherein at least one of, (A) said active pharmaceutical ingredient comprises at least one covalently bonded amine group that is subject to conversion to nitrosamine; or (B) said solid oral pharmaceutical composition comprises at least one amine that is subject to conversion to nitrosamine, and wherein said solid oral pharmaceutical composition comprises nitrosamine inhibitor in an amount at least sufficient to reduce the amount of nitrosamine formed in said solid oral pharmaceutical composition, compared to the amount of nitrosamine formed in a comparative solid oral pharmaceutical composition that is free of nitrosamine inhibitor.

21. The method of claim 20, wherein said intraganular composition comprises said first nitrosamine inhibitor comprising mannitol; and said granulation solution comprises said second nitrosamine inhibitor comprising mannitol, and said solvent comprises water.

22. The method of claim 21, wherein said first nitrosamine inhibitor comprising mannitol and said second nitrosamine inhibitor comprising mannitol, are the same.

23. The method of claim 22, wherein said second nitrosamine inhibitor is present in an amount of from 5 percent by weight to 55 percent by weight, and said first nitrosamine inhibitor is present in an amount of from 45 percent by weight to 95 percent by weight, the percent weights in each case being based on the total weight of said first nitrosamine inhibitor and of said second nitrosamine inhibitor.

24. The method of claim 20, wherein said granulated composition or said final blend, is subjected to tableting to form tablets.

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