I International Bureau (10) International Publication Number (43) International Publication Date

Transcription

1 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2013/ A2 23 May 2013 ( ) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 9/20 ( ) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (21) International Application Number: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, PCT/TR20 12/ ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (22) International Filing Date: NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, 8 August 2012 ( ) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (25) Filing Language: English ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 201 1/ August ( ) TR GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (72) Inventor; and TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (71) Applicant : BILGIC, Mahmut [TR/TR]; Yildiz Teknik EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Universitesi Davutpasa Kampusu, Teknoloji Gelistirme MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Bolgesi D Blok, Esenler - Istanbul (TR). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (74) Agent: KARLD3AG, Gulben; Yildiz Teknik Universitesi ML, MR, NE, SN, TD, TG). Davutpasa Kampusu, Teknoloji Gelistirme Bolgesi D Blok, Published: Esenler - Istanbul (TR). without international search report and to be republished (81) Designated States (unless otherwise indicated, for every upon receipt of that report (Rule 48.2(g)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, < o o (54) Title: TABLET FORMS COMPRISING QUETIAPINE FUMARATE (57) Abstract: The present invention relates to formulations formulated in tablet form comprising quetiapine fumarate and prepara tion thereof.

2 TABLET FORMS COMPRISING QUETIAPINE FUMARATE The present invention relates to formulations comprising quetiapine fumarate and preparation thereof. Background of the Invention 2-{2-[Dibenzo[b,f](l,4) thiazepine-ll-yl) piperazine-l-yl]ethoxy}ethanol or quetiapine showed with Formula(I) which was first disclosed in the patent numbered US (A) is a dibenzothiazepine-derivative antipsychotic agent. (I) Formula 1 Quetiapine, which is structurally in white solid form, slightly dissolves in water though it has good solubility in alcohol. Quetiapine is used in schizophrenia, depressive episodes related to bipolar disorder, acute manic episodes related to bipolar disorder and continuous treatment of bipolar disorders. The formulations comprising quetiapine are generally in form of oral conventional tablet r film coated tablet. The product called SEROQUEL which is sold on the market by Astrazeneca comprises quetiapine as the active agent and it is in form of film coated tablet comprising 25, 100, 200, 300 mg of quetiapine or prolonged release tablet comprising 50, 200, 300, 400 g of quetiapine. Quetiapine was described as slow release tablet, optionally film coated tablet comprising film forming agent as water insoluble excipient, water soluble binder, and optionally lubricant in the patent application numbered WO/2010/ In this patent application, it was aimed to prevent sudden release of quetiapine by using water insoluble excipients and water soluble binder in the same formulation and a retarding effect was observed. Due to the reasons that failure to obtain free flow of the granules obtained in preparation of the formulations formulated in said tablet forms in the prior art and/or failure to reduce possible

3 friction in interfaces of the tablets, proper flow of the mixture is not enabled. Not being able to obtain a proper flow leads to observation of changes in tablet weight and increase in relative standard deviation values. These changes occurring in tablet weight cause loss of weight uniformity; therefore, a sufficiently effective treatment cannot be performed. Moreover, this situation poses further problems in quality and control phases. As can be seen, there is need for new approaches in order to obtain oral dosage forms produced in the manner that no change is observed in unit dosage weight for the purpose of performing an effective treatment by obtaining weight uniformity and furthermore, for the purpose of preventing problems arising from failure to provide weight uniformity in production and quality control phases. As a result of the studies conducted in line with this requirement, the inventors have seen that the formulations developed for preparation of the tablet forms comprising quetiapine fumarate according to present invention can solve the problems in the prior art such as particle flow and loss of weight uniformity caused by particle flow. The inventors have surprisingly seen that weight changes are minimized by providing a proper particle flow during the production of the formulations comprising quetiapine fumarate having an average particle size of µη in a therapeutically effective amount; glidant in the range of 0.5-5%, preferably in the range of 1-3%; diluent in the range of 5-30%, preferably in the range of 10-25% in proportion to unit dose amount. It has been found that various dosage forms obtained with the formulations prepared according to the present invention, for instance tablets, have low relative standard deviation in tablet weight; as a result, appropriate dosing is provided with these dosage forms. According to this, the first aspect of the present invention is the pharmaceutical formulations comprising quetiapine fumarate characterized in that the formulations comprise quetiapine fumarate in a therapeutically effective amount having an average particle size of µ ; glidant in the range of 0.5-5%, preferably in the range of 1-3% and diluent in the range of 5-30%, preferably in the range of 10-25% in proportion to unit dose amount. The formulations of the present invention comprising quetiapine fumarate can be formulated in the form of conventional tablet, film coated tablet, fast release tablet, slow release tablet, controlled release tablet or modified release tablet. The formulations prepared according to the present invention are preferably in film coated tablet form.

