Pharmaceutical dosage form comprising sertraline

Abstract

The invention relates to a pharmaceutical dosage form for oral administration comprising (i) an intragranular phase, which comprises Sertraline or a physiologically acceptable salt thereof; one or more intragranular fillers (preferably selected from one or more sugar alcohols or sugars; preferably mannitol or lactose, more preferably mannitol); one or more intragranular antioxidants (preferably selected from butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), tocopherol or derivatives thereof, ascorbic acid or derivatives thereof, sodium metabisulphite, propyl gallate, sodium thiosulphate, or any combination thereof, more preferably ascorbic acid); (ii) an extragranular phase, which comprises one or more extragranular fillers (preferably mannitol, microcrystalline cellulose, lactose, or any combination thereof); and (iii) optionally, a film coating. The invention further relates to a process for manufacture by wet granulation, wherein the antioxidant is preferably dissolved in the granulation liquid.

Description

Pharmaceutical dosage form comprising Sertraline

[0001] Priority is claimed of Slovenian patent application no. SI P202400177 that was filed on 23 December 2025.

[0002] The invention relates to a pharmaceutical dosage form for oral administration comprising (i) an intragranular phase, which comprises Sertraline or a physiologically acceptable salt thereof; one or more intragranular fillers (preferably one or more sugar alcohols (such as mannitol) or sugars (such as lactose); more preferably mannitol); and one or more intragranular antioxidants (preferably selected from butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), tocopherol or derivatives thereof, ascorbic acid or derivatives thereof, sodium metabisulphite, propyl gallate, sodium thiosulphate, or any combination thereof, more preferably ascorbic acid or derivatives thereof);(ii) an extragranular phase, which comprises one or more extragranular fillers (preferably mannitol, microcrystalline cellulose, lactose, or any combination thereof); and(iii) optionally, a film coating.

[0003] The invention further relates to a process for manufacture of the pharmaceutical dosage form by wet granulation, wherein the antioxidant is dissolved in the granulation liquid.

[0004] Many active substances contain a secondary amine group in their structure, which in the presence of nitrite can oxidize to aN-nitrosamine impurity of the active substance.

[0005] The unexpected detection of nitrosamine impurities in human medicines has recently seen global regulators act to understand the risks of these contaminations to patients and to limit their presence . Over 300 nitrosamines are known, many of which are highly potent mutagenic carcinogens (R. Ruepp et al., Front. Med., 19 November 2021, Sec. Regulatory Science, Volume 8 - 2021 | https: / / doi.org / 10.3389 / fined.2021.782536).

[0006] Sertraline (ATCN06AB06, CAS 79617-96-2) is useful to treat major depressive disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and premenstrual dysphoric disorder.

[0007] Sertraline is commercialized under the trade name Zoloft® (Pfizer, Roerig). The product is supplied for oral administration as scored tablets containing Sertraline hydrochloride equivalent to 25, 50 and 100 mg of Sertraline, dibasic calcium phosphate dihydrate, hydroxypropyl cellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, synthetic yellow iron oxide (in 100 mg tablet), and titanium dioxide.

[0008] Sertraline is further commercialized under the trade names Sertraline Accord® (Accord Healthcare) and Tresleen® (Pfizer). The product is supplied for oral administration as capsule shaped, film coated tablets containing Sertraline hydrochloride equivalent to 50 and 100 mg of Sertraline. The excipients are in the tablet core - calcium hydrogen phosphate dihydrate (E341), microcrystalline cellulose (E460), hydroxypropyl cellulose (E463), sodium starch glycolate (Type A) (E468) and magnesium stearate (E470b); and in the film-coating - Opadry White containing: hypromellose 2910 (5mPa.s) (E464), macrogol 400 (E1521), polysorbate-80 (E433) and titanium dioxide (E171).

[0009] Sertraline is also commercialized under the trade name Adjuvin® (GL Pharma). The product is supplied for oral administration as film coated tablets containing Sertraline hydrochloride equivalent to 100 mg of Sertraline. The excipients are in the tablet core - calcium hydrogen phosphate dihydrate, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate (Type A), magnesium stearate, and polysorbate 80; and in the film-coating - hypromellose, propylene glycol and titanium dioxide.

[0010] Sertraline is prone to formation of a nitrosamine; the N-methyl functional group of Sertraline is a precursor for N-nitrosation on the secondary amine group yielding N-nitroso-Sertraline:

[0011] Because nitrosamines are probable or possible human carcinogens, FDA recommends that manufacturers consider the potential causes of nitrosamine formation and evaluate the risk for nitrosamine contamination or formation in their APIs and drug products (FDA Guidance for Industry, Control of Nitrosamine Impurities in Human Drugs, February 2021).

[0012] There is a demand for pharmaceutical dosage forms that do not contain nitrosamines and that do not form N-nitrosamines upon storage.

[0013] WO 2021 259396 relates to a pharmaceutical composition comprising Varenicline and pharmaceutically acceptable acid. The examples describe compositions comprising Varenicline tartrate, tartaric acid and microcrystalline cellulose.

[0014] WO 2023 / 119100 relates to a formulation comprising therapeutically active agent, one or more stabilizing agents, and one or more pharmaceutically acceptable excipients. In the description, Sertraline is listed among the active ingredients. The examples describe compositions comprising varenicline tartrate, bumetanide, carbamazepine or amitriptyline hydrochloride. Antioxidants as ascorbic acids, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT) used as stabilizing agents and microcrystalline cellulose, lactose anhydrous or anhydrous dibasic calcium phosphate or their mixture used as fillers.

[0015] WO 2024 / 127365 relates to a pharmaceutical composition comprising an amine drug and nitrite quencher. In the description, Sertraline is listed among the active ingredients. Examples describe multiparticulate dosage form as inert core coated with the drug layer comprising duloxetine and / or mannitol and / or ascorbic acid. It has been observed that a formulation containing ascorbic acid, without mannitol, significantly improves the stability of the formulation. Moreover, the results indicated that this improvement was greater than in formulations containing both mannitol and ascorbic acid.

[0016] CN 115 721 724 relates to a pharmaceutical composition comprising a secondary amine compound and a pharmaceutically acceptable acid. In the description, Sertraline is listed among the active ingredients.

[0017] The pharmaceutical dosage forms of Sertraline according to the prior art are not satisfactory in every aspect and there is a demand for improved dosage forms.

[0018] It is an object according to the invention to provide a dosage form of Sertraline that has advantages compared to the dosage forms of the prior art. The invention aims at providing an optimized formulation in which the formation of N-nitroso-Sertraline is suppressed as much as possible. The dosage form should have a satisfactory shelf-life and storage stability and should not require high contents of excipients with stabilizing effect in order to suppress formation of N-nitroso-Sertraline.

[0019] This object has been achieved by the subject-matter of the patent claims.

[0020] It has been surprisingly found that the choice of filler in the pharmaceutical composition affects the formation of N-nitroso-Sertraline impurities. When testing different fillers, it was discovered that replacing calcium hydrogen phosphate and part of the microcrystalline cellulose with mannitol reduces impurity formation. Additionally, mannitol alone as a filler significantly limits the formation of N-nitroso-Sertraline. It was further shown that compositions comprising lactose provide compositions with N-nitroso-Sertraline impurities within desired limits. Compositions containing calcium hydrogen phosphate were most prone to N-nitroso-Sertraline impurity formation, therefore the dosage form according to the invention is preferably free of calcium hydrogen phosphate.

[0021] Further, it has been surprisingly found that using mannitol as a filler in the intragranular phase has an even greater effect on reducing nitroso impurity formation.

[0022] Still further, it has been surprisingly found that combining mannitol with ascorbic acid as an antioxidant significantly limits the formation of N-nitroso-Sertraline compared to using either ascorbicacid or mannitol alone. When combined with mannitol, lower amounts of ascorbic acid are required to keep N-nitroso-Sertraline impurity levels under the safe limit of 0.5 ppm.

[0023] Moreover, it has been surprisingly found that incorporating ascorbic acid in the wet-granulate phase is more effective in mitigating impurity formation than adding ascorbic acid to the extragranular phase. Using ascorbic acid dissolved in the granulation liquid is also more effective in mitigating impurity formation than adding ascorbic acid to the mixture of powders for granulation.

