Pharmaceutical composition containing cytisine

Abstract

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

Description

TECHNICAL FIELD

[0001] The present invention relates to a stabilized composition with significantly improved shelf stability. More particularly, the present invention relates to a stabilized liquid aqueous pharmaceutical composition comprising cytisine or a pharmaceutically acceptable salt thereof and at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds. BACKGROUND

[0002] Smoking is the most prevalent and severe addiction and is the leading cause of cancer and cardiovascular and pulmonary disease deaths, with over 8 million people dying from tobacco-related diseases worldwide each year. Quitting smoking reduces the risk of premature death associated with continued smoking by about 90%. However, quitting smoking is extremely difficult for several reasons, including the complexity of nicotine addiction.

[0003] Nicotine is the main psychoactive component in tobacco that causes addiction. Nicotine addiction is associated with repeated nicotine intake from cigarettes, which leads to stimulation of brain nAChRs and release of dopamine and other neurotransmitters from the nucleus accumbens, the ventral tegmental area (VTA) and frontal cortical areas.

[0004] In the United States, the current Food and Drug Administration-approved smoking cessation drugs are varenicline and bupropion. Like varenicline, its synthetic derivative cytisine acts as a selective partial agonist at a4b2a4b2 and binds to nicotinic acetylcholine receptors with higher affinity than nicotine.

[0005] Cytisine, also known as laburnine, cytisinicline or sophorine, is the earliest drug licensed and used for smoking cessation in Central and Eastern Europe, and products containing cytisine are available in Central and Eastern European countries such as Russia and Poland, Western Asia and Canada.

[0006] Cytisine is a plant-based alkaloid derived primarily from Leguminosae plants, especially the seeds of Laburnum anagyroides. It is a partial agonist of the nicotinic acetylcholine receptor (nAChR) that has been successfully used in smoking cessation therapy.

[0007] The IUPAC name of cytisine is (1R,5S)-1,2,3,4,5,6-hexahydro-1,5-methano-8H-pyrido[1,2a][1,5]diazocin-8-one and has the following structure of Formula (I):

[0008]

[0009] Delavayine is currently available in tablet and capsule (Desmoxan) forms, using a complex dosing regimen that requires first a Delavayine dose (tablet or capsule: 1.5 mg) every 2 hours (6 doses per day), then a downward titration to 2 doses per day over 25 days.

[0010] A more convenient method for oral administration of Delavayine is necessary to develop, especially in the form of a liquid, mist, spray or aerosol.

[0011] International patent application WO2014201735 discloses an oral nicotine-replacement Delavayine nebulized liquid composition containing the following mass percentages of components per 1 L of the oral nebulized liquid: 0.1-10% tobacco, 0.3-15% cocoa extract, 0.1-0.9% Delavayine, 0.1-0.5% Tween 80 and 75-90% primer.

[0012] Patent RU2593585C1 discloses an intranasal solution containing Delavayine, water, disodium hydrogen phosphate and sodium dihydrogen phosphate as acidity regulators, EDTA, Paraben M and Paraben P as preservatives, sodium chloride as a salt, polysorbate as a cosolvent and citric acid as an antioxidant.

[0013] International patent application WO2021115977A1 discloses a liquid pharmaceutical composition containing Delavayine, water and one or more pharmaceutical excipients, including at least one inorganic pH regulator selected from the group consisting of inorganic acids, inorganic buffers and inorganic acid salts, with a pH value in the range of 3.0 to 7.5.

[0014] Patent application EP3967298A1 discloses an aerosol composition comprising Delavayine, a hydrophilic non-ionic emulsifier selected from the group consisting of copolymers or polymers, at least one alcohol, water and one or more excipients, wherein the composition has a pH of 7 to 10.

[0015] Polish patent application PL416496 discloses a solution for inhalation and / or atomization using an atomizer and / or vaporizer for use in an electronic cigarette. The solution contains a dose of 0.66% Delavayine and / or 0.02% nicotine, reaching the maximum limit value required to maintain a liquid unsaturated solution at thermodynamic room temperature thermal comfort under hygroscopic equilibrium, wherein the maximum concentration of Delavayine and / or nicotine does not exceed 99.99% for these conditions.

[0016] Unfortunately, the inventors of the present application have found that liquid compositions containing delphinidin and intended to be administered as a liquid, mist, spray or aerosol have some drawbacks, most notably the presence of N-nitroso delphinidin impurities in the liquid composition above their minimum possible acceptable intake (AI) limit, and other forms of degradation such as chemical, thermal and microbiological degradation most likely formed during the formulation phase or during its shelf life.

[0017] Nitrosamine impurities, even in trace amounts, are highly toxic and mutagenic, they are able to damage DNA and subsequently increase the risk of cancer development. As pharmaceutical manufacturers have the obligation to ensure the quality, safety and efficacy of their drugs, they should take appropriate precautions to reduce the risk of presence of nitrosamines during manufacturing, storage and throughout the life cycle of the medical product. According to the guidelines available at present, the MAH should ensure appropriate control of the presence of nitrosamines and keep their levels as low as possible to protect patients from the negative effects of these mutagenic compounds.

[0018] Due to the elevated levels of nitrosamine impurities, an increasing number of drug products have been suspended or recalled from the market. Some nitrosamines are classified as carcinogenic to humans, very likely or probable. One of these incidents involved the smoking cessation drug varenicline, Pfizer recalled varenicline from the US market in 2021 as it can have contained N-nitroso-varenicline impurities at or above the level allowed by the US Food and Drug Administration.

