USOOS9484378 United States Patent 11) fu) Patent Number: 5,948,437 Parikh et al. (35) Date of Patent: Sep. 7, 1999 [54] PHARMACEUTICAL COMPOSITIONS 3.765. 2/1995 Ine ta USING THIAZEPINE 918 3)98 tandhrg FOREIGN PATENT DOCUMENTS [75] Taventors: Bhavaish Vinod Parikh, Hockessin, Del; Robert Joseph Timko, West $463047 41987 Ansan Chester, Pa; William Joseph Addicks, TILL) 1584 Barope Pat. Of Morgaoiown, W. Va. 157605 10/1985 _Eurepean Pa Off 2oee2 "sy1987 European Pat. Of 73], Assignee: Zeneea Limited, United Kingdom 253841 1/1988 Faropean Pat. Of (7a) Asi . 24st AL 11988 Puropean Pat Of; 2250807980 European Pa Of [21] Appl. No. O8/864,306 284869 BI 1993 Paropean Pa. Of oo aeowo02 1988 France [22] Filed: May 28, 1997 3733540 4/1988 Germany assi4 121977 Japan Related US. Application Data cacasian ‘apises Iepan [60] Provisional application No. SODISAIS, May 31, 1936, 62.149682 711987 Japan ater cose) 1/988 Japan el ae eon 63101334 5/1988 Japon [52] US.ch S264; 424470, 424458; fee aioe pis s1a2it e-v7al6! e/tons Japon [58] Feld of Search 4241464, 401; "795528 11/1979 Suh Aca Sivan; saoissi aoest i076 Uaied Kingdom {583801 3/1981 Unied Kingdom 156) References Cited 219889341988 United Kingdom 2210300 13/1989 Unied Kington US. PATENT DOCUMENTS wossusia) ‘Sio8s WIPO nn WO STOO 1/087 WIPO 065,143 1/1962. Cisenson ta WosD0I1s 31992 Wir 3017 O/1971 Chratenson eal Worn aim. Wir 3an0790 31075 Lowey a 126889 1nt98 Shor Primary Exaniner—Turman K. Page 4259,814 31981. Lowey ‘Assistant Examiner—Willam E. Benston, Se Gina 1982 Guy ca A3s7aH0 111982 Schon 571 ABSTRACT 300172 1/1980. Scho ea {90.393 6/1088 Schr eta “The invention relates to sustsined release formulations com 4510340 91988 Danse a prising. 11-[4-[2-2-hydronyethoxy)ethyl]-1-piperazinyl) esos. 71987 Lowey Alibeavofb.] [Alhiazepine or a pharmacsutically aocept- Ao 2es 988 Alderman able sal thereof, fo methods of eating psychotic states and YRSR Tok avd a hyperactivity uilizing the sustained release formulations 1840.229 71089 Gaylord eta ain o a process for preparing the sustained release forms teres ise Spetant ant pres for preparing the Sse ees Abigaas "41980 Lovegrove et S26 145 11002 Pees ta 15 Claims, 2 Drawing Sheets i. eee 100 | 2} @ gz? 2 © z 50 _ B40 |e Example 8 5 -eS.ampie 9 | : 4 Example 10) 2 0 o 8 10 Time (Hours) 2 4 16 185,948,437 Sheet 1 of 2 Sep. 7, 1999 US, Patent © | OL bh a O} ejdwexy -¥ 6 9\dwexy ——) g ejdwexy —e— (sanopy) owt OL 8 9 v j 0 06 0OL Ob L aunBiy paseajay %U.S. Patent Sep. 7, 1999 Sheet 2 of 2 5,948,437 Figure 2 + Example 12 se Example 2 ~~ Example 1 400 Plasma concentration (ng/mL) 100 Time (hours) after dosing5,948,437 1 PHARMACEUTICAL COMPOSITIONS. USING THIAZEPINE, ‘This application chums the benefit of U.S, Provisional Application No. 60/018.816, fled on May 31, 1996. ‘The present invention relates toa pharmaceutical com- position and more particulary to a sustained release phar- maceutical composition comprising 11-[4-[2-Q- hydroxyethoxyethyl}-1-piperazinyl dibenzo[b,f]L1.4] thiazepine ora pharmaceutically acceptable salt thereo. It is desirable in the treatment of a number of diseases, both therapeutically and prophylactically, to provide the active pharmaceutical ingredient in & sustained release form. Desirably the sustained release provides a generally uniform and constant rate of release over an extended period of time Which achieves a stable and desired blood (plasma) level of the active ingredient without the need for frequent admin- istration of the medicament. ‘While there are numerous sustained release formulations Known ia the art which utilize gelling agents, such as hydroxypropyl methylcellulose, it has been found to be dificult to formulate sustained release formulations of soluble medicaments and gelling agents, such as hydox~ Yyropyl methyleliulose, for several easons. First of ll, active ingredients which are soluble in water tend to gen erate a sustained release product which is susceptible 0 a phenomenon known as dose dumping. That is, release of the active ingredient is delayed for a time but once release begins to occur the rate of release is very high. Moreover, fluctuations tend to occur in the plasma concentrations ofthe active ingredient which increases the likelibood of toxic Funther, some degree of diucnal variation in plasma concen tration of the active ingredient has also been observed. Finally, it has been found to be difficult to achieve the desired dissolution proiles orto conte the rate of release of the soluble medicament ‘Accordingly, « nced exists for sustained release formu lations of soluble medicaments, such as, L1[4-[ hydroxyethoxy)ethy!]-1-piperazinyl}dibenzof).t][1,4] thiazepine or a pharmaccuically acceptable salt, which overcome, or atleast alleviate, one or more of the above deseribed difficulties and which further provide the advan- tagcous property of allowing the active medicament to be administered less frequently, e.g. once a day, while ac ing blood (plasma) levels similar to those attained by administering smaller doses of the medicament more frequently, eg. two oF more times daily FIG. 1 shows the release (dissolution) profiles of the sustained release formulations of Examples 8, 9 and 10 Which are obtained by immersing suitable tablet in 750 ml. of 0.1 N HC for 2 hours at 37° C. and a speed of 100 ppm and then adding 250 mL. of 02 M sodium phosphate bulfer to the dissolution media to afford a pH of 62. FIG, 2 shows the plasma concentration versus time profes of the active ingredient for the sustained release formulations of examples I and 2 and the immediate release formulation of example 12. ‘The compound, 11-[4-(2-(2-hydroxyethoxy)ethyl]- Lpiperszinyl}-dibenzofb,{[14}hiazepine (see Formula 1 below), and its pharmaceutically acceptable salts exhibit useful antidopaminergic ativity and may be used, for 0 6 oe O ‘example, as an antipsychotic agent (for example, for the management of the manifestations of psychotic disorders) oF as a treatment for hyperactivity. It is @ compound of par- ticular interest since it may be used as an antipsychotic agent ‘with a substantial reduction in the potential to cause side effects such as acute dystonia, acule dyskinesia, pseudo- Parkinsonism and tardive dyskinesia which side-effects may result from the use of other antipsychotics or neuroleptics The preparation, physical properties and beneficial phar- macological properties of I -[4-[2-2- bydroxyethoxy) 28 ethyl} 1 -piperazinyleibenzofb,f[1,4]-hiazepine, and its ‘pharmaceutically acceptable salts are deseribed in published European Patents EP 240,228 and 282,236 as well as in U:S. Pat. No. 4,879,288, the entire contents of which are herein incorporated by reference. ‘According to the present invention there is provided a sustained release formulation comprising a gelling agent, preferably hydroxypropyl methylcellulose, and 1144.[2-2. hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo-[b.f][ 1.4] thiazepine, or @ pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients, Preferably, the sistained release. formulation ‘comprises « hydrophilic matrix comprising a gelling agent, preferably hydroxypropyl methylcellulose, and 1144-[2-(2 hydroxyethoxy)ethy! -Ipiperazinyv dibenzo-[b.tT[L4] thiazepine, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients. "The term gelling agent as used herein means any substance, particularly a hydrophilic substance, whieh forms ‘gel when in contact with water and thus includes such substances as hydroxypropyl methylcellulose, hydroxypropylceitulose, hydroxymethyleellulose, hydroxyethylcellulose, ‘hydroxypropyl. ethylcellulose, methylcellulose, ethylcellulose, carboxyethyleellulose, ca boxymethyl hydroxyethyleeliulose, earhomer, sodiam ccarboxymethylcellulose, polyvinylpyrvolidone, andthe like, ‘or mixiures thereof. The gelling agent is preferably bydrox- ypropy! methyleelilose ‘The amount of gelling agent, preferably hydroxypropyl methylcellulose, is preferably selected suct that the active ingredient is released from the Formulation, in a controlled fashion, over a petiod of 4 hours or longer, preferably over 4 period of 8 hours or longer and in particular over a perio fof between 8 and 24 hours, that i so that atleast 60% ofthe active ingredient has been released atthe end of this period. The gelling agent, preferably hydroxypropyl methyleellulose, is eoaveniently present in about 5 to 50% (by Weight), more convenienily about 5 to 40%, most ‘conveniently about 8 to 35% and in particular about 10 10 35%. It is gonerally preferred that the gelling agent, prefer- bly hydroxypropyl methyleeltulose is present in sbout 10 10 30%, more preferably about 15 10 30%.