Solid oral pharmaceutical compositions containing alkyl 3,4,5-trihydroxybenzoates as nitrosamine inhibitors

Abstract

The present invention provides (a) an active pharmaceutical ingredient; (b) a linear or branched C1-C 10 A solid oral pharmaceutical composition comprising a nitrosamine inhibitor containing an alkyl 3,4,5-trihydroxybenzoate; and (c) a pharmaceutically acceptable excipient, wherein at least one of the following applies: (i) the active pharmaceutical ingredient has at least one covalently bound amine group that undergoes conversion to a nitrosamine; or (ii) the solid oral pharmaceutical composition has at least one amine, other than the amine group, covalently bound to or in the active pharmaceutical ingredient that undergoes conversion to a nitrosamine. The nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamines produced in the solid oral pharmaceutical composition compared to the amount of nitrosamines produced in a comparable solid oral pharmaceutical composition without the nitrosamine inhibitor.

Description

[Technical Field]

[0001] Cross-reference to related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 443,792, filed February 7, 2023, entitled "Solid Oral Pharmaceutical Compositions Including Alkyl 3,4,5-Trihydroxybenzoate as a Nitrosamine Inhibitor," the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to an active pharmaceutical ingredient, a linear or branched C1-C 10 A solid oral pharmaceutical composition comprising a nitrosamine inhibitor comprising an alkyl 3,4,5-trihydroxybenzoate and a pharmaceutically acceptable excipient, wherein the nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamines produced in the solid oral pharmaceutical composition compared to the amount of nitrosamines produced in a comparable solid oral pharmaceutical composition without the nitrosamine inhibitor. [Background technology]

[0003] Nitrosamines may form over time in solid oral pharmaceutical compositions, such as during storage and / or transportation. Nitrosamines are considered undesirable contaminants due to their associated potential mutagenic effects. Nitrosamines are typically formed from secondary aliphatic amines, and in some cases, at a slower rate, from tertiary aliphatic amines. Sources of nitrosamines include active pharmaceutical agents that have at least one amine group covalently bound to or within them, which undergo conversion to a nitrosamine, and / or at least one amine present in the solid oral pharmaceutical composition that is not covalently bound to or within the active pharmaceutical agent, which undergoes conversion to a nitrosamine. Nitrosamine formation is typically also associated with the presence of a nitrosating agent, such as nitrite (NO₂) and / or dinitrogen trioxide (NO₂).

[0004] It would be desirable to develop new solid oral pharmaceutical compositions that have reduced levels of nitrosamine formation. It would also be desirable for such newly developed solid oral pharmaceutical compositions to contain excipients that meet regulatory requirements, including maximum daily exposure requirements. summary

[0005] In accordance with the present invention, there is provided a pharmaceutical composition comprising: (a) an active pharmaceutical ingredient; (b) a linear or branched C1-C 10 Alkyl (c) a nitrosamine inhibitor having a 3,4,5-trihydroxybenzoate; and Solid oral pharmaceutical compositions are provided having pharmaceutically acceptable excipients, wherein at least one of the following applies: (i) the active pharmaceutical ingredient has at least one covalently bonded amine group that undergoes conversion to a nitrosamine; and / or (ii) the solid oral pharmaceutical composition has at least one amine, other than the amine group, covalently bonded to / in the active pharmaceutical ingredient that undergoes conversion to a nitrosamine. The nitrosamine inhibitors are effective in reducing the amount of nitrosamines produced in the solid oral pharmaceutical composition compared to the amount of nitrosamines produced in a comparative solid oral pharmaceutical composition that does not have the nitrosamine inhibitor. It is present in at least an amount sufficient to reduce the amount of nitrosamines produced in the composition.

[0006] The features which characterize the present invention are pointed out with particularity in the claims annexed to and forming a part of this disclosure. These and other features of the present invention, the advantages of its implementation, and particular objects attained by its uses will be more fully understood from the following detailed description, which illustrates and describes non-limiting embodiments of the invention. [Brief explanation of the drawings]

[0007] [Figure 1] FIG. 1 is a graphical representation of a plot of nitroso-sertraline produced as a function of time in a comparative solid oral pharmaceutical composition and a solid oral pharmaceutical composition according to the present invention, as described in more detail in the Examples; [Figure 2] FIG. 2 is a graphical representation of plots of nitroso-sertraline produced in comparative solid oral pharmaceutical compositions manufactured intra-granularly and extra-granularly and in solid oral pharmaceutical compositions according to the present invention, as described in more detail in the Examples; [Figure 3]FIG. 3 is a graphical representation of a plot of nitroso-sertraline produced in a comparative solid oral pharmaceutical composition and a solid oral pharmaceutical composition according to the invention over a three month period at 40° C. / 75% RH, as described in more detail in the Examples; and [Figure 4] FIG. 4 is a graphical representation of a plot of nitroso-sertraline produced in a comparative solid oral pharmaceutical composition and a solid oral pharmaceutical composition according to the invention over a one-month period at 50° C. and ambient humidity, as described in more detail in the Examples.

