Pharmaceutical composition containing cyticine

Abstract

The present invention relates to a stabilized composition with significantly improved shelf-life stability. More specifically, the present invention relates to a stable liquid aqueous pharmaceutical composition comprising cyticine or a pharmaceutically acceptable salt thereof, at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds. The present invention also relates to the use of at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds for stabilizing a liquid aqueous pharmaceutical composition comprising cyticine.

Description

[Technical Field]

[0001] The present invention relates to a stabilized composition with significantly improved shelf-life stability. More specifically, the present invention relates to a stabilized liquid aqueous pharmaceutical composition comprising cyticine or a pharmaceutically acceptable salt thereof and at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds. [Background technology]

[0002] Smoking is the most widespread and serious addiction, a leading cause of death from cancer, as well as cardiovascular and lung diseases, with over 8 million people dying worldwide each year from tobacco-related illnesses. Quitting smoking reduces the risk of premature death associated with continued smoking by approximately 90%. However, quitting smoking is extremely difficult for several reasons, including the complexity of nicotine addiction.

[0003] Nicotine is the primary psychoactive component of tobacco that causes addiction. Nicotine addiction is associated with repeated nicotine intake from tobacco, which leads to stimulation of the brain's nAChRs, as well as the release of dopamine and other neurotransmitters from the nucleus accumbens, ventral tegmental area (VTA), and prefrontal cortex regions.

[0004] In the United States, the smoking cessation aids currently approved by the Food and Drug Administration are varenicline and bupropion. Like varenicline, its synthetic derivative, cyticine, acts as a selective partial agonist at α4β2 and binds to nicotinic acetylcholine receptors with higher affinity than nicotine.

[0005] Cyticine, also known as baptitoxin, cyticinecrine, or sophorine, is one of the oldest drugs approved and used for smoking cessation in Central and Eastern Europe. Products containing cyticine are available in Central and Eastern European countries such as Russia and Poland, as well as in Western Asia and Canada.

[0006] Cyticine is a plant alkaloid primarily derived from leguminous plants (particularly the seeds of Laburnum anagyroides). It is a nicotinic acetylcholine receptor (nAChR) partial agonist that has been successfully used in smoking cessation therapy.

[0007] The IUPAC name for cyticine is (1R,5S)-1,2,3,4,5,6-hexahydro1,5-methano-8H-pyrido[1,2a][1,5]diazosin-8-one, and its structure is given by the following formula (I).

[0008] [ka]

[0009] It has the following characteristics. Cytisine is currently available in tablet (Tabex®, Recigar®) and capsule (Desmoxan) form, and involves a complex dosing regimen that requires initially one dose of cytisine (tablet or capsule: 1.5 mg) every two hours (six doses per day), and then gradually decreasing to two doses per day over 25 days.

[0010] This complex dosing regimen necessitates the development of more convenient methods for the oral administration of cyticine, particularly in the form of liquid, mist, spray, or aerosol.

[0011] International Patent Application No. 2014201735 discloses an oral nicotine-substituted cyticine spray liquid composition containing the following components by mass percentage per liter of oral spray liquid: tobacco 0.1-10%, cocoa extract 0.3-15%, cyticine 0.1-0.9%, TWEEN® 80 0.1-0.5%, and primer 75-90%.

[0012] Russian Patent No. 2593585(C1) discloses an intranasal solution containing cyticine, water, sodium hydrogen phosphate and sodium dihydrogen phosphate as acidity modifiers, EDTA, methylparaben (paraben M) and propylparaben (paraben P) as preservatives, sodium chloride as a salt, polysorbate as a cosolvent, and citric acid as an antioxidant.

[0013] International Publication No. 2021115977(A1) of an international patent application discloses a liquid pharmaceutical composition comprising cyticine, water, and one or more pharmaceutical excipients, the composition comprising at least one inorganic pH adjuster selected from the group consisting of inorganic acids, inorganic buffers, and inorganic salts, and having a pH value in the range of 3.0 to 7.5.

[0014] European Patent Application Publication No. 3967298(A1) discloses an aerosol composition comprising a hydrophilic nonionic emulsifier of the group cyticine, copolymer, or polymer, at least one alcohol, water, and one or more excipients, the composition having a pH of 7 to 10.

[0015] Polish Patent Application No. 416496 discloses a solution for inhalation and / or spraying using an atomizer and / or vaporizer used in electronic cigarettes. The solution contains a dose of 0.66% cyticine and / or 0.02% nicotine up to the maximum value necessary to maintain a liquid unsaturated solution in a thermodynamic room-temperature thermal comfort state at hygroscopic equilibrium, and the maximum concentration of cyticine and / or nicotine under these conditions does not exceed 99.99%.

[0016] However, the inventors of the present invention have found several drawbacks to liquid compositions containing cyticine and intended to be administered as liquids, mists, sprays, or aerosols. Most notably, they have found that N-nitrosocyticine impurities in the liquid compositions may be present in amounts exceeding their lowest possible acceptable intake (AI) limit, as well as other forms of degradation, such as chemical degradation, thermal degradation, and microbiological degradation, which are most likely to occur during the formulation stage or throughout their shelf life.

[0017] Nitrosamine impurities, even in trace amounts, are highly toxic and mutagenic, potentially damaging DNA and subsequently increasing the risk of cancer. Drug manufacturers have an obligation to ensure the quality, safety, and efficacy of their pharmaceuticals, and therefore should take appropriate precautions to reduce the risk of nitrosamine presence during manufacturing, storage, and throughout the entire lifecycle of the drug. According to currently available guidelines, MAHs should ensure adequate control of nitrosamine presence and keep their levels as low as possible to protect patients from the adverse effects of these mutagenic compounds.