4 Quetiapine fumarate comprised in the formulation of the present invention is in the range of g, preferably in the range of mg and more preferably in the range of mg. Quetiapine fumarate comprised in the formulation of the present invention is in the range of 15-85%, preferably in the range of 20-75%, more preferably in the range of 25-60% in proportion to total weight of tablet. The inventors have found that providing proper flow of the particles, and particle sizes of the active agent and the other excipients used in providing weight uniformity of the tablet forms obtained are important in preparation of the formulations of the present invention. Particularly, the particle size of the active agent quetiapine used in the formulation is an important parameter in flow of the granules obtained and therefore in minimizing the weight changes of the tablets which are end products. According to this, the active agent quetiapine fumarate having average particle size of µηι is used preferably in the range of µ within the scope of the present invention. and more preferably in the range of µπι On the other hand, the inventors have found that the ratio of diluent: glidant has also an important effect on proper free flow of the particles and on weight uniformity of the tablets obtained as the end product during the preparation of the formulations. According to this, it has been seen that change in tablet weight is reduced during tablet production in the formulations wherein the ratio of diluentglidant is in the range of 30:1 to 2:1, preferably in the range of 25:1 to 3:1, more preferably in the range of 20:1 to 5:1; thus, the tablets obtained present weight uniformity and provide an effective treatment. According to this, another aspect of the present invention is the formulations comprising quetiapine fumarate characterized in that the ratio of diluent:glidant comprised in the formulations is in the range of 30:1 to 2:1, preferably in the range of 25:1 to 3:1, more preferably in the range of 20:1 to 5:1. The glidant used in the formulation of the present invention can be selected from, but not limited to, a group comprising calcium phosphate, tribasic cellulose, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, starch and talc or a combination thereof. Preferably, colloidal silicone dioxide is used. The diluent used in the formulation of the present invention can be selected from, but not limited to, a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic

5 calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, lactose monohydrate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, maltitol, starch, dextrin, maltodextrin, xylitol or combinations thereof. Preferably, lactose monohydrate is used. According to this, another aspect of the present invention is the pharmaceutical formulations comprising quetiapine fumarate characterized in that said formulations comprise quetiapine fumarate in a therapeutically effective amount having a particle size of µ ; colloidal silicone dioxide in the range of 0.5-8%, preferably in the range of 1-5% and lactose monohydrate in the range of 5-40%, preferably in the range of 0-30% in proportion to unit dose amount. The inventors have also found that the particle size of the excipients used in the formulation has a considerable effect on the homogeneity of the formulation. Accordingly, it has been observed that diluent used in the formulation has an important effect on obtaining a homogeneous tablet formulation and thus the dose uniformity of the tablets. The inventors have seen that the homogeneity of the formulation is provided and the tablet dose is adjusted during tablet production in the case that lactose monohydrate having average particle size in the range of µη, preferably µ ι and more preferably µ η is used; thus, the tablets obtained have weight uniformity and an effective treatment is provided. Another aspect of the present invention is the formulations comprising quetiapine fumarate characterized in that lactose monohydrate having average particle size in the range of µ ι, preferably µιη and more preferably µ η is used as diluent. Another aspect of the present invention is the formulations comprising quetiapine fumarate characterized in that said formulations comprise quetiapine fumarate in a therapeutically effective amount having a particle size of µ ; colloidal silicone dioxide in the range of 0.5-8%, preferably in the range of 1-5% and lactose monohydrate in the range of 5-40%, preferably in the range of 10-30% in proportion to unit dose amount having average particle size in the range of µπ, preferably µιη and more preferably µηι. In another aspect, the subject of the present invention is the pharmaceutical formulations comprising quetiapine fumarate, characterized in that the ratio of lactose monohydratexolloidal silicone dioxide comprised in the formulations is in the range of 30:1 to 2:1, preferably in the range of 25:1 to 3:1, more preferably in the range of 20:1 to 5:1.

