CA2141691C - Solid pharmaceutical dosage forms having an extended two-stage release profile and production thereof - Google Patents
Solid pharmaceutical dosage forms having an extended two-stage release profile and production thereof Download PDFInfo
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- CA2141691C CA2141691C CA002141691A CA2141691A CA2141691C CA 2141691 C CA2141691 C CA 2141691C CA 002141691 A CA002141691 A CA 002141691A CA 2141691 A CA2141691 A CA 2141691A CA 2141691 C CA2141691 C CA 2141691C
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- water
- casein
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2063—Proteins, e.g. gelatin
-
- 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
- A61K31/13—Amines
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1658—Proteins, e.g. albumin, gelatin
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
The present invention provides solid pharmaceutical compositions in dosage form containing an active ingredient ar princ-iple, preferably memantine, which exhibit an extended two-phase release profile and which are characterized by the presence of both a water-soluble and a water-insoluble salt of casein, preferably sodium and calcium caseinate, in the matrix thereof, in broad proportions and in a total amount between 5 and 98% by weight of the composition, and with a process for the production there-of.
Description
~;..~r0 94/03158 2 ~ ~. ~ S ~ ~ PCT/EP93/02074 SOLID PHARMACEUTICAL DOSAGE FORMS HAVING AN EXTENDED
TWO-STAGE RELEASE PRO~'I~E AND PRODUCTION THEREOF
HACKGROUND OF T'HE INVENTION
a F~.el:d of Invention The present ihv~nt~.on ~,s -concerned with sol~.d pharma~
ceut~.aal compos3.tion~ in dosage o=m which exhibi an extended 'matr~:x~control,led twa-phase release profila and which are characterized by the presence in the matr ix of bo~h a wager-~o~.ubies end a water-~insolub~.e saJ.t of 'casein, preferably sodium and calcium caseinate, respectively, in a total 'amount bet~,aee~ 5 and ~$~ bx weight of the composi-tion, and with' a process for the pror3ucta.on hereof . ~, ~~~-t or a? l o~ the insoluble casein sal t may be replaced b~~
a salt ox' so'l.ut~on of a po~.yval~nt 3.ncluding bivalent canon, e.g.,: the calcium 'canon, adapted to form the ~~zater-.insoluble ca.s.e:.~ :a~Lt ice, ~itu,. Thd 3.nTrari~~.on s krarv.i.irlli.a~l.y auyta;o~.e =or she ~rovasiors oz solid pnarmaceu-~t3.cal, dosage ' dorms ~.n which the 'active subs ancE oz 0 principle i,s memar~tine .
Hackqround of the Invention and ~P~-~.ar Art Solid oral drug compasit'ions or preparat~:csns having a seta=ded x~el~ase ~ so-called retarder;~ or extended-release r~apar.ati~:.s, ar2~'~roduc-t~ from wi~ich zee active ingrsdienz 5 is released over an extended period of time and hence exhibit a, prolonged effect, with ~'re~ultant plasma levels V4'O 94/0315 : P~'/Ef93/a2074'v... ., 2141~~1 being, adapted to therapeutic requirements Also, a poly-phase re~.eas~ profile can be employed to attain the desired therapeut3.c ob,~ectives. However, this do~s'not necessarily mean that long-lasting effective blood level concentrations are consistently achieved. Moreover, systemic side effects and undesirable local effects within the gastrointestinal tract due to excessive local concentrations and resulting erratic plasma levels, ras~ec*~ave?~~; a.;.:, t~ ba arb~,d.ed.
In conventional procedures for the preparation of solid phaxmaceu,t~.ca~. dosage forms hav~.ng an extended rtal ~a~as5. .~,-.....Cq K ~ ... ~.i..e~.~ .~
........,:... w,- -'~ ~. Wx':1, w:nr"!, ~c"~.ve S'LL'S :.321ce .~.i,i ~il~
mayor ty of cases is e~.ther g~.ven extended-release proper ties by the annlication of va~~,ous caat~.ngs or by being embedded in a macramo~,ecu~.ar substance from which it is slowly released. ~, The most ~.mportant control procedures for the release of an active pharmaceutical from a solid dosage farm are the f~:lm-coating and the mats~.x procedures: In film coat~g procedu~ces. film-~form~:ng polymers are employed to 2d. provide sustained release of the ac ~i~re s;~b.s ta.:ce ~.n a d.~-ff~..zs; ~n-wb.~.tr cw?.eu "~rner. csowaver. suci~ an approach is r rdiaaavantageous 3f r dur~.ng 3,n~estion of the oral dosage fOZm, the film is prematurely braaChed, aS by chewing oy abrasion, thereby releasing an excessive amount of active ~S ingredient; which can; result in undesirable effects from such. excessive single-shot drug release.
In the matrix-controlled release approach; lipophilic subs Lances; e. g. , higher aLcohols, waxes'; or 3nso~:e~ble thermopl.a ts, aye employed; it being a'disadvantage that ~0 , synthetic polymers not only generally contain var_,r,~;ng ~
amounts of undesirable monomers but that moreover a complete release of 'drug from the matrix is frequently not es~eczed inpractice.
TWO-STAGE RELEASE PRO~'I~E AND PRODUCTION THEREOF
HACKGROUND OF T'HE INVENTION
a F~.el:d of Invention The present ihv~nt~.on ~,s -concerned with sol~.d pharma~
ceut~.aal compos3.tion~ in dosage o=m which exhibi an extended 'matr~:x~control,led twa-phase release profila and which are characterized by the presence in the matr ix of bo~h a wager-~o~.ubies end a water-~insolub~.e saJ.t of 'casein, preferably sodium and calcium caseinate, respectively, in a total 'amount bet~,aee~ 5 and ~$~ bx weight of the composi-tion, and with' a process for the pror3ucta.on hereof . ~, ~~~-t or a? l o~ the insoluble casein sal t may be replaced b~~
a salt ox' so'l.ut~on of a po~.yval~nt 3.ncluding bivalent canon, e.g.,: the calcium 'canon, adapted to form the ~~zater-.insoluble ca.s.e:.~ :a~Lt ice, ~itu,. Thd 3.nTrari~~.on s krarv.i.irlli.a~l.y auyta;o~.e =or she ~rovasiors oz solid pnarmaceu-~t3.cal, dosage ' dorms ~.n which the 'active subs ancE oz 0 principle i,s memar~tine .
Hackqround of the Invention and ~P~-~.ar Art Solid oral drug compasit'ions or preparat~:csns having a seta=ded x~el~ase ~ so-called retarder;~ or extended-release r~apar.ati~:.s, ar2~'~roduc-t~ from wi~ich zee active ingrsdienz 5 is released over an extended period of time and hence exhibit a, prolonged effect, with ~'re~ultant plasma levels V4'O 94/0315 : P~'/Ef93/a2074'v... ., 2141~~1 being, adapted to therapeutic requirements Also, a poly-phase re~.eas~ profile can be employed to attain the desired therapeut3.c ob,~ectives. However, this do~s'not necessarily mean that long-lasting effective blood level concentrations are consistently achieved. Moreover, systemic side effects and undesirable local effects within the gastrointestinal tract due to excessive local concentrations and resulting erratic plasma levels, ras~ec*~ave?~~; a.;.:, t~ ba arb~,d.ed.
In conventional procedures for the preparation of solid phaxmaceu,t~.ca~. dosage forms hav~.ng an extended rtal ~a~as5. .~,-.....Cq K ~ ... ~.i..e~.~ .~
........,:... w,- -'~ ~. Wx':1, w:nr"!, ~c"~.ve S'LL'S :.321ce .~.i,i ~il~
mayor ty of cases is e~.ther g~.ven extended-release proper ties by the annlication of va~~,ous caat~.ngs or by being embedded in a macramo~,ecu~.ar substance from which it is slowly released. ~, The most ~.mportant control procedures for the release of an active pharmaceutical from a solid dosage farm are the f~:lm-coating and the mats~.x procedures: In film coat~g procedu~ces. film-~form~:ng polymers are employed to 2d. provide sustained release of the ac ~i~re s;~b.s ta.:ce ~.n a d.~-ff~..zs; ~n-wb.~.tr cw?.eu "~rner. csowaver. suci~ an approach is r rdiaaavantageous 3f r dur~.ng 3,n~estion of the oral dosage fOZm, the film is prematurely braaChed, aS by chewing oy abrasion, thereby releasing an excessive amount of active ~S ingredient; which can; result in undesirable effects from such. excessive single-shot drug release.
In the matrix-controlled release approach; lipophilic subs Lances; e. g. , higher aLcohols, waxes'; or 3nso~:e~ble thermopl.a ts, aye employed; it being a'disadvantage that ~0 , synthetic polymers not only generally contain var_,r,~;ng ~
amounts of undesirable monomers but that moreover a complete release of 'drug from the matrix is frequently not es~eczed inpractice.
'JVO ~4/U3158 - 2 ~ ~ ~ ~ (~ ~ PCTlEP93/02(~74 The USA 4, 665, 081 Patent describes a nifedepin formula for oral administration, wh~.~h contains casein and inorgan-is additives se~.ected from magnesium silicate, oxide, or aluminatemetasilicate, synthetic hydrotalc and magnesium aluminum oxide, thexeby ensuring that the active substance provided that a gastric juice-resistant aux~.liary agent is included - is not released in the stomach but is rather rapidly rl a~c~ ~ n tha ant-a~c~.i..o ~.s~s. r~.,.~~1 3~~.~.rir..~...'.
cause; on'the one hand, a retarded release ~:elati~re to the LO. time of administration b~zt, on the other hand, due to the s .a ~ .~ t :.i..: -.... ,~ a..s. ~ w ~ L~ r" y ~~,~ r: ej r, -..~t:.:..,.~ ,.~..:.$,~~.::.,,.~.:.. ...:1 v...... r.aT.~W.~.,il~, a .,7. :1 3xila C......,...
'tration which is li~~ly to result ,in undesirabJ.e side effects.
Phazm: Acts Fielv. 66; No. 4, 120-129. (1991) describes ~:5 an ~ ibuprofen formula cdnteining ' casein or ge~.atine which causes an el:e~rated rate of di~so~,ution and release r~spec~ively, of the ae~ive substance.
Pharmaceutical Technology 9_, X60-374 (1990) examines the infl,uence~ of tl~e p~esende of s~dium caseinate on the 2D. rate of release of an active su~sta~an,ce. H~ra, toot a~
e:~ a na-~ d:.Jsb~.~,.~-~.., yn p~.c~,x.iar, of c;na.aro-ci~iazide and hydrochlo=oth~.az~.de, is renorte3.
Thn ~~_a 0 4~~ 1 ()0 Pate..~.4 discloses forla..zlav.i:ox~s p~=mitting controlled release ~:n the stomach and in the 25 intestine in response to the enzymes con~ained therein:
For this purpose, a gel. matrix; e.g:~, of alginate or ca=boxymethyl cellulose, carragl~eenin, or the like is ennployed, which contains imbedded therein a protein, such as calcium caseinate, and which comprises a further drug or 30 ~ food ~ subs~Gance which ~.e ~ bondab~e ~o the protein . Although a controlled release is enabled thdreby,-such effect is achieved by the i.nco~poration nf;protein in a surrounding matrix-forming gel;
cause; on'the one hand, a retarded release ~:elati~re to the LO. time of administration b~zt, on the other hand, due to the s .a ~ .~ t :.i..: -.... ,~ a..s. ~ w ~ L~ r" y ~~,~ r: ej r, -..~t:.:..,.~ ,.~..:.$,~~.::.,,.~.:.. ...:1 v...... r.aT.~W.~.,il~, a .,7. :1 3xila C......,...
'tration which is li~~ly to result ,in undesirabJ.e side effects.
Phazm: Acts Fielv. 66; No. 4, 120-129. (1991) describes ~:5 an ~ ibuprofen formula cdnteining ' casein or ge~.atine which causes an el:e~rated rate of di~so~,ution and release r~spec~ively, of the ae~ive substance.
Pharmaceutical Technology 9_, X60-374 (1990) examines the infl,uence~ of tl~e p~esende of s~dium caseinate on the 2D. rate of release of an active su~sta~an,ce. H~ra, toot a~
e:~ a na-~ d:.Jsb~.~,.~-~.., yn p~.c~,x.iar, of c;na.aro-ci~iazide and hydrochlo=oth~.az~.de, is renorte3.