[0008] In Figures 1 to 4, like letters and headings have the same components and / or the same meaning, as the case may be, unless otherwise stated. Summary of the Invention

[0009] As used herein, the articles "a," "an," and "the" include plural referents unless expressly and unambiguously limited to one referent.

[0010] Unless otherwise stated, all ranges or ratios disclosed herein are intended to encompass any and all values ​​and subranges or subratios subsumed therein. For example, a range or ratio of "1 to 10" is deemed to encompass any and all values ​​therebetween, inclusive of the recited end values ​​(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10), and all subranges between a minimum value of 1 and a maximum value of 10 (inclusive), i.e., all subranges or subratios beginning with a minimum value of 1 or greater and ending with a maximum value of 10 or less (e.g., but not limited to, 1 to 6.1, 3.5 to 7.8, and 5.5 to 10).

[0011] Unless otherwise indicated, as used herein, left-to-right representations of linking groups, such as divalent linking groups, encompass other suitable orientations, including, but not limited to, right-to-left orientations. For non-limiting illustrative purposes, divalent linking groups,

[0012] [ka]

[0013] or its equivalent, -C(O)O-, its right-to-left representation

[0014] [ka]

[0015] or the equivalents -O(O)C- or -OC(O)-.

[0016] Except in the examples or where otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and the like used in the specification and claims are intended to be modified in all instances by the term "about."

[0017] As used herein, "at least one" is synonymous with "one or more," regardless 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" mean any one of A, B, or C, or any combination of two or more of A, B, or C, respectively. 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] As used herein, "selected from" is synonymous with "chosen from," regardless of whether the elements are listed conjunctively or disjunctively. Furthermore, the phrases "selected from A, B, and C" and "selected from A, B, or C" mean any one of A, B, or C, or any combination of any two or more of A, B, or C, respectively. 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.

[0019] All documents referred to herein (including, but not limited to, issued patents and patent applications) are incorporated by reference in their entirety unless otherwise stated.

[0020] As used herein, the term "aliphatic group" and similar terms such as "aliphatic substituent" refer to a linear or branched aliphatic group and / or a cycloaliphatic group that is not aromatic and has at least one carbon-carbon unsaturated bond (e.g., at least one alkene bond (-C=C-) and / or at least one alkene bond (-C=C-)). "Aliphatic groups" refers to alicyclic groups that optionally contain a cycloaliphatic bond (-C≡C-). In some embodiments, straight chain or branched aliphatic groups herein contain 1 to 10 carbon atoms, and alicyclic groups contain 3 to 10 carbon atoms.

[0021] As used herein, references to a "straight or branched" group (such as a straight or branched alkyl) are intended to include, in this specification, a methylene group or a methyl group; a straight chain C-C 10 Straight-chain groups such as alkyl groups; and branched C3-C 10 Suitable branched groups such as alkyl groups are intended to include:

[0022] As used herein, the term "alkyl" refers to a linear or branched, cyclic or acyclic C-C 10A straight chain or branched alkyl is a C1-C alkyl, such as a C1-C5 alkyl, such as a C2-C5 alkyl, such as a C2-C4 alkyl. 10 The various alkyl groups of the present invention can be selected from, but are not limited to, the examples of alkyl groups further described herein. The alkyl group can include a "cycloalkyl" group. As used herein, the term "cycloalkyl" refers to a group that is suitably cyclic, such as C3-C6. 10 Cycloalkyl groups (including, but not limited to, cyclic C3-C8 alkyl or cyclic C5-C7 alkyl) are also included.

[0023] 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.

[0024] As used herein, the term "nitrosamine" and similar terms such as "nitrosamines," "nitrosamine group," and "nitrosamine groups" encompass and are interchangeable with "N-nitrosamine," "N-nitrosamines," "N-nitrosamine group," and "N-nitrosamine groups."

[0025] According to some embodiments of the present invention, the nitrosamines whose production is reduced by the solid oral pharmaceutical composition of the present invention are represented by the following formula (A):

[0026] [ka]

[0027] With respect to formula (A), R 1 and R 2 are each independently an aliphatic group, e.g., a straight-chain or or branched aliphatic groups, e.g., linear or branched C-C 10 alkyl groups such as alkyl groups, or C3-C 10 In some embodiments, R is an alicyclic group such as a cycloalkyl group. 1 and R 2 together form a cyclic group, for example, an alicyclic group having 2 to 10 carbon atoms, such as 2 to 10 methylene groups (—CH—). According to some further embodiments: R 1 is a straight chain or branched C1-C 10 Alkyl group or C3-C 10 is a cycloalkyl group; R 2 is an active pharmaceutical ingredient in which the nitrosamine group is a moiety of the active pharmaceutical ingredient, which in some embodiments is described as an N-nitrosamine active pharmaceutical ingredient. According to some still further embodiments, R 1 and R 2 together form a cyclic group, e.g., an alicyclic group having 2 to 10 carbon atoms, such as 2 to 10 methylene groups (—CH—), which ring is fused and / or bonded (e.g., by a single bond) to at least one other ring (not shown) (e.g., an aliphatic and / or aromatic ring) of the active pharmaceutical ingredient, which in some embodiments is described as an N-nitrosamine active pharmaceutical ingredient.

