AU1132299A - Process for the preparation of an oral solid dosage form containing diclofenac - Google Patents
Process for the preparation of an oral solid dosage form containing diclofenac Download PDFInfo
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- AU1132299A AU1132299A AU11322/99A AU1132299A AU1132299A AU 1132299 A AU1132299 A AU 1132299A AU 11322/99 A AU11322/99 A AU 11322/99A AU 1132299 A AU1132299 A AU 1132299A AU 1132299 A AU1132299 A AU 1132299A
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- inclusion compound
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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Description
Our Ref': i.1 I~O 111 00 1) 11 Regulation 3 At\I s RAI. IA Pawtnts Act 1000Q ORIGIN AL COMPE .I'E SPECIFICATIION ST'ANDARD) PATEiNT Novnrtis AG Se hwarzwaldallce 213 Cl1-4C0SS Basel
SWITZERLAND
Address (br Service', Invention Title: DAVIES COLLISON CAVE Patent Trade Mlark Attornevs Level 10, 10 flaraek Street SYDNEY NSW 2000 Process for the preparation of an oral solid dostijue form containirng diclol'enuc 'I'he following statenient is a full description of this invention, including the best method of perfortnm it known to mez.- 5020 4-1958C/A f~~or the pre iirit on of an oral solid d 1 Co niilti) f! Ile presnt invention reltes to a novel advantaCus Process for the Pre-Paraio Of all oral solid dosage forM containing diclofeflaC or a pharmaceuticaIlly acetal SatheJ3Qf, to th incl~iO~ coniO~ido coenac or a pharua-eu~llclY acceptable salt thereof With y-Cyclodutlfl useful as intentiediate for said proceS as w4ella oapocs o h prepamttion d- said inclusion compound.
A variety of theraPeutic agents of differetstructure espec'ially I amatoriya antiflalmtatory drugs (NS&lD), is a,.ailable for the wratment of paiful inflaiuiLY dsseeg heuiatiSmi Numbtered among this group of NSA1Ds of filSt choice is the sodium salt of diclofenic1 which h,,s lon en~ introducLed in numerous COUntrias under the registered trademarkz voitame® (Ciba-ceigy) and which is avztilable in different dosage formTs such IS drag&S., suppflsitolles or injection solutions.
Quite generally the oral Pdil~t~o of this theraputiC agent in. solid dosage forms such as tablets at dmudeS &WS adatas SOverother, for example pameteral, dosage form&~ DiSes that hnve to be tmated by administering injections are felt Purely subjectively to be mome serious than other diseae in the treatment of which the adminitration of tablets or dxagdes is little noticed. The suitability of such dosage forms for sefmedicati6Xl by patients themselves is esoncially advntkgeous, whereas Pamenrl dosag forMs aide fronm a few e-tCeptiofls, have to be administered by the physician or authorised auxiliary medical perOnnel.
With the excption of less directly compressble therapeutic agents such &s acetlsldicYlic acid, pbenobubit~fle' pheltcetifl, coffein, ascorbic acid, ammntfium chloride or potassum chloride, tablets or drag~z aM prepaed in multi-step processes in which granulates wre formed as intermediates. Granulates can be produced by differet methods, typically by moist granulation or conmpacting, The Pgranulates; are subsequently compressed to tablets technical literature t-AeS the unequivocal view that the direct ConlipreSSO.1Of IortVth ti c wtolgranuihlwfnainhsavnae ve i oI fgaxlt whchhvet prepared il ist te with an additional procCss stp So far il is nkit known of diclofeflac or a salt thercof that this impoltant therapeutic dtrug can be compressed diret to brteak-rosistaflt tablets.