[0018] The number of drugs being withdrawn from the market or recalled due to high levels of nitrosamine impurities is increasing. Some nitrosamines are classified as potentially carcinogenic or likely carcinogenic in humans. One such incident involved varenicline, a smoking cessation aid that Pfizer recalled from the U.S. market in 2021 because it may have contained N-nitroso-varenicline impurities at levels exceeding those permitted by the U.S. Food and Drug Administration.

[0019] The presence of nitrosamine impurities in commercially available pharmaceuticals is becoming a significant concern for the pharmaceutical industry, in accordance with regulatory guidelines on identification, acceptable limits, and reduction strategies to reduce them to below acceptable levels. There are several mechanisms by which nitrosamine impurities can form. According to the publicly available CHMP Article 5(3) View and Question-and-Answer document EMA / 409815 / 2020, there are several underlying factors that contribute to the formation of N-nitrosamines in pharmaceuticals. Some of these factors include: · The reaction of nitrosatable nitrogen functional groups in APIs or their impurities / degradants with nitrosating agents present in the final product components during formulation or storage. Several examples have been reported indicating that amine functional groups are vulnerable to nitrosation and the formation of corresponding N-nitroso impurities (i.e., NO-APIs). Secondary amines seem to be particularly vulnerable to this reaction, although some observations have also been made in the case of tertiary amines. Labile amines can also be formed by degradation (e.g., hydrolysis) during formulation or storage. · Oxidation of hydrazine or other amine-containing functional groups present in the active substance or their impurities / degradants (e.g., derived from hydrazones and hydrazides) during either the active substance manufacturing process or storage. This root cause has also been observed during the manufacture and storage of final products containing such functional groups. Potential oxidizing agents include oxygen and peroxides (impurities commonly found in some excipients).

[0020] The inventors have found that cytisine decomposes during the formulation and / or storage of liquid aqueous compositions because it contains an aliphatic secondary amine group that decomposes via various processes including oxidative degradation and / or interaction with other components (including reactions with nitrite impurities in excipients that can form nitrosating agents under specific conditions and react with labile secondary amines to form N-nitrosocytisine impurity (II) that exceeds its lowest recommended acceptable intake (AI) limit value, but not limited to this).

[0021]

Chemical formula

[0022] Therefore, it is necessary to develop a stable pharmaceutical composition containing cytisine or its pharmaceutically acceptable salt, which has an improved storage life and a significantly reduced susceptibility to oxidative degradation and / or nitrosation during storage life, as well as other forms of degradation such as chemical degradation, thermal degradation, and microbiological degradation.

Summary of the Invention

[0023] By using at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds and pyrosulfite compounds in the composition, the inventors of the present invention can obtain improvements in stability, particularly stability against nitrosation and / or oxidative decomposition, as well as chemical stability, thermal stability and microbiological stability. It has been discovered that at least one antioxidant is present within a specific range based on the total weight of the pharmaceutical composition within a specific pH range.

[0024] An object of the present invention is a liquid aqueous pharmaceutical composition comprising cytisine or a pharmaceutically acceptable salt thereof and at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds and pyrosulfite compounds, wherein the at least one antioxidant is present in an amount of 0.01% to 2.0% by weight based on the total weight of the pharmaceutical composition, and the pH of the liquid aqueous composition is within the range of 5.0 to 7.0.

[0025] Another aspect of the present invention is the use of the liquid aqueous pharmaceutical composition for use in the treatment of smoking addiction and other forms of nicotine addiction.

[0026] Another aspect of the present invention is the use of at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds and pyrosulfite compounds for stabilizing a liquid aqueous pharmaceutical composition containing cytisine.

[0027] Definitions In this specification and the claims, singular expressions preceded by the general articles "a", "an" or "the" shall include the plural unless the context clearly indicates otherwise. Numerical ranges defined by lower and upper endpoints shall include the recited endpoints. The percentages (%) disclosed are, unless otherwise specified, always weight percentages based on the total weight of the pharmaceutical composition.

[0028] The term "antioxidant" refers to a substance that can slow down or prevent the oxidation of other substances. Oxidation reactions can generate free radicals, which can trigger damaging chain reactions. Antioxidants prevent these chain reactions by removing free radical intermediates and inhibit other oxidation reactions by being oxidized themselves; therefore, antioxidants can be considered reducing agents.

[0029] The term "nitrosation" refers to a reaction in which an NO group is introduced into an organic molecule.

[0030] The term "sulfite" refers to the anion SO3 2- This refers to any salt that includes [the specified element].

[0031] The term "bisulfite" refers to the anion HSO3. - This refers to any salt that includes [the specified element].

[0032] The term "pyrosulfite" refers to the anion S2O5 2- This refers to any salt that includes [the specified element].

[0033] The term "acceptable intake (AI) limit" refers to the upper limit of N-nitrosamines that may be present in pharmaceuticals and are classified as "cohort of concern" substances according to the ICH M7(R1) guidelines, and in the context of the present invention, it refers to the upper limit of N-nitrosocyticine impurities that may be present in liquid aqueous pharmaceutical compositions containing cyticine.

[0034] In the context of the present invention, the term "stabilization" refers to a process that protects a liquid aqueous composition from nitrosation and / or oxidative degradation of the liquid aqueous composition, as well as other forms of degradation during the formulation process and / or during its shelf life, such as chemical degradation, thermal degradation and microbiological degradation. [Modes for carrying out the invention]

[0035] A first aspect of the present invention is a liquid aqueous pharmaceutical composition comprising cyticine or a pharmaceutically acceptable salt thereof and at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds and pyrosulfite compounds, wherein the at least one antioxidant is present in an amount of 0.01% to 2.0% by weight based on the total weight of the pharmaceutical composition, and the pH of the liquid aqueous composition is in the range of 5.0 to 7.0.