Thn ~~_a 0 4~~ 1 ()0 Pate..~.4 discloses forla..zlav.i:ox~s p~=mitting controlled release ~:n the stomach and in the 25 intestine in response to the enzymes con~ained therein:
For this purpose, a gel. matrix; e.g:~, of alginate or ca=boxymethyl cellulose, carragl~eenin, or the like is ennployed, which contains imbedded therein a protein, such as calcium caseinate, and which comprises a further drug or 30 ~ food ~ subs~Gance which ~.e ~ bondab~e ~o the protein . Although a controlled release is enabled thdreby,-such effect is achieved by the i.nco~poration nf;protein in a surrounding matrix-forming gel;
3 a W0 94103158 ~ . ~ ~ ~ ~ PCTlEP93l02074vT2 GB-A 2 207 353 also describes formulations with a con-trolled release; containing; calcium-free mixtures of alginic acid salts and cas~inate: The protracted release is; however, based on a surrounding gel-matrix principle of he type referred to above.
~t is appa=ent to one skilled ~.n the art that the ava:Llable technology for effea~~.ve arid reliable extended "'e=~.~_; es~~aci~.l;~ a,-;z:~..r~,~ta~ga re:~;ease pharmaceutical dosage forms; mill leaves much to be desired.
o~J~e~c~ aF ~~~ ~rrvErrT~cor~ , w w is acco~d,i_~.g? y as cb~ac~ of the present i~renzion to grovaLde a pharmaceutical dosage ' farm which is character-ized by an extended eontro~.3;ed-release profile such +~..t:a the active substance can be r~onven~:ently and reliably ~~.5 released ove= an extended period in at least two ( 2 ) stages ~
'and a process for the production thereof : tether obi ects of the invention. wild. become apparent hereinafter; and still others will be obvious to one skilled in the art to which he present invention pertains, 2Q SU:'~=i..a'~ ''~~ T:-'~S Sh"V~:~'"'y ~Ow 'fi'ne inven~~.on then, comprises the fo~.low~:ng ; in tar olio, separately or ire combination:
A solid pharmaceutical c~os~tion in dosage form having a matrix-controlled extended two-stage release 25' profile comprising an effective amount of at least one pharmaceutically-act3:ve ingd e3ien t or pr wa.._~ ' ~~ l~~'" r Niil6raiia he matrix consists:essentially of a cambinat3on of a water-soluble salt of casein and a water- nsaluble salt of casein, the total water-soluble and water-inspluble casein-30 saZ content'comgrising between 5~ and 98% of the total ~
weight of the pharmaceutical compositior~;~ a1.1 salts and canons being pha-rmacologically acceptable; such a comppsi-tion wherein the'water-soluble and water-insoluble casein ~' WO 94/03ISfi . ~ ~ ~ PGT/EP93/020?4 salts comprise between 10~ and 90~ by weight of the pharmaceutical composition, preferably between 30$ and 80~
by weight; such a composition wherein the pharmaceutical composition comprises between about 5~ and ~5~ of a water-insoluble casein salt based upon the total casein salt content, preferably between about ZO% and 70~ by weight;
such a composition wherein the water-insoluble casein salt i s calcium cassinate : su.ch a ~maos i tic.~. ,ah sr ai:: t.' :a h a ter -soluble ca~.cium salt is sodium caseiriate; such a composi-tion wherein the ~ha~cmaceut~:cal camposition comprises an p-n.sr c~~ ~v1n ~ w......:~,..~ i .~..~ ..,.., s..~,.~.1. .i.~.
~r,:.r.. ~ ' ,~ ~3 '' ..r ~~r,. .. v..~...~es.:w.:...A.... iV4....,.........~j ..r.e r~.n~:.!
"ia u4~W .. i..~.n or Pepsin or both,, and such a cc~mposit~.on wherein the active ingredient is memantine:
Moreover, a procaas for the preparation of a solid ~.5 pharmaceut~.cal composition in dosage' form having a matrix-controlled,two~stage release profile comprising an effec-tive amount of at least ona pharmaceutically~act~.ve ingred~.ent or px~~:nca.pl:e, wherein the matrix consists essentially of a dombination ,of a water-soluble salt of ~0 casein and a water-insoluble saga cf casein, comprisa~,g ~h~, sa of : : :~.,.. ., ..:~ , p r_~ss_..~, ~~~r~~ ,a.. , ax~-adi,ng. pallaziza.ng.
or ~tabletting, ~.n dry or wet manner, of a m~:xture compr~! s-ing the at least one ac~.ve' ingred~a ent ~,~, ad.~~i~ture jai th both a waterdsoluble and a water-inspluble salt of casein 25 oz., aLtarna ~.v~ly, a water-solubla salt 'of casein and a silt or solution of a polyvalent cat~:on which is adapted to ~oxm a water-insoluble salt of casein in s~.tu, the total mater-saiuble and - wa-ter~-insoluble casein salt content -of the admixture in the final composi.t~.on comprising between 30., 5$ and 98~ ~of ,the total weight of the pharma~~utical composition; all salts and canons being pharmacologically acceptable; such a process with all the characteristics set forth for the compos3,tion.
,<~.-.
wo 9aio~~ss . P~,-riE~3~ozo7a:
2~.4~.691 The Present Invention According to the practice of the present invention, the, problem is solved by providing a solid pharmaceutical composition ~,n dosage farm conta:Lning a pharmaceutically-effective amount of ono or more active substances and the usual auxiliary agents and addit~.ves; but also a total of between 5 and 98~, preferably l0 to 90%, and especially 30 to $0~ -- based on t.h~ tai wea gh ~ of ~.~e c~.:: p.c~i, ~ic:~ -of a combination of a water-soluble and a wa~er~-insoluble salt c~f casein. A pharmaceutical ~orrnulatior~ of this tape can .~~,~,ri too tr ea tea j - ~., ~.' ',.. 'L~3v.:~.4 ;:Ia J ZC7 py O~J'~.~ ~, V"~'..~1'yl L~...
scalid dosage dorms having ~ two-~pha~a matr~.x~controlled extended release prof3.~:e: Thi s ~.ncludes tl~e employment oz procedures krio~n ire the pharmaceutical industry, such as ~.5 , compressing; granu~.~ting; extruding, palletizing, and tabl~tting ~.n dry or wed manner. It is of course also posszble to combine a var~.ety of procedures to provide the des~.red pradue~ formulation in any one of various forms such as ablets, dragees, pellets; gr~rnules, and the like.
z0 The amount of active substance pse.sent can be v~' es'. ;~ride~~
;~
da~~~.darg ~:~:~:y :~a:i~a~:on 'ta b~ treated and ~cne type of --dosage form desired; for example, from O.OI to 90~, bused on the total weight of the ~ha~~c.~=a~cal composi t~.on.
Quite unpredictably, it has been found that the 25 pharmacokinatic properties of the solid dosage forms according to the pre~en~ invent~.on are not a~~ected by the manufacturing method employed or tha var3a~ions arising in practice, e.g., the compression forces ut~.lixed.
The casein em~al:oyed can k~e a commercially available :30 product, and the molecular weight and~water content thereof ;
may vary considerably, for example between MW 1$000 and MW
30000 Daltons - depending upon the Origin thereof, without detracting from its operativeness'according to the present 'N10 94!03158 . PCT/EI'93/02074 v'~~~~, invention. Casein is of course a substance approved for use under food legislation throughout .the cidilized world.
A dasein salt of a monovalent ration, such as lithium, potassium, ammonium, and preferably sodium, is used as 'the 5: water-soluble casein salt.
The water-~.nsolubl~ caseinate i's a salt of casein with ~ gol.yval.ent cat,ion, which term as used he~aa.n includes bivalent canons. 'these include; e.g:, calcium, magne-sium, zinc, manganese; aluminum; iron, or ma.xtures thereof particularly preferred ~;~ dalc~.um: ~'he water-insoluble ca~einate can be used as such.
Tn add3.tio;n, it is possible to in~l.ud~ in tk~e composi-t on, contain~.ng a soluble casein salt; a physiologicallyr corcpatible poly~ralent cati.on, ~:n zh~ form o~ a salt thereof 1-5 which is soluble in water or gastric fluid, optionally in soluti on in water, in amounts such tha w a par t of the soluble caseinate is converted to an insoluble aaseinate, thereby transforming a part of the soluble case~,.n salt tb an insoluble casein salt in situ, as by gastric fluid upon 2Q ingestion.' A part or X11 of the insoluble salt may be provided in ~h3.s manner Preferred s-alts. a..ncluda the V~lcyi4e; ~luy~r~ate, carb~natG; ~.actate, and sacch~ra~ce abdt in ga,rticu7.ar, ca~.cium chloride, ca~:cium gluconate, calcium hydrogen pnosphate; calcium Lactate, 25 calcium ~--saccharate, calcium levulinate, and their hydra~ces, or mixtures thereof; are preferred saps for prcaviding the aqueous polyvalent, includ~.ng bivalent, catinu, wh~.ch ~n~y '~e used as s~:ch ar, if desirad, be solvaved by sample dissolution of the salt; ~.g., in water, 30 and optionally used in ,a normal gr~~aulat~ion procedure.
The wsight/weight ratio of soluble to insoluble caseinate is between 5 and 95%; preferably between 5 and g0~ , end ;nor c ' Fre~ e~ bly ' between 20 and i 0% , posed on .the ' _ 7 r IaJCD 94/O~1S8 ~ ~ 4 ~ 6 ~ ~ P~C1C/EP93102074 ,.~
total caseinate content of the composition. Most preferred is a ' we3ghvt/weight ratio of between 30 and 60s. The amounts of the aforementioned ionic compounds and their solutions required for the production of the desired amount and ratio of i,nsol~ble caseinate ~n situ are dependent on the type off; catian, its counter-ion, and the molecular weight of the casein employed, as will be readily under-r. '6'~ 1 "~,'J 1:" ~~ 7.i. w stood b~ ~",.d, ~.,c ~..~~ be ~ ~a~a a ~. ,~ . - in ~'~w..~..i:vww......,W ~r~C. sl5.w..l.J.Cu the art~since it involves ox~Zy basic chemistry.
According to the 3,nv~nt~.on, quite unpredictab~,y and ~,'~ ~ ~-~-~~eGt;s~.x , a s;.~:ial4:.. ' ~ ~ ~ a~ """'.~ ..,n~~~-",:,.~..r...:,...
~1.~ ~, t1 LI ~'!~''.~,..s ~ ~..,._....~L
extended ro~.ease of a~ctivs plnarrnac~utical ingredient is thus ach~.ev~d with tha speci~~.ed combination of matrix--~or~ming substances a.lon~ and without the necessity of any embedded d~r surrounding external p~oteizy.
Comman auxiliary agents and additives or excipients which may be enployed to complete the pharmaceutical composition used as matrix are components well known in the pharmaoeu~tical industr~,r; Theses include, for example, ~ablettixa.g aids , such as highl;~ ~ ~ seer ~e s,~I ~ ~a c .;ba~g:~eai .~, ~~ra~ta; nicrocr~y~zaia~.ne cexlulose, lactose;
talc, colorants such as iron oxides or qui z~oline yellow, ~i~ments such as ti.tar~.u.r.: d' oxide and balciu~-~ ca~bonaz~, gl.yce~rlmanostearate, g:lyceryl behenate; sodium stear~,rl-fumarate; ste~ri~ acid, cetyl. pal.mitate, long-chain partial glxGerides, cellulose powder; mannitol; cal.CiuD1 DhoSTJ}'7.~'t'a, silicon dioxide, colloidal s~.licon dioxide, silicon dioxide l~ydrare; end goLyethylene glycol, preferably of a moleau~.ar weight 1;500 to 6,0~O,Dal,~on; and the like.