[0028] The solid oral pharmaceutical compositions of the present invention contain an active pharmaceutical ingredient. In some embodiments, the active pharmaceutical ingredient comprises at least one covalently bonded amine group that undergoes conversion to a nitrosamine. In some embodiments, the covalently bonded amine groups of the active pharmaceutical ingredient are each independently a secondary aliphatic amine. In 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):

[0029] [ka]

[0030] With respect to formula (B), R 3 is an aliphatic group, for example a linear or branched aliphatic group, for example a linear or branched C-C 10 alkyl groups such as alkyl groups, or C3-C 10 and alicyclic groups such as cycloalkyl groups. The amine group represented by formula (B) is covalently attached to and extends from the active pharmaceutical ingredient.

[0031] [ka]

[0032] With respect to formula (C), ring A is C3-C 10 An aliphatic ring, such as a cycloalkyl ring, is typically an aliphatic ring that is fused and / or bonded (e.g., by a single bond) to at least one other ring (not shown) (e.g., an aliphatic ring and / or an aromatic ring) of the active pharmaceutical ingredient.

[0033] In some embodiments, the solid oral pharmaceutical composition contains at least one amine, other than the covalently bonded amine of the active pharmaceutical ingredient, that has undergone conversion to a nitrosamine, referred to herein and in some embodiments as a free amine. The free amine of the solid oral pharmaceutical composition, in some embodiments, is present in / with the pharmaceutically acceptable excipient and / or the active pharmaceutical ingredient. In some embodiments, the free amine is an aliphatic amine, such as a linear or branched aliphatic amine and / or a cycloaliphatic amine. In some further embodiments, the free amine is a secondary aliphatic amine. In some embodiments, the free amine is represented by formula (D):

[0034] [ka]

[0035] With respect to formula (D), R 4 and R 5 are each independently an aliphatic group, for example, a linear or branched aliphatic group, for example, a linear or branched C-C 10 alkyl groups such as alkyl groups, or C3-C 10 In some embodiments, R is an alicyclic group such as a cycloalkyl group. 4 and R 5 together form a cyclic group, for example an alicyclic group having 2 to 10 carbon atoms, such as a methylene group (-CH2-).

[0036] The active pharmaceutical ingredient of the solid oral pharmaceutical composition of the present invention comprises a synthetic and / or natural active pharmaceutical ingredient and / or a pharmaceutically acceptable salt thereof, including, but not limited to, an HCl salt thereof. Common types of active pharmaceutical ingredients include, but are not limited to: analgesics; hypertensives, such as angiotensin II receptor blockers (ARBs) (e.g., sartans such as azilsartan, candesartan, irbesartan, olmesartan, losartan, valsartan, telmisartan, and eprosartan); further hypertensives, such as beta-blockers (e.g., propranolol, sotalol, acebutolol, metoprolol, atenolol, and labetolol); histamine H2 receptor antagonists (or histamine-2 blockers) (e.g., cimetidine, ranitidine, nizatidine, and famotidine); antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) (e.g., sertraline, citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, and vortioxetine).

[0037] In some embodiments, the active pharmaceutical ingredient comprises at least one of an angiotensin II receptor blocker, a histamine H2 receptor antagonist, a selective serotonin reuptake inhibitor, and / or a pharmaceutically acceptable salt thereof.

[0038] In some aspects of the invention, the active pharmaceutical ingredient comprises at least one covalently bound amine group that undergoes conversion to a nitrosamine.

[0039] According to some further embodiments, the active pharmaceutical ingredient comprises at least one of sertraline or a pharmaceutically acceptable salt of sertraline.

[0040] Sertraline can be represented by the following formula (Ia):

[0041] [ka]

[0042] The chemical name of sertraline, represented by formula (Ia), is (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine.

[0043] Formula (Ib) below is a representative structure of N-nitrososertraline.

[0044] [ka]

[0045] The chemical name of N-nitrososertraline, represented by formula (Ib), is N-((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-N-methylnitrousamide.

[0046] The active pharmaceutical ingredient is present in the solid oral pharmaceutical composition in any suitable amount, e.g., a pharmaceutically effective amount. In some embodiments, the active pharmaceutical ingredient is present in the solid oral pharmaceutical composition in an amount of 10 to 60 weight percent, 20 to 50 weight percent, or 30 to 40 weight percent, in each case the weight percentage is based on the total weight of the solid oral pharmaceutical composition.