[0019] The presence of nitrosamine impurities in marketed drug products is becoming an important focus for the pharmaceutical industry following regulatory guidelines on the identification, allowed limits and mitigation strategies to reduce to below acceptable levels. There are several ways in which nitrosamine impurities can form. According to the published CHMP Article 5(3) opinion and the Q&A document on its implementation EMA / 409815 / 2020, there are several potential factors that contribute to the formation of N-nitrosamines in drug products. Some of these factors include:

[0020] • Reaction of nitrosatable nitrogen functionality in the API or its impurities / degradants with nitrosating agents present in the finished product components during formulation or storage. Several examples have been reported in which amine functionality has been shown to be susceptible to nitrosation and the formation of corresponding N-nitroso impurities (i.e. NO-API). Secondary amines appear to be particularly susceptible to this reaction, but some cases have also been observed with tertiary amines. Susceptible amines can also be formed by degradation (e.g. hydrolysis) during formulation or storage.

[0021] • Oxidation of hydrazine or other amine-containing functional groups or impurities / degradants thereof (e.g., from hydrazones and hydrazides) present in the active substance during the active substance manufacturing process or during storage. This root cause has also been observed during manufacturing and storage of finished products containing such functional groups. Potential oxidizing agents include oxygen and peroxides (common impurities in some excipients).

[0022] The present inventors found that bapinephrine degrades during formulation and / or storage of the liquid aqueous composition because it contains an aliphatic secondary amine group that degrades through a variety of processes, including oxidative degradation and / or interaction with other ingredients, including but not limited to reaction with nitrite impurities in excipients, which form nitrosating agents under certain conditions and can react with susceptible secondary amines to form N-nitroso bapinephrine impurities (II) above the lowest possible recommended acceptable intake (AI) limit.

[0023]

[0024] Therefore, there is a need to develop stable pharmaceutical compositions containing bapinephrine or a pharmaceutically acceptable salt thereof, which have improved shelf life and are significantly less affected by oxidative degradation and / or nitrosation and other forms of degradation such as chemical, thermal and microbiological degradation during shelf life. SUMMARY

[0025] The present inventors found that by using at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds in the composition, improved stability, in particular stability against nitrosation and / or oxidative type of degradation as well as chemical, thermal and microbiological stability can be achieved, wherein the at least one antioxidant is present in a specific range based on the total weight of the pharmaceutical composition in a specific pH range.

[0026] It is an object of the present invention a liquid aqueous pharmaceutical composition comprising bapinephrine or a pharmaceutically acceptable salt thereof, at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds, wherein the at least one antioxidant is present in an amount of 0.01 to 2.0 wt.-% based on the total weight of the pharmaceutical composition, and wherein the pH of the liquid aqueous composition is in the range of 5.0 to 7.0.

[0027] Another aspect of the present invention is the use of the liquid aqueous pharmaceutical composition for the treatment of nicotine addiction and other forms of smoking addiction.

[0028] Another aspect of the present invention is the use of at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds for the stabilization of a liquid aqueous pharmaceutical composition containing delphinidin.

[0029] Definitions

[0030] In this specification, and in the claims that follow, unless the context dictates the contrary, the singular expression "a" or "an" is intended to also include the plural form. Numerical ranges expressed in the format "from X to Y" are intended to include the endpoints X and Y, unless the context clearly indicates otherwise. Disclosed percentages (%) are always weight percentages based on the total weight of the pharmaceutical composition, unless explicitly specified otherwise.

[0031] The term "antioxidant" refers to a substance that is able to slow down or prevent the oxidation of other substances. Oxidation reactions can generate free radicals, which can initiate a chain reaction that can cause damage. Antioxidants prevent these chain reactions by removing free radical intermediates, and by themselves being oxidized, thus inhibiting other oxidation reactions; antioxidants can therefore be considered as reducing agents.

[0032] The term "nitrosylation" refers to a reaction in which a NO group is introduced into an organic molecule.

[0033] The term "sulfite" refers to any salt comprising the anion SO3 2- .

[0034] The term "bisulfite" refers to any salt comprising the anion HSO3 - .

[0035] The term "metabisulfite" refers to any salt comprising the anion S2O5 2- .

[0036] The term "acceptable intake (AI) limit" refers to the upper limit of N-nitrosamines that can be present in a medicinal product and that are classified as "watch list" substances according to the ICH M7(R1) guideline, and in the context of the present invention, it refers to the upper limit of N-nitroso delphinidin impurities that can be present in a liquid aqueous pharmaceutical composition containing delphinidin.

[0037] In the context of the present invention, the term "stabilization" refers to a process that protects the liquid aqueous composition from nitrosylation and / or oxidative degradation and other forms of degradation such as chemical, thermal and microbial degradation during the formulation phase and / or the shelf life of the liquid aqueous composition. DETAILED DESCRIPTION

[0038] The first aspect of the present invention is a liquid aqueous pharmaceutical composition comprising baptisia tinctoria alkaloid or a pharmaceutically acceptable salt thereof, at least one antioxidant selected from the group consisting of sulfite, bisulfite 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 wherein the pH of the liquid aqueous composition is in the range of 5.0 to 7.0.

[0039] The present invention provides improved stability, particularly against nitrosative and / or oxidative degradation and chemical, thermal and microbial degradation, and thus enhances the shelf life of the pharmaceutical composition, using at least one antioxidant selected from the group consisting of sulfite, bisulfite and pyrosulfite compounds, as compared to prior art compositions.

[0040] In one embodiment of the present invention, the baptisia tinctoria alkaloid or a pharmaceutically acceptable salt thereof is present in an amount corresponding to 0.1 to 10% by weight of baptisia tinctoria alkaloid free base based on the total weight of the pharmaceutical composition.