[0036] The present invention provides, compared to prior art compositions, improved stability, particularly against nitrosation and / or oxidative degradation, as well as stability against chemical degradation, thermal degradation and microbiological degradation, by using at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds and pyrosulfite compounds, thereby improving the shelf life of pharmaceutical compositions.

[0037] In one embodiment of the present invention, cyticine or a pharmaceutically acceptable salt thereof is present in an amount equivalent to 0.1% to 10% by weight of free cyticine base based on the total weight of the pharmaceutical composition.

[0038] In one embodiment, pharmaceutically acceptable salts of cyticine may include, but are not limited to, addition salts of inorganic or organic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, tartaric acid, lactic acid, succinic acid, and formic acid.

[0039] The terms "sulfite," "bisulfite," and "pyrosulfite" refer to sulfite ions (SO3) that can be derived from any pharmaceutically acceptable source or precursor (i.e., sulfite compounds, bisulfite compounds, and pyrosulfite compounds), respectively. 2- ) bisulfite ion (HSO3 - ) and pyrosulfite ions (S2O5 2-This is understood to mean, and such sources or precursors are exemplified, but are not limited to, ammonium salts, alkali metal salts, alkaline earth metal salts and amine salts, and mixed salts of alkali metals and organic compounds. Examples of alkali metal salts include sodium salts and potassium salts, examples of alkaline earth metal salts include calcium salts, magnesium salts, strontium salts and barium salts, and examples of amine salts include salts of amines that are primary, secondary or tertiary lower alkylamines such as methylamine, ethylamine, isopropylamine, n-butylamine, diethylamine and triethylamine.

[0040] In one embodiment of the present invention, at least one antioxidant is selected from sodium sulfite, potassium sulfite, sodium bisulfite, potassium bisulfite, sodium pyrosulfite, and potassium pyrosulfite.

[0041] In a preferred embodiment, at least one antioxidant is sodium sulfite, sodium bisulfite and / or sodium pyrosulfite.

[0042] In one embodiment, the liquid aqueous pharmaceutical composition of the present invention contains at least one antioxidant in an amount of 0.01% to 2.0% by weight, more preferably 0.01% to 1.0% by weight, based on the total weight of the pharmaceutical composition.

[0043] In the most preferred modification of the above embodiment, at least one antioxidant is sodium sulfite, sodium bisulfite, or sodium pyrosulfite, present in an amount of 0.01% to 2.0% by weight, more preferably 0.01% to 1.0% by weight, based on the total weight of the pharmaceutical composition.

[0044] In one embodiment of the present invention, the pH of the liquid aqueous pharmaceutical composition is in the range of 5.0 to 7.0.

[0045] In one embodiment of the present invention, the pH of the liquid aqueous composition is preferably in the range of 5.2 to 6.7, more preferably 5.5 to 6.4, and most preferably 5.8 to 6.1.

[0046] In the most preferred modification of the present invention, the pH of the liquid aqueous pharmaceutical composition is adjusted using an inorganic pH adjuster.

[0047] In one embodiment of the present invention, the inorganic pH adjuster is at least one inorganic salt, the inorganic salt being a salt obtained by partial neutralization of an inorganic dibasic acid or polybasic acid. Preferably, the inorganic dibasic acid or polybasic acid is sulfuric acid and phosphoric acid. More preferably, the inorganic salt is selected from disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, dipotassium hydrogen phosphate and potassium dihydrogen phosphate, or a mixture thereof.

[0048] In one embodiment of the present invention, the inorganic pH adjuster is at least one inorganic salt, the inorganic salt being selected from disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, or a mixture thereof.

[0049] In one embodiment of the present invention, the inorganic pH adjuster is at least one inorganic salt, which is selected from disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, or a mixture thereof, and is present in an amount of 0.05% to 10% by weight based on the total weight of the pharmaceutical composition.

[0050] In its most preferred embodiment, the composition of the present invention contains no further organic pH adjusters.

[0051] Cyticine has an aliphatic secondary amine group and is readily decomposed during the manufacturing process or storage by nitrosation and / or oxidative decomposition reactions to form the corresponding N-nitrosamine impurity, i.e., N-nitrosocyticine. Nitrosamine impurities are potentially carcinogenic, and all MAHs / applicants of human pharmaceuticals should ensure that the presence of nitrosamine impurities in their pharmaceuticals is reduced as much as possible and controlled to below the limits set out under the ICH M7(R1) principle for "cohort of concern" substances in pharmaceuticals.

[0052] The CHMP's assessment report on its opinion on nitrosamine impurities in human medicinal products, pursuant to Article 5(3) of Regulation (EC) 726 / 2004, contains general guidelines and recommendations for reducing and preventing the presence of nitrosamines in human medicinal products. Based on the details of the publicly available CHMP Article 5(3) opinion and the question-and-answer document on its implementation, EMA / 409815 / 2020, the acceptable intake (AI) limit for nitrosocyticine impurities was determined.

[0053] These guidelines have recently been revised, establishing a novel approach to setting limits for nitrosamines based on robust scientific knowledge of carcinogenicity. According to this, if an N-nitrosamine is identified without sufficient substance-specific data to derive a substance-specific lifetime exposure limit as recommended in the ICH M7(R2) guidelines, the AI ​​should be established using the N-nitrosamine carcinogenicity classification approach (CPCA) unless other robust data are available to override this AI. This new document describes an approach to assigning N-nitrosamine impurities to predicted carcinogenicity categories and corresponding tolerable intake (AI) limits based on assessments that activate or deactivate structural features present in the molecule, resulting in five predicted carcinogenicity categories and associated AI limits for N-nitrosamines, ranging from carcinogenicity category 1 with a recommended AI limit of 18 ng / day to carcinogenicity category 5 with a recommended AI limit of 1500 ng / day.