[0047] The nitrosamine inhibitor of the solid oral pharmaceutical composition of the present invention comprises at least one alkyl 3,4,5-trihydroxybenzoate, such as a linear or branched C1-C 10In some embodiments, the alkyl 3,4,5-trihydroxybenzoate may be represented by the following formula (II):

[0048] [ka]

[0049] With respect to formula (II), R 6 is a straight chain or branched C1-C 10 Alkyl groups, e.g., linear or branched In some embodiments of the present invention, R in formula (II) is a branched C2-C5 alkyl group. 6 is an n-propyl or iso-propyl group.

[0050] The alkyl 3,4,5-trihydroxybenzoate is an alkyl gallate, e.g., a linear or branched C1-C gallate. 10 Alkyl or gallate may also be described as straight chain or branched C2-C5 alkyl.

[0051] In some aspects of the invention, the nitrosamine inhibitor comprises n-propyl 3,4,5-trihydroxybenzoate (or n-propyl gallate).

[0052] According to some embodiments, the nitrosamine inhibitor of the solid oral pharmaceutical composition of the present invention comprises at least one alkyl 3,4,5-trihydroxybenzoate, such as a linear or branched C1-C 10 According to some embodiments, the nitrosamine inhibitor of the solid oral pharmaceutical composition of the present invention consists essentially of alkyl 3,4,5-trihydroxybenzoate or linear or branched C2-C5 alkyl 3,4,5-trihydroxybenzoate. 10It consists of alkyl 3,4,5-trihydroxybenzoate or linear or branched C2-C5 alkyl 3,4,5-trihydroxybenzoate.

[0053] In accordance with the present invention, the nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamines produced in the solid oral pharmaceutical composition compared to the amount of nitrosamines produced in a comparable solid oral pharmaceutical composition without the nitrosamine inhibitor.

[0054] As used herein, the phrase "comparative solid oral pharmaceutical composition without the nitrosamine inhibitor" refers to a comparative composition that contains the same active pharmaceutical ingredient, the same pharmaceutically acceptable excipients in the same relative amounts as a solid oral pharmaceutical composition according to the present invention, does not contain the nitrosamine inhibitor, and is manufactured and evaluated under the same conditions as a solid oral pharmaceutical composition according to the present invention.

[0055] The amount of nitrosamines produced in the inventive and comparative solid oral pharmaceutical compositions can be measured by art-recognized analytical methods. In some embodiments, the amount of nitrosamines produced in the inventive and comparative solid oral pharmaceutical compositions is measured using liquid chromatography-mass spectrometry (LC-MS).

[0056] According to some embodiments, the initial (or to) amount (or level) of nitrosamines is measured immediately after preparation of the inventive and comparative solid oral pharmaceutical compositions. The inventive and comparative solid oral pharmaceutical compositions are then typically subjected to accelerated testing under controlled conditions of elevated temperature, e.g., 50°C or 70°C, and elevated relative humidity (RH), e.g., 70% RH or 75% RH. Test samples are typically removed and analyzed over a period of time, such as several days (e.g., 3, 6, and / or 30 days), to determine the amount of nitrosamines produced.

[0057] According to some embodiments, the reduction in the amount of nitrosamines produced over a period of time in a solid oral pharmaceutical composition of the present invention is characterized as a percent reduction relative to the amount of nitrosamines produced in a comparative solid oral pharmaceutical composition, and is calculated using the following equation -(1):

[0058]

number

[0059] Regarding equation (1), "t x The comparative amount of nitrosamines produced in the comparative solid oral pharmaceutical composition is x Furthermore, with respect to equation (1), "t x The present invention's amount of nitrosamines produced in the solid oral pharmaceutical composition according to the present invention is x This refers to the amount of nitrosamine produced at a given time point.

[0060] In some aspects of the invention, the amount of nitrosamines produced in a solid oral pharmaceutical composition according to the 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, compared to the amount of nitrosamines produced in a comparable solid oral pharmaceutical composition without the nitrosamine inhibitor under the same testing and environmental conditions and for the same period of time.

[0061] In some further aspects of the invention, the amount of nitrosamines produced in a solid oral pharmaceutical composition according to the invention is reduced by at least 75 percent by weight compared to the amount of nitrosamines produced in the comparable solid oral pharmaceutical composition without the nitrosamine inhibitor under the same testing and environmental conditions and for the same period of time.

[0062] In some further aspects of the invention, the amount of nitrosamines produced in a solid oral pharmaceutical composition according to the 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, compared to the amount of nitrosamines produced in the comparable solid oral pharmaceutical composition without the nitrosamine inhibitor under the same testing and environmental conditions and for the same period of time.

[0063] In some further aspects of the invention, the amount of nitrosamines produced in a solid oral pharmaceutical composition according to the invention is reduced by 92 to 100 weight percent, or 100 weight percent, or by 93 to 98 weight percent, or 98 weight percent, compared to the amount of nitrosamines produced in the comparative solid oral pharmaceutical composition without the nitrosamine inhibitor under the same testing and environmental conditions and for the same period of time.