[0024] A first aspect according to the invention relates to a pharmaceutical dosage form for oral administration comprising or essentially consisting of:(i) an intragranular phase, which comprises or essentially consists of:- Sertraline or a physiologically acceptable salt thereof; preferably Sertraline hydrochloride; - one or more intragranular fillers; preferably selected from(ia) one or more sugar alcohols; preferably selected from alditol, mannitol, meglumine, xylitol, isomalt, sorbitol, lactitol, pentitol, arabitol, ribitol, galactitol, erythritol, and any combination thereof; more preferably mannitol; or(ib) one or more sugars; preferably selected from lactose anhydrous and monohydrate, compressible sugar, fructose, dextrates, saccharose, raffinose, trehalose or mixture thereof; more preferably lactose;most preferably intragranular filler is selected from mannitol;- one or more intragranular antioxidants; preferably selected from butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), tocopherol or derivatives thereof, ascorbic acid or derivatives thereof, sodium metabisulphite, propyl gallate, sodium thiosulphate, or any combination thereof; more preferably ascorbic acid;- optionally, one or more intragranular disintegrants; preferably sodium carboxymethyl starch; - optionally, one or more intragranular binders; preferably hydroxypropyl cellulose;(ii) an extragranular phase, which comprises or essentially consists of:- one or more extragranular fillers; preferably selected from one or more sugar alcohols, microcrystalline cellulose, lactose (anhydrous and monohydrate), compressible sugar, fructose, dextrates, saccharose, raffinose, trehalose or mixture thereof, or any combination thereof; more preferably selected from alditol, mannitol, meglumine, xylitol, isomalt, sorbitol, lactitol, pentitol, arabitol, ribitol, galactitol, erythritol, and any combination thereof; microcrystalline cellulose, lactose, or any combination thereof; still more preferably mannitol, microcrystalline cellulose, lactose, or any combination thereof;- optionally, one or more extragranular antioxidants; preferably selected from butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), tocopherol or derivatives thereof, ascorbicacid or derivatives thereof, sodium metabisulphite, propyl gallate, sodium thiosulphate, or any combination thereof; more preferably ascorbic acid;- optionally, one or more extragranular disintegrants; preferably sodium carboxymethyl starch; - optionally, one or more extragranular lubricants; preferably magnesium stearate, talc or a combination thereof; and(iii) optionally, a film coating.

[0025] Unless expressly stated otherwise, percentages are expressed as weight percentages = wt.-%, i.e., calculated by dividing the mass of the component by the total weight of tablet core then multiplying this by 100.

[0026] For the purpose of the specification, "essentially consisting of' means that specific further components can be present, namely those not materially affecting the essential characteristics of the composition or dosage form. Preferably, "essentially consisting of' means that the recited components amount to at least 95 wt.-%, more preferably at least 98 wt.-%, still more preferably at least 99 wt.-%, and yet more preferably at least 99.5 wt.-%.

[0027] Preferably, the dosage form is a tablet, preferably a film-coated tablet.

[0028] In the preferred embodiments, the pharmaceutical dosage form according to the invention is wet granulated, i.e., the process of manufacture involves wet granulation, preferably aqueous wet granulation.

[0029] Preferably, the dosage form according to the invention does not contain intragranular microcrystalline cellulose.

[0030] Preferably, the dosage form according to the invention does not contain tartaric acid.

[0031] Preferably, the dosage form according to the invention does not contain calcium hydrogen phosphate.

[0032] In preferred embodiments, the intragranular phase of the pharmaceutical dosage form comprises Sertraline or a physiologically acceptable salt thereof, mannitol or lactose or a mixture thereof and antioxidant.

[0033] In preferred embodiments, the intragranular phase of the pharmaceutical dosage form comprises Sertraline or a physiologically acceptable salt thereof, mannitol and antioxidant selected from ascorbic acid.

[0034] In preferred embodiments, the pharmaceutical dosage form according to the invention comprises(i) an intragranular phase, which comprises or essentially consists of:- Sertraline, preferably Sertraline hydrochloride;- one or more intragranular fillers selected from one or more sugar alcohols or sugars; preferably mannitol or lactose; more preferably mannitol;- one or more intragranular antioxidants selected from ascorbic acid or derivatives thereof, buty- lated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof; preferably ascorbic acid; and(ii) an extragranular phase, which comprises or essentially consists of- one or more fillers; preferably mannitol, microcrystalline cellulose, lactose, or any combination thereof.

[0035] Preferably, the total weight content of the intragranular phase is within the range of 65±22.5 wt.-%, preferably 65±20 wt.-%, more preferably 65±17.5 wt.-%, still more preferably 65±15 wt.-%, yet more preferably 65±12.5 wt.-%, even more preferably 65±10 wt.-%, most preferably 65±7.5 wt.-%, and in particular 65±5 wt.-%, in each case relative to the total weight of the tablet core.

[0036] Preferably, the total weight content of the extragranular phase is within the range of 33±22.5 wt.-%, preferably 33±20 wt.-%, more preferably 33±17.5 wt.-%, still more preferably 33±15 wt.-%, yet more preferably 33±12.5 wt.-%, even more preferably 33±10 wt.-%, most preferably 33±7.5 wt.-%, and in particular 33±5 wt.-%, in each case relative to the total weight of the tablet core.

[0037] In preferred embodiments, Sertraline is present as Sertraline hydrochloride.

[0038] Preferably, the weight content of the Sertraline is at most 75 wt.%, preferably at most 60 wt.%, more preferably at most 50 wt.%, still more preferably at most 40 wt.%, yet more preferably at most 35 wt.%, even more preferably at most 30 wt.%, in each case based upon an equivalent weight of the salt form of Sertraline hydrochloride and, in each case relative to the total weight of the tablet core.

[0039] Preferably, the weight content of the Sertraline is at least 5 wt.%, preferably at least 7.5wt.%, more preferably at least 10 wt.-%, still more preferably at least 12.5 wt.%, yet more preferably at least 15 wt.%, even more preferably at least 17.5 wt.%, most preferably at least 20 wt.%, and in particular at least 25 wt.-% in each case based upon an equivalent weight of the salt form of Sertraline hydrochloride and, in each case relative to the total weight of the tablet core.

[0040] Preferably, the dose of the Sertraline is within the range of 1 to 300 mg, more preferably 20 to 280 mg, still more preferably 25 to 200 mg, most preferably 25 mg, 50 mg, 100 mg, 150 mg or 200 mg. The dose of Sertraline is preferably expressed as weight equivalent dose of the non-salt form of Sertraline. For example, 28 mg Sertraline hydrochloride correspond to a weight equivalent dose of 25 mg of the non-salt form of Sertraline, 66.95 mg Sertraline hydrochloride correspond to a weight equivalent dose of 50 mg of the non-salt form of Sertraline, and 111.90 mg Sertraline hydrochloride correspond to a weight equivalent dose of 100 mg of the non-salt form of Sertraline.

[0041] In preferred embodiments, essentially the total amount of the Sertraline contained in the dosage form is contained in the intragranular phase.

[0042] Preferably, the Sertraline or the physiologically acceptable salt thereof is the sole pharmacologically active ingredient contained in the dosage form.

[0043] The dosage form according to the invention comprises one or more fillers. For the purpose of the specification, the term "filler" is to be used interchangeably with the term "diluent" .

[0044] Suitable fillers are known to the skilled person and include e.g. starch, com starch, potato starch, pregelatinized starch, dry starch, disaccharides, lactose, cellulose, maltodextrins, cellulose derivatives, such as microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, sorbitol, erythritol, xylitol, trehalose, sucrose or other sugars or sugar derivatives dextrates, dextrose, isomalt, and mixtures thereof.

[0045] Preferred fillers are lactose, starch, microcrystalline cellulose, dextrates, dextrose, sugar alcohols selected from the group comprising alditol, mannitol, meglumine, xylitol, isomalt, sorbitol, lactitol, pentitol, arabitol, ribitol, galactitol, erythritol, and any combination thereof; preferably mannitol, microcrystalline cellulose, lactose, or any combination thereof.

[0046] Preferably, the dosage form according to the invention comprises one or more intragranular fdlers and one or more extragranular fdlers.

[0047] Preferably, the one or more intragranular fdlers and the one or more extragranular fdlers independently of one another comprise or essentially consist of sugar alcohols (preferably mannitol), microcrystalline cellulose, sugars (preferably lactose), or any combination thereof, most preferably mannitol.

[0048] Preferably, sugars are selected from lactose, compressible sugar, fructose, dextrates, saccharose, raffinose, trehalose or mixture thereof.

[0049] Suitable lactose derivates are not particularly limited and include lactose anhydrous or monohydrate, spray-dried lactose, coprocessed lactose monohydrate and povidone, coprocessed lactose monohydrate and com starch, coprocessed lactose monohydrate and powder cellulose.

[0050] Suitable mannitol derivates are not particularly limited and include mannitol powder, crystalline mannitol (a, [3 and 5 modifications, with the [3 modification preferred), crystallized mannitol, spray-dried mannitol, granulated mannitol, coprocessed com starch and mannitol, coprocessed mannitol and sorbitol. In preferred embodiments, the dosage form according to the invention comprises one or more intragranular fillers, preferably comprising or essentially consisting of mannitol or lactose, more preferably of mannitol; and one or more extragranular fillers, preferably comprising or essentially consisting of mannitol, microcrystalline cellulose, lactose, or any combination thereof.

[0051] Preferably, the total weight content of the one or more intragranular fillers, preferably mannitol or lactose, more preferably mannitol, is within the range of from 0.1 to 60 wt.-%, preferably from 10 to 40 wt.-%, more preferably from 15 to 35 wt.-%, in each case relative to the total weight of the tablet core.

[0052] Preferably, the total weight content of the one or more extragranular fillers, preferably mannitol, microcrystalline cellulose, lactose, or any combination thereof, is within the range of from 0.1 to 60 wt.-%, preferably from 10 to 40 wt.-%, more preferably from 15 to 35 wt.-% in each case relative to the total weight of the tablet core.

[0053] The dosage form according to the invention comprises one or more intragranular antioxidants.

[0054] In other embodiments, the dosage form according to the invention additionally comprises one or more extragranular antioxidants.

[0055] In other embodiments, the dosage form according to the invention does not comprise any extragranular antioxidant.

[0056] Preferably, the one or more intragranular antioxidants and the one or more extragranular antioxidants independently of one another comprise or essentially consist of butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), tocopherol or derivatives thereof, ascorbic acid or derivatives thereof, sodium metabisulphite, propyl gallate, sodium thiosulphate, or any combination thereof; preferably ascorbic acid or a derivative thereof.

[0057] Suitable ascorbic acid derivatives are not particularly limited and include physiologically acceptable salts and esters. Preferred examples of derivatives of ascorbic acid according to the invention are magnesium 1-ascorbic acid 2-phosphate, sodium 1-ascorbic acid 2-phosphate, 1-ascorbic acid 2-glu-coside, 1-ascorbic acid ethyl ester, 3 -O-ethyl -1-ascorbic acid, 2-O-a-d-glucopyranosyl-l-ascorbic acid, 1-ascorbic acid 2-phosphate sesquimagnesium salt hydrate, 1-ascorbyl 2,6-dibutyrate, glyceryl ascorbate, (+)-5,6-O-isopropylidene-l-ascorbic acid, and the like.

[0058] Preferably, the one or more intragranular antioxidants and the one or more extragranular antioxidants independently of one another comprise or essentially consist of ascorbic acid or a derivative thereof (preferably ascorbic acid), butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof; more preferably ascorbic acid.

[0059] In preferred embodiments, the one or more intragranular antioxidants and the one or more extragranular antioxidants independently of one another comprise or essentially consist of ascorbic acid or a derivative thereof, preferably ascorbic acid.

[0060] Preferably, the total weight content of the one or more intragranular and / or extragranular antioxidants, preferably ascorbic acid, is within the range of 0.01 - 3 wt.-%, preferably 0.02 - 2.5 wt.-%, more preferably 0.02 - 1.5 wt.-%, most preferably 0.02 - 1.0 wt.-%, in each case relative to the total weight of the tablet core.

[0061] In other embodiments, the one or more intragranular antioxidants and the one or more extragranular antioxidants independently of one another comprise or essentially consist of butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof.

[0062] Preferably, the total weight content of the one or more intragranular and / or extragranular antioxidants, preferably butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof, is within the range of 0.01 - 3 wt.-%, preferably 0.02 - 2.5 wt.-%, more preferably 0.02 - 1.5 wt.-%, most preferably 0.02 - 1.0 wt.-%, in each case relative to the total weight of the tablet core.

[0063] In further embodiments, the one or more intragranular antioxidants and the one or more extra-granular antioxidants independently of one another comprise or essentially consist of ascorbic acid, butylated hydroxytoluene (BHT), or any combination thereof.

[0064] Preferably, the total weight content of the one or more intragranular and / or extragranular antioxidants, preferably ascorbic acid, butylated hydroxytoluene (BHT), or any combination thereof, is within the range of 0.01 - 3 wt.-%, preferably 0.02 - 2.5 wt.-%, more preferably 0.02 - 1.5 wt.-%, most preferably 0.02 - 1.0 wt.-%, in each case relative to the total weight of the tablet core.

[0065] In further embodiments, the one or more intragranular antioxidants and the one or more extragranular antioxidants independently of one another comprise or essentially consist of ascorbic acid, butylated hydroxy anisole (BHA), or any combination thereof.

[0066] Preferably, the total weight content of the one or more intragranular and / or extragranular antioxidants, preferably ascorbic acid, butylated hydroxy anisole (BHA), or any combination thereof, is within the range of 0.01 - 3 wt.-%, preferably 0.02 - 2.5 wt.-%, more preferably 0.02 - 1.5 wt.-%, most preferably 0.02 -1.0 wt.-%, in each case relative to the total weight of the tablet core.

[0067] In preferred embodiments, essentially the total amount of the one or more antioxidants contained in the dosage form, preferably ascorbic acid and / or butylated hydroxytoluene (BHT) and / or butylated hydroxy anisole (BHA), still more preferably ascorbic acid, is contained in the intragranular phase.

[0068] In preferred embodiments, the dosage form is obtained by a process involving wet granulation of a mixture of powders for granulation with a granulation liquid, wherein essentially the total amount of the one or more antioxidants contained in the dosage form, preferably ascorbic acid and / or butylated hydroxytoluene (BHT) and / or butylated hydroxy anisole (BHA), still more preferably ascorbic acid, is dissolved in the granulation liquid.

[0069] In other embodiments, the dosage form is obtained by a process involving wet granulation of a mixture of powders for granulation with a granulation liquid, wherein essentially the total amount of the one or more antioxidants contained in the dosage form, preferably ascorbic acid and / or butylated hydroxytoluene (BHT) and / or butylated hydroxy anisole (BHA), still more preferably ascorbic acid, is added to the mixture of powders for granulation.

[0070] In preferred embodiments, the dosage form according to the invention comprises one or more intragranular disintegrants and / or one or more extragranular disintegrants.

[0071] Suitable disintegrants are known to the skilled person and include e.g. crosslinked polyvinylpyrrolidone, polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose, carboxymethylcellulose sodium and / or carboxymethylcellulose calcium, polacrilin potassium, glycine, guar gum, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, starch, modified starch such as pregelatinized starch or a starch derivative such as sodium carboxymethyl starch (preferably type A) and hydroxypropyl starch.

[0072] Preferably, the one or more intragranular disintegrants and / or the one or more disintegrants independently of one another comprise or essentially consist of a starch or a starch derivative; preferably sodium carboxymethyl starch (preferably type A).

[0073] In preferred embodiments, a first fraction of sodium carboxymethyl starch (preferably type A) is contained in the intragranular phase and a second fraction of sodium carboxymethyl starch (preferably type A) is contained in the extragranular phase.

[0074] Preferably, the total weight content of the one or more intragranular and / or extragranular disintegrants, preferably sodium carboxymethyl starch (preferably type A), is within the range of 0.5-10.0 wt.-%, preferably 1.0-9.5 wt.-%, more preferably 1.5 - 8.5 wt.-%, still more preferably 1.75 - 8.0 wt.-%, yet more preferably 2.0 - 7.5 wt.-%, in each case relative to the total weight of the tablet core.

[0075] In preferred embodiments, the dosage form according to the invention comprises one or more intragranular binders.

[0076] In other embodiments, the dosage form according to the invention additionally comprises one or more extragranular binders.

[0077] In other preferred embodiments, the dosage form according to the invention does not comprise any extragranular binder.

[0078] Suitable binders are known to the skilled person and include e.g. polysaccharides such as starches preferably selected from com starch, pregelatinized starch, celluloses, modified celluloses such as cellulose ethers preferably selected from hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), methyl cellulose (MC) and hydroxypropyl methyl cellulose (HPMC), carboxymethylcellulose sodium and synthetic polymers such as polyvinylpyrrolidone, copovidone, polyethylene oxide and natural polymers such as gelatin, guar gum and sodium alginate.

[0079] Preferably, the one or more intragranular binders comprise or essentially consist of a cellulose ether; preferably hydroxypropyl cellulose.

[0080] Preferably, the total weight content of the one or more intragranular binders, preferably hydroxypropyl cellulose, is within the range of 1.0 - 7.0 wt.-%, preferably 1.5 - 6.5 wt.-%, more preferably 1.8 - 6.0 wt.-%, still more preferably 2.0 - 5.5 wt.-%, yet more preferably 2.5 - 5.0wt.-%, even more preferably 2.8 - 4.5 wt.-%, most preferably 3.0 - 4.0 wt.-%, in each case relative to the total weight of the tablet core.

[0081] In preferred embodiments, essentially the total amount of the one or more binders contained in the dosage form, preferably hydroxypropyl cellulose, is contained in the intragranular phase.

[0082] In preferred embodiments, the dosage form according to the invention comprises one or more extragranular lubricants.

[0083] In preferred embodiments, the dosage form according to the invention additionally comprises one or more intragranular lubricants.

[0084] In other preferred embodiments, the dosage form according to the invention does not comprise any intragranular lubricant.

[0085] Suitable lubricants are known to the skilled person and include e.g. talc, silica, sodium stearyl fumarate, stearic acid, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, colloidal silicon dioxide, stearic acid, magnesium oxide, calcium stearate, zinc stearate and magnesium stearate.

[0086] Preferably, the one or more extragranular lubricants comprise or essentially consist of magnesium stearate and talc.

[0087] Preferably, the total weight content of the one or more extragranular lubricants, preferably magnesium stearate and talc, is within the range of 1.0 - 7.0 wt.-%, preferably 1.2 - 60 wt.-%, more preferably 1.4 - 5.0 wt.-%, still more preferably 1.5 - 4.0 wt.-%, yet more preferably 1.5 - 3.5 wt.-%, even more preferably 1.6 - 3.0 wt.-%, most preferably 1.8 - 3.0 wt.-%, in each case relative to the total weight of the tablet core.

[0088] In preferred embodiments, essentially the total amount of the one or more lubricants contained in the dosage form, preferably magnesium stearate and talc, is contained in the extragranular phase.

[0089] In particularly preferred embodiments, the dosage form according to the invention comprises - Sertraline or a physiologically acceptable salt thereof; preferably Sertraline hydrochloride;- one or more antioxidants comprising or essentially consisting of ascorbic acid or derivatives thereof, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof; preferably ascorbic acid; preferably only in the intragranular phase;- one or more fdlers; preferably mannitol, microcrystalline cellulose, lactose, or any combination thereof; preferably in the intragranular phase and also in the extragranular phase;- one or more disintegrants; preferably sodium carboxymethyl starch (preferably type A); preferably in the intragranular phase and also in the extragranular phase;- one or more binders; preferably hydroxypropyl cellulose; preferably only in the intragranular phase; andone or more lubricants; preferably magnesium stearate and talc; preferably only in the extragranular phase.

[0090] In particularly preferred embodiments,- the dose of the Sertraline is within the range of 1 to 300 mg, more preferably 20 to 280 mg and most preferably 25 to 200 mg, in each case based upon an equivalent weight of the non-salt form of Sertraline; and / or- the total weight content of the one or more intragranular and / or extragranular antioxidants, preferably ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof, still more preferably ascorbic acid, is within the range of 0.01 - 3 wt.-%, preferably 0.02 - 2.5 wt.-%, more preferably 0.02 - 1.5 wt.-%, most preferably 0.02 - 1.0 wt.-%, and / or- the total weight content of intragranular fdler selected from mannitol or lactose or a mixture thereof, still more preferably mannitol, is within the range of 0.1 to 60 wt.-%, preferably from 10 to 40 wt.- %, more preferably from 15 to 35 wt.-%, and / or- the total weight content of extragranular fdler selected from mannitol, microcrystalline cellulose or lactose or a mixture thereof, is within the range of from 0.1 to 60 wt.-%, preferably from 10 to 40 wt.-%, more preferably from 15 to 35 wt.-% and / or- the total weight content of the one or more intragranular and / or extragranular disintegrants, preferably sodium carboxymethyl starch (preferably type A), is within the range of 0.5-10.0 wt.-%, preferably 1.0-9.5 wt.-%, more preferably 1.5 - 8.5 wt.-%, still more preferably 1.75 - 8.0 wt.-%, yetmore preferably 2.0 - 7.5 wt.-%, and / or- the total weight content of the one or more binders, preferably hydroxypropyl cellulose, is within the range of 1.0 - 7.0 wt.-%, preferably 1.5 - 6.5 wt.-%, more preferably 1.8 - 6.0 wt.-%, still more preferably 2.0 - 5.5 wt.-%, yet more preferably 2.5 - 5.0 wt.-%, even more preferably 2.8 - 4.5 wt.-%, most preferably 3.0 - 4.0 wt.-%, and / or- the total weight content of the one or more lubricants, preferably magnesium stearate and talc, is within the range of 1.0 - 7.0 wt.-%, preferably 1.2 - 6.0 wt.-%, more preferably 1.4 - 5.0 wt.-%, still more preferably 1.5 - 4.0 wt.-%, yet more preferably 1.5 - 3.5 wt.-%, even more preferably 1.6-3.0 wt.-%, most preferably 1.8 - 3.0 wt.-%,in each case relative to the total weight of the tablet core.

[0091] In preferred embodiments, the dosage form according to the invention comprises a fdm coating.

[0092] Preferably, the fdm coating is based on hypromellose (HPMC, hydroxypropyl methyl cellulose) .

[0093] In preferred embodiments, the dosage form according to the invention, which comprises 200 mg of Sertraline (weight equivalent dose of non-salt form of Sertraline), has a total weight within the range of 870±45 mg, preferably 870±40 mg, more preferably 870±35 mg, still more preferably 870±30 mg, yet more preferably 870±25 mg, even more preferably 870±20 mg, most preferably 870±15 mg, and in particular 870±10 mg.

[0094] In preferred embodiments, the dosage form according to the invention, which comprises 150 mg of Sertraline (weight equivalent dose of non-salt form of Sertraline), has a total weight within the range of 650±45 mg, preferably 650±40 mg, more preferably 650±35 mg, still more preferably 650±30 mg, yet more preferably 650±25 mg, even more preferably 650±20 mg, most preferably 650±15 mg, and in particular 650±10 mg.

[0095] In preferred embodiments, the dosage form according to the invention, which comprises 100 mg of Sertraline (weight equivalent dose of non-salt form of Sertraline), has a total weight within the range of 435±45 mg, preferably 435±40 mg, more preferably 435±35 mg, still more preferably 435±30 mg, yet more preferably 435±25 mg, even more preferably 435±20 mg, most preferably 435±15 mg, and in particular 435±10 mg.

[0096] In preferred embodiments, the dosage form according to the invention, which comprises 50 mg of Sertraline (weight equivalent dose of non-salt form of Sertraline), has a total weight within the range of 217±45 mg, preferably 217±40 mg, more preferably 217±35 mg, still more preferably 217±30 mg, yet more preferably 217±25 mg, even more preferably 217±20 mg, most preferably 217±15 mg, and in particular 217± 10 mg .

[0097] In preferred embodiments, the dosage form according to the invention, which comprises 25 mg of Sertraline (weight equivalent dose of non-salt form of Sertraline), has a total weight within the range of 110±45 mg, preferably 110±40 mg, more preferably 110±35 mg, still more preferably 110±30 mg, yet more preferably 110±25 mg, even more preferably 110±20 mg, most preferably 110±15 mg, and in particular 110±10 mg.

[0098] In preferred embodiments, the dosage form according to the invention under in vitro conditions provides immediate release of Sertraline.

[0099] Preferably, the dosage form releases within 30 minutes at least 50 wt.-%, preferably at least 60 wt.-%, more preferably at least 70 wt.-%, still more preferably at least 80 wt.-% of the Sertraline that was originally contained in the dosage form, using USP apparatus 1, basket - 20 mesh, in a media having pH 4.5, at 37°C and 100 rpm.

[0100] In preferred embodiments, the dosage form according to the invention is prepared by wet-granulation.

[0101] The granulation liquid is preferably selected from water or organic solvents selected from alcohol such as ethanol, methanol, propanol or an aqueous mixture thereof, preferably water or aqueous mixture of alcohol is used.

[0102] In preferred embodiments, the pharmaceutical dosage form according to the invention is obtained or obtainable by a process comprising steps of:mixing and optionally sieving starting materials Sertraline hydrochloride, one or more fillers, one or more disintegrants and optionally one or more antioxidants to obtain homogenized powder mixture;- transferring the homogenized powder mixture into a fluid bed granulator;- preparing a granulating liquid by mixing of water or organic solvent such as ethanol, methanol, propanol or an aqueous mixture thereof, and dissolving one or more binders and optionally one or more antioxidants, such as ascorbic acid, in the granulating liquid;- spraying the granulating liquid onto the homogenized powder mixture in the fluid bed granulator; - after spraying is finished, drying the thus obtained granules and then sieving to obtain sieved granules;- mixing and optionally sieving one or more fillers, one or more disintegrants, one or more lubricants and optionally one or more antioxidants, such as ascorbic acid;- mixing these excipients with the sieved granules to obtain a compression mixture;- compressing the compression mixture to obtain tablet cores; and- optionally, film-coating the tablet cores.

[0103] In preferred embodiments, the pharmaceutical dosage form according to the invention is obtained or obtainable by a process comprising steps of:- mixing and optionally sieving starting materials Sertraline hydrochloride, mannitol or lactose, preferably mannitol, carboxymethyl starch (preferably type A) and optionally ascorbic acid or a derivative thereof, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof, preferably ascorbic acid, to obtain homogenized powder mixture;- transferring the homogenized powder mixture into a fluid bed granulator;- preparing a granulating liquid by mixing of purified water, hydroxypropyl cellulose (HPC) and optionally ascorbic acid or a derivative thereof, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof, preferably ascorbic acid;- spraying the granulating liquid onto the homogenized powder mixture in the fluid bed granulator; - after spraying is finished, drying the thus obtained granules and then sieving to obtain sieved granules,- mixing and optionally sieving mannitol, microcrystalline cellulose, lactose, or any combination thereof, carboxymethyl starch (preferably type A), talc and magnesium stearate and optionally ascorbic acid;mixing these excipients with the sieved granules to obtain a compression mixture; compressing the compression mixture to obtain tablet cores; andoptionally, film coating the tablet cores, wherein the film coating is based on hypromellose.

[0104] In preferred embodiments, the pharmaceutical dosage form according to the invention is obtained or obtainable by a process comprising steps of:- mixing and optionally sieving starting materials Sertraline hydrochloride, mannitol or lactose, preferably mannitol, carboxymethyl starch (preferably type A), to obtain homogenized powder mixture; - transferring the homogenized powder mixture into a fluid bed granulator;- preparing a granulating liquid by mixing of purified water, hydroxypropyl cellulose (HPC) and an antioxidant selected from ascorbic acid or a derivative thereof, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof, preferably ascorbic acid;- spraying the granulating liquid onto the homogenized powder mixture in the fluid bed granulator; - after spraying is finished, drying the thus obtained granules and then sieving to obtain sieved granules,- mixing and optionally sieving mannitol, microcrystalline cellulose, lactose, or any combination thereof, carboxymethyl starch (preferably type A), talc and magnesium stearate;- mixing these excipients with the sieved granules to obtain a compression mixture;- compressing the compression mixture to obtain tablet cores; and- optionally, film coating the tablet cores, wherein the film coating is based on hypromellose.

[0105] Another aspect according to the invention relates to a packaging comprising the pharmaceutical dosage form according to the invention as described above.

[0106] Preferably, the packaging is a blister packaging.

[0107] Preferably, the packaging comprises a multilayer film.

[0108] Preferably, the multilayer film comprises one or more layers that comprise or essentially consist of a metal; preferably aluminum.

[0109] Preferably, the multilayer film comprises one or more layers that comprise or essentially consist of a polymer selected from polyvinyl chloride (PVC) and polyvinylidene dichloride (PVDC).

[0110] Preferably, after storage under accelerated storage conditions (40°C / 75 % RH for 3 months), the dosage form in the packaging according to the invention has a content of N-nitroso-Sertraline of at most 0.5 ppm, preferably at most 0.4 ppm, in each case by weight (ppmw). Short-term storing under accelerated storage conditions provides for a correlation with long term stability under normal ambient conditions.Examples

[0111] The following examples further illustrate the invention but are not to be construed as limiting its scope:

[0112] Methods

[0113] The analytical method used for quantitation of nitroso sertraline was an external standard, gradient HPLC method coupled with a triple -quadrupole mass spectrometer. The separation was performed using YMC-Triart C18 100x2.1 mm (3 pm particles) column with a combination of 0.3 % acetic acid (A) and acetonitrile (B) as mobile phase. The elution parameters were as follows: injection volume 5 pl, flow rate 0.4 ml / min, column temperature 30 °C, gradient O' = 40 % B, 2' = 40 % B, 6' = 90 % B, 15' = 90 % B. A selective MRM transition method (335 > 275) was used for detection of the analyte. To prepare samples, a solvent with 1 g / 1 of ascorbic acid in 50 % acetonitrile was used. Sample solution was prepared at about 5 mg sertraline / ml and compared against a standard solution of 2.5 ng nitroso sertraline / ml.

[0114] Comparative Example A - the role of filler (absence of antioxidant):

[0115] Film coated tablets were prepared by wet granulation.

[0116] Sertraline hydrochloride, intragranular filler (mannitol or microcrystalline cellulose (MCC)) and intragranular disintegrant (a first part of sodium carboxymethyl starch A) were sieved in case lumps were present in individual starting materials. Afterwards, the starting materials were transferred into a fluid bed granulator. Granulating liquid (purified water and intragranular binder (hydroxypropyl cellulose (HPC))) was sprayed onto the homogenized powder mixture. After spraying was finished, the thus obtained wetted powder mixture was dried and then sieved to obtain sieved granules.

[0117] Extragranular filler (mannitol or calcium hydrogen phosphate or microcrystalline cellulose (MCC)), extragranular disintegrant (a second part of sodium carboxymethyl starch A), and extragranular lubricant (talc and magnesium stearate) were sieved in case lumps were present in the individual starting materials. Then excipients were mixed with the sieved granules to obtain a compression mixture which was then compressed to obtain tablet cores.

[0118] A commercial coating mixture (ready-to-use mixture of Hypromellose (HPMC), Type 2910 (6 cP) (72.0% w / w), titanium dioxide, E171 (16.0% w / w), talc (7.0% w / w) and propylene glycol (5.0% w / w)) was dispersed in purified water and mixed in a stainless-steel vessel to obtain a homogeneous film coating dispersion. The tablet cores were coated by spraying of the film coating dispersion onto the tablet cores and drying.

[0119] The film coated tablets were packed in aluminum (Alu / Alu) blisters. The formation of N-ni-troso-Sertraline both during the manufacturing process (tO) and under accelerated storage conditions (60°C / 8 days and 50°C / 75% RH / 1 month and 40°C / 75% RH / 3 months) was examined.

[0120] The composition of the various tablets and the results are compiled in the table here below:1223.8 mg corresponds to 200 mg of Sertraline;2does not appear in the final product since it evaporates during drying process.3analysis was not performed

[0121] The experimental data clearly indicate that using mannitol alone as an intragranular filler and also as an extragranular filler (Example 4) is the most effective approach in slowing down the formation of N-nitroso-Sertraline. When mannitol is used as intragranular filler, it has an even greater effect on reducing formation of N-nitroso-Sertraline. Under accelerated storage conditions (50°C, 75% RH and 40°C, 75% RH) after 1 month and after 3 months mannitol alone provides the best results. Using mannitol as an extragranular filler in combination with microcrystalline cellulose as an intragranular filler was also effective in reducing the formation of N-nitroso-Sertraline (Example 3). In contrast, compositions with calcium hydrogen phosphate as extragranular filler (Examples 1 and 2) were most prone to formation of N-nitroso-Sertraline impurity.

[0122] The results indicate that 60°C represents an extreme condition, leading to N-nitroso-Sertraline impurity levels higher than those observed at 40°C / 75% RH after 3 months. Specifically, the impurity levels of approximately 0.70 ppm observed after 8 days at 60°C suggest that these would correspond to less than 0.50 ppm under the 40°C / 75% RH condition after 3 months.Example B - the role of antioxidant:

[0123] Film coated tablets were prepared by wet granulation in accordance with Example 1.

[0124] Sertraline hydrochloride, intragranular filler (microcrystalline cellulose (MCC)) and intragran-ular disintegrant (a first part of sodium carboxymethyl starch A) were sieved in case lumps were present in individual starting materials. Afterwards, the starting materials were transferred into a fluid bed granulator. Granulating liquid (purified water and intragranular binder (hydroxypropyl cellulose (HPC))) was sprayed onto the homogenized powder mixture. In case of Examples 5 - 7, intragranular antioxidant (ascorbic acid) was dissolved in the granulating liquid for wet granulation. After spraying was finished, the thus obtained wetted powder mixture was dried and then sieved to obtain sieved granules.

[0125] Extragranular filler (calcium hydrogen phosphate), extragranular disintegrant (a second part of sodium carboxymethyl starch A), extragranular lubricant (talc and magnesium stearate) and in case of Example 8 extragranular antioxidant (ascorbic acid) were sieved in case lumps were present in the individual starting materials. Then excipients were mixed with the sieved granules to obtain a compression mixture which was then compressed to obtain tablet cores.

[0126] A commercial coating mixture (ready-to-use mixture of Hypromellose (HPMC), Type 2910 (6 cP) (72.0% w / w), titanium dioxide, E171 (16.0% w / w), talc (7.0% w / w) and propylene glycol (5.0% w / w)) was dispersed in purified water and mixed in a stainless-steel vessel to obtain a homogeneous film coating dispersion. The tablet cores were coated by spraying of the film coating dispersion onto the tablet cores and drying.

[0127] The film coated tablets were packed in aluminum (Alu / Alu) blisters. The formation of N-ni-troso-Sertraline both during the manufacturing process (tO) and under accelerated storage conditions (60°C / 8 days and 40°C / 75% RH / 3 months) was examined.

[0128] The composition of the various tablets and the results are compiled in the table here below:1corresponds to 200 mg of Sertraline2does not appear in the final product since it evaporates during drying process.

[0129] It becomes clear from the above experimental data that ascorbic acid as intragranular antioxidant (Examples 5-7) effectively slows down the formation of the N-nitroso-Sertraline impurity under accelerated storage conditions (40°C, 75% RH / 3 months). It appears that the amount of ascorbic acid (5 wt.-%, 2.5 wt.-% and 1 wt.-%) does not significantly influence the impurity levels, as all tested concentrations result in impurity levels below the safe limit of 0.5 ppm after 3 months under condition 40°C, 75% RH.

[0130] When ascorbic acid is used as extragranular antioxidant and added directly to the compression mixture (Example 8), its effectiveness decreases. Although acceptable levels are maintained after 3 months at 40°C, 75% RH (0.47 ppm), the results are less consistent compared to incorporation as an intragranular antioxidant in the granulation liquid.

[0131] Example C - the role of antioxidant and filler on the formation of N-nitroso-Sertraline:

[0132] Film coated tablets were prepared by wet granulation in accordance with Examples A and B.

[0133] Sertraline hydrochloride, intragranular filler (mannitol or lactose), intragranular disintegrant (a first part of sodium carboxymethyl starch A) were sieved in case lumps were present in individual starting materials. Afterwards, the starting materials were transferred into a fluid bed granulator. In case of Experiment 17 and Experiments 22-24 yellow ferric oxide was mixed with part of mannitol and sieved to obtain triturate, which was added into a fluid bed granulator. Granulating liquid (purified water and intragranular binder (hydroxypropyl cellulose (HPC))) were sprayed onto the homogenized powder mix-ture. Intragranular antioxidant (ascorbic acid, BHA or BHT) was either dissolved in the granulating liquid for wet granulation (Examples 9-12,15-21 and 22-24), or alternatively added and homogenized together with the other powdery excipients (Examples 13 and 14). After spraying was finished, the thus obtained wetted powder mixture was dried and then sieved to obtain sieved granules.

[0134] Extragranular filler (mannitol or cellulose microcrystalline or lactose), extragranular disinte-grant (a second part of sodium carboxymethyl starch A), and extragranular lubricant (talc and magnesium stearate) were sieved in case lumps were present in the individual starting materials. Then excipients were mixed with the sieved granules to obtain a compression mixture which was then compressed to obtain tablet cores.

[0135] A commercial coating mixture (ready-to-use mixture of Hypromellose (HPMC), Type 2910 (6 cP) (72.0% w / w), titanium dioxide, E171 (16.0% w / w), talc (7.0% w / w) and propylene glycol (5.0% w / w)) was dispersed in purified water and mixed with a stainless-steel vessel to obtain a homogeneous film coating dispersion. The tablet cores were coated by spraying of the film coating dispersion onto the tablet cores and drying.

[0136] The film coated tablets were packed in aluminum (Alu / Alu) blisters. The formation of N-ni-troso-Sertraline both during the manufacturing process (tO) and under accelerated storage conditions (60°C / 8 days and 50°C / 75% RH / 1 month and 40°C / 75% RH / 3 months and 40°C / 75% RH / 6 months) was examined.

[0137] The composition of the various tablets and the results are compiled in the tables here below:1223.8 mg corresponds to 200 mg of Sertraline, 28.0 mg corresponds to 25 mg of Sertraline, 55.95 mg corresponds to 50 mg of Sertraline, 11.90 mg corresponds to 100 mg of Sertraline.2does not appear in the final product since it evaporates during drying process.3analysis was not performed

[0138] It becomes clear from the above experimental data that using ascorbic acid in combination with mannitol as a filler significantly reduces the formation of the N-nitroso-Sertraline impurity compared to using either ascorbic acid or mannitol alone. Furthermore, when combined with mannitol, lower amounts of ascorbic acid are required to keep the N-nitroso-Sertraline impurity levels under the safe limit 0.5 ppm, compared to other fillers. Moreover, the use of ascorbic acid dissolved in the granulation liquid is more effective in mitigation impurity formation than addition of ascorbic acid to the mixture of powders for granulation. Using lactose in compression mixture gives similar results on accelerated conditions (60°C, 8 days) as using mannitol in compression mixture in combination with mannitol and ascorbic in granulate (Examples 15 and 18). Antioxidants BHA and BHT used in granulation liquid (Example 20 and 21) give higher concentrations of N-nitroso-sertraline (0.70 and 0.73 ppm after 8 days on 60°C) than ascorbic acid. Also adding ferric oxide to granulate gives better stability results after 8 days on 60°C (experiment 17) compared to the same formulation without ferric oxide (experiment 15).

Claims

Patent claims:

1. A pharmaceutical dosage form for oral administration comprising or essentially consisting of:(i) an intragranular phase, which comprises or essentially consists of:- Sertraline or a physiologically acceptable salt thereof;- one or more intragranular fdlers; preferably mannitol and / or lactose;- one or more intragranular antioxidants;- optionally, one or more intragranular disintegrants; and- optionally, one or more intragranular binders;(ii) an extragranular phase, which comprises or essentially consists of:- one or more extragranular fdlers;- optionally, one or more extragranular antioxidants;- optionally, one or more extragranular disintegrants;- optionally, one or more extragranular lubricants; and(iii) optionally, a fdm coating.

2. The dosage form according to claim 1, which is a fdm-coated tablet.

3. The dosage form according to claim 1 or 2, which is wet-granulated.

4. The dosage form according to any of the preceding claims, which does not contain intragranular microcrystalline cellulose.

5. The dosage form according to any of the preceding claims, which does not contain tartaric acid.

6. The dosage form according to any of the preceding claims, which does not contain calcium hydrogen phosphate.

7. The dosage form according to any of the preceding claims, wherein Sertraline is present as Sertraline hydrochloride.

8. The dosage form according to any of the preceding claims, wherein the weight content of the Sertraline is at most 40 wt.%, yet more preferably at most 35 wt.%, even more preferably at most 30 wt.%, in each case based upon an equivalent weight of the salt form of Sertraline hydrochloride and, in each case relative to the total weight of the tablet core.

9. The dosage form according to any of the preceding claims, wherein the weight content of the Sertraline is at least 5 wt.%, preferably at least 7.5wt.%, more preferably at least 10 wt.-%, still more preferably at least 12.5 wt.%, yet more preferably at least 15 wt.%, even more preferably at least 17.5 wt.%, most preferably at least 20 wt.%, and in particular at least 25 wt.-%in each casebased upon an equivalent weight of the salt form of Sertraline hydrochloride and, in each case relative to the total weight of the tablet core.

10. The dosage form according to any of the preceding claims, wherein the weight content the dose of the Sertraline is within the range of 1 to 300 mg, preferably 20 to 280 mg, still more preferably 25 to 250 mg, most preferably 25 mg, 50 mg, 100 mg, 150 mg or 200 mg.

11. The dosage form according to any of the preceding claims, wherein essentially the total amount of the Sertraline contained in the dosage form is contained in the intragranular phase.

12. The dosage form according to any of the preceding claims, wherein the Sertraline or the physiologically acceptable salt thereof is the sole pharmacologically active ingredient contained in the dosage form.

13. The dosage form according to any of the preceding claims, which comprises one or more intragranular fillers and one or more extragranular fillers.

14. The dosage form according to claim 13, wherein the one or more intragranular fillers and the one or more extragranular fillers independently of one another comprise or essentially consist of sugar alcohols (preferably mannitol), microcrystalline cellulose, lactose, or any combination thereof.

15. The dosage form according to claim 13 or 14, wherein the one or more intragranular fillers comprise or essentially consist of mannitol or lactose and the one or more extragranular fillers comprise or essentially consist of mannitol, microcrystalline cellulose, lactose, or any combination thereof.

16. The dosage form according to any of the preceding claims, wherein the total weight content of the one or more intragranular fillers, preferably mannitol or lactose, is within the range of from 0.1 to 60 wt.-%, preferably from 10 to 40 wt.-%, more preferably from 15 to 35 wt.-%, in each case relative to the total weight of the tablet core.

17. The dosage form according to any of the preceding claims, wherein the total weight content of the one or more extragranular fillers, preferably mannitol, microcrystalline cellulose, lactose, or any combination thereof, is within the range of from 0.1 to 60 wt.-%, preferably from 10 to 40 wt.-%, more preferably from 15 to 35 wt.-% in each case relative to the total weight of the tablet core.

18. The dosage form according to any of the preceding claims, which does not comprise any extragranular antioxidants.

19. The dosage form according to any of the preceding claims, the one or more intragranular antioxidants and the one or more extragranular antioxidants independently of one another comprise oressentially consist of butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), tocopherol or derivatives thereof, ascorbic acid or derivatives thereof, sodium metabisulphite, propyl gallate, sodium thiosulphate, or any combination thereof; preferably ascorbic acid or a derivative thereof.

20. The dosage form according to any of the preceding claims, wherein the one or more intragranular antioxidants and the one or more extragranular antioxidants independently of one another comprise or essentially consist of ascorbic acid or a derivative thereof (preferably ascorbic acid), butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof; more preferably ascorbic acid.

21. The dosage form according to any of the preceding claims, wherein the total weight content of the one or more intragranular and / or extragranular antioxidants, preferably ascorbic acid, is within the range of 0.01 - 3 wt.-%, preferably 0.02 - 2.5 wt.-%, more preferably 0.02 - 1.5 wt.-%, most preferably 0.02 - 1.0 wt.-%, in each case relative to the total weight of the tablet core.

22. The dosage form according to any of the preceding claims, wherein the total weight content of the one or more intragranular and / or extragranular antioxidants, preferably butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof, is within the range of 0.01 - 3 wt.-%, preferably 0.02 - 2.5 wt.-%, more preferably 0.02 - 1.5 wt.-%, most preferably 0.02 - 1.0 wt.-%, in each case relative to the total weight of the tablet core.

23. The dosage form according to any of the preceding claims, wherein the total weight content of the one or more intragranular and / or extragranular antioxidants, preferably ascorbic acid, butylated hydroxytoluene (BHT), or any combination thereof, is within the range of 0.01 - 3 wt.-%, preferably 0.02 - 2.5 wt.-%, more preferably 0.02 - 1.5 wt.-%, most preferably 0.02 - 1.0 wt.-%, in each case relative to the total weight of the tablet core.

24. The dosage form according to any of the preceding claims, wherein the total weight content of the one or more intragranular and / or extragranular antioxidants, preferably ascorbic acid, butylated hydroxy anisole (BHA), or any combination thereof, is within the range of 0.01 - 3 wt.-%, preferably 0.02 - 2.5 wt.-%, more preferably 0.02 - 1.5 wt.-%, most preferably 0.02 - 1.0 wt.-%, in each case relative to the total weight of the tablet core.

25. The dosage form according to any of the preceding claims, wherein essentially the total amount of the one or more antioxidants contained in the dosage form, preferably ascorbic acid and / or butylated hydroxytoluene (BHT) and / or butylated hydroxy anisole (BHA), still more preferably ascorbic acid, is contained in the intragranular phase.

26. The dosage form according to any of the preceding claims, which is obtained by a process involving wet granulation of a mixture of powders for granulation with a granulation liquid, whereinessentially the total amount of the one or more antioxidants contained in the dosage form, preferably ascorbic acid and / or butylated hydroxytoluene (BHT) and / or butylated hydroxy anisole (BHA), still more preferably ascorbic acid, is dissolved in the granulation liquid.

27. The dosage form according to any of the preceding claims, which is obtained by a process involving wet granulation of a mixture of powders for granulation with a granulation liquid, wherein essentially the total amount of the one or more antioxidants contained in the dosage form, preferably ascorbic acid and / or butylated hydroxytoluene (BHT) and / or butylated hydroxy anisole (BHA), still more preferably ascorbic acid, is added to the mixture of powders for granulation.

28. The dosage form according to any of the preceding claims, which comprises one or more intra- granular disintegrants and / or one or more extragranular disintegrants.

29. The dosage form according to claim 28, wherein the one or more intragranular disintegrants and / or the one or more disintegrants independently of one another comprise or essentially consist of a starch or a starch derivative; preferably sodium carboxymethyl starch (preferably type A).

30. The dosage form according to claim 29, wherein a first fraction of sodium carboxymethyl starch (preferably type A) is contained in the intragranular phase and a second fraction of sodium carboxymethyl starch (preferably type A) is contained in the extragranular phase.

31. The dosage form according to any of claims 28 to 30, wherein the total weight content of the one or more intragranular and / or extragranular disintegrants, preferably sodium carboxymethyl starch (preferably type A), is within the range of 0.5-10.0 wt.-%, preferably 1.0-9.5 wt.-%, more preferably 1.5 - 8.5 wt.-%, still more preferably 1.75 - 8.0 wt.-%, yet more preferably 2.0 - 7.5 wt.-%, in each case relative to the total weight of the tablet core.

32. The dosage form according to any of the preceding claims, which comprises one or more intragranular binders.

33. The dosage form according to claim 32, wherein the one or more binders comprise or essentially consist of a cellulose ether; preferably hydroxypropyl cellulose.

34. The dosage form according to claim 32 and 33, wherein the total weight content of the one or more intragranular binders, preferably hydroxypropyl cellulose, is within the range of 1.0 - 7.0 wt.-%, preferably 1.5 - 6.5 wt.-%, more preferably 1.8 - 6.0 wt.-%, still more preferably 2.0 - 5.5 wt.-%, yetmore preferably 2.5 - 5.0wt.-%, even more preferably 2.8 - 4.5 wt.-%, most preferably 3.0 - 4.0 wt.-%, in each case relative to the total weight of the tablet core.

35. The dosage form according to any of claims 32 to 34, which comprises an intragranular phase and an extragranular phase, wherein essentially the total amount of the one or more binders contained in the dosage form, preferably hydroxypropyl cellulose, is contained in the intragranular phase.

36. The dosage form according to any of the preceding claims, which comprises one or more extra- granular lubricants.

37. The dosage form according to claim 35, wherein the one or more lubricants comprise or essentially consist of a magnesium stearate and talc.

38. The dosage form according to any of claims 36 and 37, wherein the total weight content of the one or more lubricants, preferably magnesium stearate and talc, is within the range of 1.0 - 7.0 wt.-%, preferably 1.2 - 6.0 wt.-%, more preferably 1.4 - 5.0 wt.-%, still more preferably 1.5 - 4.0 wt.-%, yet more preferably 1.5 - 3.5 wt.-%, even more preferably 1.6 - 3.0 wt.-%, most preferably 1.8 - 3.0 wt.-%, in each case relative to the total weight of the tablet core.

39. The dosage form according to any of claims 36 to 38, wherein essentially the total amount of the one or more lubricants contained in the dosage form, preferably magnesium stearate and talc, is contained in the extragranular phase.

40. The dosage form according to any of the preceding claims, which comprisesSertraline or a physiologically acceptable salt thereof; preferably Sertraline hydrochloride; one or more antioxidants comprising or essentially consisting of ascorbic acid and derivatives thereof, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof; still more preferably ascorbic acid;one or more fdlers; preferably mannitol, microcrystalline cellulose, lactose, or any combination thereof;one or more disintegrants; preferably sodium carboxymethyl starch (preferably type A); one or more binders; preferably hydroxypropyl cellulose; andone or more lubricants; preferably magnesium stearate and talc.

41. The dosage form according to claim 40, wherein the dose of the Sertraline is within the range of 1 to 300 mg, more preferably 20 to 280 mg and most preferably 25 to 200 mg, in each case based upon an equivalent weight of the non-salt form of Sertraline42. The dosage form according to claim 40, wherein the total weight content of the one or more intragranular and / or extragranular antioxidants, preferably ascorbic acid, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof, still more preferably ascorbic acid, is within the range of 0.01 - 3 wt.-%, preferably 0.02 - 2.5 wt.-%, more preferably 0.02 - 1.5 wt.-%, most preferably 0.02 - 1.0 wt.-%, in each case relative to the total weight of the tablet core.

43. The dosage form according to any of the preceding claims, wherein the total weight content of intragranular fdler, preferably mannitol or lactose, more preferably mannitol, is within the range of 0.1 to 60 wt.-%, preferably from 10 to 40 wt.-%, more preferably from 15 to 35 wt.-% in each case relative to the total weight of the tablet core.

44. The dosage form according to any of claim, wherein the total weight content of extragranular filler, preferably mannitol, microcrystalline cellulose or lactose is within the range of within the range of from 0.1 to 60 wt.-%, preferably from 10 to 40 wt.-%, more preferably from 15 to 35 wt.-%, in each case relative to the total weight of the tablet core.

45. The dosage form according to any of the preceding claims, wherein the total weight content of the one or more intragranular and / or extragranular disintegrants, preferably sodium carboxymethyl starch (preferably type A), is within the range of 0.5-10.0 wt.-%, preferably 1.0-9.5 wt.-%, more preferably 1.5 - 8.5 wt.-%, still more preferably 1.75 - 8.0 wt.-%, yet more preferably 2.0 - 7.5 wt.-%, in each case relative to the total weight of the tablet core.

46. The dosage form according to any of the preceding claims, wherein the total weight content of the one or more binders, preferably hydroxypropyl cellulose, is within the range of 1.0 - 7.0 wt.- %, preferably 1.5 - 6.5 wt.-%, more preferably 1.8 - 6.0 wt.-%, still more preferably 2.0 - 5.5 wt.-%, yet more preferably 2.5 - 5.0wt.-%, even more preferably 2.8 - 4.5 wt.-%, most preferably 3.0 - 4.0 wt.-%, in each case relative to the total weight of the tablet core.

47. The dosage form according to any of the preceding claims, wherein the total weight content of the one or more lubricants, preferably magnesium stearate and talc, is within the range of 1.0 - 7.0 wt.-%, preferably 1.2 - 6.0 wt.-%, more preferably 1.4 - 5.0 wt.-%, still more preferably 1.5 - 4.0 wt.-%, yet more preferably 1.5 - 3.5 wt.-%, even more preferably 1.6 - 3.0 wt.-%, most preferably 1.8 - 3.0 wt.-%, in each case relative to the total weight of the tablet core.

48. The dosage form according to any of the preceding claims, which comprises a film coating.

49. The dosage form according to claim 48, wherein the film coating is based on hypromellose.

50. The dosage form according to any of the preceding claims, which under in vitro conditions provides immediate release of Sertraline.

51. The dosage form according to any of the preceding claims, which is obtained or obtainable by a process comprising steps of:mixing and optionally sieving starting materials Sertraline hydrochloride, one or more fillers, one or more disintegrants and optionally one or more antioxidants to obtain homogenized powder mixture;transferring homogenized powder mixture into a fluid bed granulator;preparing granulating liquid by mixing of water or organic solvent such as ethanol, methanol, propanol or aqueous mixture thereof and dissolving one or more binders and optionally one or more antioxidants, such as ascorbic acid, in the granulating liquid;spraying the granulating liquid onto the homogenized powder mixture in the fluid bed granulator; after spraying is finished, drying the thus obtained granules and then sieving to obtain sieved granules;mixing and optionally sieving one or more fillers, one or more disintegrants, one or more lubricants and optionally one or more antioxidants;mixing these excipients with the sieved granules to obtain a compression mixture; compressing the compression mixture to obtain tablet cores;optionally, film-coating the tablet cores.

52. The dosage form according to any of the preceding claims, which is obtained or obtainable by a process comprising steps of:mixing and optionally sieving starting materials Sertraline hydrochloride, mannitol or lactose, preferably mannitol, carboxymethyl starch (preferably type A) and optionally ascorbic acid or a derivative thereof, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof, preferably ascorbic acid, to obtain homogenized powder mixture; transferring the homogenized powder mixture into a fluid bed granulator;preparing a granulating liquid by mixing of purified water, hydroxypropyl cellulose (HPC) and optionally ascorbic acid or a derivative thereof, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof, preferably ascorbic acid;spraying the granulating liquid onto the homogenized powder mixture in the fluid bed granulator; after spraying is finished, drying the thus obtained granules and then sieving to obtain sieved granules,mixing and optionally sieving mannitol, microcrystalline cellulose, lactose, or any combination thereof, carboxymethyl starch (preferably type A), talc and magnesium stearate and optionally ascorbic acid;mixing these excipients with the sieved granules to obtain a compression mixture; compressing the compression mixture to obtain tablet cores; andoptionally, film coating the tablet cores, wherein the film coating is based on hypromellose.

53. The dosage form according to any of the preceding claims, which is obtained or obtainable by a process comprising steps of:mixing and optionally sieving starting materials Sertraline hydrochloride, mannitol or lactose, preferably mannitol, carboxymethyl starch (preferably type A) to obtain homogenized powder mixture;transferring the homogenized powder mixture into a fluid bed granulator;preparing a granulating liquid by mixing of purified water, hydroxypropyl cellulose (HPC) and antioxidant selected from ascorbic acid or a derivative thereof, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), or any combination thereof, preferably ascorbic acid; spraying the granulating liquid onto the homogenized powder mixture in the fluid bed granulator; after spraying is finished, drying the thus obtained granules and then sieving to obtain sieved granules,mixing and optionally sieving mannitol, microcrystalline cellulose, lactose, or any combination thereof, carboxymethyl starch (preferably type A), talc and magnesium stearate;mixing these excipients with the sieved granules to obtain a compression mixture; compressing the compression mixture to obtain tablet cores; andoptionally, film coating the tablet cores, wherein the film coating is based on hypromellose.

54. A packaging comprising the pharmaceutical dosage form according to any of the preceding claims.

55. The packaging according to claim 54, which is a blister packaging.

56. The packaging according to claims 54 and 55, wherein the packaging comprises a multilayer film.

57. The packaging according to claim 56, wherein the multilayer film comprises one or more layers that comprise or essentially consist of a metal; preferably aluminum.

58. The packaging according to claim 56 or 57, wherein the multilayer film comprises one or more layers that comprise or essentially consist of a polymer selected from polyvinyl chloride (PVC) and polyvinylidene dichloride (PVDC).

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