A further advantage of tablets anid dragdes obtained by direct compression results froln the increased concenitration of the thierafxtic agent. which can usually Ne raised to over 51A,~ by Weight. Usually. therefore, smaller amounts of excipiets are required for direct compremssion than.. for the comresion of granulate&. Gi.ven a predete-nninedC tabltste therefore, it is possible to increase the concentrion of therapeutic agent or, given a predeca-infed dow-, to reduce the size of the tabl.L Hence it is the object of this inveatiofl to prepare solid o~ral dosage forms such as tablets or drages containing the therapeutic drug diclofela, or a phanuaceutica-llY acceptable salt tereof, by direct comipresion~. TIhis object is achieved by utilisationl of the surprisinig discover that the therapeutic drug diclofeilac, or a salt tharco t with .y.cyclodelxtrili formis a. defined inclusion compound that can be compressed direct to tablets or dz&i Accordingly, the invention velates to a process for the preparationi of a conipe-S' dosage forn for the therapeutic drug diclofenic: or a ph-mannCtutically acceptable salt. thmrof, which comprises preparing an inclusion compound consisting of diclofelnic, or a phannacetlticallY acceptable sWt thereof.,and y-cychlexuinfl and com-ressing aid inclusion compound directly, with the addition of optional e-xcipients conventionally employed in the preparation of selid dosage forms, and, if desired, further proc~'sifg the compressed tablet core so obtained to another solid dosage form.
A further objoct of the invention is the inclusion compound as defined herin formed frmm diclofenac, or a pharaceliticaIIy acceptable salt therof. and y-cycodewrt1in, which can be used as intermediate in the procms for the prepantiifl of a directly compressed dw;4-e form. The eharacterisable inclusion compound formed from diclofeflac sodium salt and y-cyclode~xtfin is especially preferred.
A fiurther object of the invention is the process icr t preparation of salid inclusion compound.
S-3 '111c terms used throughout this specification ame df -ted as followS within die scope of the R description of the present. invention, 'Me termi "compressedi dosage, form' emlbraces tablets or drag~es that rdisinegrate in the- 'I stomach or in the interonnecting part of the gastrointmstinal tract (duodanum) and which are able to release_ the therapeutic drug diclofenac or a pharmaceutically acceptable salOt thereof, with or wvithout controlled release of the active drug.
Tablets or dra g~5es (without control of drug release) =x -sinigle-dose, solid dosage farnis for peroral administation that can be prepared by direct comupression of the inclusion compound formed from diclofenac, or a pharmaceticeally acceptable salt thereof, and y-cyclodextrin, with or without the addition of suitable excipients, by mueans of standard tabletting methods, Dragt~s are distinguished from tablets by providintgthem with an additional coating, typically a sugar, shellac, coloured or film coating.
*Compressed dosage forms with controlled release of therapeutic drug are. distinguished by accelerated or delayed, as wvell as quantitatively controlled, release of drug. Thus tiblets with accelerated release of therapeutic dnig are foamed wvith disintegrants such as sa:) inked polyvinyl pyrrolidone (Polyplasdone® XL or KollidonO CL) or reactive e~xeipients (eflervescent. mixtures) that effect rapid disintegration of dhe tablet in the *presence of water, for example so-called effervvescent tablets that contain an acid in solid form, typically citric acid, which acts in wvater on a bms containing chemically combined carbon dioxide, for example sodium hydrogencarbonate or sodiumn carbonate, and releases carbon dioxide- Compressed dosag forms with delayed release and, preferably, quantitativealy controlled release, of the therapeutic drug are defined in the technical literature by differnt terius such as enteric-coated