Pharmaceutical compositions comprising vortioxetine hydrobromide with improved nitrosamine impurity profile

Abstract

The present invention relates to a stable solid pharmaceutical composition comprising vortioxetine hydrobromide or pharmaceutically acceptable salt / derivative thereof with improved nitrosamine impurity profile wherein the composition comprising vortioxetine hydrobromide and the pharmaceutically acceptable salt thereof and has manufactured by using wet granulation method by employing water as the granulation solvent.

Description

[0001] PHARMACEUTICAL COMPOSITIONS COMPRISING VORTIOXETINE HYDROBROMIDE WITH IMPROVED NITROSAMINE IMPURITY PROFILE

[0002] Technical Field

[0003] The present invention relates to a stable pharmaceutical composition comprising vortioxetine hydrobromide or pharmaceutically acceptable salt / derivatives thereof with improved nitrosamine impurity profile wherein the composition comprising vortioxetine hydrobromide and at least one pharmaceutically acceptable excipient which was manufactured by using wet granulation method by employing water as the granulation solvent.

[0004] Background Of The Invention

[0005] Vortioxetine is an antidepressant used for the treatment of major depressive disorder (MDD). It functions as an antagonist for 5-HT3, 5-HT7 and 5-HT1D receptors, a partial agonist for 5- HT1B receptors, an agonist for 5-HT1A receptors, and an inhibitor of the serotonin (5-HT) transporter (SERT). Moreover, it has demonstrated to enhance the levels of the neurotransmitters serotonin, noradrenalin, dopamine, acetylcholine and histamine in specific areas of the brain.

[0006] The chemical name of vortioxetine is l-[2-(2, 4-dimethyl-phenylsulfanyl)-phenyl]-piperazine and has an empirical formula of CisH22N2S.HBr and its relative molecular mass is 298.45 mg / mol as a free base and 379.36 mg / mol as the hydrobromide salt. The chemical structure of Vortioxetine is shown in the Formula I.

[0007] Formula I

[0008] Vortioxetine hydrobromide (Vortioxetine HBr) appears as a white to very slightly beige powder, non-hygroscopic, soluble in methanol and ethanol and slightly soluble in water and aqueous solutions at pH 2.0 to 8.3. Its pKa is 9.1 as the free base and 3.0 as the salt.

[0009] Vortioxetine HBr was first commercially authorized in FDA by the U.S. Food &Drug Administration in September 2013. The medicinal product of it available on the market at film- coated tablet comprising Vortioxetine as the HBr salt and as an oral drop solution comprising Vortioxetine as the DL lactate salt under the name of the BRINTELLIX " which are used for the treatment of major depressive disorder (MDD) in adults.

[0010] Vortioxetine base and its pharmaceutically acceptable acid addition salts first have been described in EP 1436271 by H. Lundbeck A / S.

[0011] According to its manufacturing process, vortioxetine could pose a potential risk of nitrosamine formation due to containing a secondary amine group.

[0012] Nitrosamines are a class of organic compounds to which we are exposed at low levels in our daily lives, found in sources such as water, foods, even some drugs.

[0013] However, most recently, it has been realized that, some nitrosamines in the pharmaceutical formulation may increase the risk of the cancer if people are exposed to them above acceptable intake levels over a long period of time. Thus, these are classified as probable human carcinogens (substances that could cause cancer). Because of that, the presence of nitrosamines in pharmaceutical compositions is required to be mitigated as much as possible and to ensure that the levels of these impurities do not exceed strict limits.

[0014] Nitrosamines can be found naturally in the environment and could generate with a trigger such as oxidative environment, reagents, temperature and acidic conditions. Specifically, a nitrosamine impurity originates from the nitrosation of a reagent by a nitrosating agent. Nitrosatable compounds and nitrosating agents can be introduced at various points in the manufacturing process of the drug subdtance or drug product, such as in the chemicals and solvents utilized, or they may emerge as a result of the degradation of the drug substance during the shelf-life of the drug product. As a result, a carryover could be present from drug substance to the drug products.

[0015] The prevailing strategy for mitigating nitrosamine impurities in active pharmaceutical ingredients and / or the final dosage form is to modify the synthesis pathways to eliminate nitrosable compounds and nitrosating agents capable of generating nitrosamines, which could contaminate the final drug product. Furthermore, if the active pharmaceutical ingredient (API) is a secondary amine and is manufactured using a method such as wet granulation, the presence of water, which serves as the granulation solvent, can potentially dissolve trace nitrite. Then, the dissolved nitrite could be turned into the nitrosamine impurity during the removing the granulation solvent during or after due to the drying process.

[0016] However, the inventors of the present invention have surprisingly found that the amount of the nitrosamine already present in the drug product, vortioxetine hydrobromide, does not increase during the production of the final product; even when employing potentially triggering process steps for nitrosamine formation, such as granulation and drying processes during the wet granulation.