6 In another aspect, the subject of the present invention is the pharmaceutical formulations comprising quetiapine fumarate as active agent, at least one glidant, at least one diluent and in addition, at least one pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can comprise quetiapine fumarate as the active agent; at least one glidant, preferably colloidal silicone dioxide; at least one diluent, preferably lactose monohydrate and furthermore, one or more of the pharmaceutically acceptable excipients such as binder, disintegrant, lubricant, anti adherent and film coating agent. The binder used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group comprising alginic acid, chitosan, carbomer, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, dextrin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, gelatine, hypromellose, magnesium aluminium silicate, starch, corn starch, maltodextrin, polyethylene oxide and povidone or combinations thereof. Preferably, povidone or corn starch or a combination thereof is used. More preferably, a combination which is composed of povidone and corn starch is used. A problem seen in dosage forms suitable for oral use such as tablet or film coated tablet is dissolution rates of these dosage forms in the body. It has been found that dissolution rates of the tablet forms obtained by using a binder combination comprising povidone and corn starch are high in the formulation of the present invention. The inventors have seen that the tablets, which are end products, have high dissolution rate in the case that the ratio of corn starch:povidone is in the range of 20: 1 to 3:1, preferably in the range of 15:1 to :1. In another aspect, the present invention is the pharmaceutical formulations comprising quetiapine characterized in comprising a binder combination which comprises povidone and corn starch wherein the ratio of corn starch:povidone is in the range of 20:1 to 3:1, preferably in the range of 15:1 to 5:1. The lubricant that can be used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group comprising PEG 6000, sodium benzoate, calcium stearate, glyceryl monostearate, magnesium stearate, polyvinyl alcohol, potassium benzoate, stearic acid and talc. The disintegrant that can be used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcry stall ine cellulose, silicone dioxide, croscarmellose

7 sodium, crospovidone, hydroxypropyl cellulose, methylcellulose, povidone, magnesium aluminum silicate, sodium alginate, sodium starch glycolate and starch or combinations thereof. The antiadherent that can be used in the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group comprising leucine, L-leucine, D-leucine, DLleucine, isoleucine, valine, talc, methionine, cysteine and phenylalanine or combinations thereof. The film coating agent that can be used in the pharmaceutical formulation of the present invention can be composed of ethyl cellulose, hydroxymethyl cellulose, polyethylene glycol, cellulose acetate phthalate, hydroxypropyl-methylcellulose phthalate and/or a combination thereof and also the excipients such as titanium oxide, iron oxide can be added to these substances. Furthermore, various film coating agents that are commercially available can be used as the coating agent. The solvents that can be used in preparation of the pharmaceutical formulation of the present invention can be selected from, but not limited to, a group comprising ethanol, methanol, deionized water, benzene, ethylene glycol. Preferably, deionized water is used. The pharmaceutical formulation of the present invention can comprise quetiapine fumarate in the range of 15-85%, the glidant in the range of 0.5-5%, the diluent in the range of 5-30%, the binder in the range of 5-35%, the disintegrant in the range of 1-10%, the lubricant in the range of 0.5-5%, the antiadherent in the range of 1-7% in proportion to total dosage weight. Optionally, the film coating agent can be used in the range of 2-15% in proportion to tablet weight before film coating in the case that the dosage form is tablet. Another aspect of the present invention is that the pharmaceutical composition prepared according to the said invention is used in treatment of the diseases such as agitation, acute psychosis, bipolar disorder, dementia, depression, mania, obsessive-compulsive and schizophrenia. Another aspect of the present invention is that the process that shall be used in preparation of the tablets comprising quetiapine fumarate of the present invention comprises the following steps: preparing a granulation solution comprising binder; granulating quetiapine fumarate, the disintegrant and the diluent with the granulation solution and mixing the granules obtained with the glidant and at least one excipient; compressing the final mixture in tablet form by adding the lubricant into the mixture and optionally coating the tablets with the film coating solution.