tablet%, tablets with modified drug release, releas systemns or oral theraputic systems, T1hese definitions meet a therapeutically deterrmined objective, typically the delayed release of a drug to effect a reduction of local ovmioncetrations because of the risk of irritation to gastric or intestinal mucasa (ulcer problems), reduction of the release of a loading dose administered in initial overoncetration, or Prolonged reease. A widte range of dosage forms ame known whose properties are defined by terms such as sustained release, controlled release, prolonged release, repa orpa e ees or delayed release. The preferrd dosage forms are controlled release or sustained release fonus that not only delay realeasc Of the active dn over a Period of timei but a lso release it III a controlled amount. Such dosage forms =r knio\ i as oral osmotic systenms (OtROS), coated tabkls, matrix tablets, film- mosted tablets, press-coated tablets, rautilaye tablets and the like A pharlaccuically ac-ptabl salt of diclofenac, o-?6dciepeyiiiiopi -ya7, Ktic acid, q.v. Merck Inde-x, Eleventh Edition No. 307 1, is prefeably the sodium or potassium salt ndalso the salt with an amnine, e.t. a mono-, di- ortiC diethylanfe ortrithyinmiifl, hydroxy-C,-Calkylwnlil 1 eg ethanola mine, etg- diniethylethanal Anfl sir aaenr ammnonium salt. e.g. the tetranmethylammofliurn salt or t choline salt of diclofenac- The respective inclusion compound consisting of diclofenac, orw a phanilaccutically acceptble slt threofand ~is novel and is an objec of the invention.Th foltowving Chchetisti daaariven for the inclusion t-*mpound of dieclofeniac sodium salt with y-eyedodextuin, hereinafter wefered to as y-cyclodextin. dicof =ic sodium: 1. ERnmental analysis (based on the anhydrous; sample), Elemient theory found y-cyclodemtin-dklfe&c-Na- C 46,11% 45.73% H 5.68% &.36 N 0.87% 1.15% Cl 4,39% 4,35% Na 1.42% 1,43 t y-cyclodextrndclofnc-K C 45,61% 45.75% Fl 5.58 5,53 N 0.86 0.8211 C1 4,35 4,41 %c K 2.40%236 2. Thernm-ainti nlystg): The saniples ame stored for 9 days at S2 weiatke humidity and room temperature, The mlewumenent is made using the Perkin-Elmier TUS 2 theanogravimetric systrem.
Substaire diclofenat-,Na diclefenac-K y-Cyrio&extrin Tentperature up to 10011C up to 200TC up to 2SOC up to 100TC up to 200C up to 28011C up to 1OT~ up to 20(PC up to 280TC lip to 1QDPC up to 200TC up to 28000C up to 100 0
C
up to 20011C up to 28000C 20.7 15.7%; 17.3 9; 13.7% 463 10.5%; yldxti t di co f imac-Na YcnIdi-diofn ac- K :1 3. Diffemrential scnnning, calarim.etrv DS) Tlit samples are sLtnmd foar 9 dznys at R2 relative humidity and room temprturmh mm-aunmment is mnade using a Fkarldn-Elrner the-mioanalyser (Series 7).
Substance Peak [QCj dictofenaL-Na 4 dlcifenac-K y-cydladtinjota'N Y-ctcd if&Cl o ft ac-Kia 56.6 114.2 130.3 29579 1003s 130-1 127.2 1S0-6 78-1 216.3 All [jig] 19 6 4 Rn X-paj'w auaLnsi The measumenult Is Made using a Guitier nue-a (FR &lulla-NnUS n amam gjeuiy. lbc dikgrarns ue reccorded by copper-Kctl-radiaUtfL At 15 XIOx& 0 )o \%ray film. A dineram Lo zimrf quar c-Id in die szom film is uSed fxr lixaigthe civnera radius, The ftQ)Nwing Table lists the 1itiic, distanc -s (d-v ahes ad ah relati i ttmit dfth mo st jimportant reifle-ves vvih &-values >1.5-10-10 nmI)d-va1ues [ItV~ IuTntds 14,60 S avtuw wa 7,70 wrg 7.30 \MAk w-tv weak- -S m) k" 4,86 NeAk 4,60 \TIY wa 4,39 wery N\TAk h 4f06 3.65 ea aIUCS ,ra d-vdus w nl nenite 8.20 vmr Nvak 7.50MM 7.30 y"t Stxlg 6,70
NV
6.50 Nwak 5.95 \t eak 5.71 x m 4,749v N"eak 4,61 wxy weak, \wAk 4.41 -wak 4,37 Ivkle 4,26 a~acl 4,20 NVCAk 4,12 VVAk 4,04 ael 3,.91 wrxy N\eAk 314 wxV.Y we&k 1.78 W Nve e 3.73 Weak 3,6 7 vexY \\T.A 3.64
V
3.50 .vry Avak 'Th dehfrne sdinvicy~dCtffl1A1 mixture is pre-pare by &,my iixing thce si IFS 4$supplied by RrukerX'I Ti v aumx ,ur ,I3veA in cjj t l. 'ThInNp of' the htuds is dsrbdin more detail by qua1i(ying- affixe&Is: 'st a trn;A stngavarg; wvk wak; b bpmad.
DIcdfrvxaC-,Na y-yQldti 1639 a\,,b 1576 vst 1556 %it 1508 vst 1391 N-sI 93 wVk 86$ av K,-9 'av 116 av 46 s1 17 ws 1'36-9 av, 944 av r54 wiSt 70 'IN 1414 LIv 1369 av 1157sq 941 at 758 axv 708 av DIcthIf0eIU-NR+ 1556 av 1508 av 1389 av,b 93av 714 av Djcdoatdn 1504 a 1468 at 452 st 306 w 1146 w 951 wv 768 av 7146 av 717w utae f nac-N indusion emtpd.
1634 wkt 1560 wVIt I 5Q04 av 1377 av\Ib 941 ar 860 \\tkb 7m av inbisoi cpd.
1506s"A 1472 ow 4456st 1315 av 1144 w 939 N,.
7745 "V 744 w 702 wv lhtespectram wrt mded vvitl a Jarko 710 didirgr, h.
The molar dipticity ftx xtro diclofen=i &-diui 102 6 M cin- and for [GL=n~idfe 84i~sin 6 M1 (at 272 umi in 69 inN phcvsphart, buffer sitlution, pH 7A4).
flxcipients customaniiN u1e tcor the pmparatikin of solid do~ip &orns amt prefdbl e=ptents tir tahtri. espeially LhQ&N that are suiable rbr dirw~ o-irx-ion& eu mvider bW=e~ such as staRthi, potaro scarob, Nvh\at staruh and corn qmvrlh, xegistere tmxamaik A-,ic,&1 a0) I-hn k etui or Prai® igldspso ,iRica, Aew'siO 'marnivol, lzzwlwse- and also P-ohlwyne yl'~o, Prfe&xably havinl,, nwlecular mass of 4 WO to 6 MNX, c-twsslinL-d poLyvitayl pjwoidcA-(Piyladoc
XL
or Kolfidon® C e-ssinktd Casbxyiuethyl f.Vllutosa (Aediscll® cmc--XL).
lkd Ccietm [NpiictIC (Nyma)), czubNwethyl stam-h [RxlotabO (Mmedali) ar trinicOje (Schowdtms)] dica'dcium phQoThiwo, eg. Emeo ®.ornv Liakum.i Thke additien of mimnor anmounts of -fidais \:tch as n vnegu,,,ut Pite al ,sxo ,u Fturher eciri MncM are sit ioonisc d tatlln, 11lum1in ium s tleaa, s teaiv ;Tid. Pat IIi 6c acid.
skimmed milk powder. stearvi. cetyl and inyrist alrohoLN LanetteC® 0, paruffin o~r khdmenated fats, Wiffirespect to tahldtin&. atenti is dmaN,. Io theivtv technica ftratiure on t sub*. L The conipmesion to tahltvmnres nan tv canried out in a conwuenional tnbkuling machie, e~.in an EK-4) Kmh e-enhic tableatiog iuachime preteably at a wompreWsOn greater tha w Q 10 4 The tablet cives may ary-in shape and bet~r example, airular, Oval, blng cylintdrical and the lke., and iny also vary in size depeudiq om the coce trativl lof therapeutic drag, Tlwey may furthermore be trainparet, colourles, coloured and also niarked as to impart to these- pwdwts an individual appearanze- and to Inake them instantly magnisable The ws oa dyes can srv to enhance the appearance as well as to identify ,h oupositim&s Des suitable fior use in OaniTacy typically inclutie can, ro s iroin oxWides or chimOrhyll, The compressed tablet cow~s forn-d by direct tabletting can, if desired 1 .be ftlrther p.-cssed in per se known mainner in another solid dosage forni, typically to dm gdtes that -ire provided with an additional coating, e.g. a sugar, shellac, coloured or film coating.
Attention is drawn to the numerous known niethods emiployed in dhe art of tablettiiig, e.g.
spray coating in a 0 uidised bed, e.g. by thd known meit!3d u-siag appiwatus available from Aei-oiatic, Gllatt. Wurster or i-l0tltlin, in a spray vat by the Accela Coma~ method, or to the submerged-coil coating muethod. The excipients commonly used in confOechonii% aro, employed in such nids.
A furthex object oi this invention is die Ier se known process for tie preparn tion of the inclusion comptound of diclofenac, or a pharmaceutically Acceptable salt thereof, in y-cyelodwxtin, which comprises reacting diclofenac, or a pharmiaceutically acceptable salt thereof, with y-cyclodextrin in the pivsenc of water.
This process can he carried out using a numiber of process variants, typically by a) adding water to a mixture of diclofeniac, or b phamRntceutically aceptable salt thereof.
with -y-ctclodextrin, and stirring the mixture at elevated temperature, preferably in the range Crumn 50-60'-C, and then, without or after cooling, precipitating or crystallising 'J~e.
resultant inclusion eompound. or b) dding wvater to a mixture of dielofcenac. or flt vilt thereof and -cychodextfin, and subsequently precipitating or crystallising the rstiltant inclusion compound. or c) in any ortder, adding a minor amiount of water first to diclofenac or to the salt thereof or y..cyclodextrin, kneading or agitatingp the moistennd paste and adding therelto the second component of the inclusion compound, or d) preparing .ftn aqueous suspensioni oi diclofennc, or the salt thereof, and y-cyclodextrin, converting said suspension into a solution by adjusting the pH to the alkl~ine range, typically by adding a base such as a solution of ammonia or dilute aqueous sodium or potassium hydroxide solution, and thereafter noulising this solution with an acid or a buffer solution. convenitntly by adding dilute aqueous sul furic acid or hydrochloric acid or a.-tic acid, and subsequently precipitating or crysthllising the resultant inclusion compound.
and then, after carrying out -any one of process variants a) to purifying or isolating tie resultant inelusion ecnipound.
I.
0 p
V
I
Ii.
I
N
I
j _12- Trhe inclusion compound can k' purified or isolated by washing thc pnwcipitatod or crystaflisud product with a minor amount otf all organic solvent, e.g. ethallol or acetonle, ill which in particular diclofenac or the salt thereof dissolves more readily than E~lio inclusion compound.
y-Cyclodextrin is also known as eyclooctaamylose, q~v, Merck Index, Eleventh Edition, INo. 2724. This excipient is a commercially available (Wacker Chemie) degradation product of starch and consists of 8 glucose units that ore linked to one another in cyclic conformation through glycosidic bonds.
Snecification: water conmemt when filled-, DME (dertrse equivalent): ignition residuc: milnium conc. of y-cyclodextrin: colic, of ot-cyclodextrim.
cone:. 0 J3.cyclod extrnll covc. otf linecar oligosaccitrides: turiidity of a 10 5) solution at 420 rni: (I cm layer thickness): manufacturer: 6.6 t% 0.05 <10.05 >99.5 96 1 1401 <0.1 %(mnl x.) 0.16 Wacker Cheii (DE) Exam'ple I 1. 1 preparation of the inclusion compound: 12.31 g (38.7 mmol) of diclofenac sodium and 50. 19 g (38.7 rnmol) of y-cyclodexctrin are dissolved In c, 1150 ml of water at 75TC. The solution is filtered and slowly allowed to cool to wron temperature, whereupon colourless naedle-shaped crystals precipitate. After standing for 3 days in a refrigeraitor, te crystals arm isolated by centrifugation at 10"C and 400 rpmi. The crstalline residue is washed with a small amount of ice-water and dried to constant weight at 401C in a drying oven under vacuum 200 mbar). Yield: 39,30 g (62.9 of theory) based on the anhydrous substance (water content: 7.31 after Karl-Fischer titration).
'p I2 13 1.2 Direct tabletting:.
Y..cyclodextrin-diclffl&c sodium Avicci® PH 102 polyvinyl pyrrolidofle
PXL
Aerosl®O 200 maxgnesiuml Stcarate 100o ,ig (69.9 35 111 (245 6 mg 4,2 'X) 1Intg 0.7 1Intg 0.7%9) Y.Cy-clod.rdiofkac-,odiunI is mixed with 0.5-.0 Magnesium stearate and pressed to talbetS Of 250 Ing Wight at a pre-%ure of about 130 MN/m2 in a Komhe DSKi I118 eccetric tabletting machine equipped with compacting presure repistration and a plain punch of' 9 mm diamieter. The& tablets obtained have a height of 3.0 0,01 mmi and a breaking resistance of 120 ±32 N measured in a Schicuniger 6 D fmactogmapht't (Schleuniger frofttroflic AG, CHA4501 Solothurn).
gl,m1 MI y-eyclodextin-dicloteflac-soium, Avit®A PH 102 polyvinyl pyrrolidone
PXL
Acmoil® 200 magnesiumf stearate 250.0 rng (6109 87.5 tug 15.0 119 4,2 Ing (0-7 2.5 mug 'Ili inclusion compound and the emcipients Mr mixed in a Turbula®D T2C mixer for mein.. The magnesiumn stearate Is added to this mixture and mixing is continued for 3 nun.. then 359 mg of t formulation mixture are filled into each of the mnatrices and processed to tablets at about 80 WmNIT in a Korsch DS~.i 118 eccentric tablatting manchine with compacting pressure registration und a plain punch of 6 mm diamneter. The tablets obtained have a height of 4.2 0.04 mm and a breaking resistance of 160 ±23 N measured in a Schleufliger 6 D fractographef.
I -14y-cylodtrindicofenc-sdi~ifl250.0 ng (67.8 corn starch 49.6 nig (15.2 Na-carboxymethyl starch M95 mg (6.0 Acrosil® 200 4.5 nig (1.4 V magnesium stearate 2.1 ing SThe inclusion compound and the c,-cipients arc mixed in a Thrbula® T2C mixer for I' 15 min.. The miagnesiuni stearate is added to this mixture and mixing is cozitinued for F' :3 muin.. Ilion 326 mug of the fornrnlatioii mixture are filled into cat of the^ nitrices and processed to tablets at about 180NMN/ni 2 in a 1(orsch DSKi I11& eccentric tablett machine with comipacting pressuro registration und a plain punch of 9 itir diameter. Thie tablets obtained have a height of 4.0 0.05 mim and a breaking resistanca of 110± 21 N rn. easurd in a Sebleuniger 6 D t'ractgrapher.
diclofe-nae-Nzi 50,0 inig (15.4 y-ycodxuir200,0 in- (61,4 %A) corn starch 49,6 ing Na-carboxyrnethyl star -h 19,5 mug Aerosil® 200 4,5 mug magnesiuni stearate 2,1 aug Diclafentic-Na. y-cyclodextrin and Na-carboxyrnethyl starch 32,4 g corn starh und 2,2 g ARROSIL are admixed for 15 minutes in a mixer "Kitchen Aid" (Hobalt, Regensdorf CH) at speed level 1. 100 g water is added in portions, and the mixture oblaiiied is mixed for further 15 minutes. The mixture is meshed through a screen and dried until a moisture content of about 10 (relative to the mass of the dry composition) is reached. The powder is admixed for IS minutes in the TURBULA mixer with the remaining amounts of corn starch and ABROSIL The mnagnesium stemrte is then added and the mixture is further mixed for another 3 minutes. Then, 326 mug of the formulation mixture arm filled ito each of the matrices and processed to tablets at about 150 MN/rn 2 in a Korseb p DSKi 11IS eccentric tabletting machine with compacting pressure registration und a plain I kL~MLI-Zt*~I ~U1I-- punch of 9 mm diameter. The tablas obtained have a hight of 4.M 0.02 mm and a beaing rsisimce of 195 22 N.
axample In a manner nnalogous to Example 1 tablets are manufhctured chamctiVAzd by a content of 261 mg y-cycode rin-diclofena-potaiui. the tablets obtained have a height of 3,4 ±0,1 mm and a breaking resistance of 180 ±26 N.
Example 6 In a manner analogos to Example 3 tablets manufactured carmacterizd by a comten of 261 mg! y eydr -tiicllooh'ffLc nwum. Te tables obtainet have a heighit of 0,1 mm and a bm'nitig resistance of 190± 22 N.
Claims (5)
- 4. A procms according to cli 1, wherain the tablets arc Curther processcd to dragdoeS. S. The inclusioa compound formled from diclofenaic or a pharmaccutically acceptnblu Salt thereof and y-cyciodextrin.
- 6. The inclusion compound formed fronm diclofenac sodium and y-cyclode~tflfl
- 7. A process for the preparatioli of the inclusion compound as claimed in either claim 6 or claim 7, which cornpises reacting diclofenkc, or a pharmaceutically acceptable salt thereof, with I-yclodCxtrl in the presence of water.
- 8.A pirocess according to claimi 7, which comnpris a) adding water to a mixure of diclofeflac, or a pharmaceutically acceptable salt thereof, wvith y-cyclodextrin,. and stirring the mixture at elevated temperature, and, without or after cooling, precipittinlg or tafllislflg the resultant inclusion compound, or b) adding water to a mixture of diclotertac, or the salt thereof, with -p.cyclodextin, and subsequentlY precipitating or crystallising the resultant inclusion compound,. or c) in any order, adding a minor amount of water first to diclofenric or to the salt thereof or y-qyelodextrifl. kneading or agitating the moistened paste anid adding thereto the second ZL-- I I*YI~ IW~MIII~ ~C~D
- 17- coillponelO1 of the inclusion compound, or d) preparing an aqueous suspension of diclofenac, or the salt tereof, and y-cyclode-rin, converting said suspension into a solution by adjusting te pH to tde .Lkaline range. and thereafter neutralising this solution with an acid or a buffe solution, and suhsequ~tlY precipitating or arystallising the resultant inclusion compound, and then, after carying out any one of press variants a) to purifying or isolating the resultant inclusion LompuuUU, DATED this 1Sth day of january 1999 NOVArIS AG Sv Its Patent Attorneys DAVIES COtLISON CAVE
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU11322/99A AU732785B2 (en) | 1993-06-08 | 1999-01-13 | Process for the preparation of an oral solid dosage form containing diclofenac |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1711/93 | 1993-06-08 | ||
| AU69712/94A AU6971294A (en) | 1993-06-08 | 1994-05-24 | Process for the preparation of an oral solid dosage form containing diclofenac |
| AU11322/99A AU732785B2 (en) | 1993-06-08 | 1999-01-13 | Process for the preparation of an oral solid dosage form containing diclofenac |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU69712/94A Division AU6971294A (en) | 1993-06-08 | 1994-05-24 | Process for the preparation of an oral solid dosage form containing diclofenac |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU1132299A true AU1132299A (en) | 1999-03-04 |
| AU732785B2 AU732785B2 (en) | 2001-04-26 |
Family
ID=3753164
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU11322/99A Expired AU732785B2 (en) | 1993-06-08 | 1999-01-13 | Process for the preparation of an oral solid dosage form containing diclofenac |
Country Status (1)
| Country | Link |
|---|---|
| AU (1) | AU732785B2 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5959632A (en) * | 1982-09-28 | 1984-04-05 | Teikoku Chem Ind Corp Ltd | Sustained release composition |
| JPS5984821A (en) * | 1982-11-04 | 1984-05-16 | Teikoku Chem Ind Corp Ltd | Slowly solubilized composition |
| FR2660195B1 (en) * | 1990-03-28 | 1994-10-07 | Crinex Sa Laboratoires | PHARMACEUTICAL CHEWING, ANTI-INFLAMMATORY AND / OR ANALGESIC COMPOSITION. |
-
1999
- 1999-01-13 AU AU11322/99A patent/AU732785B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| AU732785B2 (en) | 2001-04-26 |
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| FGA | Letters patent sealed or granted (standard patent) |