[0054] The inventors of this invention have developed a stable liquid aqueous pharmaceutical composition of cyticine containing N-nitrosocyticine impurities with the lowest possible recommended AI limit of less than 18 ng / day, because these guidelines are constantly changing and not consistent worldwide. By doing so, the inventors have ensured that even if guidelines change further, the liquid aqueous composition of this invention will contain the lowest possible amount of N-nitrosocyticine in the liquid aqueous composition, and that this amount will not increase over its shelf life. Converting the AI ​​limit (ng) to the specification limit (ppm) of a particular pharmaceutical is calculated by dividing the above limit (ng) by the maximum daily dose (mg) of a given product as reflected in the SmPC. Since the cyticine reference product, 1.5 mg film-coated tablets (Tabex®), is taken six times a day (every two hours) according to the SmPC, the AI ​​limit of N-nitrosocyticine was calculated using a maximum daily dose (MDD) of 9.0 mg, and as a result, the AI ​​limit for the liquid aqueous composition of this invention was calculated. As a result, the lowest possible recommended AI limit for N-nitrosocyticine in products containing cyticine is set to parts per million (ppm) using the above formula.

[0055] The inventors of the present invention unexpectedly discovered that by adding at least one antioxidant from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds to a formulation within a pH range of 5.0 to 7.0, preferably 5.2 to 6.7, more preferably 5.5 to 6.4, and most preferably 5.8 to 6.1, N-nitrosocyticine impurities were suppressed over a long period of time to the lowest possible recommended tolerable intake (AI) limit of 2.0 ppm under accelerated conditions (40°C / relative humidity (RH) 75%), and therefore the shelf life of the liquid aqueous composition was improved.

[0056] In one embodiment, at least one antioxidant from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds may form a nitrosating agent under certain conditions and act as an inhibitor in blocking nitrosamine formation from secondary amines by reacting with a source of nitrosation reactions, such as a nitrite in an excipient, which may react with a fragile secondary amine to form an N-nitrosocyticine impurity.

[0057] The inventors of the present invention have also found that when using at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds, a pH range of 5.0 to 7.0 for the liquid aqueous pharmaceutical composition is crucial for maintaining the levels of known impurities such as N-formylcythicine (FO) and N-methylcythicine (MO) below 0.5%, a single unknown impurity below 0.20%, and total impurities below 1.0% under accelerated storage conditions. At pH values ​​below 5.0 and above 7.0, chemical impurities were observed to increase significantly beyond their acceptable limits. Furthermore, at pH above 7.0, changes in the physical appearance of the composition at high temperatures were observed, specifically, the composition yellowed after one month of storage at 40°C / 75%RH.

[0058] The inventors of the present invention conducted experiments to stabilize liquid aqueous compositions using several different antioxidant and pH range combinations, and surprisingly found that chemical stability, as well as stability against oxidative decomposition and / or nitrosation, was observed only when at least one antioxidant selected from the group consisting of sulfites, bisulfites, and pyrosulfites was added to the liquid aqueous composition in a pH range of 5.0 to 7.0, preferably 5.2 to 6.7, more preferably 5.5 to 6.4, and most preferably 5.8 to 6.1.

[0059] It is well known that as the proportion of undissociated drugs increases, so does the permeability through the oral mucosa. It was extremely important that cyticine was not absorbed into the body from the oral cavity. The high oral absorption rate of cyticine in its undissociated form at alkaline pH is expected to affect the bioequivalence of the liquid aqueous composition compared to cyticine in tablet form. The inventors of the present invention have found a way to avoid this problem by developing a liquid aqueous composition containing at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds that is bioequivalent to cyticine tablets (Tabex®) by maintaining the pH value of the liquid composition within the range of 5.0 to 7.0, preferably 5.2 to 6.7, more preferably 5.5 to 6.4, and most preferably 5.8 to 6.1.

[0060] It is widely accepted in the industry that if the formulation itself does not have sufficient antimicrobial activity, antimicrobial preservatives may be added to pharmaceutical formulations, especially aqueous formulations. This is done to prevent microbial contamination of the product under normal storage and use conditions, particularly in the case of multi-dose containers, which could endanger patients by infecting them and causing the formulation to spoil. To ensure that such activity is not impaired by storage, the antimicrobial activity of the formulation in its final container is tested throughout its shelf life. Pharmaceutical formulations must demonstrate, throughout development and throughout their shelf life, that their antimicrobial activity helps protect against adverse effects that may result from microbial contamination or microbial growth during storage and use of the formulation, or, if necessary, with the addition of appropriate preservatives.

[0061] The inventors of the present invention have found that by adding an antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds within a pH range of 5.0 to 7.0, preferably 5.2 to 6.7, more preferably 5.5 to 6.4, and most preferably 5.8 to 6.1, the liquid aqueous pharmaceutical product of the present invention can be protected from microbial growth. This eliminates the need for the addition of any additional preservatives, such as sodium benzoate, paraben M, or paraben P, used in prior art documents such as Russian Patent No. 2593585C1 and International Publication No. 2021115977A1, which do not necessarily protect the aqueous composition as shown in efficacy tests for antimicrobial preservation.

[0062] Surprisingly, the inventors of the present invention have discovered that by stabilizing the liquid composition against nitrosation and / or oxidative decomposition, the shelf life of the liquid aqueous composition is extended, it becomes chemically stable, inhibits microbial growth, and becomes biologically equivalent to the reference tablet (Tabex®), and all of these effects are achieved only by adding at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds to the liquid aqueous composition within a pH range of 5.0 to 7.0, preferably 5.2 to 6.7, more preferably 5.5 to 6.4, and most preferably 5.8 to 6.1.