Acti~re eingredierzts or mixtures thereof, which can be used t~ provide an effect~~ve amount caf the active pharma-ceutical princip~.e o~ ingredient in the campositions of the a.nvention; encompass 'innumerable pharmaceutically-active WO 94/03L58 ' .. .: '~ ~? ~ ~; p~/E~3/02074 compounds which are suitable for extremely varied fields of end-use application. They include tranquillizers such as chlorpromazine and benzodiazepines such as diazepam;
muscle relaxants such as mephenesin; an~ihypertensive agents such as a-methyldopa, centrally-acting analgetics such as morphine: peripherally-acting ana~,get~,cs such as paracetamol~ non-steraidal antiphlogistics such as ibupro-den; local, an~9th~t~.cs such as b~~~~c~a ~~; spasm.cl y ti~a such as papaverines prostaglandins such as PEG2, antibiot-~.0 ics such as p~nicill~.n and tet~acycl~:z~~a ag~lnts influencing . ~i.. Z,.. V a ~~ 3-, y a. y~ Y...c. 3.:.."~,.., q L n v : .t.. ~
_ ~ ~ ~ , ......,........ ...~. ~,,, ..w.... ......c ~ uw..: 8~ iucaua. ~ ,...n 2 ; a17.. ...r ~..I~,~ QILS.~I
therapeutic a~~nts such as amantad~:ne, L~dopa; s~legil~,ne, bxomocr~.p~ineand me~ix~r~eantim~zari ~ls suoh as chloro-quine, corticosteroids such as dexamethasone; androgens such as ' methyltestostesone~ ~strogens such as ethiny~.~s~tradiol; gastagens ~u~ as levonorgestrel:
symp~~hometics ~u~h as adrenalin; substances having cardiovascular effect such as nitroglyc~xin; diu=etics such as hydrachlprothiazid~~ anthslmintics such as praziquantel:
~0. B~bloGkers such as ~timo~:ol; ~32_~-blockbrs such as ca~~tida.T..e;
.--! ta.~' ::.. :...r. as ~~c acid, and the , ~,iite ~Efective .._..~ ~ r,,...
amounts o~ such pharmaceutioelly-active principles or ingredients are well known in the ar t Most preferred i,s memantine:
2a The readily-produced formulations according to the invention, u~aon ingestion, advantageously result in a cont~olled two-phase release of 'the active ingredient,, with an amount of active subs.tance'adapted to the therapeutical goal being released ~and'avai~able in the first phase, i.e., :~C1 in the stomach; as well as in the s''econd phase , i . a . , in ~
the intestines where, after-a slight- delay, a renewed liberation 'of active ingredient is effected, the remainder of the active ingredient being released over a pxede-w~ ~aio3~s$ . ~ ~ ~ ~ ~ ~ 1 ~c.-rm~3ioao~a ~v ,_ .
termined time period, thereby attaining an effective adaptation to the total active substance availability requirements, with the partial release in each stage resulting in corresponding desirable plasma levels. Local 3 excess concentrati~ns of active substance are thus avoided:
This two~phase pharmaceutically-active ~Lngredient;
a.g., drug or vitamin, libe~r~ation profile ~.s substantially independent of the enZvmes con~s~d in, ~~,~ , 4h~,N s.'..o? cga ~~' environment of the stomach and intestines, as shown in the 1,Q following examples, a resu~,t w~h~.ch hithar~to has not been Td3~~ '~ ~~~~ p~hs ~~.~y~wy.I :~.~~~ ~~. ~~ G~w»~r' ~ ~ _ r. ~~ V ~~/m.rrW ~~. nJW ryl~ .W rYWYiW Iw r,r.~w~ Y
,However; if a change ~.n the release rate is required in one or the other of the 'two liberation phases which might be necessary or desirable in view of the type of 15 active substance employed, the physiology of the patient, or the degree of seriousness of the- ailment ytreated;
enxy~es such as pepsin; ar~d/ar pancrea tin can of caurse be included 3.n ~h~ formulation in suitable amounts, as we? ? as numerous Q~hes enzymes or polymer-enzyme products such as 2d neat=al, acid; or alkaline protease, or anv of the forego-,~rs"~,, nr~~a.~r ~ ~y iy..~~::.:.i.'cw ~ a'W.i..v"~'~~'aar t~ t"~17 eT.a'7yi.ane-_ 'maa.~ic acid or anhydride E) polymer (as in USA
3, ?51 ~ 561 ~ . This does not change the tvo-ph~e prc=i1e It is only the rate o~ liberation within he phases which ~2~, pan thus be slightly varied:
The mechanism of the extended two~stage release can be e~plaa:ned as Follows:
The use ~f a water-in~oluDie caseinate, e:g., calcium ~aseir~ate ~ results - in' the foz-mation of a matrix tablet .~ 30 , The drug is ~ re~.eased independently of the pH of the dissolution medium in a d3,ffusion-controlled manner. In otk~er words, due t~ the presence of the insoluble casein-ate, there is an extended release in both stages, the IO -WO 94/03158 ~ ~ ~, ~ ~ ~ 9 ~ PCT/EP93/02074 extent of retardation being dependent on the amount of insoluble caseinate iz~ the formulation, as sk~own in Study' and correspond~.ng F2G. 5:
In alkaline medium; the insoluble caseinate graduaJ.l~r becomes degraded, equivalent ~o an at~tanuation of the matrix-effect. Subsequ~ntl,~, the retax~dat:Lon i,s diminished and the drug,release rake increases, which can be seen in the second stage, although also in this second stage drug release is extended.
HRIEF DESCRIPTZGN OF THE DPAV~INGS
y~ s,...,.:._,.=,.es a ~ ~.x'41 ~'S'~'x ~~ 1~,,~ ~,~~~r_".D~'=eri ra,~ ~3t~73Sl.~S .
for a better understarrd~.ng of the present invention, wherein:
FAG. 1 is a graph of a biphasic drug ~aberation profile showing: release of caff~ane over a period of time in accord with Study 1. of 'this app~:~.ca Lion wi tk~out anzx;ne and jai h medium change after two hours.
Fi,G. 2 ; i~ the same according to Stud; 2 of~ t:~i;~
appLicati;on ~a~.th enzyme and w~.th medium change after two ~0 hours.
~ ,a l cs ~."p, o.f C'T I~ '~ ~ C o ~ ' '~ h 'f n it A y.
s_~z~.__g ..h_ b~~h~aia Memantin~ over a p~r~.aa of ~ci.me in accord with Study 3 of th=.s aonl.ication without enzvyme and wi h medium change after two hours.
Fl' G . 4 ~, s the same as FzGS . 1 and ~ , but in accord with Study, 4 of this applicat~.on' without en~~rme and f~r~.th msd3.um change-after two hours, and r iG. a ~.s a graph 'i3.lus-crating the , d~renderce of d~ ag release on 'the ~.nsoluble caseinata content of a dosage foam 3 according ;to the invention, showing the percent caffeine ~ p released over a period of time with calcium caoeinate cc~nte~n~t of the formula~~.on varying from 0 to 100 0 , th~.s libe=anon prori3.e ' being determinaci in a simu fated ga~yc ,~.-..
WO 9~d/03IS8 . PCT/F.P93/020?a'.:
environment at a pH of 1.2 without added enzyme.
SPECIFIC DESCRIPTION OF THE INVENTION
The invention will now be described in greater detail with references try the following Examples; which are not to be donstrued as limit~Lng.
Production of the Druq Formulation Exa~le 1 Active Substances and Additives ~3Qr~ar1y Yh. t~a~r..?-:y memantine HCI 20.0 7:0 sodium caseinat~ 46.8 Ca~..C.~..9.1TT1 CaSa'~ T'?ata J_ Aerosi~. 200 ( f~.n~ly~d~.vid~d SiOz ) . 1 s 0 magnesium stearate ~..0 All components with the exception of magnesium ~.5 s~earate are homogeneously distributed in a'suitable mixer such as a D~.osna~ mix~r~ subsequent3,y magnesium steaxate is added and the mixture passed through a screen of an average (U.S. Standard Sieve Series) mesh size o~: 300 um. After a further mixing of the material t~ be campressed, tablets 20 having a mass of 100 mg and a d~.enteter of 6 mm are produced o~ a suitahla tabl:~tt-~.n,n. :~,~,~..~.we ~~si., ~,,:,, ' ~_=~.~
....s ...,.~:~es-~ t ~ ~ '.' o.. W .r r. vi.~auZr ,5.j~.uai of O 1ZN .
Example 2 Active Substances and Additives Percent by WeiQht 25 caf~exne 20.0 sodium casei~ata X5.0 calcium-chloride x 2Hz0 3.0 A~.:osi? 2pp'~ l - 0 magnesium stearate : 1.0 30 The caf seine and sodium ~ easeinate components are mixed in a suitable fluid~.z~d bed granulation machine; such as the Aeromatic ~T~EA 1~. The granulation of a 500 g batch ~ys ~f~ected with 40C? mi oz an aqueous fluid contaia~ing 3 g WO 94/03158 . 21 ~ 16 J ~ p~/Egg3102074 calcium chloride dihydrate in dissolved form at a pump rate o 14 ml/min, aninlet temper~,tu=e o ~0C, an outlet temperature o 32 C, and at an atomi~i.ng p=ensure on . the binary nozzle of about 2 bar. After a redryi,ng n 10 min at 60 ~ and a weak su~aply of fresh air, the granulate is separated from the coarse portion (>1:0 mm) and rom the ~
( e0 : l5mm ) and; af~~r admiring with Aeros3:l and f~:ne portion magnesium stearate ~ is compressed u~.ing a force of camp_Qs-sion of 8 kN in~a tablets having a we:Lght of 100 rng and a diameter o 6 mm.
~w 5:.,":, ;~ ?
~..., _ Active Substances and Addit3.ves Percent b Wei ht piroxicam ' ~~.0 sodium ~aseinat~ C5.0 , calc~.um hydrogen phosphate + Z~IzO 3.8 Av~Lcel pH I02' microcrystalline c~~;lulose g . 2 Aerosil 2f0 1.0 magnesium stea~ate 1.0 All compr~ner~ts except iar magnesium stearate are 2C?, , homogeneously distributed in a su~:~table, mixer, e.g. , a T an a ~ m a ~~ ,..r ... ~" ,Jr...... ',"~ ~,r.ar.~ ~,,~
.r'~w.rS 4.Ia~1 id V d. !r ' 41r 1 C.~~prd, and 4h8 ' ~',s.r ~i~
v , .r.
...
mixture passed through a scre~:n of an average (U. S:
Standard Sieve Series) mesh size of 300 um. After further mixing o the compressed maps, tab~,ets are produced on a suitable Vie? ~.eting machine, having a mass oz 1.00 mg and a diameter o 6 mm; wi h a compression rorce of 8 kN
being applied.
Ea~am~pie 4 Active Substances and Additives Percent by We~.~ r~ht ibuprofen . 77.0 sodium caseinate X0.0 ca~,cium ch~.oride + zH2~ 1.0 Aerosi2 200 ~ 1:0 magnesium stearate 1.0 WO 94/03158 . PCT/EP93/02074r . ;
~By spraying a' suitable granulating, 13,c~uid such as an ethanol/water mixture (v/v 3/2) or a colloid--containing granulating liquid such as gel.atine/water (L/30), a crust granulate or an adhesive granulate is ~ir~t produced from the ibuprofen. , The, granulate is mixed with ~h~ remaining components in a suitable' mixer and is compressed, usa....~g s cc.~p-ess' c-:
force of Z5 kN, into tablets having a mass of 520 mg and a diameter of 12 mm.
a:a ~~1 n ~
A~t3,ve Substances and'~dditiv s percent b Wei ht memarrtin~-Hel 20 : 0 sodium caseinate 45:0 calc~.u~n cas~inate ~ 32.0 2a All components are homogeneously distributed, using a suitable mixer end; in a mixing kneader; 'ase then intimate-ly wetted .y~~,th a suitable plasz~cizi.ng liquid; such as purified water or an ethanal/water rnixtuso, (v/v 3/2) to an extent of about 60~ v/v based on the solid pardon: The ~.~S.Ll~::t.3ll."~, m~99~S ~ 5 1 °~,rrv'",.~'.'~w~,',i ~'.'~': tai~,r ' uy~ i3 avr. oa'W ~~CaeZ'-yr on a aistribu~cing roll-type extruder with an aper~ured disk-»diameter of 1. Smm. The thus-obtaa.,:ad; s~".,.~a.,°:-ds ay=
divided and filleted on' a spheronizer to Norm pellets of a diameter of 18 mm: Subsequently,- he pezlets are either 2S. loaded into cagsules or are compressed into tablets after admixing w~.th 1% Aerosil and i~ magnesium stoarate.