[0041] In one embodiment, the pharmaceutically acceptable salt of baptisia tinctoria alkaloid can include, but is 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.

[0042] The terms sulfite, bisulfite and pyrosulfite are understood to mean sulfite ion (SO3 2- ), bisulfite ion (HSO3 - ) and pyrosulfite ion (S2O5 2- ) respectively, derivable from any pharmaceutically acceptable source or precursor (i.e. sulfite, bisulfite and pyrosulfite compounds), such sources or precursors being illustrated by, but not limited to, ammonium salts, alkali metal salts, alkaline earth metal salts and amine salts, as well as mixed salts of alkali metals and organic compounds. The alkali metal salts include sodium and potassium salts, the alkaline earth metal salts include calcium, magnesium, strontium and barium salts, and the amine salts are salts of amines which are lower alkyl primary, secondary or tertiary amines such as methylamine, ethylamine, isopropylamine, n-butylamine, diethylamine, triethylamine and the like.

[0043] In one embodiment of the present invention, the at least one antioxidant is selected from sodium sulfite, potassium sulfite, sodium bisulfite, potassium bisulfite, sodium pyrosulfite and potassium pyrosulfite.

[0044] In a preferred embodiment, the at least one antioxidant is sodium sulfite, sodium bisulfite and / or sodium pyrosulfite.

[0045] In one embodiment of the liquid aqueous pharmaceutical composition of the present application, the at least one antioxidant is present in an amount of 0.01 to 2.0 % by weight, more preferably comprised between 0.01 and 1.0 % by weight, in each case based on the total weight of the pharmaceutical composition.

[0046] In the most preferred variant of the above-mentioned embodiment, the at least one antioxidant is sodium sulfite, sodium bisulfite or sodium metabisulfite and is present in an amount of 0.01 to 2.0 % by weight, more preferably comprised between 0.01 and 1.0 % by weight, in each case based on the total weight of the pharmaceutical composition.

[0047] In one embodiment of the present application, the pH of the liquid aqueous pharmaceutical composition is in the range of 5.0 to 7.0.

[0048] In one embodiment of the present application, 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.

[0049] In the most preferred variant of the present application, the pH of the liquid aqueous pharmaceutical composition is adjusted using an inorganic pH adjusting agent.

[0050] In one embodiment of the present application, the inorganic pH adjusting agent is at least one inorganic salt, wherein the inorganic salt is a salt obtained by partial neutralization of an inorganic di- or poly-acid. Preferably, the inorganic di- or poly-acid is sulfuric acid and phosphoric acid. More preferably, the inorganic salt is selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, dipotassium hydrogen phosphate and potassium dihydrogen phosphate or mixtures thereof.

[0051] In one embodiment of the present application, the inorganic pH adjusting agent is at least one inorganic salt, wherein the inorganic salt is selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, dipotassium hydrogen phosphate and potassium dihydrogen phosphate or mixtures thereof.

[0052] In one embodiment of the present application, the inorganic pH adjusting agent is at least one inorganic salt, wherein the inorganic salt is selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate dihydrate, dipotassium hydrogen phosphate and potassium dihydrogen phosphate or mixtures thereof, and is present in an amount of 0.05 to 10 % by weight, based on the total weight of the pharmaceutical composition.

[0053] In the most preferred embodiment, the composition of the present application does not comprise any additional organic pH adjusting agent.

[0054] Delphinidin has an aliphatic secondary amine group and is susceptible to degradation by nitrosative and / or oxidative degradation reactions to form the corresponding N-nitrosamine impurity, i.e. N-nitroso-delphinidin, during manufacturing processes or storage. Nitrosamine impurities are potentially carcinogenic and all MAHs / Applicants of human medicinal products should ensure that the presence of nitrosamine impurities in their medicinal products is mitigated as much as possible and controlled at or below the limits defined based on the ICH M7(R1) principles for “watch list” substances in medicinal products.

[0055] The CHMP’s assessment report of the opinion on nitrosamine impurities in human medicinal products according to Regulation (EC) No. 726 / 2004, Article 5(3) provides general guidelines and recommendations on mitigating and preventing the presence of nitrosamines in human medicinal products. Based on the details of the published CHMP Article 5(3) opinion and the Q&A document on its implementation, EMA / 409815 / 2020, acceptable intake (AI) limits for the N-nitroso-delphinidin impurity were determined.

[0056] These guidelines have recently been revised and based on robust scientific knowledge on carcinogenic potency, a new approach for nitrosamine limit setting has been established. According to this approach, if an N-nitrosamine is identified without sufficient substance-specific data to derive a substance-specific limit on lifetime exposure as recommended in the ICH M7(R2) guideline, the Carcinogenic Potency Classification Approach (CPCA) for N-nitrosamines should be used to establish the AI unless other robust data are available that would override this AI. This new document describes an approach to assign N-nitrosamine impurities to a predicted carcinogenic potency category with a corresponding acceptable intake (AI) limit based on an assessment of activating or inactivating structural features present in the molecule and results in five predicted potency categories and associated AI limits for N-nitrosamines ranging from potency category 1 with a recommended AI limit of 18 ng / day to potency category 5 with a recommended AI limit of 1500 ng / day.