[0063] In one embodiment of the present invention, the liquid aqueous pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0064] The pharmaceutical excipients used to prepare the liquid aqueous pharmaceutical composition of the present invention are known in the art and can be selected by those skilled in the art according to their function. In this regard, see Handbook of Pharmaceutical Excipients, 9, edited by Paul J Sheskey et al. th You can refer to edition, Pharmaceutical Press (2020).

[0065] According to one embodiment of the liquid aqueous pharmaceutical composition of the present invention, one or more pharmaceutically acceptable excipients are selected from the group consisting of cosolvents, sweeteners, and flavoring agents.

[0066] The liquid aqueous pharmaceutical composition of the present invention may contain at least one co-solvent to assist in the dissolution of additives in the composition.

[0067] In one embodiment of the liquid aqueous pharmaceutical composition of the present invention, the cosolvent is selected from the group consisting of propylene glycol, polyethylene glycol, glycerin, and mixtures thereof.

[0068] In one embodiment of the liquid aqueous pharmaceutical composition of the present invention, the cosolvent is selected from the group consisting of propylene glycol, polyethylene glycol, glycerin, and mixtures thereof, and the cosolvent is present in an amount of 5% to 50% by weight based on the total weight of the pharmaceutical composition.

[0069] To enhance the flavor of the liquid aqueous pharmaceutical composition, the liquid aqueous pharmaceutical composition of the present invention may also contain at least one sweetener and / or at least one flavoring agent.

[0070] In one embodiment of the liquid aqueous pharmaceutical composition of the present invention, the sweetener is selected from erythritol, fructose, dextrose, saccharin, sorbitol, xylitol, mannitol, maltose, maltitol, maltitol solution, liquid glucose, inulin, isomalt, sodium saccharin, sodium cyclamate, sucralose, sucrose, acesulfame potassium, or aspartame.

[0071] In the most preferred modification of the above embodiment, the sweetener is selected from xylitol, mannitol, acesulfame K, aspartame, erythritol, maltitol, or sucrose, and the sweetener is present in an amount of 1% to 20% by weight based on the total weight of the pharmaceutical composition.

[0072] In one embodiment of the liquid aqueous pharmaceutical composition of the present invention, the flavoring agent, at least one flavor, may be selected from the group including mint flavor, tropical flavor, banana flavor, cherry flavor, or orange flavor.

[0073] In one embodiment of the liquid aqueous pharmaceutical composition of the present invention, the flavoring agent is selected from the group consisting of mint flavor, tropical flavor, banana flavor, cherry flavor, and orange flavor, and the flavoring agent is present in an amount of 0.01% to 5% by weight based on the total weight of the pharmaceutical composition.

[0074] In one embodiment, the liquid aqueous pharmaceutical composition according to the present invention includes the following:

[0075] [Table 1]

[0076] In preferred modifications of the above embodiments, the liquid aqueous pharmaceutical composition according to the present invention includes the following:

[0077] [Table 2]

[0078] One embodiment of the present invention is a method for preparing a stabilized liquid aqueous composition comprising cyticine or a pharmaceutically acceptable salt thereof, comprising: i) To provide an aqueous cyticine solution, ii) Adding at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds, iii) Optionally, the addition of further pharmaceutically acceptable excipients, iv) Adjusting the pH to a value within the range of 5.0 to 7.0 by adding at least one inorganic pH adjusting agent, v) Finally, add water to adjust the final volume. Here, at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds is present in an amount of 0.01% to 2.0% by weight based on the total weight of the pharmaceutical composition.

[0079] In one embodiment, when preparing an aqueous cytidine solution, 90% of the total amount of water used in the composition is used to dissolve the cytidine, and then at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds, an optionally present pharmaceutically acceptable excipient, and at least one inorganic pH adjuster are added to adjust the pH to the range of 5.0 to 7.0. The remaining water added in the final step of preparing the composition to its final volume does not affect the pH range of 5.0 to 7.0.

[0080] In one embodiment, the liquid aqueous pharmaceutical composition of the present invention is suitable for administration as a mist, spray, or aerosol.

[0081] In one embodiment, the liquid aqueous pharmaceutical composition of the present invention can be transferred to a bottle equipped with a sprayer capable of dispensing 1.5 mg of cyticine per application.

[0082] One embodiment of the present invention provides a liquid aqueous pharmaceutical composition comprising cyticine and at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds and pyrosulfite compounds, wherein the at least one antioxidant is present in an amount of 0.01% to 2.0% by weight based on the total weight of the pharmaceutical composition, and the pH of the liquid aqueous composition is in the range of 5.0 to 7.0, preferably 5.2 to 6.7, more preferably 5.5 to 6.4, and most preferably 5.8 to 6.1, for oral use in the treatment of smoking addiction and other forms of nicotine addiction.

[0083] One embodiment of the present invention involves the use of at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds for stabilizing a liquid aqueous pharmaceutical composition containing cyticine, wherein the at least one antioxidant is present in an amount ranging from 0.01% to 2.0% by weight based on the total weight of the pharmaceutical composition, and the pH of the liquid aqueous composition is in the range of 5.0 to 7.0, preferably 5.2 to 6.7, more preferably 5.5 to 6.4, and most preferably 5.8 to 6.1.