[0017] Therefore, the present invention relates to a stable solid pharmaceutical composition comprising vortioxetine hydrobromide or pharmaceutically acceptable salt / derivatives thereof and at least one pharmaceutically acceptable excipient, wherein the improved stability profiles with lower levels of nitrosamine impurities are achieved, even though the developed pharmaceutical composition is manufactured by using wet granulation method with water as the granulation solvent.

[0018] Summary Of The Invention

[0019] The object of this invention is to develop a stable pharmaceutical composition comprising a therapeutically effective amount of vortioxetine hydrobromide or pharmaceutically acceptable salt / derivatives thereof and at least one pharmaceutically acceptable excipient wherein the nitrosamine impurity profile of the composition is remarkably improved.

[0020] Another object of the present invention is to provide a preparation method of a pharmaceutical composition of vortioxetine hydrobromide wherein the pharmaceutical composition herein disclosed can be manufactured into solid dosage forms, such as tablets.

[0021] Wet granulation is one of the manufacturing methods that commences by adding the granulating solution or solvent to the mixed powders under shear to obtain granules with the strongest form of adhesion between particles, which is achieved when the granulation solvent, such as water, is eventually evaporated.

[0022] According to the literature, the formation of nitrosamines in drug products during drying step could be attributed to the interaction of drug substances containing nitrates / nitrites with water, which serves as a source of oxygen in a strongly possible oxidation reaction.

[0023] Another object of the present invention is to provide a stable solid pharmaceutical composition manufactured by using wet granulation method, including the steps of: a) obtaining the powder blend comprising vortioxetine hydrobromide and at least one pharmaceutical acceptable excipient; b) obtaining granulation solution comprising proper amount of binder and granulation solvent; c) obtaining granule by adding the granulation solution on to the powder blend; d) removing the solvent by heating to obtain the dried granule.

[0024] Another object of the present invention is to provide a stable pharmaceutical composition comprising vortioxetine hydrobromide or pharmaceutically acceptable salt / derivatives thereof and at least one pharmaceutically acceptable excipient manufactured using wet granulation process with a low amount of nitrosamine impurity, wherein the step of evaporating of granulation solvent occurs at a specified product temperature range 22°C - 28°C.

[0025] Detailed Description Of The Invention

[0026] The present invention provides a pharmaceutical composition comprises vortioxetine hydrobromide or pharmaceutically acceptable salt / derivatives thereof as active substance and pharmaceutically acceptable excipient manufactured by using wet granulation method.

[0027] Vortioxetine hydrobromide is classified as BCS (Biopharmaceutics Classification System) class I or III compound which means that it exhibits high solubility and high permeability.

[0028] Vortioxetine as a base form has a high potency of nitrosamine impurity risk due to its chemical structure. The structure itself includes a secondary amine group. In a secondary amine group, two of the hydrogens in an ammonia molecule have been replaced by hydrocarbon groups. At this level, you are only likely to come across simple ones where both of the hydrocarbon groups are alkyl groups and both are the same.

[0029] The secondary amine groups are strongly likely to nitrosating by nitrosating agents.

[0030] The nitrosating agents are nitrites and nitrates.

[0031] Since there is a secondary group in the chemical structure of vortioxetine, the nitrosamine impurities are explored and identified. The names of the impurities are N-nitroso piperazine monomer, N-nitroso piperazine dimer and N-nitroso vortioxetine.

[0032] The manufacturing method of the present invention is designed as wet granulation in which the water is the granulation solvent.

[0033] The preferred embodiment of the present invention provides pharmaceutical compositions such as powders, granules, tablets and capsules thereof. Moreover, the pharmaceutical composition is also provided for the immediate release solid dosage form containing the active ingredient, diluent, disintegrant, binder, lubricant and solvent.

[0034] In a preferred embodiment, the pharmaceutical composition comprising at least one diluent which can be selected from dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, lactose monohydrate, mannitol, primarily calcium salts and the like and mixtures thereof. Preferably, diluent is mannitol and microcrystalline cellulose.

[0035] In a preferred embodiment, the pharmaceutical composition comprising at least one disintegrant which can be selected from croscarmellose sodium, sodium starch glycolate, crospovidone, corn starch, pregelatinized starch, low-substituted hydroxypropyl cellulose and microcrystalline cellulose. Preferably, the disintegrant is sodium starch glycolate.

[0036] In a preferred embodiment, the pharmaceutical composition comprises at least a binder which can be selected from hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol, or mixtures thereof. Preferably, the binder is hydroxypropyl methylcellulose.

[0037] In a preferred embodiment, the pharmaceutical composition comprising at least one lubricant which can be selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof. Preferably, the lubricant is magnesium stearate.

[0038] Manufacturing process is as presented below: a. Binder is dissolved in water. b. Vortioxetine hydrobromide, diluent(s) is weighed, sifted, transferred to High Shear Mixer (HSM) device and mixed. c. The powder blend in step b is mixed with the binder solution at step a, to carry out the granulation process. d. The granule in step c is sieved, dried with fluid-bed dryer till the product temperature is between 30°C - 32°C to get maximum 1% humidity level and sifted. e. Disintegrant is added to the sifted granules and mixed. f. Lubricant is weighed and added to the powder blend in step e, mixed. g. Tablet compression is performed with the powder in step f.