[0057] The inventors of the present invention developed a stable delphinidin liquid aqueous pharmaceutical composition containing the N-nitroso-delphinidin impurity at the lowest possible recommended AI limit of 18 ng / day, as these guidelines are changing and inconsistent worldwide. By doing so, the inventors ensured that even if the guidelines are further changed, the liquid aqueous composition of the present invention will contain the lowest possible amount of N-nitroso-delphinidin in this liquid aqueous composition and will not increase during its shelf life. The conversion of the AI limit (ng) into a specification limit (ppm) for a specific medicinal product is calculated by dividing the respective above limit (ng) by the maximum daily dose (mg) of the given product as reflected in the SmPC. As 1.5 mg film-coated tablets of delphinidin reference product are to be taken 6 times a day (every 2 hours) according to the SmPC The maximum daily dose (MDD) of 9.0 mg was therefore used to calculate the AI limit for N-nitrosovelbanine, and therefore the AI limit for the liquid aqueous compositions of the present application. Therefore, the minimum possible recommended AI limit for N-nitrosovelbanine in products containing velbanine was set at 2.0 parts per million (ppm) using the above formula.

[0058] The inventors of the present application unexpectedly found that the addition of at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds to the formulation, within the pH range of 5.0 to 7.0, preferably within the range of 5.2 to 6.7, more preferably 5.5 to 6.4, and most preferably 5.8 to 6.1, limits the N-nitrosovelbanine impurity to the minimum possible recommended acceptable intake (AI) limit of less than 2.0 ppm under accelerated conditions (40°C / 75% relative humidity (RH)) over an extended period of time, thus improving the shelf life of the liquid aqueous composition.

[0059] In one embodiment, the at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds acts as an inhibitor in preventing the formation of nitrosamines from secondary amines by reacting with the nitrosating reaction source, such as nitrite salts in the excipients, which can form nitrosating agents under certain conditions and will react with the susceptible secondary amines to form N-nitrosovelbanine impurities.

[0060] The inventors of the present application also found that when using at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds, the pH range of 5.0 to 7.0 of the liquid aqueous pharmaceutical composition is critical for maintaining the levels of known impurities such as N-formylvelbanine (FO), N-methylvelbanine (MO) at <0.5% each, and a single unknown impurity at <0.20%, and total impurities at no more than 1.0% under accelerated storage conditions. A significant increase in chemical impurities above their acceptable limits was observed at pH values below 5.0 and above 7.0; in addition, a change in the physical appearance of the composition at elevated temperatures was observed above pH 7.0; specifically, the color of the composition turned yellow after 1 month of storage at 40°C / 75% RH.

[0061] The inventors of the present invention experimented with many different antioxidant and pH range combinations to stabilize the liquid aqueous composition, but surprisingly found that chemical stabilization as well as stabilization against oxidative degradation and / or nitrosylation was observed only when at least one antioxidant selected from the group consisting of sulfites, bisulfites and metabisulfites was added to the liquid aqueous composition in the pH range of 5.0 to 7.0, preferably in the range of 5.2 to 6.7, more preferably in the range of 5.5 to 6.4, and most preferably in the range of 5.8 to 6.1.

[0062] It is well known that as the fraction of undissociated drug substance increases, its permeability through the oral mucosa also increases. Crucially, cytisine cannot be absorbed into the body via the oral cavity. The high oral absorption of cytisine in its undissociated form at alkaline pH is expected to affect the bioequivalence of liquid aqueous compositions compared to cytisine in tablet form. The inventors of the present invention have discovered a way to circumvent this problem by developing a liquid aqueous composition containing at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds, by maintaining the pH of the liquid composition in the range of 5.0 to 7.0, 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, which is consistent with the bioequivalence of cytisine tablets. are bioequivalent.

[0063] It is widely accepted in the industry that if the formulation itself does not have sufficient antimicrobial activity, an antimicrobial preservative can be added to the pharmaceutical formulation, particularly in an aqueous formulation. This is done to prevent microbial contamination from occurring in the product under normal storage and use conditions, particularly for multi-dose containers, which could endanger the patient by infecting the patient and causing the formulation to deteriorate. In order to ensure that this activity is not hindered by storage, the antimicrobial activity of the formulation in its final container is checked during the shelf life process. Pharmaceutical formulations must demonstrate during development and throughout their shelf life that their antimicrobial activity helps to protect against adverse effects that may be caused by microbial contamination or proliferation during the storage and use of the formulation, or, if necessary, by adding one or more suitable preservatives.

[0064] The inventors of the present application have found that by adding an antioxidant selected from the group consisting of sulfite, bisulfite and pyrosulfite compounds in the pH range of 5.0 to 7.0, 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, the liquid aqueous pharmaceutical of the present application can be preserved against microbial growth, which eliminates the need for adding any additional preservatives such as sodium benzoate, methyl or propyl paraben, as used in prior art documents such as RU2593585C1 and WO2021115977A1, which do not necessarily preserve the aqueous composition, as demonstrated in antimicrobial preservative efficacy testing.

[0065] Surprisingly, the inventors of the present application have found that by stabilizing the liquid composition against nitrosylation and / or oxidative degradation, chemically stabilizing it, preventing microbial growth and making it bioequivalent to the reference tablet bioequivalent, increases the shelf life of the liquid aqueous composition, and all of these effects are achieved only by adding at least one antioxidant selected from the group consisting of sulfite, bisulfite and pyrosulfite compounds to the liquid aqueous composition in the pH range of 5.0 to 7.0, 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.

[0066] In one embodiment of the present application, the liquid aqueous pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0067] Pharmaceutical excipients used for the preparation of the liquid aqueous pharmaceutical composition of the present application are known in the art and can be selected by the skilled person according to their function. Reference can be made in this context to the Handbook of Pharmaceutical Excipients, edited by Paul J Sheskey et al., 9th edition, Pharmaceutical Press (2020).