[0084] The present invention includes the following embodiments. 1. A liquid aqueous pharmaceutical composition comprising cyticine or a pharmaceutically acceptable salt thereof and at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds and pyrosulfite compounds, wherein the antioxidant is present in an amount of 0.01% to 2.0% by weight based on the total weight of the pharmaceutical composition, and the pH of the liquid aqueous composition is in the range of 5.0 to 7.0. 2. The liquid aqueous pharmaceutical composition according to Embodiment 1, wherein the antioxidant is selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds, and is present in an amount of 0.01% to 1.0% by weight based on the total weight of the pharmaceutical composition. 3. The liquid aqueous pharmaceutical composition according to Embodiment 1 or 2, wherein the antioxidant is selected from sodium sulfite, potassium sulfite, sodium bisulfite, potassium bisulfite, sodium pyrosulfite, and potassium pyrosulfite. 4. The liquid aqueous pharmaceutical composition according to Embodiment 3, wherein the antioxidant is sodium sulfite or sodium pyrosulfite. 5. A liquid aqueous pharmaceutical composition according to any one of Embodiments 1 to 4, wherein the pH of the liquid aqueous pharmaceutical composition is 5.2 to 6.7, more preferably 5.5 to 6.4, and most preferably 5.8 to 6.1. 6. A liquid aqueous pharmaceutical composition according to any one of Embodiments 1 to 5, wherein cyticine or a pharmaceutically acceptable salt thereof is present in an amount equivalent to 0.1% to 10% by weight of free cyticine base based on the total weight of the pharmaceutical composition. 7. The liquid aqueous pharmaceutical composition according to any one of Embodiments 1 to 6, wherein the liquid aqueous pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. 8. A liquid aqueous pharmaceutical composition according to any one of Embodiments 1 to 7, having the following composition:

[0085] [Table 3] 9. A liquid aqueous pharmaceutical composition according to any one of Embodiments 1 to 8, having the following composition:

[0086] [Table 4] 10. A liquid aqueous pharmaceutical composition according to any one of Embodiments 1 to 9, for use in the treatment of smoking addiction and other forms of nicotine addiction. 11. A liquid aqueous pharmaceutical composition for use according to Embodiment 10, wherein the liquid composition is intended for administration into the oral cavity of a target by mist, spray, or aerosol. 12. Use of at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds for stabilizing a liquid aqueous pharmaceutical composition containing cyticine, wherein the antioxidant is present in an amount of 0.01% to 2.0% by weight based on the total weight of the pharmaceutical composition, and the pH of the liquid aqueous composition is in the range of 5.0 to 7.0.

[0087] Experiment Department Measurement equipment, conditions, and protocols: Method for measuring pH: In accordance with European Pharmacopoeia 2.2.3, the pH is measured at room temperature (20-25°C) and atmospheric pressure using a potentiometric pH meter calibrated with buffer solutions of 2.00, 4.01, and 7.00 (e.g., 913 pH Meter Lab, LL-Unitrode easy Clean 1m).

[0088] Detection of chemical purity: Chemical purity analysis was performed using high-performance liquid chromatography equipped with a PDA detector, sample cooling system, and column thermostat.

[0089] [Table 5]

[0090] Detection of N-nitrosocyticine impurities: Analysis for the detection of acceptable intake (AI) levels of N-nitrosocyticine was performed using liquid chromatography equipped with an MS detector, such as a Shimadzu Nexera X2 LC MS 8040 or equivalent with a Phenomenex Luna Omega 1.6 μm 2.1 × 100 mm column. [Examples]

[0091] The following examples illustrate the present invention in detail, but should not be construed as limiting the invention.

[0092] Example 1: Preparation of a cyticine liquid composition using sodium pyrosulfite as an antioxidant at pH 6.1. The quantitative composition of this formulation is shown in the table below. Cyticine was dissolved in 90% of the total amount of water used in the composition together with sodium pyrosulfite, then propylene glycol, xylitol, and mint flavoring were added, and the pH of the formulation was adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, after which the remaining water was added to the desired volume.

[0093] The completed pharmaceutical composition is transferred to an HDPE bottle equipped with a sprayer.

[0094] [Table 6]

[0095] Example 2: Preparation of a cyticine liquid composition using sodium pyrosulfite as an antioxidant at pH 5.8. The quantitative composition of this formulation is shown in the table below. Cyticine was dissolved in 90% of the total amount of water used in the composition with sodium pyrosulfite, then propylene glycol, xylitol, and mint flavoring were added, and the pH of the formulation was adjusted to 5.8 by adding sodium dihydrogen phosphate dihydrate, after which the remaining water was added to the desired volume.

[0096] The completed pharmaceutical composition is transferred to an HDPE bottle equipped with a sprayer.

[0097] [Table 7]

[0098] Example 3: Preparation of a cyticine liquid composition using sodium sulfite as an antioxidant at pH 6.1. The quantitative composition of this formulation is shown in the table below. Cyticine was dissolved with sodium sulfite in 90% of the total amount of water used in the composition, then propylene glycol, xylitol, and mint flavoring were added, and the pH of the formulation was adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, after which the remaining water was added to the desired volume.

[0099] The completed pharmaceutical composition is transferred to an HDPE bottle equipped with a sprayer.

[0100] [Table 8]

[0101] Example 4: Preparation of a cyticine liquid composition using sodium bisulfite as an antioxidant at pH 6.1. The quantitative composition of this formulation is shown in the table below. Cyticine was dissolved in 90% of the total amount of water used in the composition with sodium bisulfite, then propylene glycol, xylitol, and mint flavoring were added, and the pH of the formulation was adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, after which the remaining water was added to the desired volume.

[0102] The completed pharmaceutical composition is transferred to an HDPE bottle equipped with a sprayer.

[0103] [Table 9]

[0104] Comparative Example 1: Preparation of a cyticine liquid composition using maleic acid as an antioxidant at pH 6.1. The quantitative composition of this formulation is shown in the table below. Cyticine was dissolved with maleic acid in 90% of the total amount of water used in the composition, then propylene glycol, xylitol, and mint flavoring were added, and the pH of the formulation was adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, after which the remaining water was added to the desired volume.

[0105] [Table 10]

[0106] Comparative Example 2: Preparation of a cyticine liquid composition using sodium thiosulfate as an antioxidant at pH 6.1. The quantitative composition of this formulation is shown in the table below. Cyticine was dissolved in 90% of the total amount of water used in the composition with sodium thiosulfate, then propylene glycol, xylitol, and mint flavoring were added, and the pH of the formulation was adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, after which the remaining water was added to the desired volume.