II : Libe.t a. Lion o~ Release Tes-cs The media used in all dysso~.u~ion tests is either simulated gastric fluid ( pH 12 ) or imu~.at~d intestinal.' 30 fluid'(pH 7:5). To more close2y approach in vivo-condi tions, pepsin ;'(gastric fluid) and pancreatin (intestinal fluid) are added.' Tn the chapter "Test Solutions" of the U.S. Pharmacopoea'XXTI, the compos3aions of the two media - 14 '-PcrlE~mazo7a ,d,,0 X4103158 2 U.S. Pharmacopoea XXII, the compositions of the two media are eXactly described as follows "Gastric Fluid; Simulated, TS---Dissolve 2.0 g of sodium chloride and 3.2 g of pepsin in 7.0 mL of hydrochloric acid arid suf~i~ient wa-~er to make 1000 mL. This test solution, has a pH of about ~. . 2 ; " __ "2ntestinaJ. fluid, ~~.mulated, TS--Dissolve 6.8 g of manobasic potaas~.um phosphate in 250 mL of water, mix, and add x;90 mL of 0.2 N sod~,um hydroxide and 400 mL of water. Add 10.0 g ref ~ancreat~.r~; mix; and adjust the r ~~,:, ~ +~ selu~~ wi.~.~,. Q . 2 N sodium h ydroxide to a pH
of 7:5 t 0.1. Dil.uta with water to 1000 mL:"
1. F~etarded reZea~e of an act~.ve substance in res once to the insoluble dase3:nate content , The following bas~.c Formula ~.s dompressed:
cas. T. e1x'le Z0 0 Ca-caseina~e 0 ~ 78.0 (based on the total casein con~ent) Aaros3.l 200 1w 0 magnesium stearate 1.0 N.~.as 'e.in:a,.te :ad 100 ~5 Fight di.fferenz compressive masses , o= varying. ~va~
caseinate and ~a-caseinate proportions (added as such) are formulated by using the tabletting auxiliaries Aerosi.l and Zg magnes~.um stearate: As no other auxiliaries are added, a true picture c~ the release properties is obtained.
The total case~.nate portion amounts to 78~. The ~ ~W r.~.~ ~n r. r1 n T
pu~~l C.i. ~tZ~ Gil l:. liZ~:~' W .ti. ~~ a.L G'~ vVi~p~. G~"~sG~d .~raa ~a _. '.,u' WaA~ie:W.r~~u Exacta 1'm at an ad,~usted speed of 30 ~trokes/m~.n, using ,~ 3Q compressing ,tools of 6 mm, flat .without facette, at a constant force of compression of 8 kN to form tablets having an individual weight of 100 mg Dosage =arm grodu~ia are oi~tazned having a Ca casein-~, 5 _ WO 94/U3158 . ~ : ~ ~' ~ '~; PCT/EP93/OZ074 ~~r~
ate content of 0, 10, 20, 00, ~0, 50, 70 and 100%, the liberation profi~.e of which is deterrniried at pH 1.2 (simulation of gastric environment).
FZC. 5 shows the dependence of drug release-on the insoluble caseinate, i.e.; calcium casoinate, content of the dosage forma ,and thus th~ extent of retardation. The tablet formulations employed in this study correspond to the basic formula of. Ix: 1 just her~in;abavA provided.
The . d~sso~.ution e~ ~0% of tota3. caffe~.n~ content Za ~ccuz~ n tk~e cafe of 20% Ca-~caseir~~te ( ne=centa~e related to tratal caseiria~~ ) at ~; ~n ma,_~. ~ ~s . 1:'.',' ~:~ ;~ ~':~r ~
"a-caaein,ate F=1.25). at 2$5 main with 50% Ca-caseinate ( ~'~2. 2 ) , and at: 350 min w~Lth a Carca~aihate contEnt of 100%
(r~2."75). These data are the results of d~asolution tests in ,. gastric ,fl.uid ' ( PH ; 1:,2 ) w~,thout added enzyme:
~t has ~hus been establas~ned'that the r~leas~ in this gastric'environment,can be inhibited by the combination of insoluble caseinat~' with soluble casein~te; depending on the relative proportions thereof, a-vasying xetardation is .20 obviously achieved" This pexmit5 the ~el~ction of highly-des~~abh~ individuar.~ ~-e.~.~.ee, ~ cy'''_,e, v~ep,ar::v:~g -~.:
t::a a~ i~-a au~StaI"~Ce and she yype of indicat~.on ~o bd treated. ' 2. Liberation: or Release profile of caseinate t~ble~s 25~ c~mnressed at a varyin4 force of cambressi'on The fo7.lowing formulation with a Ca-c~seinate propar-tion of the total caseinateconten~ of 40% is compressed in accor~c~ w~.t~ t'~e afoyementianed condi:td.ons a-G forces of GOmpression of between 4 and 12 kN into tablets having an W~ 94/03158 . ~~ ~ C 1PGTlEP93lOZ074 individual weight of 100 mg:
caf f eine 20 : 0 Na-caseinate ~ 45 . 8 Ca-caseinate 31.2 Aerosil 200 y~0 magnesium stearate l.0 Zt has been found that varying forces of compression w~.thin these ranges have no bearing or e~fsc~ on the release prof3.le.
lp 8 . Addi lion of ~ol~valent salt to the soluble caseinaite to '.,. ~, na ~!-'hn 4 rc rr1 "1-vl o raa rs~ ~a~n;
i ... ~i .u.~
_o_s__ _.s__ _s_-,...._.~
'the following ,basic m~tr~.x formulation is produced in the foregoin;g manner with admixture and/or'granulation and in accord pith the foregoing corrditians ( see Examples 1-5 ) 15 caffeine ~ ~ 2C1. 0 NaCaseinate &5.0 Ca-salt, optionaslv in aqueous solution x Aerosil , I.0 magnesium st~arate 1.0 20 Avicel pH'102 ad 100 ca~r~i.ate.~v ~or.~x~=t..__~_g ~ so? ~.:~la "" , ""
ca~..~e~ ~.a ~e example -cne ria~aseinate, zo an insoluble; e.g:, calcium, salt, the insoluble ration content can be readily deter-mined; e:g., the Calcium content is normally 1.5~
to 1.'7~
'~5 by weight, but can op-tzon~lly be made even higher, so the t an amount as suggestzd below according;'to the pre~enz invention can be readily determined and the desired mount o= i;nsoLui~le casein ' salt thereby calculated and thus-p=ov~:aed .
30 , ~ The ~ollQwing pharmaceutically-;suitable calcium salts ' can; for example, be used in the foregoing formulation to, provide an insoluble casein salt in situ i n a formulation ~~ zhe invex~ionv, '~O 94103Z5~ . PC'T/Ek'93/0~074'~~~, .
~~~ ~~
. , Amount X employed in the Formula:
calcium chloride x 2Hz0 ~
Calcium gluconate: x H20 l~ 9 calcium carbonate 2:~
calcium hydrogen phosphate x 2HzQ 4,Z
calcium lactate x SHZC? 7.5 , ca~:cium nitrite x 4HzC7 5.8 calcium-D-saccharate r~,1 c~Zcium levu~:3,nate The compositions 'off the ~orego3.ng foxmulae are CC7~IIIDx'es~2d uTli~~:...'" ~hlra ~~G.~..=°.~~:~. ~.'~..C:"..~~~
v,.C:.~r'r':.;,'~ :a' 3 t c .constant'farce a~ campzession o~E 8 1~N into tablets having an indiv~.dual weight oz 1G0 mg and are found to have the same two-phase extended sel.ease profile as a unit dosage . mat=3:x conta3:ning the same proportions o~ ' soluble and inso3.uble casein salts ~;n solid corm but present as sudh in he ' beginning admi~sture _ Tt has been fo~xnd that all calcium salt_~ used in this manner produce ia~~olub~:e casein' salt-containing matr3.ce~
ha~r~:ng almost identical l~.beration ~x~ofiles. The t:~-valuQs var~r wiahin a riar~r~~r ra.~ga ' o= ~~.~,,:: ~,~~ a~~ ~.1~ :,.yra;
wa~,a ;:ic tpo-va~.ues vary besween 2~2 and X95 min.
Identical r~~ults are a.~so obtained ~r~.th soluta ors ~r other polyvalent '3.ons besides calc~.um, fox example;
,25 megnes~:um, zinc, and aluminum sa3ts:
<'4.. Influence o~ the incuba ion medium ' A variety of compresseei dosage form products produced-' a.crb::3ir~.g ~~ Sy:I with vaxying proPox~ions of insolubl.e caseinate, preferably 'calcium 'cas2inate, ~ ire now examined ,~ 3Q 'as to their drug-liberation profil~ with changing med~;a ' both with and wi-~hout enzymes.
The reswlts aye shown 3n Studies 1 and 2 and their co~-~.~aspondihg figures Fi~G. i and FIG: Z. The figures (FS~S. 1 and 2) resulting from these. studies show the 35 biphase profiles of the compositions produced according to _ lg _ .: ~~ 94/03iS~ ~ PCTlEP93l42474 the invention witrn a Ca-caseinate portion of 30 , 9:0 and 50~
by weight; the results being shown in' the following TABLE
l (medium change after 2 hours):
TABLE '1 tso ( min ) t9o ( m~.n ) ~~I Ca-caseinatet & ) 30 40 5~ 30 40 ' S(J
1Y2~7.5 without enzyme Study L ) ( F1G: ~, ) ; ~~1 x.35 143 232 300 3?6 ~.0 ~; : ~/~7. 5 with enzyme ( Study 2 ) ( FxG' 3 ) . 112 x.23 13.2 195 2?n 33g thus, FZ~. l shows the dissolu~ion'curvos oz three tables formulations (produced a~cordirrg, to xI.1) with varying Ca;caseinate contents: 30,;40 and 505.
pissolutic~n media used, are simulated grit=ic ( phase I, ) and intestinal (phase;2) fl;uids'without enzymes.
?'n F'~G. 2 th~ d~;ssblution behavior of the above-mentioned tablet formul.atioz~s are g~aphicall.y shown again, but in this ca~g the disso~.u~iorz media respectively 2.C? .contained pepsin ( phase 1 a and nancraa~ira l nh~ase 2 ) .
.year yy daxivacl zrom r y~~ . l and 2 ~i~az ct~a~.r~ly' in alkaline ( j;ntes~inaT ) medium tl~e rate of dr~xg release can be cont~oll.ed by the, content of water-insoluble Ca-caseinate. The h~.ghe,r the Ca-caseinate concentrat:.an in 2~ the tablet' forznulati on; the slower the drug releasa. In other words: Ca-ca~eina~te is exhibiting a retarding ~~~t.
A comparison between FIGS. 1 and 2 sows that control of drug release-rate by,varying the'Ca-caseinate content is 30 not influenced by the presence'of enzymes in the dissolu-tion'm~dia;' thus mimicking in wivo conditions.
Only 'the r~m~ to a v 4a~n ' ~.~~y lc a- d=ug release is reduced by a f actor VV~ 94/03IS8 ~ PC:'I'/E~'93102074'w '~ ~ 1'416;9 3.
F ~ ~ v ~ .
xhus; surprisingly enough, it has been found that the desired liberatioxa profile is relatively ~.ndependent of the enzyme pr~s~nt. ~'he low enzyme-induced acceleration virtually,~nsures a 100~'relea~e in the second phase after about f i.ve ( 5 ) hou=s .
5 . Release ~ of Memantine ~ om tablets accordingy to the Invention ( Study 3 ) A form~la~3c~n produced according to Examp~l~ I.1. is tested, as above, at ~aH x : 2/pH 7 . 5 ( vrithout enzyme; medium ch~x~ae after ~ hr~urs ~ . mhe ts~o-p~wse lz!a~~: w t'_.an ~ ~~
r= -shown in F>:G : ~ , 6'. ~elea a of caffeine from a formula ion according to the invention ( Study 4, ) A formulation produced accord~.ng to Ea~ample I.2 is tested; as move, at pH 1. 2/pH 74 ( without enzyme, medium change a~~er ~ hours). Here; tore; a'twa-phase liberation paofile ar.zsea as shown in FIG 4:
FZG. 3 graphically shows the release profile of a memantine'formulati,on produced'according to z.l, and FI,G.