[0064] The nitrosamine inhibitor may be present in a solid oral pharmaceutical composition according to the present invention in any amount, provided that such amount is at least sufficient to reduce the amount of nitrosamines produced in the solid oral pharmaceutical composition compared to the amount of nitrosamines produced in a comparable solid oral pharmaceutical composition lacking the nitrosamine inhibitor.

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

[0066] In some further embodiments, the nitrosamine inhibitor is present in an amount of 0.05 to 4 weight percent, or 0.05 to 3 weight percent, or 0.05 to 2.5 weight percent based on the weight of the active pharmaceutical ingredient, including the amounts set forth below. It is present in amounts of

[0067] In some still further aspects of the invention, the nitrosamine inhibitor is present in an amount of 0.5 to 3 weight percent, or 0.5 to 2.5 weight percent, based on the weight of the active pharmaceutical ingredient, including the amounts set forth below.

[0068] The nitrosamine inhibitor, in some aspects, is introduced into the solid oral pharmaceutical composition by at least one of an intra-granular addition method and / or an extra-granular addition method. Any art-recognized intra-granular addition method and any art-recognized extra-granular addition method can be used.

[0069] The solid oral pharmaceutical composition of the present invention contains at least one pharmaceutically acceptable excipient. Types 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 starch, polymeric sugars, sugar alcohols, and cellulose derivatives; disintegrants such as starch, cellulose derivatives, alginates, and crospovidone (cross-linked polyvinylpyrrolidone); lubricants such as silicon anhydride and other silica compounds; and lubricants such as stearic acid and salts of stearic acid.

[0070] In some aspects, the 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, cross-linked polyvinylpyrrolidone, silica, titanium dioxide, gelatin, or a triglyceride.

[0071] The pharmaceutically acceptable excipient can be present in any suitable amount in the solid oral pharmaceutical composition of the present invention, hi some embodiments, the pharmaceutically acceptable excipient is present in an amount of 0.05 to 99.5 weight percent, or 5 to 95 weight percent, or 10 to 90 weight percent, in each case the weight percentage is based on the total weight of the solid oral pharmaceutical composition.

[0072] The solid oral pharmaceutical composition of the present invention can be in any suitable form. In 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 composition of the present invention can be formed into tablets, capsules, and / or free-flowing granules according to art-recognized methods.

[0073] The present invention may be further characterized by one or more of the following non-limiting terms.

[0074] Item 1: (a) Active pharmaceutical ingredients; (b) Linear or branched C1-C 10 Nitrosamine inhibitors having alkyl 3,4,5-trihydroxybenzoates; and (c) pharmaceutically acceptable excipients; 1. A solid oral pharmaceutical composition comprising: At least one of (i) or (ii) below: (i) the active pharmaceutical ingredient has at least one covalently bound amine group that undergoes conversion to a nitrosamine; or (ii) the solid oral pharmaceutical composition has at least one amine that undergoes conversion to a nitrosamine; A solid oral pharmaceutical composition, wherein the nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamines produced in the solid oral pharmaceutical composition compared to the amount of nitrosamines produced in a comparable solid oral pharmaceutical composition not having the nitrosamine inhibitor.

[0075] Item 2: The solid oral pharmaceutical composition of Item 1, wherein the active pharmaceutical ingredient comprises at least one of an angiotensin II receptor blocker, a beta-blocker, a histamine H2 receptor antagonist, a selective serotonin reuptake inhibitor, or one or more pharmaceutically acceptable salts thereof.

[0076] Item 3: The solid oral pharmaceutical composition of Item 1 or 2, wherein the active pharmaceutical ingredient has at least one covalently bound amine group that undergoes conversion to a nitrosamine.

[0077] Item 4: The solid oral pharmaceutical composition of any one of Items 1 to 3, wherein the active pharmaceutical ingredient comprises at least one of sertraline or a pharmaceutically acceptable salt of sertraline.

[0078] Item 5: The solid oral pharmaceutical composition of any one of Items 1 to 4, wherein the nitrosamine inhibitor comprises a linear or branched C2-C5 alkyl 3,4,5-trihydroxybenzoate.

[0079] Item 6: The solid oral pharmaceutical composition of any one of Items 1 to 5, wherein the nitrosamine inhibitor comprises n-propyl 3,4,5-trihydroxybenzoate.

[0080] Item 7: The solid oral pharmaceutical composition of any one of Items 1 to 6, wherein the amount of the nitrosamine inhibitor is at least 0.05 weight percent based on the weight of the active pharmaceutical ingredient.

[0081] Item 8: The solid oral pharmaceutical composition of any one of Items 1 to 7, wherein the amount of the nitrosamine inhibitor is 0.05 to 4 weight percent, or 0.05 to 3 weight percent, or 0.05 to 2.5 weight percent, relative to the weight of the active pharmaceutical ingredient.