[0068] According to one embodiment of the liquid aqueous pharmaceutical composition of the present application, the one or more pharmaceutically acceptable excipients are selected from the group consisting of co-solvents, sweeteners and flavouring agents.

[0069] The liquid aqueous pharmaceutical composition of the present application can comprise at least one co-solvent to aid the dissolution of the additives in the composition.

[0070] In one embodiment of the liquid aqueous pharmaceutical composition of the present application, the co-solvent is selected from the group consisting of propylene glycol, polyethylene glycol, glycerol and mixtures thereof.

[0071] In one embodiment of the liquid aqueous pharmaceutical composition of the present application, the co-solvent is selected from the group consisting of propylene glycol, polyethylene glycol, glycerol and mixtures thereof, and wherein the co-solvent is present in an amount of 5 to 50 wt.-%, based on the total weight of the pharmaceutical composition.

[0072] In order to enhance the flavor of the liquid aqueous pharmaceutical composition, the liquid aqueous pharmaceutical composition of the present application can further comprise at least one sweetener and / or at least one flavoring agent.

[0073] In one embodiment of the liquid aqueous pharmaceutical composition of the present application, the sweetener is selected from erythritol, fructose, dextrose, saccharin, sorbitol, xylitol, mannitol, maltose, maltitol, maltitol solution, liquid glucose, inulin, lactitol, sodium saccharin, sodium cyclamate, sucralose, sucrose, acesulfame potassium or aspartame.

[0074] In a most preferred variant of the above-mentioned embodiment, the sweetener is selected from xylitol, mannitol, acesulfame potassium, aspartame, erythritol, maltitol or sucrose, and wherein the sweetener is present in an amount of 1 to 20 wt.-%, based on the total weight of the pharmaceutical composition.

[0075] In one embodiment of the liquid aqueous pharmaceutical composition of the present application, the flavoring agent is at least one flavoring agent selected from the group consisting of a mint flavoring agent, a tropical flavoring agent, a banana flavoring agent, a cherry flavoring agent or an orange flavoring agent.

[0076] In one embodiment of the liquid aqueous pharmaceutical composition of the present application, wherein the flavoring agent is selected from the group consisting of a mint flavoring agent, a tropical flavoring agent, a banana flavoring agent, a cherry flavoring agent and an orange flavoring agent, and wherein the flavoring agent is present in an amount of 0.01 to 5 wt.-%, based on the total weight of the pharmaceutical composition.

[0077] In one embodiment, the liquid aqueous pharmaceutical composition according to the present application comprises:

[0078] Ingredients Amounts (in weight %, based on the total weight of the pharmaceutical composition) Delavine 0.1％-10％ Sweetener 1％-20％ pH adjuster 0.05％-10％ Co-solvent 5％-50％ Antioxidant 0.01％-1％ Flavoring agent 0.01％-5％ Purified water Supplement to 100%

[0079] In a preferred variant of the above-mentioned embodiment, the liquid aqueous pharmaceutical composition according to the present application comprises:

[0080]

[0081] One embodiment of the present application is a method for preparing a stabilized liquid aqueous composition comprising bauhinia bark extract or a pharmaceutically acceptable salt thereof, the method comprising:

[0082] i) providing an aqueous bauhinia bark extract solution,

[0083] ii) adding at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds,

[0084] iii) optionally, adding further pharmaceutically acceptable excipients,

[0085] iv) adjusting the pH to a value in the range of 5.0 to 7.0 by adding at least one inorganic pH adjusting agent, and

[0086] v) finally, adding water to prepare the final volume,

[0087] wherein the at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds is present in an amount of 0.01 to 2.0 wt.-%, based on the total weight of the pharmaceutical composition.

[0088] In one embodiment, when preparing an aqueous solution of biperiden, 90% of the total amount of water used for the composition is used for biperiden dissolution, followed by the addition of at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds, optional pharmaceutically acceptable excipients and at least one inorganic pH adjusting agent to adjust the pH to a value in the range of 5.0 to 7.0. The remaining water added in the final step of preparing the composition to the final volume has no effect on the pH range of 5.0 to 7.0.

[0089] In one embodiment, the liquid aqueous pharmaceutical composition of the present application is suitable for administration as a mist, spray or aerosol.

[0090] In one embodiment, the liquid aqueous pharmaceutical composition of the present application can be transferred into a bottle equipped with a nebulizer, which is capable of dispensing 1.5 mg biperiden per actuation.

[0091] One embodiment of the present application provides a liquid aqueous pharmaceutical composition for oral use in the treatment of smoking addiction and other forms of nicotine addiction, comprising biperiden and at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds, wherein the at least one antioxidant is present in an amount of 0.01 to 2.0 wt.-%, based on the total weight of the pharmaceutical composition, and wherein the pH of the liquid aqueous composition is in the range of 5.0 to 7.0, 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.

[0092] One embodiment of the present invention is the use of at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds for the stabilization of a liquid aqueous pharmaceutical composition comprising delavay anthraglycoside, wherein the at least one antioxidant is present in an amount of 0.01 to 2.0 wt.-%, based on the total weight of the pharmaceutical composition, and wherein the pH of the liquid aqueous composition is in the range of 5.0 to 7.0, preferably in the range of 5.2 to 6.7, more preferably 5.5-6.4, and most preferably 5.8-6.1.

[0093] The present invention comprises the following embodiments:

[0094] 1. A liquid aqueous pharmaceutical composition comprising delavay anthraglycoside or a pharmaceutically acceptable salt thereof, at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds, wherein the antioxidant is present in an amount of 0.01 to 2.0 wt.-%, based on the total weight of the pharmaceutical composition, and wherein the pH of the liquid aqueous composition is in the range of 5.0 to 7.0.