[0107] [Table 11]

[0108] Comparative Example 3: Preparation of a cyticine liquid composition using sodium ascorbate as an antioxidant at pH 6.1. The quantitative composition of this formulation is shown in the table below. Cyticine was dissolved in 90% of the total amount of water used in the composition together with sodium ascorbate, then propylene glycol, xylitol, and mint flavoring were added, and the pH of the formulation was adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, after which the remaining water was added to the desired volume.

[0109] [Table 12]

[0110] Comparative Example 4: Preparation of a cyticine liquid composition using butylated hydroxytoluene (BHT) as an antioxidant at pH 6.1. The quantitative composition of this formulation is shown in the table below. Cyticine was dissolved in 90% of the total amount of water used in the composition, then BHT, propylene glycol, xylitol, and mint flavoring were added, and the pH of the formulation was adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, after which the remaining water was added to the desired volume.

[0111] The BHT in the composition remains insoluble and is observed to exist as a suspension.

[0112] [Table 13]

[0113] Comparative Example 5: Preparation of a cyticine liquid composition without antioxidants at pH 6.1. The quantitative composition of this formulation is shown in the table below. Cyticine was dissolved in 90% of the total amount of water used in the composition, then propylene glycol, xylitol, and mint flavoring were added, and the pH of the formulation was adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, after which the remaining water was added to the desired volume.

[0114] [Table 14]

[0115] Comparative Example 6: Preparation of a liquid composition of cyticine at pH 4.5 The quantitative composition of this formulation is shown in the table below. Cyticine was dissolved in 90% of the total amount of water used in the composition, then propylene glycol, xylitol, and mint flavoring were added, and the pH of the formulation was adjusted to 4.5 by adding citrate buffer stabilized with HCl or NaOH solution to a pH of 4.5, after which the remaining water was added to the desired volume.

[0116] [Table 15]

[0117] Comparative Example 7: Preparation of a liquid composition of cyticine at pH 8.7 The quantitative composition of this formulation is shown in the table below. Cyticine was dissolved in 90% of the total amount of water used in the composition, then propylene glycol, xylitol, and mint flavoring were added, and the pH of the formulation was adjusted to 8.7 by adding phosphate buffer, after which the remaining water was added to the desired volume.

[0118] [Table 16]

[0119] Comparative Example 8: Liquid composition of cyticine according to Example 2 of Russian Patent No. 2593585 A liquid cyticine composition was prepared as described in Example 2 of Russian Patent No. 2593585, and its quantitative composition is shown in the table below.

[0120] [Table 17]

[0121] Comparative Example 9: A liquid composition of cyticine according to composition 13 of the International Patent Application, International Publication No. 2021115977(A1). A liquid cyticine composition was prepared as described in composition 13 of the international patent application, International Publication No. 2021115977(A1), and its quantitative composition is shown in the table below.

[0122] [Table 18]

[0123] Comparative study on the chemical stability of liquid pharmaceutical compositions using various antioxidants. The chemical stability of the pH 6.1 aqueous liquid compositions of the present invention, containing sodium pyrosulfite as an antioxidant and sodium sulfite as an antioxidant, as described in Examples 1 and 3, was tested under accelerated storage conditions (40°C / 75%RH) in comparison with the pH 6.1 liquid compositions containing different antioxidants, as described in Comparative Examples 1 and 3. All samples were stored in an artificial climate chamber, and samples were taken at intervals of 0, 1, and 2 months and analyzed by HPLC.

[0124] The stability test results suggest that, in contrast to the compositions of Examples 1 and 3, which contained sodium pyrosulfite and sodium sulfite, respectively, when different antioxidants were used, a significant increase in chemical impurities exceeding the permissible limit was observed at pH 6.1 under accelerated storage conditions.

[0125] [Table 19]

[0126] Comparative test on the chemical stability of liquid pharmaceutical compositions at different pH levels. The chemical stability of the pH 6.1 liquid aqueous compositions of the present invention, containing sodium pyrosulfite as an antioxidant and sodium sulfite as an antioxidant, as described in Examples 1 and 3, was compared with the pH 4.5 and pH 8.7 liquid compositions containing sodium sulfite as an antioxidant described in Comparative Examples 6 and 7, and the pH 7.7 composition of Example 2 of Russian Patent No. 2593585 (Comparative Example 8), under accelerated storage conditions (40°C / 75%RH). All samples were stored in an artificial climate chamber, and samples were taken at intervals of 0, 1, and 2 months and analyzed by HPLC. All values ​​for chemical impurity content are expressed as percentages (%).

[0127] The stability test results suggest that at pH values ​​below 5.0 and above 7.0, chemical impurities significantly increased beyond acceptable limits under accelerated storage conditions. However, the compositions of Examples 1 and 3 are stable and meet the requirements for cystine-containing pharmaceuticals (FO impurities ≤ 0.5%, ME impurities ≤ 0.5%, maximum single unknown impurity ≤ 0.2%, total impurities ≤ 1.0%).

[0128] The accelerated testing of the composition of Example 2 (Comparative Example 8) of Russian Patent No. 2593585 was continued for 6 months, and the total impurities exceeded 1.0%, indicating that the cystine-containing pharmaceutical did not meet the specifications.