[0082] Item 9: The solid oral pharmaceutical composition of any one of Items 1 to 8, wherein the amount of the nitrosamine inhibitor is 0.5 to 3 weight percent, or 0.5 to 2.5 weight percent, relative to the weight of the active pharmaceutical ingredient.

[0083] Item 10: The solid oral pharmaceutical composition of any one of Items 1 to 8, wherein the amount of nitrosamines generated in the solid oral pharmaceutical composition 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, compared to the amount of nitrosamines generated in the comparative solid oral pharmaceutical composition not having the nitrosamine inhibitor.

[0084] Item 11: The solid oral pharmaceutical composition of any one of Items 1 to 10, wherein the amount of nitrosamines produced in the solid oral pharmaceutical composition is reduced by at least 75 percent by weight compared to the amount of nitrosamines produced in the comparative solid oral pharmaceutical composition not having the nitrosamine inhibitor.

[0085] Item 12: The solid oral pharmaceutical composition of any of Items 1 to 11, wherein the amount of nitrosamines generated in the solid oral pharmaceutical composition is reduced by at least 80 percent by weight compared to the amount of nitrosamines generated in the comparative solid oral pharmaceutical composition not containing the nitrosamine inhibitor.

[0086] Item 13: The solid oral pharmaceutical composition of any of Items 1 to 12, wherein the amount of nitrosamines generated in the solid oral pharmaceutical composition is reduced by at least 80 weight percent, or at least 85 weight percent, or at least 90 weight percent, or at least 95 weight percent compared to the amount of nitrosamines generated in the comparative solid oral pharmaceutical composition not having the nitrosamine inhibitor.

[0087] Item 14: The amount of nitrosamines generated in the solid oral pharmaceutical composition is reduced by 92 to less than 100 weight percent, or 100 weight percent, or by 93 to less than 98 weight percent, or 98 weight percent, compared to the amount of nitrosamines generated in the comparative solid oral pharmaceutical composition not having the nitrosamine inhibitor.

[0088] Item 15: The solid oral pharmaceutical composition of any one of Items 1 to 14, wherein the nitrosamine inhibitor is introduced into the solid oral pharmaceutical composition by at least one of an intra-granular method or an extra-granular method.

[0089] Item 16: The solid oral pharmaceutical composition of any one of Items 1 to 15, wherein the pharmaceutically acceptable excipient comprises at least one of a diluent, a binder, a compression aid, a granulating agent, a disintegrant, a glidant, or a lubricant.

[0090] Item 17: The solid oral pharmaceutical composition of any one of Items 1 to 16, wherein the 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, cross-linked polyvinylpyrrolidone, silica, titanium dioxide, gelatin, and triglycerides.

[0091] Item 18: The solid oral pharmaceutical composition of any one of Items 1 to 17, wherein the solid oral pharmaceutical composition is in a form selected from tablets, capsules, and free-flowing granules.

[0092] The present invention is more particularly described in the following examples, which are intended to be illustrative only, and numerous modifications and variations thereof will be apparent to those skilled in the art. Unless otherwise specified, all parts and percentages are by weight. [Example]

[0093] Part 1 of the Examples below describes the preparation and evaluation of comparative solid oral pharmaceutical compositions and compositions of the invention containing different levels of n-propyl 3,4,5-trihydroxybenzoate as the nitrosamine inhibitor. Part 2 of the Examples below describes the preparation and evaluation of comparative solid oral pharmaceutical compositions and compositions of the invention with intragranular and extragranular addition of n-propyl 3,4,5-trihydroxybenzoate. Part 3 of the Examples below describes the preparation and evaluation of comparative solid oral pharmaceutical compositions and compositions of the invention evaluated at 40°C for 3 months and at 50°C for 1 month.

[0094] Part 1 Solid oral pharmaceutical compositions according to the present invention (Examples (Ex) 1-4) were prepared by dissolving n-propyl 3,4,5-trihydroxybenzoate in ethanol, adding it to microcrystalline cellulose (AVICEL PH 102, commercially available from DuPont) (MCC), and then drying it in an oven at 40°C for 4 hours to produce n-propyl 3,4,5-trihydroxybenzoate-loaded MCC. The n-propyl 3,4,5-trihydroxybenzoate-loaded MCC was prepared by mixing sertraline and microcrystalline cellulose (AVICEL PH 102) in appropriate amounts to achieve n-propyl 3,4,5-trihydroxybenzoate levels of 0.1, 0.5, 1, and 2 weight percent (the weight percentages in each case being based on the weight of sertraline). 102). Comparative Example (CE-1) was prepared according to Exs. 1-4, but without the addition of n-propyl 3,4,5-trihydroxybenzoate. Comparative (CE-1) and inventive solid oral pharmaceutical compositions (Exs. 1-4) contained sertraline and microcrystalline cellulose in a weight ratio of 1.25:1; were granulated and tableted using the same method and under the same conditions to prepare test samples; and were evaluated by liquid chromatography-mass spectrometry (LC-MS) to determine the initial (t0) amount of nitroso-sertraline. The comparative and inventive test samples were then placed under ambient RH and 70°C conditions. Samples were removed and evaluated on days 3 and 6, and the amount of nitroso-sertraline produced was measured by LC-MS analysis. The results are summarized in Table 1 below and graphically depicted in Figure 1 of the drawings. In Figure 1, the term "PG" refers to n-propyl gallate (i.e., n-propyl 3,4,5-trihydroxybenzoate).