~t is appa=ent to one skilled ~.n the art that the ava:Llable technology for effea~~.ve arid reliable extended "'e=~.~_; es~~aci~.l;~ a,-;z:~..r~,~ta~ga re:~;ease pharmaceutical dosage forms; mill leaves much to be desired.
o~J~e~c~ aF ~~~ ~rrvErrT~cor~ , w w is acco~d,i_~.g? y as cb~ac~ of the present i~renzion to grovaLde a pharmaceutical dosage ' farm which is character-ized by an extended eontro~.3;ed-release profile such +~..t:a the active substance can be r~onven~:ently and reliably ~~.5 released ove= an extended period in at least two ( 2 ) stages ~
'and a process for the production thereof : tether obi ects of the invention. wild. become apparent hereinafter; and still others will be obvious to one skilled in the art to which he present invention pertains, 2Q SU:'~=i..a'~ ''~~ T:-'~S Sh"V~:~'"'y ~Ow 'fi'ne inven~~.on then, comprises the fo~.low~:ng ; in tar olio, separately or ire combination:
A solid pharmaceutical c~os~tion in dosage form having a matrix-controlled extended two-stage release 25' profile comprising an effective amount of at least one pharmaceutically-act3:ve ingd e3ien t or pr wa.._~ ' ~~ l~~'" r Niil6raiia he matrix consists:essentially of a cambinat3on of a water-soluble salt of casein and a water- nsaluble salt of casein, the total water-soluble and water-inspluble casein-30 saZ content'comgrising between 5~ and 98% of the total ~
weight of the pharmaceutical compositior~;~ a1.1 salts and canons being pha-rmacologically acceptable; such a comppsi-tion wherein the'water-soluble and water-insoluble casein ~' WO 94/03ISfi . ~ ~ ~ PGT/EP93/020?4 salts comprise between 10~ and 90~ by weight of the pharmaceutical composition, preferably between 30$ and 80~
by weight; such a composition wherein the pharmaceutical composition comprises between about 5~ and ~5~ of a water-insoluble casein salt based upon the total casein salt content, preferably between about ZO% and 70~ by weight;
such a composition wherein the water-insoluble casein salt i s calcium cassinate : su.ch a ~maos i tic.~. ,ah sr ai:: t.' :a h a ter -soluble ca~.cium salt is sodium caseiriate; such a composi-tion wherein the ~ha~cmaceut~:cal camposition comprises an p-n.sr c~~ ~v1n ~ w......:~,..~ i .~..~ ..,.., s..~,.~.1. .i.~.
~r,:.r.. ~ ' ,~ ~3 '' ..r ~~r,. .. v..~...~es.:w.:...A.... iV4....,.........~j ..r.e r~.n~:.!
"ia u4~W .. i..~.n or Pepsin or both,, and such a cc~mposit~.on wherein the active ingredient is memantine:
Moreover, a procaas for the preparation of a solid ~.5 pharmaceut~.cal composition in dosage' form having a matrix-controlled,two~stage release profile comprising an effec-tive amount of at least ona pharmaceutically~act~.ve ingred~.ent or px~~:nca.pl:e, wherein the matrix consists essentially of a dombination ,of a water-soluble salt of ~0 casein and a water-insoluble saga cf casein, comprisa~,g ~h~, sa of : : :~.,.. ., ..:~ , p r_~ss_..~, ~~~r~~ ,a.. , ax~-adi,ng. pallaziza.ng.
or ~tabletting, ~.n dry or wet manner, of a m~:xture compr~! s-ing the at least one ac~.ve' ingred~a ent ~,~, ad.~~i~ture jai th both a waterdsoluble and a water-inspluble salt of casein 25 oz., aLtarna ~.v~ly, a water-solubla salt 'of casein and a silt or solution of a polyvalent cat~:on which is adapted to ~oxm a water-insoluble salt of casein in s~.tu, the total mater-saiuble and - wa-ter~-insoluble casein salt content -of the admixture in the final composi.t~.on comprising between 30., 5$ and 98~ ~of ,the total weight of the pharma~~utical composition; all salts and canons being pharmacologically acceptable; such a process with all the characteristics set forth for the compos3,tion.
,<~.-.
wo 9aio~~ss . P~,-riE~3~ozo7a:
2~.4~.691 The Present Invention According to the practice of the present invention, the, problem is solved by providing a solid pharmaceutical composition ~,n dosage farm conta:Lning a pharmaceutically-effective amount of ono or more active substances and the usual auxiliary agents and addit~.ves; but also a total of between 5 and 98~, preferably l0 to 90%, and especially 30 to $0~ -- based on t.h~ tai wea gh ~ of ~.~e c~.:: p.c~i, ~ic:~ -of a combination of a water-soluble and a wa~er~-insoluble salt c~f casein. A pharmaceutical ~orrnulatior~ of this tape can .~~,~,ri too tr ea tea j - ~., ~.' ',.. 'L~3v.:~.4 ;:Ia J ZC7 py O~J'~.~ ~, V"~'..~1'yl L~...
scalid dosage dorms having ~ two-~pha~a matr~.x~controlled extended release prof3.~:e: Thi s ~.ncludes tl~e employment oz procedures krio~n ire the pharmaceutical industry, such as ~.5 , compressing; granu~.~ting; extruding, palletizing, and tabl~tting ~.n dry or wed manner. It is of course also posszble to combine a var~.ety of procedures to provide the des~.red pradue~ formulation in any one of various forms such as ablets, dragees, pellets; gr~rnules, and the like.
z0 The amount of active substance pse.sent can be v~' es'. ;~ride~~
;~
da~~~.darg ~:~:~:y :~a:i~a~:on 'ta b~ treated and ~cne type of --dosage form desired; for example, from O.OI to 90~, bused on the total weight of the ~ha~~c.~=a~cal composi t~.on.
Quite unpredictably, it has been found that the 25 pharmacokinatic properties of the solid dosage forms according to the pre~en~ invent~.on are not a~~ected by the manufacturing method employed or tha var3a~ions arising in practice, e.g., the compression forces ut~.lixed.
The casein em~al:oyed can k~e a commercially available :30 product, and the molecular weight and~water content thereof ;
may vary considerably, for example between MW 1$000 and MW
30000 Daltons - depending upon the Origin thereof, without detracting from its operativeness'according to the present 'N10 94!03158 . PCT/EI'93/02074 v'~~~~, invention. Casein is of course a substance approved for use under food legislation throughout .the cidilized world.
A dasein salt of a monovalent ration, such as lithium, potassium, ammonium, and preferably sodium, is used as 'the 5: water-soluble casein salt.
The water-~.nsolubl~ caseinate i's a salt of casein with ~ gol.yval.ent cat,ion, which term as used he~aa.n includes bivalent canons. 'these include; e.g:, calcium, magne-sium, zinc, manganese; aluminum; iron, or ma.xtures thereof particularly preferred ~;~ dalc~.um: ~'he water-insoluble ca~einate can be used as such.
Tn add3.tio;n, it is possible to in~l.ud~ in tk~e composi-t on, contain~.ng a soluble casein salt; a physiologicallyr corcpatible poly~ralent cati.on, ~:n zh~ form o~ a salt thereof 1-5 which is soluble in water or gastric fluid, optionally in soluti on in water, in amounts such tha w a par t of the soluble caseinate is converted to an insoluble aaseinate, thereby transforming a part of the soluble case~,.n salt tb an insoluble casein salt in situ, as by gastric fluid upon 2Q ingestion.' A part or X11 of the insoluble salt may be provided in ~h3.s manner Preferred s-alts. a..ncluda the V~lcyi4e; ~luy~r~ate, carb~natG; ~.actate, and sacch~ra~ce abdt in ga,rticu7.ar, ca~.cium chloride, ca~:cium gluconate, calcium hydrogen pnosphate; calcium Lactate, 25 calcium ~--saccharate, calcium levulinate, and their hydra~ces, or mixtures thereof; are preferred saps for prcaviding the aqueous polyvalent, includ~.ng bivalent, catinu, wh~.ch ~n~y '~e used as s~:ch ar, if desirad, be solvaved by sample dissolution of the salt; ~.g., in water, 30 and optionally used in ,a normal gr~~aulat~ion procedure.
The wsight/weight ratio of soluble to insoluble caseinate is between 5 and 95%; preferably between 5 and g0~ , end ;nor c ' Fre~ e~ bly ' between 20 and i 0% , posed on .the ' _ 7 r IaJCD 94/O~1S8 ~ ~ 4 ~ 6 ~ ~ P~C1C/EP93102074 ,.~
total caseinate content of the composition. Most preferred is a ' we3ghvt/weight ratio of between 30 and 60s. The amounts of the aforementioned ionic compounds and their solutions required for the production of the desired amount and ratio of i,nsol~ble caseinate ~n situ are dependent on the type off; catian, its counter-ion, and the molecular weight of the casein employed, as will be readily under-r. '6'~ 1 "~,'J 1:" ~~ 7.i. w stood b~ ~",.d, ~.,c ~..~~ be ~ ~a~a a ~. ,~ . - in ~'~w..~..i:vww......,W ~r~C. sl5.w..l.J.Cu the art~since it involves ox~Zy basic chemistry.
According to the 3,nv~nt~.on, quite unpredictab~,y and ~,'~ ~ ~-~-~~eGt;s~.x , a s;.~:ial4:.. ' ~ ~ ~ a~ """'.~ ..,n~~~-",:,.~..r...:,...
~1.~ ~, t1 LI ~'!~''.~,..s ~ ~..,._....~L
extended ro~.ease of a~ctivs plnarrnac~utical ingredient is thus ach~.ev~d with tha speci~~.ed combination of matrix--~or~ming substances a.lon~ and without the necessity of any embedded d~r surrounding external p~oteizy.
Comman auxiliary agents and additives or excipients which may be enployed to complete the pharmaceutical composition used as matrix are components well known in the pharmaoeu~tical industr~,r; Theses include, for example, ~ablettixa.g aids , such as highl;~ ~ ~ seer ~e s,~I ~ ~a c .;ba~g:~eai .~, ~~ra~ta; nicrocr~y~zaia~.ne cexlulose, lactose;
talc, colorants such as iron oxides or qui z~oline yellow, ~i~ments such as ti.tar~.u.r.: d' oxide and balciu~-~ ca~bonaz~, gl.yce~rlmanostearate, g:lyceryl behenate; sodium stear~,rl-fumarate; ste~ri~ acid, cetyl. pal.mitate, long-chain partial glxGerides, cellulose powder; mannitol; cal.CiuD1 DhoSTJ}'7.~'t'a, silicon dioxide, colloidal s~.licon dioxide, silicon dioxide l~ydrare; end goLyethylene glycol, preferably of a moleau~.ar weight 1;500 to 6,0~O,Dal,~on; and the like.