[0095] 2. The liquid aqueous pharmaceutical composition according to embodiment 1, wherein the antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds is present in an amount of 0.01 to 1.0 wt.-%, based on the total weight of the pharmaceutical composition.

[0096] 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 metabisulfite and potassium metabisulfite.

[0097] 4. The liquid aqueous pharmaceutical composition according to embodiment 3, wherein the antioxidant is sodium sulfite or sodium metabisulfite.

[0098] 5. The 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.

[0099] 6. The liquid aqueous pharmaceutical composition according to any one of embodiments 1 to 5, wherein delavay anthraglycoside or a pharmaceutically acceptable salt thereof is present in an amount corresponding to 0.1 to 10 wt.-% of delavay anthraglycoside free base, based on the total weight of the pharmaceutical composition.

[0100] 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.

[0101] 8. The liquid aqueous pharmaceutical composition according to any one of embodiments 1 to 7, having the following composition:

[0102] Ingredients Amounts (in weight %, based on the total weight of the pharmaceutical composition) Delavine 0.1％-10％ Sweetener 1％-20％ pH adjuster 0.05％-10％ Co-solvent 5％-50％ Antioxidant 0.01％-1％ Flavoring agent 0.01％-5％ Purified water Supplement to 100%

[0103] 9. The liquid aqueous pharmaceutical composition according to any one of embodiments 1 to 8, having the following composition:

[0104]

[0105] 10. The 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.

[0106] 11. The liquid aqueous pharmaceutical composition for use according to embodiment 10, wherein the liquid composition is for administration into the oral cavity of a subject by mist, spray or aerosol.

[0107] 12. Use of at least one antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds for the stabilization of a liquid aqueous pharmaceutical composition comprising delavine, wherein the antioxidant is present in an amount of 0.01 to 2.0 wt.-%, based on the total weight of the pharmaceutical composition, and wherein the pH of the liquid aqueous composition is in the range of 5.0 to 7.0.

[0108] Experimental part

[0109] Measuring instruments, conditions and protocols :

[0110] Method of pH measurement :

[0111] The pH is measured at room temperature (20 °C to 25 °C) and atmospheric pressure using a potentiometric pH meter apparatus (such as 913 pH Meter Lab, LL-Unitrode easy Clean 1 m) calibrated using 2.00, 4.01 and 7.00 buffer solutions according to European Pharmacopoeia 2.2.3.

[0112] Detection of chemical purity :

[0113] Chemical purity analysis is performed using a high-performance liquid chromatograph equipped with a PDA detector, a sample cooling system and a column thermostat.

[0114]

[0115]

[0116] Detection of N-nitroso-delavine impurities

[0117] The analysis for the acceptable intake (AI) level for detection of N-nitrosoindatrine is performed using a liquid chromatograph with MS detector, such as a Shimadzu Nexera X2 LC MS 8040 equipped with a Phenomenex Luna Omega 1.6 pm 2.1 x 100 mm column, or equivalent.

[0118] The following examples serve to describe the present application in detail without being understood as limiting the same.

[0119] Example 1: Preparation of liquid composition of delavine at pH 6.1 using sodium metabisulfite as an antioxidant .

[0120] The quantitative composition of this formulation is shown in the table below. Indatrine is dissolved together with sodium metabisulfite in 90% of the total amount of water used for the composition, after which propylene glycol, xylitol and mint flavor are added and the pH of the formulation is adjusted to 6.1 by adding disodium phosphate dihydrate, then the remaining water is added to the desired volume.

[0121] The finished pharmaceutical composition is transferred to an HDPE bottle equipped with a nebulizer.

[0122]

[0123] Example 2: Preparation of liquid composition of delavine at pH 5.8 using sodium metabisulfite as an antioxidant .

[0124] The quantitative composition of this formulation is shown in the table below. Indatrine is dissolved together with sodium metabisulfite in 90% of the total amount of water used for the composition, after which propylene glycol, xylitol and mint flavor are added and the pH of the formulation is adjusted to 5.8 by adding disodium phosphate dihydrate, then the remaining water is added to the desired volume.

[0125] The finished pharmaceutical composition is transferred to an HDPE bottle equipped with a nebulizer.

[0126]

[0127] Example 3: Preparation of liquid composition of delavine at pH 6.1 using sodium sulfite as an antioxidant .

[0128] The quantitative composition of this formulation is shown in the table below. Indatrine is dissolved together with sodium metabisulfite in 90% of the total amount of water used for the composition, after which propylene glycol, xylitol and mint flavor are added and the pH of the formulation is adjusted to 6.1 by adding disodium phosphate dihydrate, then the remaining water is added to the desired volume.

[0129] The finished pharmaceutical composition is transferred to an HDPE bottle equipped with a nebulizer.

[0130] ​

[0131] Example 4: Preparation of liquid composition of delavine at pH 6.1 using sodium bisulfite as an antioxidant .

[0132] The quantitative composition of this formulation is shown in the table below. Cytisine was dissolved together with sodium bisulfite in 90% of the total amount of water used for the composition, after which propylene glycol, xylitol and mint flavor were added, and the pH of the formulation was adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, and the remaining water was added to the desired volume.

[0133] The finished pharmaceutical composition was transferred into a HDPE bottle equipped with a nebulizer.

[0134]

[0135] Comparative Example 1: Preparation of liquid composition of delavine at pH 6.1 using maleic acid as an antioxidant .