[0095] [Table 1]

[0096] With reference to Table 1, on day 3, the solid oral pharmaceutical compositions of Inventive Examples 1-4 exhibited the following percent (weight) reductions in the production of nitroso-sertraline relative to the amount / weight of nitrosamines produced in Comparative Example CE-1: 39.5%, 71.6%, 84.1%, and 95.8%, respectively. Further with reference to Table 1, on day 6, the solid oral pharmaceutical compositions of Inventive Examples 1-4 exhibited the following percent (weight) reductions in the production of nitroso-sertraline relative to the amount / weight of nitrosamines produced in CE-1: 25.6%, 78.8%, 82.7%, and 95.4%, respectively.

[0097] Part 2 In the comparative (CE-1) and inventive (Ex 5 and 6) examples below, the weight ratio of sertraline to microcrystalline cellulose (AVICEL PH 102, commercially available from DuPont) (MCC) was 1.25:1. Inventive Example 6 (Ex-6) corresponds to Ex-3 in Part-1 and was prepared as described therein. The composition of Inventive Example 5 was n- Propyl 3,4,5-trihydroxybenzoate was dissolved in ethanol, water was added (qs), and then intragranularly added (by spray application) to hydroxypropyl cellulose (HPC) and sertraline to provide 1 weight percent n-propyl 3,4,5-trihydroxybenzoate based on the weight of sertraline. (MCC was added later after high-shear granulation and fluid-bed drying.) Comparative Example (CE-1) did not contain n-propyl 3,4,5-trihydroxybenzoate and was the same as Comparative Example (CE-1) in Part 1. Comparative Example (CE-1) and inventive test samples (Ex5 and 6) were evaluated by LC-MS to determine the initial (t0) amount of nitroso-sertraline. The comparative and inventive test samples were then subjected to ambient RH and 70°C conditions. Samples were removed and evaluated on days 3 and 6, and the amount of nitroso-sertraline produced was measured by LC-MS analysis. The results are summarized in Table 2 below and graphically depicted in Figure 2 of the drawings. In Figure 2, the term "PG" means n-propyl gallate (i.e., n-propyl 3,4,5-trihydroxybenzoate). In Figure 2: the term "Extra-G" means that n-propyl 3,4,5-trihydroxybenzoate was added extragranularly; the term "Intra-G" means that n-propyl 3,4,5-trihydroxybenzoate was added intragranularly.

[0098] [Table 2]

[0099] With reference to Table 2, on day 3, the solid oral pharmaceutical compositions of Inventive Examples 5 and 6 exhibited the following percent (weight) reduction in nitroso-sertraline formation relative to the amount / weight of nitrosamines formed in Comparative Example CE-1: 93.3% and 84.0%, respectively. Further with reference to Table 2, on day 6, the solid oral pharmaceutical compositions of Inventive Examples 5 and 6 exhibited the following percent (weight) reduction in nitroso-sertraline formation relative to the amount / weight of nitrosamines formed in CE-1: 92.2% and 82.7%, respectively. The results summarized in Table 2 and graphically depicted in Figure 2 demonstrate that solid oral pharmaceutical compositions according to the present invention produce similarly desirable results with respect to the reduction in nitroso-sertraline formation, regardless of whether n-propyl 3,4,5-trihydroxybenzoate is incorporated intragranularly or extragranularly into the composition.

[0100] Part-3 In this Part-3: a comparative solid oral pharmaceutical composition (CE-1) containing no n-propyl 3,4,5-trihydroxybenzoate; and a solid oral pharmaceutical composition of the present invention (Ex-7) containing 1 weight percent n-propyl 3,4,5-trihydroxybenzoate based on the weight of sertraline were prepared according to the descriptions for CE-1 and Ex-3 in Part-1, respectively.

[0101] The comparative (CE-1) and inventive (Ex-7) solid oral pharmaceutical compositions were evaluated by LC-MS. The initial (t0) amount of nitroso-sertraline was determined by LC-MS analysis. The comparative (CE-1) and inventive (Ex-7) test samples were then placed under conditions of 75% RH and 40°C. Samples were removed and evaluated at 0.5, 1, 2, and 3 months, and the amount of nitroso-sertraline produced was measured by LC-MS analysis. The results are summarized in Table 3 below and graphically represented in the bar graph of Figure 3 of the drawings. In Figure 3, the term "PG" refers to n-propyl gallate (i.e., n-propyl 3,4,5-trihydroxybenzoate); the term "nitroso-Sert" refers to nitroso-sertraline.