Acti~re eingredierzts or mixtures thereof, which can be used t~ provide an effect~~ve amount caf the active pharma-ceutical princip~.e o~ ingredient in the campositions of the a.nvention; encompass 'innumerable pharmaceutically-active WO 94/03L58 ' .. .: '~ ~? ~ ~; p~/E~3/02074 compounds which are suitable for extremely varied fields of end-use application. They include tranquillizers such as chlorpromazine and benzodiazepines such as diazepam;
muscle relaxants such as mephenesin; an~ihypertensive agents such as a-methyldopa, centrally-acting analgetics such as morphine: peripherally-acting ana~,get~,cs such as paracetamol~ non-steraidal antiphlogistics such as ibupro-den; local, an~9th~t~.cs such as b~~~~c~a ~~; spasm.cl y ti~a such as papaverines prostaglandins such as PEG2, antibiot-~.0 ics such as p~nicill~.n and tet~acycl~:z~~a ag~lnts influencing . ~i.. Z,.. V a ~~ 3-, y a. y~ Y...c. 3.:.."~,.., q L n v : .t.. ~
_ ~ ~ ~ , ......,........ ...~. ~,,, ..w.... ......c ~ uw..: 8~ iucaua. ~ ,...n 2 ; a17.. ...r ~..I~,~ QILS.~I
therapeutic a~~nts such as amantad~:ne, L~dopa; s~legil~,ne, bxomocr~.p~ineand me~ix~r~eantim~zari ~ls suoh as chloro-quine, corticosteroids such as dexamethasone; androgens such as ' methyltestostesone~ ~strogens such as ethiny~.~s~tradiol; gastagens ~u~ as levonorgestrel:
symp~~hometics ~u~h as adrenalin; substances having cardiovascular effect such as nitroglyc~xin; diu=etics such as hydrachlprothiazid~~ anthslmintics such as praziquantel:
~0. B~bloGkers such as ~timo~:ol; ~32_~-blockbrs such as ca~~tida.T..e;
.--! ta.~' ::.. :...r. as ~~c acid, and the , ~,iite ~Efective .._..~ ~ r,,...
amounts o~ such pharmaceutioelly-active principles or ingredients are well known in the ar t Most preferred i,s memantine:
2a The readily-produced formulations according to the invention, u~aon ingestion, advantageously result in a cont~olled two-phase release of 'the active ingredient,, with an amount of active subs.tance'adapted to the therapeutical goal being released ~and'avai~able in the first phase, i.e., :~C1 in the stomach; as well as in the s''econd phase , i . a . , in ~
the intestines where, after-a slight- delay, a renewed liberation 'of active ingredient is effected, the remainder of the active ingredient being released over a pxede-w~ ~aio3~s$ . ~ ~ ~ ~ ~ ~ 1 ~c.-rm~3ioao~a ~v ,_ .
termined time period, thereby attaining an effective adaptation to the total active substance availability requirements, with the partial release in each stage resulting in corresponding desirable plasma levels. Local 3 excess concentrati~ns of active substance are thus avoided:
This two~phase pharmaceutically-active ~Lngredient;
a.g., drug or vitamin, libe~r~ation profile ~.s substantially independent of the enZvmes con~s~d in, ~~,~ , 4h~,N s.'..o? cga ~~' environment of the stomach and intestines, as shown in the 1,Q following examples, a resu~,t w~h~.ch hithar~to has not been Td3~~ '~ ~~~~ p~hs ~~.~y~wy.I :~.~~~ ~~. ~~ G~w»~r' ~ ~ _ r. ~~ V ~~/m.rrW ~~. nJW ryl~ .W rYWYiW Iw r,r.~w~ Y
,However; if a change ~.n the release rate is required in one or the other of the 'two liberation phases which might be necessary or desirable in view of the type of 15 active substance employed, the physiology of the patient, or the degree of seriousness of the- ailment ytreated;
enxy~es such as pepsin; ar~d/ar pancrea tin can of caurse be included 3.n ~h~ formulation in suitable amounts, as we? ? as numerous Q~hes enzymes or polymer-enzyme products such as 2d neat=al, acid; or alkaline protease, or anv of the forego-,~rs"~,, nr~~a.~r ~ ~y iy..~~::.:.i.'cw ~ a'W.i..v"~'~~'aar t~ t"~17 eT.a'7yi.ane-_ 'maa.~ic acid or anhydride E) polymer (as in USA
3, ?51 ~ 561 ~ . This does not change the tvo-ph~e prc=i1e It is only the rate o~ liberation within he phases which ~2~, pan thus be slightly varied:
The mechanism of the extended two~stage release can be e~plaa:ned as Follows:
The use ~f a water-in~oluDie caseinate, e:g., calcium ~aseir~ate ~ results - in' the foz-mation of a matrix tablet .~ 30 , The drug is ~ re~.eased independently of the pH of the dissolution medium in a d3,ffusion-controlled manner. In otk~er words, due t~ the presence of the insoluble casein-ate, there is an extended release in both stages, the IO -WO 94/03158 ~ ~ ~, ~ ~ ~ 9 ~ PCT/EP93/02074 extent of retardation being dependent on the amount of insoluble caseinate iz~ the formulation, as sk~own in Study' and correspond~.ng F2G. 5:
In alkaline medium; the insoluble caseinate graduaJ.l~r becomes degraded, equivalent ~o an at~tanuation of the matrix-effect. Subsequ~ntl,~, the retax~dat:Lon i,s diminished and the drug,release rake increases, which can be seen in the second stage, although also in this second stage drug release is extended.
HRIEF DESCRIPTZGN OF THE DPAV~INGS
y~ s,...,.:._,.=,.es a ~ ~.x'41 ~'S'~'x ~~ 1~,,~ ~,~~~r_".D~'=eri ra,~ ~3t~73Sl.~S .
for a better understarrd~.ng of the present invention, wherein:
FAG. 1 is a graph of a biphasic drug ~aberation profile showing: release of caff~ane over a period of time in accord with Study 1. of 'this app~:~.ca Lion wi tk~out anzx;ne and jai h medium change after two hours.
Fi,G. 2 ; i~ the same according to Stud; 2 of~ t:~i;~
appLicati;on ~a~.th enzyme and w~.th medium change after two ~0 hours.
~ ,a l cs ~."p, o.f C'T I~ '~ ~ C o ~ ' '~ h 'f n it A y.
s_~z~.__g ..h_ b~~h~aia Memantin~ over a p~r~.aa of ~ci.me in accord with Study 3 of th=.s aonl.ication without enzvyme and wi h medium change after two hours.
Fl' G . 4 ~, s the same as FzGS . 1 and ~ , but in accord with Study, 4 of this applicat~.on' without en~~rme and f~r~.th msd3.um change-after two hours, and r iG. a ~.s a graph 'i3.lus-crating the , d~renderce of d~ ag release on 'the ~.nsoluble caseinata content of a dosage foam 3 according ;to the invention, showing the percent caffeine ~ p released over a period of time with calcium caoeinate cc~nte~n~t of the formula~~.on varying from 0 to 100 0 , th~.s libe=anon prori3.e ' being determinaci in a simu fated ga~yc ,~.-..
WO 9~d/03IS8 . PCT/F.P93/020?a'.:
environment at a pH of 1.2 without added enzyme.
SPECIFIC DESCRIPTION OF THE INVENTION
The invention will now be described in greater detail with references try the following Examples; which are not to be donstrued as limit~Lng.
Production of the Druq Formulation Exa~le 1 Active Substances and Additives ~3Qr~ar1y Yh. t~a~r..?-:y memantine HCI 20.0 7:0 sodium caseinat~ 46.8 Ca~..C.~..9.1TT1 CaSa'~ T'?ata J_ Aerosi~. 200 ( f~.n~ly~d~.vid~d SiOz ) . 1 s 0 magnesium stearate ~..0 All components with the exception of magnesium ~.5 s~earate are homogeneously distributed in a'suitable mixer such as a D~.osna~ mix~r~ subsequent3,y magnesium steaxate is added and the mixture passed through a screen of an average (U.S. Standard Sieve Series) mesh size o~: 300 um. After a further mixing of the material t~ be campressed, tablets 20 having a mass of 100 mg and a d~.enteter of 6 mm are produced o~ a suitahla tabl:~tt-~.n,n. :~,~,~..~.we ~~si., ~,,:,, ' ~_=~.~
....s ...,.~:~es-~ t ~ ~ '.' o.. W .r r. vi.~auZr ,5.j~.uai of O 1ZN .
Example 2 Active Substances and Additives Percent by WeiQht 25 caf~exne 20.0 sodium casei~ata X5.0 calcium-chloride x 2Hz0 3.0 A~.:osi? 2pp'~ l - 0 magnesium stearate : 1.0 30 The caf seine and sodium ~ easeinate components are mixed in a suitable fluid~.z~d bed granulation machine; such as the Aeromatic ~T~EA 1~. The granulation of a 500 g batch ~ys ~f~ected with 40C? mi oz an aqueous fluid contaia~ing 3 g WO 94/03158 . 21 ~ 16 J ~ p~/Egg3102074 calcium chloride dihydrate in dissolved form at a pump rate o 14 ml/min, aninlet temper~,tu=e o ~0C, an outlet temperature o 32 C, and at an atomi~i.ng p=ensure on . the binary nozzle of about 2 bar. After a redryi,ng n 10 min at 60 ~ and a weak su~aply of fresh air, the granulate is separated from the coarse portion (>1:0 mm) and rom the ~
( e0 : l5mm ) and; af~~r admiring with Aeros3:l and f~:ne portion magnesium stearate ~ is compressed u~.ing a force of camp_Qs-sion of 8 kN in~a tablets having a we:Lght of 100 rng and a diameter o 6 mm.
~w 5:.,":, ;~ ?
~..., _ Active Substances and Addit3.ves Percent b Wei ht piroxicam ' ~~.0 sodium ~aseinat~ C5.0 , calc~.um hydrogen phosphate + Z~IzO 3.8 Av~Lcel pH I02' microcrystalline c~~;lulose g . 2 Aerosil 2f0 1.0 magnesium stea~ate 1.0 All compr~ner~ts except iar magnesium stearate are 2C?, , homogeneously distributed in a su~:~table, mixer, e.g. , a T an a ~ m a ~~ ,..r ... ~" ,Jr...... ',"~ ~,r.ar.~ ~,,~
.r'~w.rS 4.Ia~1 id V d. !r ' 41r 1 C.~~prd, and 4h8 ' ~',s.r ~i~
v , .r.
...
mixture passed through a scre~:n of an average (U. S:
Standard Sieve Series) mesh size of 300 um. After further mixing o the compressed maps, tab~,ets are produced on a suitable Vie? ~.eting machine, having a mass oz 1.00 mg and a diameter o 6 mm; wi h a compression rorce of 8 kN
being applied.
Ea~am~pie 4 Active Substances and Additives Percent by We~.~ r~ht ibuprofen . 77.0 sodium caseinate X0.0 ca~,cium ch~.oride + zH2~ 1.0 Aerosi2 200 ~ 1:0 magnesium stearate 1.0 WO 94/03158 . PCT/EP93/02074r . ;
~By spraying a' suitable granulating, 13,c~uid such as an ethanol/water mixture (v/v 3/2) or a colloid--containing granulating liquid such as gel.atine/water (L/30), a crust granulate or an adhesive granulate is ~ir~t produced from the ibuprofen. , The, granulate is mixed with ~h~ remaining components in a suitable' mixer and is compressed, usa....~g s cc.~p-ess' c-:
force of Z5 kN, into tablets having a mass of 520 mg and a diameter of 12 mm.
a:a ~~1 n ~
A~t3,ve Substances and'~dditiv s percent b Wei ht memarrtin~-Hel 20 : 0 sodium caseinate 45:0 calc~.u~n cas~inate ~ 32.0 2a All components are homogeneously distributed, using a suitable mixer end; in a mixing kneader; 'ase then intimate-ly wetted .y~~,th a suitable plasz~cizi.ng liquid; such as purified water or an ethanal/water rnixtuso, (v/v 3/2) to an extent of about 60~ v/v based on the solid pardon: The ~.~S.Ll~::t.3ll."~, m~99~S ~ 5 1 °~,rrv'",.~'.'~w~,',i ~'.'~': tai~,r ' uy~ i3 avr. oa'W ~~CaeZ'-yr on a aistribu~cing roll-type extruder with an aper~ured disk-»diameter of 1. Smm. The thus-obtaa.,:ad; s~".,.~a.,°:-ds ay=
divided and filleted on' a spheronizer to Norm pellets of a diameter of 18 mm: Subsequently,- he pezlets are either 2S. loaded into cagsules or are compressed into tablets after admixing w~.th 1% Aerosil and i~ magnesium stoarate.