8 The inventors have seen that one of the parameters affecting on the dissolution rates of the tablet forms is tablet hardness and thus tablet compression force applied during compressing the final pharmaceutical composition into tablets. They have observed that when tablet compression force has a value in the range of kn, preferably kn., the obtained tablet forms have optimum hardness helping to rapid dispersion of tablets for getting ready for use. According to this, the present invention is related to the process for the preparation of quetiapine fumarate formulations formulated in tablet form wherein the tablet compression force applied during compressing the final mixture into tablet form is in the range of kn, preferably kn. The inventors have seen that the phases wherein the binder and the disintegrant used in the process for production of the formulations of the present invention are added to the process affect dissolution rate of the tablet forms obtained. According to this, the inventors have seen that the tablet forms comprising quetiapine which are produced according to the process comprising the following steps dissolve in the body quickly: 5-30% of the binder is included in preparation phase of the granulation solution, 70-95% of the binder is included in the granulation phase; 55-90% of the disintegrant is included in granulation phase, 10-45% of the disintegrant is included in the mixing phase. It has been found that 95% of the tablets which are obtained in dissolution profile tests performed according to the studies conducted dissolve in 45 minutes. The tablet forms of the present invention comprising quetiapine can be prepared as specified in, but not limited to, the examples below.

9 Example 1: The tablets comprising quetiapine and preparation methods thereof. The formulations of the present invention are prepared by a method comprising the steps of: preparing a granulation solution comprising binder; granulating quetiapine fumarate having an average particle size of 175 µ η, the binder, the disintegrant and the diluent with the granulation solution and mixing the granules obtained with the glidant, the disintegrant and the antiadherent; compressing the final mixture in tablet form by adding the lubricant into the mixture. Example 2: The film coated tablets comprising quetiapine and the preparation methods thereof

10 The formulations of the present invention are prepared by a method comprising the steps of: preparing a granulation solution comprising binder; granulating quetiapine fumarate having an average particle size of 200 µ, the binder, the disintegrant and the diluent with the granulation solution and mixing the granules obtained with the glidant, the disintegrant and the antiadherent; compressing the final mixture in tablet form by adding the lubricant into the mixture and optionally coating the tablets with film coating solution. Comparative Example 1: The film coated tablets comprising quetiapine and preparation method thereof The formulations of the present invention are prepared by a method comprising the steps of: preparing a granulation solution comprising binder; granulating quetiapine fumarate having an average particle size of 300µη, the binder, the disintegrant and the diluent with the granulation solution and mixing the granules obtained with the glidant, disintegrant and the antiadherent; compressing the final mixture in tablet form by adding the lubricant into the mixture and optionally coating the tablets with film coating solution.

11 Table 1. Comparison of Percentage Values of Relative Standard Deviations (%RSD) of the Film Coated Tablets Comprising Quetiapine by Weight The inventors have compared weight changes by percentage occurring during production phase of the film coated tablets obtained with the formulations prepared according to the present invention explained in example 2 and the film coated tablets which are not formulated according to the present invention explained in comparative example 1. The results of this comparison are showed in Table 1 given above. %RSD values of the tablets obtained according to the specifications should be less than 2%. According to the results given, it has been seen that %RSD value of the tablets obtained by formulating the formulation of the present invention is less than 2%; %RSD value of the tablets given in the comparative example is much more than 2%. According to this, it has been found that changes in tablet weight of the film coated tablets obtained with the formulations comprising quetiapine fumarate having an average particle size of µη in a therapeutically effective amount; the glidant in the range of 0.5-5%, preferably in the range of 1-3% and the diluent in the range of 5-30%, preferably in the range of 10-25% in proportion to unit dose amount are quite low; therefore, said tablets provide more effective dosing and treatment by enabling weight uniformity.