[0102] [Table 3]

[0103] With reference to Table 3, the solid oral pharmaceutical composition of the present invention (Ex-7) showed the following percent (weight) reduction in the production of nitroso-sertraline relative to the amount / weight of nitrosamines produced in Comparative Example CE-1: 95.1% at 0.5 months; 93.7% at 1 month; 91.7% at 2 months; and 93.7% at 3 months.

[0104] The comparative (CE-1) and inventive (Ex-7) solid oral pharmaceutical compositions were evaluated by LC-MS to determine the initial (t0) amount of nitroso-sertraline. The comparative (CE-1) and inventive (Ex-7) test samples were then placed under ambient RH and 50°C conditions. Samples were removed and evaluated at 0.5 and 1 month, and the amount of nitroso-sertraline produced was measured by LC-MS analysis. The results are summarized in Table 4 below and graphically represented in the bar graph of Figure 4 of the drawings. In Figure 4, the term "PG" refers to n-propyl gallate (i.e., n-propyl 3,4,5-trihydroxybenzoate); the term "nitroso-Sert" refers to nitroso-sertraline.

[0105] [Table 4]

[0106] With reference to Table 4, the solid oral pharmaceutical composition of the present invention (Ex-7) showed the following percent (weight) reduction in the production of nitroso-sertraline relative to the amount / weight of nitrosamines produced in Comparative Example CE-1: 94.2% at 0.5 months; 93.0% at 1 month.

[0107] The present invention has been described with reference to specific details of particular embodiments thereof. Such details should not be considered limitations on the scope of the invention except to the extent that they are included in the appended claims. It is not intended to be.

Claims

1. (a) an active pharmaceutical ingredient; (b) Linear or branched C １ -C １０ Nitrosamine inhibitors having alkyl 3,4,5-trihydroxybenzoates; and (c) a pharmaceutically acceptable excipient; 1. A solid oral pharmaceutical composition comprising: At least one of (i) or (ii) below: (i) the active pharmaceutical ingredient has at least one covalently bonded amine group that undergoes conversion to a nitrosamine; or (ii) the solid oral pharmaceutical composition has at least one amine that undergoes conversion to a nitrosamine; A solid oral pharmaceutical composition, wherein the nitrosamine inhibitor is present in an amount at least sufficient to reduce the amount of nitrosamines produced in the solid oral pharmaceutical composition compared to the amount of nitrosamines produced in a comparable solid oral pharmaceutical composition without the nitrosamine inhibitor.

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

3. 10. The solid oral pharmaceutical composition of claim 1, wherein the active pharmaceutical ingredient has at least one covalently bound amine group that undergoes conversion to a nitrosamine.

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

5. The nitrosamine inhibitor is a linear or branched C ２ -C ５ The solid oral pharmaceutical composition of claim 1 having alkyl 3,4,5-trihydroxybenzoate.

6. 10. The solid oral pharmaceutical composition of claim 1, wherein the nitrosamine inhibitor comprises n-propyl 3,4,5-trihydroxybenzoate.

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

8. 8. The solid oral pharmaceutical composition of claim 7, wherein said amount of said nitrosamine inhibitor is from 0.05 weight percent to 4 weight percent based on the weight of said active pharmaceutical ingredient.

9. 9. The solid oral pharmaceutical composition of claim 8, wherein said amount of said nitrosamine inhibitor is from 0.5 weight percent to 3 weight percent based on the weight of said active pharmaceutical ingredient.

10. 2. The solid oral pharmaceutical composition of claim 1, wherein the amount of nitrosamines produced in the solid oral pharmaceutical composition is reduced by at least 50 percent by weight compared to the amount of nitrosamines produced in the comparative solid oral pharmaceutical composition without the nitrosamine inhibitor.

11. 2. The solid oral pharmaceutical composition of claim 1, wherein the amount of nitrosamines produced in the solid oral pharmaceutical composition is reduced by at least 75 percent by weight compared to the amount of nitrosamines produced in the comparative solid oral pharmaceutical composition not having the nitrosamine inhibitor.

12. 2. The solid oral pharmaceutical composition of claim 1, wherein the amount of nitrosamines produced in the solid oral pharmaceutical composition is reduced by at least 80 percent by weight compared to the amount of nitrosamines produced in the comparative solid oral pharmaceutical composition not having the nitrosamine inhibitor.

13. 10. The solid oral pharmaceutical composition of claim 1, wherein the nitrosamine inhibitor is incorporated into the solid oral pharmaceutical composition by at least one of an intragranular method or an extragranular method.

14. 10. The solid oral pharmaceutical composition of claim 1, wherein the 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, cross-linked polyvinylpyrrolidone, silica, titanium dioxide, gelatin, or triglycerides.

15. 10. The solid oral pharmaceutical composition of claim 1, wherein the solid oral pharmaceutical composition is in a form selected from tablets, capsules, and free-flowing granules.

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