II : Libe.t a. Lion o~ Release Tes-cs The media used in all dysso~.u~ion tests is either simulated gastric fluid ( pH 12 ) or imu~.at~d intestinal.' 30 fluid'(pH 7:5). To more close2y approach in vivo-condi tions, pepsin ;'(gastric fluid) and pancreatin (intestinal fluid) are added.' Tn the chapter "Test Solutions" of the U.S. Pharmacopoea'XXTI, the compos3aions of the two media - 14 '-PcrlE~mazo7a ,d,,0 X4103158 2 U.S. Pharmacopoea XXII, the compositions of the two media are eXactly described as follows "Gastric Fluid; Simulated, TS---Dissolve 2.0 g of sodium chloride and 3.2 g of pepsin in 7.0 mL of hydrochloric acid arid suf~i~ient wa-~er to make 1000 mL. This test solution, has a pH of about ~. . 2 ; " __ "2ntestinaJ. fluid, ~~.mulated, TS--Dissolve 6.8 g of manobasic potaas~.um phosphate in 250 mL of water, mix, and add x;90 mL of 0.2 N sod~,um hydroxide and 400 mL of water. Add 10.0 g ref ~ancreat~.r~; mix; and adjust the r ~~,:, ~ +~ selu~~ wi.~.~,. Q . 2 N sodium h ydroxide to a pH
of 7:5 t 0.1. Dil.uta with water to 1000 mL:"
1. F~etarded reZea~e of an act~.ve substance in res once to the insoluble dase3:nate content , The following bas~.c Formula ~.s dompressed:
cas. T. e1x'le Z0 0 Ca-caseina~e 0 ~ 78.0 (based on the total casein con~ent) Aaros3.l 200 1w 0 magnesium stearate 1.0 N.~.as 'e.in:a,.te :ad 100 ~5 Fight di.fferenz compressive masses , o= varying. ~va~
caseinate and ~a-caseinate proportions (added as such) are formulated by using the tabletting auxiliaries Aerosi.l and Zg magnes~.um stearate: As no other auxiliaries are added, a true picture c~ the release properties is obtained.
The total case~.nate portion amounts to 78~. The ~ ~W r.~.~ ~n r. r1 n T
pu~~l C.i. ~tZ~ Gil l:. liZ~:~' W .ti. ~~ a.L G'~ vVi~p~. G~"~sG~d .~raa ~a _. '.,u' WaA~ie:W.r~~u Exacta 1'm at an ad,~usted speed of 30 ~trokes/m~.n, using ,~ 3Q compressing ,tools of 6 mm, flat .without facette, at a constant force of compression of 8 kN to form tablets having an individual weight of 100 mg Dosage =arm grodu~ia are oi~tazned having a Ca casein-~, 5 _ WO 94/U3158 . ~ : ~ ~' ~ '~; PCT/EP93/OZ074 ~~r~
ate content of 0, 10, 20, 00, ~0, 50, 70 and 100%, the liberation profi~.e of which is deterrniried at pH 1.2 (simulation of gastric environment).
FZC. 5 shows the dependence of drug release-on the insoluble caseinate, i.e.; calcium casoinate, content of the dosage forma ,and thus th~ extent of retardation. The tablet formulations employed in this study correspond to the basic formula of. Ix: 1 just her~in;abavA provided.
The . d~sso~.ution e~ ~0% of tota3. caffe~.n~ content Za ~ccuz~ n tk~e cafe of 20% Ca-~caseir~~te ( ne=centa~e related to tratal caseiria~~ ) at ~; ~n ma,_~. ~ ~s . 1:'.',' ~:~ ;~ ~':~r ~
"a-caaein,ate F=1.25). at 2$5 main with 50% Ca-caseinate ( ~'~2. 2 ) , and at: 350 min w~Lth a Carca~aihate contEnt of 100%
(r~2."75). These data are the results of d~asolution tests in ,. gastric ,fl.uid ' ( PH ; 1:,2 ) w~,thout added enzyme:
~t has ~hus been establas~ned'that the r~leas~ in this gastric'environment,can be inhibited by the combination of insoluble caseinat~' with soluble casein~te; depending on the relative proportions thereof, a-vasying xetardation is .20 obviously achieved" This pexmit5 the ~el~ction of highly-des~~abh~ individuar.~ ~-e.~.~.ee, ~ cy'''_,e, v~ep,ar::v:~g -~.:
t::a a~ i~-a au~StaI"~Ce and she yype of indicat~.on ~o bd treated. ' 2. Liberation: or Release profile of caseinate t~ble~s 25~ c~mnressed at a varyin4 force of cambressi'on The fo7.lowing formulation with a Ca-c~seinate propar-tion of the total caseinateconten~ of 40% is compressed in accor~c~ w~.t~ t'~e afoyementianed condi:td.ons a-G forces of GOmpression of between 4 and 12 kN into tablets having an W~ 94/03158 . ~~ ~ C 1PGTlEP93lOZ074 individual weight of 100 mg:
caf f eine 20 : 0 Na-caseinate ~ 45 . 8 Ca-caseinate 31.2 Aerosil 200 y~0 magnesium stearate l.0 Zt has been found that varying forces of compression w~.thin these ranges have no bearing or e~fsc~ on the release prof3.le.
lp 8 . Addi lion of ~ol~valent salt to the soluble caseinaite to '.,. ~, na ~!-'hn 4 rc rr1 "1-vl o raa rs~ ~a~n;
i ... ~i .u.~
_o_s__ _.s__ _s_-,...._.~
'the following ,basic m~tr~.x formulation is produced in the foregoin;g manner with admixture and/or'granulation and in accord pith the foregoing corrditians ( see Examples 1-5 ) 15 caffeine ~ ~ 2C1. 0 NaCaseinate &5.0 Ca-salt, optionaslv in aqueous solution x Aerosil , I.0 magnesium st~arate 1.0 20 Avicel pH'102 ad 100 ca~r~i.ate.~v ~or.~x~=t..__~_g ~ so? ~.:~la "" , ""
ca~..~e~ ~.a ~e example -cne ria~aseinate, zo an insoluble; e.g:, calcium, salt, the insoluble ration content can be readily deter-mined; e:g., the Calcium content is normally 1.5~
to 1.'7~
'~5 by weight, but can op-tzon~lly be made even higher, so the t an amount as suggestzd below according;'to the pre~enz invention can be readily determined and the desired mount o= i;nsoLui~le casein ' salt thereby calculated and thus-p=ov~:aed .
30 , ~ The ~ollQwing pharmaceutically-;suitable calcium salts ' can; for example, be used in the foregoing formulation to, provide an insoluble casein salt in situ i n a formulation ~~ zhe invex~ionv, '~O 94103Z5~ . PC'T/Ek'93/0~074'~~~, .
~~~ ~~
. , Amount X employed in the Formula:
calcium chloride x 2Hz0 ~
Calcium gluconate: x H20 l~ 9 calcium carbonate 2:~
calcium hydrogen phosphate x 2HzQ 4,Z
calcium lactate x SHZC? 7.5 , ca~:cium nitrite x 4HzC7 5.8 calcium-D-saccharate r~,1 c~Zcium levu~:3,nate The compositions 'off the ~orego3.ng foxmulae are CC7~IIIDx'es~2d uTli~~:...'" ~hlra ~~G.~..=°.~~:~. ~.'~..C:"..~~~
v,.C:.~r'r':.;,'~ :a' 3 t c .constant'farce a~ campzession o~E 8 1~N into tablets having an indiv~.dual weight oz 1G0 mg and are found to have the same two-phase extended sel.ease profile as a unit dosage . mat=3:x conta3:ning the same proportions o~ ' soluble and inso3.uble casein salts ~;n solid corm but present as sudh in he ' beginning admi~sture _ Tt has been fo~xnd that all calcium salt_~ used in this manner produce ia~~olub~:e casein' salt-containing matr3.ce~
ha~r~:ng almost identical l~.beration ~x~ofiles. The t:~-valuQs var~r wiahin a riar~r~~r ra.~ga ' o= ~~.~,,:: ~,~~ a~~ ~.1~ :,.yra;
wa~,a ;:ic tpo-va~.ues vary besween 2~2 and X95 min.
Identical r~~ults are a.~so obtained ~r~.th soluta ors ~r other polyvalent '3.ons besides calc~.um, fox example;
,25 megnes~:um, zinc, and aluminum sa3ts:
<'4.. Influence o~ the incuba ion medium ' A variety of compresseei dosage form products produced-' a.crb::3ir~.g ~~ Sy:I with vaxying proPox~ions of insolubl.e caseinate, preferably 'calcium 'cas2inate, ~ ire now examined ,~ 3Q 'as to their drug-liberation profil~ with changing med~;a ' both with and wi-~hout enzymes.
The reswlts aye shown 3n Studies 1 and 2 and their co~-~.~aspondihg figures Fi~G. i and FIG: Z. The figures (FS~S. 1 and 2) resulting from these. studies show the 35 biphase profiles of the compositions produced according to _ lg _ .: ~~ 94/03iS~ ~ PCTlEP93l42474 the invention witrn a Ca-caseinate portion of 30 , 9:0 and 50~
by weight; the results being shown in' the following TABLE
l (medium change after 2 hours):
TABLE '1 tso ( min ) t9o ( m~.n ) ~~I Ca-caseinatet & ) 30 40 5~ 30 40 ' S(J
1Y2~7.5 without enzyme Study L ) ( F1G: ~, ) ; ~~1 x.35 143 232 300 3?6 ~.0 ~; : ~/~7. 5 with enzyme ( Study 2 ) ( FxG' 3 ) . 112 x.23 13.2 195 2?n 33g thus, FZ~. l shows the dissolu~ion'curvos oz three tables formulations (produced a~cordirrg, to xI.1) with varying Ca;caseinate contents: 30,;40 and 505.
pissolutic~n media used, are simulated grit=ic ( phase I, ) and intestinal (phase;2) fl;uids'without enzymes.
?'n F'~G. 2 th~ d~;ssblution behavior of the above-mentioned tablet formul.atioz~s are g~aphicall.y shown again, but in this ca~g the disso~.u~iorz media respectively 2.C? .contained pepsin ( phase 1 a and nancraa~ira l nh~ase 2 ) .
.year yy daxivacl zrom r y~~ . l and 2 ~i~az ct~a~.r~ly' in alkaline ( j;ntes~inaT ) medium tl~e rate of dr~xg release can be cont~oll.ed by the, content of water-insoluble Ca-caseinate. The h~.ghe,r the Ca-caseinate concentrat:.an in 2~ the tablet' forznulati on; the slower the drug releasa. In other words: Ca-ca~eina~te is exhibiting a retarding ~~~t.
A comparison between FIGS. 1 and 2 sows that control of drug release-rate by,varying the'Ca-caseinate content is 30 not influenced by the presence'of enzymes in the dissolu-tion'm~dia;' thus mimicking in wivo conditions.
Only 'the r~m~ to a v 4a~n ' ~.~~y lc a- d=ug release is reduced by a f actor VV~ 94/03IS8 ~ PC:'I'/E~'93102074'w '~ ~ 1'416;9 3.
F ~ ~ v ~ .
xhus; surprisingly enough, it has been found that the desired liberatioxa profile is relatively ~.ndependent of the enzyme pr~s~nt. ~'he low enzyme-induced acceleration virtually,~nsures a 100~'relea~e in the second phase after about f i.ve ( 5 ) hou=s .
5 . Release ~ of Memantine ~ om tablets accordingy to the Invention ( Study 3 ) A form~la~3c~n produced according to Examp~l~ I.1. is tested, as above, at ~aH x : 2/pH 7 . 5 ( vrithout enzyme; medium ch~x~ae after ~ hr~urs ~ . mhe ts~o-p~wse lz!a~~: w t'_.an ~ ~~
r= -shown in F>:G : ~ , 6'. ~elea a of caffeine from a formula ion according to the invention ( Study 4, ) A formulation produced accord~.ng to Ea~ample I.2 is tested; as move, at pH 1. 2/pH 74 ( without enzyme, medium change a~~er ~ hours). Here; tore; a'twa-phase liberation paofile ar.zsea as shown in FIG 4:
FZG. 3 graphically shows the release profile of a memantine'formulati,on produced'according to z.l, and FI,G.
4 the- di.ssoluti.an-~u~e' Qf ~ ~ff~j-~ f~~,sl a ~a c.~. r=era.:' acc"~ ~i:.~ to 1.2: ~n ao~c'rr cases, zhe dissolution media contained no enzymes.
Within the scope of simulated in vzvo conditions; the change of dissolution media 3.n each study represen is 'the passage of a solid dosage fdrrt fam the stoanach into the intestine .