[0129] [Table 20]

[0130] A comparative study on the N-nitrosocystin content in liquid pharmaceutical compositions containing various antioxidants, liquid pharmaceutical compositions without antioxidants, and prior art compositions. The N-nitrosocyticine content in the pH 6.1 liquid pharmaceutical compositions of the present invention, containing sodium pyrosulfite as an antioxidant, sodium sulfite as an antioxidant, and sodium bisulfite as an antioxidant, as described in Examples 1, 3, and 4, was compared with the liquid compositions containing different antioxidants described in Comparative Examples 1, 2, 3, 4, and Comparative Example 5 (without antioxidant), as well as the prior art compositions described in Comparative Examples 8 and 9, under normal storage conditions (25°C / 75%RH) and accelerated storage conditions (40°C / 75%RH). All samples were stored in an artificial climate chamber, and samples were taken at intervals of 1 month and 6 months. The samples were analyzed by LCMS, and the N-nitrosocyticine impurity content was expressed in parts per million (ppm).

[0131] The stability test results suggest that, in contrast to the compositions of Examples 1, 3, and 4, which contained sodium pyrosulfite, sodium sulfite, and sodium bisulfite, respectively, Comparative Example 8, under accelerated storage conditions, and the liquid compositions containing different antioxidants described in Comparative Examples 1, 2, 3, 4, and Comparative Example 5 (without antioxidants), and Comparative Example 9, all showed a significant increase in the content of N-nitrosocyticine impurities, exceeding the lowest possible recommended tolerable intake (AI) limit of 2.0 ppm.

[0132] [Table 21]

[0133] Bioavailability comparative study A comparative bioavailability study was conducted on the following cyticine formulations. - A single dose of 1.5 mg of the cyticine oral solution from Example 1 was administered under fasting conditions (A). - Administer a single dose of 1.5 mg of the cyticine oral solution from Example 1 under fasting conditions, followed by drinking water (B). - Administer a single dose of film-coated Tabex® 1.5 mg tablets with water under fasting conditions.

[0134] A randomized, open-label, single-dose, three-period, pilot, crossover bioavailability study was conducted under fasting conditions in 24 healthy volunteers.

[0135] As shown in the following table, a randomization scheme was created using the SAS® / Plan module, and blood samples were collected over a 24-hour period.

[0136]

Table 22

[0137] Bioavailability comparison data (AUC, C max and T max ) obtained for cytidine oral solution (Treatments A and B) versus Tabex® (Treatment C) are shown in the following table.

[0138]

Table 23

[0139] Surprisingly, the liquid aqueous composition of the present invention was found to be bioequivalent to the reference product Tabex®.

[0140] Antimicrobial preservative efficacy test The compositions of Example 1, Example 3 and Comparative Example 9 were tested for antimicrobial preservative efficacy. The compositions were tested using a defined microbial inoculum (listed in the following table), and the inoculated preparations were stored at a defined temperature. Typically, 1 mL or 1 g samples were removed from the containers at 0 hours and at appropriate intervals (14 and 28 days), and the viable microbial count was determined by plate count.

[0141] The acceptance criteria for antimicrobial activity evaluation are defined in the European Pharmacopoeia 5.1.3 as the log10 decrease in the viable microbial count relative to the value obtained for the inoculum. During the test, if the microbial count in the inoculated preparation decreases significantly or does not increase, as required, after a defined time and temperature, the preservation characteristics of the preparation are appropriate.

[0142] As shown in the table below, the compositions of Examples 1 and 3 did not show an increase in the number of microorganisms in the inoculated preparations after 14 and 28 days, respectively, and therefore met the requirements specified in European Pharmacopoeia 5.1.3. In contrast, the composition of Comparative Example 9 showed a significant increase in Aspergillus brasiliensis and Staphylococcus aureus, and therefore did not meet the requirements specified in European Pharmacopoeia 5.1.3.

[0143] [Table 24]

Claims

1. A liquid aqueous pharmaceutical composition comprising cyticine or a pharmaceutically acceptable salt thereof, and at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds, wherein the antioxidant is present in an amount of 0.01% to 2.0% by weight based on the total weight of the pharmaceutical composition, and the pH of the liquid aqueous composition is in the range of 5.0 to 7.

0.

2. The liquid aqueous pharmaceutical composition according to claim 1, wherein an antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds is present in an amount of 0.01% to 1.0% by weight based on the total weight of the pharmaceutical composition.

3. The liquid aqueous pharmaceutical composition according to claim 1 or 2, wherein the antioxidant is selected from sodium sulfite, potassium sulfite, sodium bisulfite, potassium bisulfite, sodium pyrosulfite, and potassium pyrosulfite.

4. The liquid aqueous pharmaceutical composition according to claim 3, wherein the antioxidant is sodium sulfite or sodium pyrosulfite.

5. The liquid aqueous pharmaceutical composition according to any one of claims 1 to 4, wherein the pH of the liquid aqueous pharmaceutical composition is 5.2 to 6.7, more preferably 5.5 to 6.4, and most preferably 5.8 to 6.

1.

6. The liquid aqueous pharmaceutical composition according to any one of claims 1 to 5, wherein cyticine or a pharmaceutically acceptable salt thereof is present in an amount equivalent to 0.1% to 10% by weight of free cyticine base based on the total weight of the pharmaceutical composition.

7. The liquid aqueous pharmaceutical composition according to any one of claims 1 to 6, wherein the liquid aqueous pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

8. A liquid aqueous pharmaceutical composition according to any one of claims 1 to 7, for use in the treatment of smoking addiction and other forms of nicotine addiction.

9. The liquid aqueous pharmaceutical composition for use according to claim 8, wherein the liquid composition is intended to be administered into the oral cavity of a target by mist, spray, or aerosol.

10. Use of at least one antioxidant selected from the group consisting of sulfite compounds, bisulfite compounds, and pyrosulfite compounds for stabilizing a liquid aqueous pharmaceutical composition containing cyticine, wherein the antioxidant is present in an amount of 0.01% to 2.0% by weight based on the total weight of the pharmaceutical composition, and the pH of the liquid aqueous composition is in the range of 5.0 to 7.0.

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