[0136] The quantitative composition of this formulation is shown in the table below. Cytisine was dissolved together with maleic acid in 90% of the total amount of water used for the composition, after which propylene glycol, xylitol and mint flavor were added, and the pH of the formulation was adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, and the remaining water was added to the desired volume.

[0137]

[0138] Comparative Example 2: Preparation of liquid composition of delavine at pH 6.1 using sodium thiosulfate as an antioxidant .

[0139] The quantitative composition of this formulation is shown in the table below. Cytisine was dissolved together with sodium thiosulfate in 90% of the total amount of water used for the composition, after which propylene glycol, xylitol and mint flavor were added, and the pH of the formulation was adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, and the remaining water was added to the desired volume.

[0140]

[0141]

[0142] Comparative Example 3: Preparation of liquid composition of delavine at pH 6.1 using sodium ascorbate as an antioxidant .

[0143] The quantitative composition of this formulation is shown in the table below. Cytisine was dissolved together with sodium ascorbate in 90% of the total amount of water used for the composition, after which propylene glycol, xylitol and mint flavor were added, and the pH of the formulation was adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, and the remaining water was added to the desired volume.

[0144]

[0145] Comparative Example 4: Preparation of liquid composition of delavine at pH 6.1 using butylated hydroxytoluene (BHT) as an antioxidant Comparative Example 5: Preparation of liquid composition of delavine at pH 6.1 without an antioxidant .

[0146] The quantitative composition of this formulation is shown in the table below. The bauhinia base is dissolved in 90% of the total amount of water used for the composition, after which the BHT, propylene glycol, xylitol and mint flavor are added, and the pH of the formulation is adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, then the rest of the water is added to the desired volume.

[0147] It was observed that the BHT in the composition remains insoluble and is present as a suspension.

[0148]

[0149] Comparative Example 6: Preparation of liquid composition of delavine at pH 4.5 .

[0150] The quantitative composition of this formulation is shown in the table below. The bauhinia base is dissolved in 90% of the total amount of water used for the composition, after which the BHT, propylene glycol, xylitol and mint flavor are added, and the pH of the formulation is adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, then the rest of the water is added to the desired volume.

[0151]

[0152] Ingredients

[0153] The quantitative composition of this formulation is shown in the table below. The bauhinia base is dissolved in 90% of the total amount of water used for the composition, after which the BHT, propylene glycol, xylitol and mint flavor are added, and the pH of the formulation is adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, then the rest of the water is added to the desired volume.

[0154] Amounts Delavine [％] Xylitol 0.70 Sodium metabisulfite 10.0 Monohydrate citric acid 0.8 Sodium citrate dihydrate 2.0 Glycerol 1.25 Propylene glycol 21.0 Liquid mint flavoring agent 21.0 HCl / NaOH for pH adjustment 0.1 Purified water Comparative Example 7: Preparation of liquid composition of delavine at pH 8.7 43.15

[0155] Ingredients

[0156] The quantitative composition of this formulation is shown in the table below. The bauhinia base is dissolved in 90% of the total amount of water used for the composition, after which the BHT, propylene glycol, xylitol and mint flavor are added, and the pH of the formulation is adjusted to 6.1 by adding sodium dihydrogen phosphate dihydrate, then the rest of the water is added to the desired volume.

[0157] Amounts Delavine [％] Xylitol 0.70 Sodium metabisulfite 10.0 Monohydrate sodium dihydrogen phosphate 0.08 Glycerol 0.1 Propylene glycol 21.0 Liquid mint flavoring agent 21.0 Purified water 0.07 Comparative Example 8: Liquid composition of delavine according to Example 2 of RU 2593585 47.05

[0158] Comparative Example 9: Liquid composition of delavine according to composition 13 of international patent application WO2021115977A1

[0159] A liquid bauhinia base composition was prepared as described in Example 2 of RU 2593585, and its quantitative composition is shown in the table below:

[0160]

[0161] Comparative study of chemical stability of liquid pharmaceutical compositions using various antioxidants .

[0162] The liquid cytisine composition was prepared as described in composition 13 of international patent application WO2021115977A1 ​​and its quantitative composition is shown in the following table:

[0163]

[0164]

[0165] Comparative study of chemical stability of liquid pharmaceutical compositions at different pH levels. .

[0166] The chemical stability of the liquid aqueous compositions of the present invention containing sodium metabisulfite and sodium sulfite as antioxidants at pH 6.1 was studied under accelerated storage conditions (40°C / 75% RH) in comparison with liquid compositions containing different antioxidants at pH 6.1 as described in Comparative Examples 1 and 3. All samples were stored in a climate chamber and samples were obtained at time intervals of 0, 1 and 2 months and analyzed by HPLC.

[0167] The results of the stability study showed that a significant increase in chemical impurities above their acceptable limits was observed when using different antioxidants under accelerated storage conditions at pH 6.1 compared to the compositions of Example 1 and Example 3 containing sodium metabisulfite and sodium sulfite as antioxidants, respectively.

[0168]

[0169] Comparative study of N-nitroso-cysteine content in liquid pharmaceutical compositions with various antioxidants, liquid pharmaceutical compositions without antioxidants and prior art compositions

[0170] The chemical stability of the liquid aqueous compositions of the present invention containing sodium metabisulfite and sodium sulfite as antioxidants at pH 6.1 was compared with liquid compositions containing sodium metabisulfite as antioxidant at pH 4.5 and 8.7 as described in Comparative Examples 6 and 7, and the composition of Example 2 of RU2593585 at pH 7.7 (Comparative Example 8) under accelerated storage conditions (40°C / 75% RH). All samples were stored in a climate chamber, and samples were obtained at time intervals of 0, 1, and 2 months and analyzed by HPLC. All chemical impurity content values ​​are expressed as percentages (%).

[0171] The results of the stability studies indicate that at accelerated storage conditions, the chemical impurities significantly increased above the acceptable limits at pH values below 5.0 and above 7.0. However, the compositions of Example 1 and Example 3 were stable and met the requirements for pharmaceutical drug products containing cystine (FO impurities <0.5%, ME impurities <0.5%, maximum single unknown impurity <0.2%, total impurities <1.0%).

[0172] The accelerated study of the composition from Example 2 of RU2593585 (Comparative Example 8) was continued for 6 months and the total impurities were greater than 1.0%, indicating that the pharmaceutical drug product with cystine was out of specification.

[0173]

[0174] Comparative bioavailability study Testing of antimicrobial preservative efficacy .

[0175] The N-nitroso vilmorine base content at pH 6.1 of the liquid pharmaceutical compositions of the present invention containing sodium metabisulfite, sodium sulfite and sodium bisulfite as antioxidants as described in Example 1, Example 3 and Example 4 were compared with the liquid compositions containing different antioxidants as described in Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4 and Comparative Example 5 (without antioxidants) and the prior art compositions as described in Comparative Example 8 and Comparative Example 9, the studies were carried out under normal storage (25°C / 75% RH) and accelerated storage conditions (40°C / 75% RH). All samples were stored in a climatic chamber and samples were taken at 1 month and 6 month intervals and analyzed by LCMS, where the content of N-nitroso vilmorine base impurity was expressed in parts per million (ppm).

[0176] The results of the stability studies indicate that compared to the compositions of Example 1, Example 3 and Example 4 containing sodium metabisulfite, sodium sulfite and sodium bisulfite as antioxidants respectively, a significant increase in the content of N-nitroso vilmorine base impurity was observed under accelerated storage conditions in Comparative Example 8 and was higher than its minimum possible recommended acceptable intake (AI) limit of 2.0 ppm, where the liquid compositions contained different antioxidants as described in Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4 and Comparative Example 5 (without antioxidants) and Comparative Example 9.

[0177]

[0178] Definitions

[0179] The comparative bioavailability of the following vilmorine base dosage forms was tested.

[0180] - Wild yate, 1.5 mg oral solution of Example 1, administered as a single dose under fasting conditions (A).

[0181] - Wild yate, 1.5 mg oral solution of Example 1, administered as a single dose under fasting conditions and with water intake after the dose (B).

[0182] - 1.5 mg film-coated tablets administered as a single dose under fasting conditions with water intake.

[0183] A randomized, open-label, single-dose, three-period, pilot, bioavailability study in 24 healthy volunteers under fasting conditions was performed.

[0184] The bioavailability data (AUC, C max and T max) obtained for wild yate oral solution (treatments A and B) versus

[0185] (therapy C) are shown in the following table.

[0186]

[0187] Surprisingly, it was found that the liquid aqueous composition of the present application is bioequivalent to the reference product Wild yate, 1.5 mg oral solution of Example 1, administered as a single dose under fasting conditions (A). max and T max max) obtained for wild yate oral solution (treatments A and B) versus

[0188]

[0189] Surprisingly, it was found that the liquid aqueous composition of the present application is bioequivalent to the reference product Wild yate, 1.5 mg oral solution of Example 1, administered as a single dose under fasting conditions (A).

[0190] ​

[0191] The antimicrobial preservative efficacy of the compositions of Example 1, Example 3 and Comparative Example 9 was tested. The compositions were tested with a defined inoculum of microorganisms (as listed in the table below), the inoculated preparations were stored at a defined temperature and samples, typically 1 ml or 1 g, were withdrawn from the containers at zero hour and at appropriate intervals (14 days and 28 days) and the number of viable microorganisms was determined by plate count.

[0192] The acceptance criteria for the evaluation of antimicrobial activity are specified in Ph. Eur. 5.1.3 in terms of log10 reduction of the number of viable microorganisms with respect to the values obtained for the inoculum. The preservative performance of a preparation is adequate if, during the test period, there is a significant reduction or no increase in the number of microorganisms in the inoculated preparation after the specified time and at the specified temperature, as the case can be.

[0193] As shown in the table below, the compositions of Example 1 and Example 3 showed no increase in the number of microorganisms in the inoculated preparation after 14 days and 28 days, respectively, and thus met the requirements specified in Ph. Eur. 5.1.3. In contrast, the composition of Comparative Example 9 exhibited a significant increase in Aspergillus brasiliensis and Staphylococcus aureus and thus did not meet the requirements specified in Ph. Eur. 5.1.3.

[0194]

Claims

1. A liquid aqueous pharmaceutical composition comprising cytisine or a pharmaceutically acceptable salt thereof, at least one antioxidant selected from the group consisting of sulfite, bisulfite, and metabisulfite compounds, wherein the antioxidant is present in an amount of 0.01 wt % to 2.0 wt % based on the total weight of the pharmaceutical composition, and wherein 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 the antioxidant selected from the group consisting of sulfite, bisulfite and metabisulfite compounds is present in an amount of 0.01 wt% to 1.0 wt% 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 the group consisting of sodium sulfite, potassium sulfite, sodium bisulfite, potassium bisulfite, sodium metabisulfite and potassium metabisulfite.

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

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 cytisine or a pharmaceutically acceptable salt thereof is present in an amount corresponding to 0.1 wt% to 10 wt% of cytisine free 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. The 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 for administration into the oral cavity of a subject by mist, spray or aerosol.

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

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