12 CLAIMS 1. A pharmaceutical formulation comprising quetiapine fumarate characterized in that the formulation comprising quetiapine fumarate having an average particle size of µ in a therapeutically effective amount; the glidant in the range of 0.5-5% and the diluent in the range of 5-30% in proportion to unit dose amount. 2. The pharmaceutical formulation according to claim 1, wherein the formulation comprises the glidant in the range of 1-3%. 3. The formulation according to claim 1 and 2, wherein the formulation comprises the diluent in the range of 10-25%. 4. The formulation according to claim 1-3, wherein the formulation is formulated in form of conventional tablet, film coated tablet, fast release tablet, slow release tablet, controlled release tablet or modified release tablet. 5. The formulation according to claim 4, wherein the formulation is formulated in form of film coated tablet. 6. The formulation according to claim 1-5, wherein the amount of quetiapine fumarate is in the range of mg. 7. The formulation according to claim 1-6, wherein the ratio of diluent:glidant is in the range of 30:1 to 2:1. 8. The formulation according to claim 1-7, wherein the ratio of diluent:glidant is in the range of 20:1 to 5:1. 9. The formulation according to claim 1-8, wherein the glidant is selected from calcium phosphate, tribasic cellulose, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, starch and talc or a combination thereof. 10. The formulation according to claim 9, wherein colloidal silicone dioxide is used as the glidant. 11. The formulation according to claim 1-10, wherein the diluent is selected from a group comprising calcium carbonate, calcium sulphate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, lactose, lactose monohydrate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, maltitol, starch, dextrin, maltodextrin, xylitol or combinations thereof. 12. The formulation according to claim 11, wherein lactose monohydrate is used as the diluent.

13 13. The formulation according to claim 11-12, wherein lactose monohydrate has average particle size in the range of µπ. 14. The formulation according to claim 1, wherein the formulation comprises quetiapine fumarate, at least one glidant, at least one diluent, and one or more of the pharmaceutically acceptable excipients such as binder, disintegrant, lubricant, antiadherent and film coating agent in addition. 15. The formulation according to claim 14, wherein the binder is selected from a group comprising alginic acid, chitosan, carbomer, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, dextrin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, gelatine, hypromellose, magnesium aluminium silicate, starch, corn starch, maltodextrin, polyethylene oxide and povidone or combinations thereof. 16. The formulation according to claim 15, wherein a combination comprising povidone and corn starch is used as the binder. 17. The formulation according to claim 6, wherein the ratio of corn starch:povidone is in the range of 20:1 to 3: The formulation according to claim 14, wherein the lubricant is selected from a group comprising PEG 6000, sodium benzoate, calcium stearate, glyceryl monostearate, magnesium stearate, polyvinyl alcohol, potassium benzoate, stearic acid and talc. 19. The formulation according to claim 14, wherein the disintegrant is selected from a group comprising carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, microcrystalline cellulose, silicone dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, methylcellulose, povidone, magnesium aluminum silicate, sodium alginate, sodium starch glycolate and starch or combinations thereof. 20. The formulation according to claim 14, wherein the antiadherant is selected from a group comprising leucine, L-leucine, D-leucine, DL- leucine, isoleucine, valine, talc, methionine, cysteine and phenylalanine or combinations thereof. 21. The formulation according to claim 14, wherein the film coating agent is composed of ethyl cellulose, hydroxymethyl cellulose, polyethylene glycol, cellulose acetate phthalate, hydroxypropyl-methylcellulose phthalate and/or a combination thereof while the excipients such as titanium dioxide, iron oxide are also added to these substances. 22. The formulation according to claim 1-21, wherein the formulation comprises quetiapine fumarate in the range of 15-85%, the glidant in the range of 0.5-5%, the diluent in the range of 5-30%, the binder in the range of 5-35%, the disintegrant in the range of 1-10%, the lubricant in the range of 0.5-5%, the antiadherent in the range of 1-7% in proportion

14 to total tablet weight and optionally the film coating agent in the range of 1-10% in proportion to total film coated tablet weight. 23. A process for the preparation of tablets comprising quetiapine fumarate according to claim 1, wherein said process comprises the steps of preparing a granulation solution comprising binder; granulating quetiapine fumarate, the disintegrant and the diluent with the granulation solution and mixing the granules obtained with the glidant and at least one excipient; compressing the final mixture obtained in tablet form by adding the lubricant into the mixture and optionally coating the tablets with the film coating solution. 24. A process according to claim 23, wherein the tablet compression force applied during compressing the final mixture into tablet form is in the range of kn.