[0039] Example-1 was analysed to investigate whether there is any possibility of nitrosamine impurity at high levels regarding possibilities due to excipient, active substance and manufacturing process. The nitrosamine impurities that were examined are N-nitroso piperazine monomer, N- nitroso piperazine dimer and N-nitroso vortioxetine.

[0040] Table-1: The result of nitrosamine impurity analysis of Example-1 with the product temperature between 30°C - 32°C

[0041] *N.D. is abbreviation for the phrase of “Not detected”. Based on the results, it was observed that N-nitroso vortioxetine is at remarkably high levels in Example-1. Thus, active substance and the excipients were analysed to find out the root-cause.

[0042] Table-2: The result of nitrosamine impurity analysis of Vortioxetine hydrobromide active substance Table-3: The result of nitrosamine impurity analysis of excipients

[0043] After the observation regarding the results in Table-1, 2 and 3, it was absolutely defined the source of N-nitroso vortioxetine impurity is the active substance. However, the quantity in active substance was much more less than the amount detected in drug product. Thus, the manufacturing process and the degradation conditions of the active substance were explored again.

[0044] Vortioxetine hydrobromide as active substance was literally declared to be degraded under high oxidative conditions. In addition, the storage temperature of the active substance is between 2°C-8°C. However, the storage temperature of the drug product is room temperature.

[0045] The manufacturing process was examined in detail for an update considering the information above.

[0046] Only process that should be improved is the drying process. The product temperature in drying process during the manufacturing process of Example-1 was between 30°C-32°C. However, regarding it is not industrially applicable to decrease the temperature till to 2°C-8°C to remove water and get low level of nitrosamine impurity, the first choice would be changing the manufacturing process completely to avoid any oxidation source.

[0047] At this point, the inventors surprisingly achieved to obtain a stable solid pharmaceutical composition manufactured by using wet granulation process which presents improved nitrosamine impurity profile, by gradually decreasing the relevant product temperature during drying process even though not removing the oxidation source, water, form the composition.

[0048] Multiple examples were planned by making changes only in the product temperature values in drying process. The working temperature range would be very narrow, because it is obvious that could be a challenge regarding to decrease humidity level of the product while trying to get less nitrosamine impurity profile at low temperature values. The maximum humidity level of the granule should be 1%.

[0049] The other parameters in the manufacturing process and the formulation details were kept same.

[0050] Table-5: Examples manufactured with different drying temperature ranges and the results of nitrosamine impurity analysis

[0051] The temperature values less than 22°C was not applicable because of facing problems while removing the water totally during drying process. It is obviously not possible to foreseen by the technical person in the art and none of the literal and experimental studies are led to continue manufacturing with wet granulation process by employing water as the granulation solvent which could be the source of oxidation reaction and cause high nitrosamine impurity levels. A stable solid pharmaceutical composition comprising vortioxetine hydrobromide manufactured by using wet granulation process with water as a granulation solvent and the total nitrosamine impurity amount is maximum 0.50%.

[0052] While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

CLAIMS1. A stable solid pharmaceutical composition comprising vortioxetine hydrobromide or pharmaceutically acceptable salt / derivative thereof and at least one pharm ceutically acceptable excipient wherein the manufacturing process is wet granulation with water as the granulation solvent and the product temperature in the drying process is between 22°C-28°C.

2. A stable solid pharmaceutical composition according to claim 1, wherein the level of total nitrosamine impurity is maximum 0.50%.

3. A stable solid pharmaceutical composition according to any one of the previous claims, wherein the dosage form is selected from powders, granules, tablets and capsules thereof.

4. A stable solid pharmaceutical composition according to any one of the previous claims, wherein at least one pharmaceutically acceptable excipient is selected from diluent, disintegrant, binder and lubricant.

5. A stable solid pharmaceutical composition according to claim 4, wherein the diluent is selected from dibasic calcium phosphate dehydrate, polysaccharides, primarily microcrystalline cellulose, lactose anhydrous, lactose monohydrate, mannitol, primarily calcium salts and mixtures thereof.

6. A stable solid pharmaceutical composition according to claim 4, wherein the disintegrant is selected croscarmellose sodium, sodium starch glycolate, crospovidone, com starch, pregelatinized starch, low- substituted hydroxypropyl cellulose and microcrystalline cellulose.

7. A stable solid pharmaceutical composition according to claim 4, wherein the binder selected from hypromellose, sodium carboxymethyl cellulose, cellulose or cellulose derivatives, povidone, starch, sucrose, polyethylene glycol and mixtures thereof.

8. A stable solid pharmaceutical composition according to claim 4, wherein the lubricant selected from sodium stearyl fumarate, magnesium stearate, calcium stearate talc, stearic acid and mixtures thereof.

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