~'spe~ra~ly the graphs of FAGS. ~ and ~, but also she plots of the other FIGS., dearly demonstrate that a change ,;, 3,0 of; pH results in a steeper slope of the dissolution curve', which means an ~ceel.erated drug ~eleas~. Translating this into human use, the value of the extended-two-stage release ;j ~~~n as a slower increase of drug concen~rat3on into the Wt~ 94/0315 - ~ ~ ~ ~ PCT/EP93/0Z074 bland, thus reducing undesirable side effects. This is particularly true for gastric side effects because, according to FIGS. 1.--4, only about 40-50~ of the drug content is released in the stomach.
Beyond ' his, a reliable slow release, generally prolongs internals b~tween application or dosing and thus improves patient compliance cons~.derab~,y.
7 , Study 5 ; which was product~,v~ of FT,O : 5 , showing ~-...~..s Trisect Inf2ucen~e of insoluble Casein on the riru Release ~0 P~o:~il.e, has already b~en fu~:~.y discussed hereinbe~ore under the h~ad~.ng c~~ 'i T_ ~
Accozdingly, it is clear that-formulations having an optimall.y~adapted release profile aan be produced in simple manner by incorporation of physiologically-compatible Z,5 components into two-phase extended-release compositions and dosage farms according to th,e p~asent invention.
Within the scope of simulated in vzvo conditions; the change of dissolution media 3.n each study represen is 'the passage of a solid dosage fdrrt fam the stoanach into the intestine .
~'spe~ra~ly the graphs of FAGS. ~ and ~, but also she plots of the other FIGS., dearly demonstrate that a change ,;, 3,0 of; pH results in a steeper slope of the dissolution curve', which means an ~ceel.erated drug ~eleas~. Translating this into human use, the value of the extended-two-stage release ;j ~~~n as a slower increase of drug concen~rat3on into the Wt~ 94/0315 - ~ ~ ~ ~ PCT/EP93/0Z074 bland, thus reducing undesirable side effects. This is particularly true for gastric side effects because, according to FIGS. 1.--4, only about 40-50~ of the drug content is released in the stomach.
Beyond ' his, a reliable slow release, generally prolongs internals b~tween application or dosing and thus improves patient compliance cons~.derab~,y.
7 , Study 5 ; which was product~,v~ of FT,O : 5 , showing ~-...~..s Trisect Inf2ucen~e of insoluble Casein on the riru Release ~0 P~o:~il.e, has already b~en fu~:~.y discussed hereinbe~ore under the h~ad~.ng c~~ 'i T_ ~
Accozdingly, it is clear that-formulations having an optimall.y~adapted release profile aan be produced in simple manner by incorporation of physiologically-compatible Z,5 components into two-phase extended-release compositions and dosage farms according to th,e p~asent invention.
Claims
Claims A solid pharmaceutical composition in dosage form having a matrix-controlled extended two-stage release profile comprising an effective amount of at least one pharmaceutically-active ingredient, wherein the matrix consists essentially of a combination of a water-soluble salt of casein and a water-insoluble salt of casein or a precursor therefor in the form of a salt of a polyvalent cation adapted to generate a water-insoluble casein salt in situ from the water-soluble casein salt, the total water-soluble and water-insoluble casein salt content comprising between 5% and 98% of the total weight of the pharmaceutical composition, all salts and cations being pharmacologically acceptable.
A pharmaceutical composition of Claim 1 wherein the water-soluble and water-insoluble casein salts comprise between 10% and 90% by weight of the pharmaceutical composition.
A pharmaceutical composition of Claim 2 wherein the water-soluble and water-insoluble casein salts comprise between 30% and 80% by weight of the pharmaceutical composition.
A pharmaceutical composition of any of Claims 1 to 3 which contains between about 5% and 95% of a water-insoluble casein salt based upon the total casein salt content.
A pharmaceutical composition of Claim 4 wherein the percentage of water-insoluble casein salt to total casein salt content is between about 20% and 70% by weight.
A pharmaceutical composition of any of Claims 1 to 5 wherein the water-insoluble casein salt is calcium caseinate.
A pharmaceutical composition of any of Claims 1 to 6 wherein the water-soluble calcium salt is sodium caseinate.
A pharmaceutical composition of any of claims 1 to 7 which contains an enzyme.
A pharmaceutical composition of Claim 8 wherein the enzyme is pancreatin or pepsin or both.
A pharmaceutical composition of any of Claims 1 to 9 wherein the active ingredient is memantine.
A process for the preparation of a solid pharmaceutical composition in dosage form having a matrix-controlled two-stage release profile comprising an effective amount of at least one pharmaceutically-active ingredient, wherein the matrix consists essentially of a combination of a water-soluble salt of casein and a water-insoluble salt of casein, comprising the step of compressing, granulating, extruding, pelletizing, or tabletting, in dry or wet manner, a mixture comprising at least one active ingredient in admixture with both a water-soluble and a water-insoluble salt of casein or a water-soluble salt of casein and a salt or solution of a polyvalent cation which is adapted to form a water-insoluble salt of casein in situ from the water-soluble casein salt.
The process of Claim 11 wherein the water-soluble and water-insoluble casein salts comprise between 5% and 98%
by weight of the pharmaceutical composition.
The process of Claim 11 wherein the composition contains between about 5% and 95% of a water-insoluble casein salt based upon the total casein salt content.
The process of Claim 11 wherein the water-insoluble casein salt is selected from calcium caseinate and sodium caseinate.
The process of Claim 11 wherein an enzyme is mixed into the pharmaceutical composition.
The process of Claim 11 for the production of a two-phase extended-release pharmaceutically-effective dosage form.
A pharmaceutical composition of Claim 1 wherein the water-soluble and water-insoluble casein salts comprise between 10% and 90% by weight of the pharmaceutical composition.
A pharmaceutical composition of Claim 2 wherein the water-soluble and water-insoluble casein salts comprise between 30% and 80% by weight of the pharmaceutical composition.
A pharmaceutical composition of any of Claims 1 to 3 which contains between about 5% and 95% of a water-insoluble casein salt based upon the total casein salt content.
A pharmaceutical composition of Claim 4 wherein the percentage of water-insoluble casein salt to total casein salt content is between about 20% and 70% by weight.
A pharmaceutical composition of any of Claims 1 to 5 wherein the water-insoluble casein salt is calcium caseinate.
A pharmaceutical composition of any of Claims 1 to 6 wherein the water-soluble calcium salt is sodium caseinate.
A pharmaceutical composition of any of claims 1 to 7 which contains an enzyme.
A pharmaceutical composition of Claim 8 wherein the enzyme is pancreatin or pepsin or both.
A pharmaceutical composition of any of Claims 1 to 9 wherein the active ingredient is memantine.
A process for the preparation of a solid pharmaceutical composition in dosage form having a matrix-controlled two-stage release profile comprising an effective amount of at least one pharmaceutically-active ingredient, wherein the matrix consists essentially of a combination of a water-soluble salt of casein and a water-insoluble salt of casein, comprising the step of compressing, granulating, extruding, pelletizing, or tabletting, in dry or wet manner, a mixture comprising at least one active ingredient in admixture with both a water-soluble and a water-insoluble salt of casein or a water-soluble salt of casein and a salt or solution of a polyvalent cation which is adapted to form a water-insoluble salt of casein in situ from the water-soluble casein salt.
The process of Claim 11 wherein the water-soluble and water-insoluble casein salts comprise between 5% and 98%
by weight of the pharmaceutical composition.
The process of Claim 11 wherein the composition contains between about 5% and 95% of a water-insoluble casein salt based upon the total casein salt content.
The process of Claim 11 wherein the water-insoluble casein salt is selected from calcium caseinate and sodium caseinate.
The process of Claim 11 wherein an enzyme is mixed into the pharmaceutical composition.
The process of Claim 11 for the production of a two-phase extended-release pharmaceutically-effective dosage form.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4225730A DE4225730C2 (en) | 1992-08-04 | 1992-08-04 | Process for the preparation of solid dosage forms with protracted 2-stage release |
| DEP4225730.1 | 1992-08-04 | ||
| PCT/EP1993/002074 WO1994003158A1 (en) | 1992-08-04 | 1993-08-04 | Solid pharmaceutical dosage forms having an extended two-stage release profile and production thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2141691A1 CA2141691A1 (en) | 1994-02-17 |
| CA2141691C true CA2141691C (en) | 2002-04-09 |
Family
ID=6464804
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002141691A Expired - Lifetime CA2141691C (en) | 1992-08-04 | 1993-08-04 | Solid pharmaceutical dosage forms having an extended two-stage release profile and production thereof |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US5382601A (en) |
| EP (1) | EP0582186B1 (en) |
| JP (1) | JP3560244B2 (en) |
| CN (1) | CN1086708A (en) |
| AT (1) | ATE176866T1 (en) |
| AU (1) | AU669731B2 (en) |
| CA (1) | CA2141691C (en) |
| DE (2) | DE4225730C2 (en) |
| DK (1) | DK0582186T3 (en) |
| ES (1) | ES2128369T3 (en) |
| GR (1) | GR3030227T3 (en) |
| IL (1) | IL106580A (en) |
| LT (1) | LT3201B (en) |
| LV (1) | LV10182B (en) |
| MX (1) | MX9304675A (en) |
| WO (1) | WO1994003158A1 (en) |
| ZA (1) | ZA935614B (en) |
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-
1992
- 1992-08-04 DE DE4225730A patent/DE4225730C2/en not_active Expired - Lifetime
-
1993
- 1993-07-23 US US08/096,952 patent/US5382601A/en not_active Expired - Lifetime
- 1993-07-28 AT AT93112018T patent/ATE176866T1/en active
- 1993-07-28 EP EP93112018A patent/EP0582186B1/en not_active Expired - Lifetime
- 1993-07-28 DE DE59309388T patent/DE59309388D1/en not_active Expired - Lifetime
- 1993-07-28 ES ES93112018T patent/ES2128369T3/en not_active Expired - Lifetime
- 1993-07-28 DK DK93112018T patent/DK0582186T3/en active
- 1993-08-03 IL IL106580A patent/IL106580A/en not_active IP Right Cessation
- 1993-08-03 ZA ZA935614A patent/ZA935614B/en unknown
- 1993-08-03 MX MX9304675A patent/MX9304675A/en unknown
- 1993-08-04 LV LVP-93-1013A patent/LV10182B/en unknown
- 1993-08-04 AU AU47069/93A patent/AU669731B2/en not_active Expired
- 1993-08-04 CN CN93116211A patent/CN1086708A/en active Pending
- 1993-08-04 CA CA002141691A patent/CA2141691C/en not_active Expired - Lifetime
- 1993-08-04 LT LTIP839A patent/LT3201B/en not_active IP Right Cessation
- 1993-08-04 JP JP50501594A patent/JP3560244B2/en not_active Expired - Fee Related
- 1993-08-04 WO PCT/EP1993/002074 patent/WO1994003158A1/en active Application Filing
-
1999
- 1999-05-14 GR GR990401314T patent/GR3030227T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ATE176866T1 (en) | 1999-03-15 |
| LTIP839A (en) | 1994-08-25 |
| JPH07509479A (en) | 1995-10-19 |
| WO1994003158A1 (en) | 1994-02-17 |
| CA2141691A1 (en) | 1994-02-17 |
| DE4225730C2 (en) | 2003-04-30 |
| DE59309388D1 (en) | 1999-04-01 |
| ES2128369T3 (en) | 1999-05-16 |
| US5382601A (en) | 1995-01-17 |
| EP0582186B1 (en) | 1999-02-24 |
| JP3560244B2 (en) | 2004-09-02 |
| LV10182A (en) | 1994-10-20 |
| IL106580A0 (en) | 1993-12-08 |
| AU4706993A (en) | 1994-03-03 |
| GR3030227T3 (en) | 1999-08-31 |
| MX9304675A (en) | 1994-03-31 |
| LV10182B (en) | 1995-04-20 |
| AU669731B2 (en) | 1996-06-20 |
| LT3201B (en) | 1995-03-27 |
| IL106580A (en) | 1998-02-08 |
| ZA935614B (en) | 1995-02-03 |
| DE4225730A1 (en) | 1994-02-10 |
| CN1086708A (en) | 1994-05-18 |
| DK0582186T3 (en) | 1999-09-27 |
| EP0582186A1 (en) | 1994-02-09 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |