CA2228048A1 - Process for preparing solid dosage forms of very low-dose drugs - Google Patents
Process for preparing solid dosage forms of very low-dose drugs Download PDFInfo
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- CA2228048A1 CA2228048A1 CA002228048A CA2228048A CA2228048A1 CA 2228048 A1 CA2228048 A1 CA 2228048A1 CA 002228048 A CA002228048 A CA 002228048A CA 2228048 A CA2228048 A CA 2228048A CA 2228048 A1 CA2228048 A1 CA 2228048A1
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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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
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
A drug formulation process which comprises admixing carrier particles with a solution of drug in water in a quantity of 1-3 % by weight of solution to total mix and a method of treatment and/or prophylaxis of dementia, which method comprises administering to the patient ¢R-(Z)!-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo ¢2.2.2!oct-3-yl)acetonitrile monohydrochloride at a daily dose below 0.01 mg/kg and pharmaceutical compositions used therein.
Description
W O 97/047S0 PCTAEPg~03326 Ch;~S FOR PREP~RING SOLID DOSAGE FORMS OF VERY LOW-DOSE DRUGS
This i.~ ,nLion relates to a method of fonn~ tinE solid dosage forms of drugs and to solid dosage forms r~ red thereby"n particular solid dosage forms CQ~ g low 5 dose of drug The invention also relates to a mP.tho~l Of t~tmPnt and/or ~l~hyla~cis of ~ementi~ and unit dosage forms useful therein.
The usual ~hgllP.n~p. in m~nllf~et lnng solid dosage forms of very low-dose drugs, for e~n ple with active doses around 5-125 micro~mmP~ g) (for Pl~m~l~ 0.00~0.1%
by weight of drug to total solid), is to ensure h- mog~ p;ly. The l~.,,.l~n;r.~l problem is how 10 to distribute the drug ;,~ ,e evenly among the large amount of ~ pa-Licles.
The .c;...~l~sl way of ,,,A,,~r~ tablets is simply to blend all the inglGdi~i~ as dry pvvvd~ and tablet them ("direct co.~.pl~c.~ n"). This is rarely s~cce~rlll for low-dose drugs; a c5~mmon problem being segregation of the powder blend during t~b1pttin~- A
v~ tinn of this mP,thl)d which has been ~uccPs~r~J1 for low-dose drugs is known as 15 '~tntn~tionll~ and is somPtimP-s refçrred to as "ordered mixing" or '';..lr~ ;vt; mixing".
Ve~y fine p&lLicles of the drug are first mixed with a small portion of P~ipient; the pf~ u~
then mixed with a slighty larger poItion of excipient and so on until the desired rnix is oblAi~e~l This rnethnd relies on the fine drug par~icles aJ:1h~rin~ ele~ slS~ A11y to the Lrger ~ );rnt ones, thus p~ Ling se&l~~~l;on The method works with some drugs, 20 but ~vecP~ss~ ~epen~s on the surface pl.,pe,L;es of both drug and excipient7 and the method is very lahonous~ EP0503521 des~rihes the ~pp~ tion of this method to steroid~ drugs with high binding af~mity and low ~IP.I~ g potential for certain excipients.
A plt;r~; l ,d Alt~rn~tive m~thod for fotmt-l~tin~ low dose drugs is known as ''wet g~tn~l1Atinnn The drug is dissolved in water or another solvent, and blpn~pd with 2~ r~r.;l~;el~l.C i~ne~ g a binder, for PY~mpl~ povidone, to form a wet mass co~ .l-g 5-20%
by weight of sol~ltinn to total weight of gr~n~ tion mix, which is then dried off in a se~ lP- step. The binder causes particles of eY~ipip~t to clump together, and as the mass dnes these clumps ("gr~nl-lPs") either contain or are coated with the drug. This is err.,elive but c~mheMomP- since the drying step l~uilt;s special eqnirmpnt and ~PnPr~lly 30 involves high tPmper~tnr~PS which may degrade labile drugs. Also, the use of the binder requires the further inr~lu~io~ of a riwnt~Pgrant such as sodium starch glycolate or starch to help the tablet, which is cohesive, to ~ pPrsp~ in the stom~rh Fluid bed ~ nnl~tion has been used to achieve content uniformity of low dose g-lOmg) tablets (Thiel et al., J. Pharm. ph~rma~ol 1986, 38, 335-343). In this 3~ process, the micronised drug is blended as a powder with other excipients, then loaded into a fluid bed granlllator~ and the powders are agglomPr~t~Pd by spraying on a solution of a binder; drying takes place concomit~ntly. The process does not require a separate dIying CONFIRMATION COPY
W O 97/04750 PCT~EP9~03326 step. but it does require the use of .l.icf~nised drug, and also il~COl~u dt~,S a s_p~atc blending step prior to gr~n~ tion It also lL .luil-,s speri~licPd eq~;p..lP-~t and precise f~ ;on of the process pa~
Another process for fonn~ tinE low dose drugs is known as carrier ~mll~tifm (lUi~hfXl et aL, Pl,~. mr--~ul ;f ~1 Te~hnology June 1988, 66-84). This fnnrtionc by spraying a sol~ of binder such as povidone in water onto relatively large excipient particles such as hydl~lls lactose and then spraying small dry drug s.~b~ e particles onto that, thus coating the ~ f --l with drug p~Licles which are stuck on by the binder. The q~ iLy of so1lltinn used was 3.3-3.5% by weight of sohltion to total gr~nlll~tion mix. The method was applied to a formulation cont~ ;n~ ~5% drug by weight. This method also l~UilcS
drying; the drug particle size needs to be very small, which often requires an e~ctra milling step and the very hne drug powder may not flow at all well; and the forrnlll~ still l~Ui~l,S a disintegrant.
Dahl et al., Drug Devek pm~ont and TndU~tri~l Pharmacy 1990, 16 (12), 1881-1891,~les( ribes the prep~r~tion of solid capsule fnrrnl~ ionc us}ng a spray-on liquid drug carrier.
The model drug is dissolved in a non-volatile solvent, propylene c~ul,onate, and sprayed onto a co,llplessible sugar at a loading of around 0.01% by weight of drug to total solid, to give a final unit dose of 3511g- The solvent, being non-volatile, ~e.~ s in the blend. It is added at around 5% by weight of the total form~ tion; lower ratios of solvent to solid res~lltPfJ in declcascd ability to f~ ~1~tP- and dissolve. The r~snltin~, sol-lcnrllat sticky, powder showed some fliffi~ tiPs in ~ltom~t~Pd f n~Ar~s~ tion - -hinps~ and would be libely to give ci~ l;rlf ~nl p~oble,l-s in tablet~ing.
YaL~owski (IJS4,489,026) ~lesoribP~s a process which involves very slowly spraying a dilute solntion of drug in a volatile inert solvent, preferably an organic solvent having a boiling point lower than 80~C, onto excipient powder in an open coating pan; a CQ~L~ luus flow of air dries the product dunng the spraying process. This process was applied to drugs with a unit dose of lOug or less. The spray rate is limited to l-lOml/min, making the process suit~hle only for very small batch-sizes (the ey~mrle quoted p,epa-t;d 1000 tablets). The weight rado of sol~lti~ n to carrier used was 15%; also, the use of volatile organic liquids is now regarded as a cig~ if ~nt hazard, ~ g solvent-recovery processes and eYplocion-proof ey~ip .f ~lt, Katdare (US4,898,736) describes a cimplifi~d version of this process, sl1it~ble for unit doses of 50-lOOO~g; the drug, dissolved in an easily evaporated solvent such as r eth~nol, meth~nol, ~ceton~ or tetrahydrofuran, is simply blended with eY~ipiPntC in a ratio of 2.26% or 6.75% and then dried, followed by lubnc~tion and tabletting. This process is in pnnciple suitable for commPrcial sc~le m~nllf~ct~lre, but does still have the problems ;~c~coci~tto.d with the use of volatile organic solvents.
W O 97~47S0 PCTi~ 26 ~ rcorr1ing to the present invention there is provided a drug form~ tinn process ~
which co~np~ ;~s ~mi~in~ calIier particles with a solutio~ of drug in water in a yu~nlil)~ of 1-3% by weight of solntion to total mix.
The resulti~ ~ ~ may be form~Jl~t~l into s~lit~bl~ unit dose p~ t;on, for 5 ~ by t~ tting and optionally film coating the tablets or by en~ )sl~ti/~n It may be co"~,ci~ient to make the initial dlug/c~l~r mix with a higher drug con~eol~,3tinn, and then in a seps~r~t~ step b~n~lin~ that with further carrier, and this may be particularly useful where a range of tablet strengths is required. The sep~-~.t~ b~ n~ling step aids drying by the ~ tion effect, that is, the r~c;~ l water is distributed through a greater (lu~l~ty of carrier powder, and by the longer mixing time. The ~ ltio~ is co~ ielllly in the range 4/1 to 40/1 c~ie /Con~entr~t~ by weight, (1epenrling upon the p~ ;ng ch~,~ ;cs of the carrier. A con~,cment ~ ltion ratio for lactose monohydrate is 10/1.
Where the ~ilntion step is not employed, ~e sohlti-)n/mix weight ratio is more 1~ ~-rf~-nbly Up to 2% by weight.
The optimum quantity of soluti-~n will depend upon the abs~"l~nt qu~lities of the carIier par~icles, the so1uhility of the drug and the ch&~ ti, i.~l;rs of the mixing device, the ~u&l~liLy of sol-~tinn being chosen so as to allow even ~lictriblltion of drug while avoiding the need for a heatedl drying step.
The mixing step is preferably camed out in a high shear mi~er.
The carrier may be any snit~hlp sohlblP, directly c~...p.~c~ ph~nn~tUl;f~11y ~cept~hlP e~ciriçnt such as anhyd~ous lactose, lactose monol~ate, .nA.n.;l~l, or an inCol~lhlp directly compressible rh~ .uli~lly acceptable eYririPnt such as l~ic~ Li~]line cP-llnlo~e or ~iir~lrinm pht~s~h~t~p~ preferably a soluble excipient.
Any drug having a ~.r~ t degree of solubility in water may be fonn-ll~tPd by theprocess of Ithe invention. The con~ç~ ti~ ~ of drug in the solution is d~openrlPnt on the unit dose of dmg required, the upper limit being depPn~Pnt on the solubility of the drug.
Duling mixing, the carrier particles are evenly coated with a very thin film of drug solution. Some of the water naturally dries off during the mixing since there is no~n~lly a small airflow through the mixer; t-h-e r~m~ining amount is so low that drying is not specifi~lly required. If the tablets are film-coated, a degree of further drying may be obtained during the coating process.
The process of the invention has a number of adv~nt~,,es - - it does no~ require any milling of the drug subst~nf e 3~ - there is no need for a drying step. This simplifies proce~cing and reduces production costs; heat liabile drugs do not suffer at the te~ )elature required for drying; for drugs WO 97/04750 PC~r/~rrl~3~6 which are highly potent, the O..~iC ~ of the d~ying step makes it easier to contain dust,~
plO~i"g safety for the factory worker - ~e use of volatiie organic scll~e~ is avoided - there is no need to add a binder S - there is no need to add a dis,nt~g~ when the e~cipient is a highly soluble one.
Option~l additives in the final mix include a ~i~integr~nt; a range of acidic orljne excipients to i,~ ve; chpmir~l stability of the drug in the forrn~ tiorl such as sodium dihydrogen citrate, p~ hly inCl~ld~pd in the initial mix; a l~b~ nt such as m~--P~ii.---- ~t~ tP; and a glidant such as colloidal silica.
The present invention further provides a ph~rrn~=Gu~ composition co.nr,. ;.c;.
a drug fonn~ tPd in accc,~ nce with the p~ocess of the invention and the use of said composition as an active the~a~uLic subst~nce.
The invention ~ itiQn~ly proYides a ph~ ce~ composition comrri~in~ a drug, obt~in~hlP- by the process of the invention and the use of said composidon as an 1~ active thPr~ ti~ sl~bst~n~e The process of the invention is pardcularly useful for fom~ ting [R-(Z)]-a-(InPthoAyi~hlo)-a-(l-azabicyclo [2.2.2]oct-3-yl)~reto~iL ;lP monoh~uchlnride (compound X) vith acdve doses around 5-125 micro&r~mm~ (,ug). Compound X and m-o.tho l~ for its ~ ion are ~ osed in EP-A-0392803, WO95/31456 and WO93/17018. The col~po~ d enh~nces acetyl~h~ linP filnction via an action at n~-~sc~ k~ ,eceptols within the central nervous system, and is therefore of pGt~ use in the tre~tmPnt andlor ~ç~phylaxis of dem~onti~ in m~mm~
In particular the invention provides a ph~rm~eelltir~l composition comrnsing a ph~rm~reuti~lly acceptable carrier and compound X at a level of up to 0.1% by weight of drug to carrier, 0% volatile organic solvent and 0% binder.
EP-A-0392803 suggests the snit~le daily dose for compound X and other compounds disclosed therein as 0.01-~mgAcg. It has been surprisingly found through minictr~tiQ~ to human p~tiPnt~c that efficacy as a cognition enh~nc~er may be obtained at daily doses below 0.01mglkg more particularly 0.003mglkg and below, for example 0.0001-0.003mg/kg, such as 0.00035-0.003mglkg, 0.0007-0.003mglkg, 0.0001-0.0007mg/lcg or 0.00035-0.00~mglkg.
Accordingly the present invention provides a method of tre~tment and/or prophylaxis of d emer ti~ and more particularly a method of çnh~ncing cognition in a patient, which method comprices ~tlmini~tering to the patient compound X at a daily dose 3~ below 0.01mglkg, more preferably 0.003mglkg or less. The invention also relates to the use of compound X in the m~mlf~cture of a mP~iic~ment for the treatmPnt and/or prophylaxis of dementia at a daily dose below 0.01mgJkg, more preferably of W O 97/047~0 PCT/~ 31C
0.003mg~k;g or less. The invention further relates to a ph~rm:lt~ ;rAlco~roc;l;~n for-the tre~tment andlor ~lopl-ylaxis of dPm~Pnti~ which c~ .. ;-ces comrolm~l X at a unit dose s~lit~ble for ~-lmini.~tr~tion at a daily dose below O.Olmgll~g, more preferably of 0.003mglkg or less, and a rnhs~fm;l. e ~ y acceptable caTTier.
S Suitable unit doses to achieve such daily doses are 5, 12.5, 25, 50 or 75~1g, < t -~d twice daily and, in the case of 5011g, once daily. Such unit doses are c~lrlll~t~d on the basis of 50-70kg individuals. The ih~ LOIl e~te-n~1~ to the method, use or co,llposiLon d~P-finPc~ above wherein compound X is provided in such unit doses.
The invendon further provides a ph~nn~e~ltic~l composition comrricin~
comro~ln~ X of the invention and/or fonn~ t~Pd in accor~ance with the process of the invention, in unit dose form sel~Pcted from the range 5-12511g per unit dose, such as 5, 12.5, 25, 50 or 75~1g per unit dose and the use of said composition as an activethera~eufic s~b~t~nce, in par~cular in the tr~tm~n~ and/or prophylaxis of d~PmPnti~
EXt~MPLE
F~ ic~r~ of c~ v~ X
To make lOOkg of blend for t~ Pttin~ or enrApsul~tion, at lOOug drug per 150mg excipient - dissolve 67g drug in lliter of water (i.e. 1% of water (1.067% of sollltion) on a weight basis) - slowly add this to lOOkg of a "direct compres~ion" grade of lactose monohydrate in a high-shear mixer-gr~n~llAt~-r - blend with 0.25kg lubri~nt (M~ )esi.l.~. stp~ratp) and 0.15kg Glidant (C~olloid~
Silica) - tablet filmco~t (optional) To make lOOkg of blend for t~hl~tting or en~ s~lAtion~ at lOOug drug per 150mg e~ripi~nt by way of a conr~ntrAt~:
- dissolve 67g drug in 0.1 liter of water - slowly add this to 9.8kg of a "direct compression" grade of lactose monohydrate and 0.2kg of acidifying agent (Sodium Dihydrogen Citrate) in a high-shear mixer-grAn~ tc)r~ followed by a fur~her 0.1 liter of water to rinse the co~t~inlo.r.c used, while mixing vigorously with a chopper speed of around 1500rpm and then raising the speed to around 3000rpm, for 10-20 minut~s total mixing time (i.e. a total of 2% of water (2.67%
of solution) is added on a weight basis relative to the amount of concentr~te) , wo g7/047SO Pcr/~. sr~
-sieve the resnlting crll~r~ t~ into a tumble-blender - blend with 88kg further lactose and 1.8kg Sodium Dihydrogen Citrate, then blend in 0.15kg Glidant (r~o~ 1 Silica) and Q25kg l~lb~ nt ~gnP~ II St~ t~) - tablet S film~o.~t (optional) To make unit doses of 75, 50, 25, 12.5 and 511g in 150mg ~Yciri~nt~ the amount of drug used in the above m~thotls is 50, 33.6, 16.8, 8.4 and 3.3g l~s~e~;Liv~ly.
This i.~ ,nLion relates to a method of fonn~ tinE solid dosage forms of drugs and to solid dosage forms r~ red thereby"n particular solid dosage forms CQ~ g low 5 dose of drug The invention also relates to a mP.tho~l Of t~tmPnt and/or ~l~hyla~cis of ~ementi~ and unit dosage forms useful therein.
The usual ~hgllP.n~p. in m~nllf~et lnng solid dosage forms of very low-dose drugs, for e~n ple with active doses around 5-125 micro~mmP~ g) (for Pl~m~l~ 0.00~0.1%
by weight of drug to total solid), is to ensure h- mog~ p;ly. The l~.,,.l~n;r.~l problem is how 10 to distribute the drug ;,~ ,e evenly among the large amount of ~ pa-Licles.
The .c;...~l~sl way of ,,,A,,~r~ tablets is simply to blend all the inglGdi~i~ as dry pvvvd~ and tablet them ("direct co.~.pl~c.~ n"). This is rarely s~cce~rlll for low-dose drugs; a c5~mmon problem being segregation of the powder blend during t~b1pttin~- A
v~ tinn of this mP,thl)d which has been ~uccPs~r~J1 for low-dose drugs is known as 15 '~tntn~tionll~ and is somPtimP-s refçrred to as "ordered mixing" or '';..lr~ ;vt; mixing".
Ve~y fine p&lLicles of the drug are first mixed with a small portion of P~ipient; the pf~ u~
then mixed with a slighty larger poItion of excipient and so on until the desired rnix is oblAi~e~l This rnethnd relies on the fine drug par~icles aJ:1h~rin~ ele~ slS~ A11y to the Lrger ~ );rnt ones, thus p~ Ling se&l~~~l;on The method works with some drugs, 20 but ~vecP~ss~ ~epen~s on the surface pl.,pe,L;es of both drug and excipient7 and the method is very lahonous~ EP0503521 des~rihes the ~pp~ tion of this method to steroid~ drugs with high binding af~mity and low ~IP.I~ g potential for certain excipients.
A plt;r~; l ,d Alt~rn~tive m~thod for fotmt-l~tin~ low dose drugs is known as ''wet g~tn~l1Atinnn The drug is dissolved in water or another solvent, and blpn~pd with 2~ r~r.;l~;el~l.C i~ne~ g a binder, for PY~mpl~ povidone, to form a wet mass co~ .l-g 5-20%
by weight of sol~ltinn to total weight of gr~n~ tion mix, which is then dried off in a se~ lP- step. The binder causes particles of eY~ipip~t to clump together, and as the mass dnes these clumps ("gr~nl-lPs") either contain or are coated with the drug. This is err.,elive but c~mheMomP- since the drying step l~uilt;s special eqnirmpnt and ~PnPr~lly 30 involves high tPmper~tnr~PS which may degrade labile drugs. Also, the use of the binder requires the further inr~lu~io~ of a riwnt~Pgrant such as sodium starch glycolate or starch to help the tablet, which is cohesive, to ~ pPrsp~ in the stom~rh Fluid bed ~ nnl~tion has been used to achieve content uniformity of low dose g-lOmg) tablets (Thiel et al., J. Pharm. ph~rma~ol 1986, 38, 335-343). In this 3~ process, the micronised drug is blended as a powder with other excipients, then loaded into a fluid bed granlllator~ and the powders are agglomPr~t~Pd by spraying on a solution of a binder; drying takes place concomit~ntly. The process does not require a separate dIying CONFIRMATION COPY
W O 97/04750 PCT~EP9~03326 step. but it does require the use of .l.icf~nised drug, and also il~COl~u dt~,S a s_p~atc blending step prior to gr~n~ tion It also lL .luil-,s speri~licPd eq~;p..lP-~t and precise f~ ;on of the process pa~
Another process for fonn~ tinE low dose drugs is known as carrier ~mll~tifm (lUi~hfXl et aL, Pl,~. mr--~ul ;f ~1 Te~hnology June 1988, 66-84). This fnnrtionc by spraying a sol~ of binder such as povidone in water onto relatively large excipient particles such as hydl~lls lactose and then spraying small dry drug s.~b~ e particles onto that, thus coating the ~ f --l with drug p~Licles which are stuck on by the binder. The q~ iLy of so1lltinn used was 3.3-3.5% by weight of sohltion to total gr~nlll~tion mix. The method was applied to a formulation cont~ ;n~ ~5% drug by weight. This method also l~UilcS
drying; the drug particle size needs to be very small, which often requires an e~ctra milling step and the very hne drug powder may not flow at all well; and the forrnlll~ still l~Ui~l,S a disintegrant.
Dahl et al., Drug Devek pm~ont and TndU~tri~l Pharmacy 1990, 16 (12), 1881-1891,~les( ribes the prep~r~tion of solid capsule fnrrnl~ ionc us}ng a spray-on liquid drug carrier.
The model drug is dissolved in a non-volatile solvent, propylene c~ul,onate, and sprayed onto a co,llplessible sugar at a loading of around 0.01% by weight of drug to total solid, to give a final unit dose of 3511g- The solvent, being non-volatile, ~e.~ s in the blend. It is added at around 5% by weight of the total form~ tion; lower ratios of solvent to solid res~lltPfJ in declcascd ability to f~ ~1~tP- and dissolve. The r~snltin~, sol-lcnrllat sticky, powder showed some fliffi~ tiPs in ~ltom~t~Pd f n~Ar~s~ tion - -hinps~ and would be libely to give ci~ l;rlf ~nl p~oble,l-s in tablet~ing.
YaL~owski (IJS4,489,026) ~lesoribP~s a process which involves very slowly spraying a dilute solntion of drug in a volatile inert solvent, preferably an organic solvent having a boiling point lower than 80~C, onto excipient powder in an open coating pan; a CQ~L~ luus flow of air dries the product dunng the spraying process. This process was applied to drugs with a unit dose of lOug or less. The spray rate is limited to l-lOml/min, making the process suit~hle only for very small batch-sizes (the ey~mrle quoted p,epa-t;d 1000 tablets). The weight rado of sol~lti~ n to carrier used was 15%; also, the use of volatile organic liquids is now regarded as a cig~ if ~nt hazard, ~ g solvent-recovery processes and eYplocion-proof ey~ip .f ~lt, Katdare (US4,898,736) describes a cimplifi~d version of this process, sl1it~ble for unit doses of 50-lOOO~g; the drug, dissolved in an easily evaporated solvent such as r eth~nol, meth~nol, ~ceton~ or tetrahydrofuran, is simply blended with eY~ipiPntC in a ratio of 2.26% or 6.75% and then dried, followed by lubnc~tion and tabletting. This process is in pnnciple suitable for commPrcial sc~le m~nllf~ct~lre, but does still have the problems ;~c~coci~tto.d with the use of volatile organic solvents.
W O 97~47S0 PCTi~ 26 ~ rcorr1ing to the present invention there is provided a drug form~ tinn process ~
which co~np~ ;~s ~mi~in~ calIier particles with a solutio~ of drug in water in a yu~nlil)~ of 1-3% by weight of solntion to total mix.
The resulti~ ~ ~ may be form~Jl~t~l into s~lit~bl~ unit dose p~ t;on, for 5 ~ by t~ tting and optionally film coating the tablets or by en~ )sl~ti/~n It may be co"~,ci~ient to make the initial dlug/c~l~r mix with a higher drug con~eol~,3tinn, and then in a seps~r~t~ step b~n~lin~ that with further carrier, and this may be particularly useful where a range of tablet strengths is required. The sep~-~.t~ b~ n~ling step aids drying by the ~ tion effect, that is, the r~c;~ l water is distributed through a greater (lu~l~ty of carrier powder, and by the longer mixing time. The ~ ltio~ is co~ ielllly in the range 4/1 to 40/1 c~ie /Con~entr~t~ by weight, (1epenrling upon the p~ ;ng ch~,~ ;cs of the carrier. A con~,cment ~ ltion ratio for lactose monohydrate is 10/1.
Where the ~ilntion step is not employed, ~e sohlti-)n/mix weight ratio is more 1~ ~-rf~-nbly Up to 2% by weight.
The optimum quantity of soluti-~n will depend upon the abs~"l~nt qu~lities of the carIier par~icles, the so1uhility of the drug and the ch&~ ti, i.~l;rs of the mixing device, the ~u&l~liLy of sol-~tinn being chosen so as to allow even ~lictriblltion of drug while avoiding the need for a heatedl drying step.
The mixing step is preferably camed out in a high shear mi~er.
The carrier may be any snit~hlp sohlblP, directly c~...p.~c~ ph~nn~tUl;f~11y ~cept~hlP e~ciriçnt such as anhyd~ous lactose, lactose monol~ate, .nA.n.;l~l, or an inCol~lhlp directly compressible rh~ .uli~lly acceptable eYririPnt such as l~ic~ Li~]line cP-llnlo~e or ~iir~lrinm pht~s~h~t~p~ preferably a soluble excipient.
Any drug having a ~.r~ t degree of solubility in water may be fonn-ll~tPd by theprocess of Ithe invention. The con~ç~ ti~ ~ of drug in the solution is d~openrlPnt on the unit dose of dmg required, the upper limit being depPn~Pnt on the solubility of the drug.
Duling mixing, the carrier particles are evenly coated with a very thin film of drug solution. Some of the water naturally dries off during the mixing since there is no~n~lly a small airflow through the mixer; t-h-e r~m~ining amount is so low that drying is not specifi~lly required. If the tablets are film-coated, a degree of further drying may be obtained during the coating process.
The process of the invention has a number of adv~nt~,,es - - it does no~ require any milling of the drug subst~nf e 3~ - there is no need for a drying step. This simplifies proce~cing and reduces production costs; heat liabile drugs do not suffer at the te~ )elature required for drying; for drugs WO 97/04750 PC~r/~rrl~3~6 which are highly potent, the O..~iC ~ of the d~ying step makes it easier to contain dust,~
plO~i"g safety for the factory worker - ~e use of volatiie organic scll~e~ is avoided - there is no need to add a binder S - there is no need to add a dis,nt~g~ when the e~cipient is a highly soluble one.
Option~l additives in the final mix include a ~i~integr~nt; a range of acidic orljne excipients to i,~ ve; chpmir~l stability of the drug in the forrn~ tiorl such as sodium dihydrogen citrate, p~ hly inCl~ld~pd in the initial mix; a l~b~ nt such as m~--P~ii.---- ~t~ tP; and a glidant such as colloidal silica.
The present invention further provides a ph~rrn~=Gu~ composition co.nr,. ;.c;.
a drug fonn~ tPd in accc,~ nce with the p~ocess of the invention and the use of said composition as an active the~a~uLic subst~nce.
The invention ~ itiQn~ly proYides a ph~ ce~ composition comrri~in~ a drug, obt~in~hlP- by the process of the invention and the use of said composidon as an 1~ active thPr~ ti~ sl~bst~n~e The process of the invention is pardcularly useful for fom~ ting [R-(Z)]-a-(InPthoAyi~hlo)-a-(l-azabicyclo [2.2.2]oct-3-yl)~reto~iL ;lP monoh~uchlnride (compound X) vith acdve doses around 5-125 micro&r~mm~ (,ug). Compound X and m-o.tho l~ for its ~ ion are ~ osed in EP-A-0392803, WO95/31456 and WO93/17018. The col~po~ d enh~nces acetyl~h~ linP filnction via an action at n~-~sc~ k~ ,eceptols within the central nervous system, and is therefore of pGt~ use in the tre~tmPnt andlor ~ç~phylaxis of dem~onti~ in m~mm~
In particular the invention provides a ph~rm~eelltir~l composition comrnsing a ph~rm~reuti~lly acceptable carrier and compound X at a level of up to 0.1% by weight of drug to carrier, 0% volatile organic solvent and 0% binder.
EP-A-0392803 suggests the snit~le daily dose for compound X and other compounds disclosed therein as 0.01-~mgAcg. It has been surprisingly found through minictr~tiQ~ to human p~tiPnt~c that efficacy as a cognition enh~nc~er may be obtained at daily doses below 0.01mglkg more particularly 0.003mglkg and below, for example 0.0001-0.003mg/kg, such as 0.00035-0.003mglkg, 0.0007-0.003mglkg, 0.0001-0.0007mg/lcg or 0.00035-0.00~mglkg.
Accordingly the present invention provides a method of tre~tment and/or prophylaxis of d emer ti~ and more particularly a method of çnh~ncing cognition in a patient, which method comprices ~tlmini~tering to the patient compound X at a daily dose 3~ below 0.01mglkg, more preferably 0.003mglkg or less. The invention also relates to the use of compound X in the m~mlf~cture of a mP~iic~ment for the treatmPnt and/or prophylaxis of dementia at a daily dose below 0.01mgJkg, more preferably of W O 97/047~0 PCT/~ 31C
0.003mg~k;g or less. The invention further relates to a ph~rm:lt~ ;rAlco~roc;l;~n for-the tre~tment andlor ~lopl-ylaxis of dPm~Pnti~ which c~ .. ;-ces comrolm~l X at a unit dose s~lit~ble for ~-lmini.~tr~tion at a daily dose below O.Olmgll~g, more preferably of 0.003mglkg or less, and a rnhs~fm;l. e ~ y acceptable caTTier.
S Suitable unit doses to achieve such daily doses are 5, 12.5, 25, 50 or 75~1g, < t -~d twice daily and, in the case of 5011g, once daily. Such unit doses are c~lrlll~t~d on the basis of 50-70kg individuals. The ih~ LOIl e~te-n~1~ to the method, use or co,llposiLon d~P-finPc~ above wherein compound X is provided in such unit doses.
The invendon further provides a ph~nn~e~ltic~l composition comrricin~
comro~ln~ X of the invention and/or fonn~ t~Pd in accor~ance with the process of the invention, in unit dose form sel~Pcted from the range 5-12511g per unit dose, such as 5, 12.5, 25, 50 or 75~1g per unit dose and the use of said composition as an activethera~eufic s~b~t~nce, in par~cular in the tr~tm~n~ and/or prophylaxis of d~PmPnti~
EXt~MPLE
F~ ic~r~ of c~ v~ X
To make lOOkg of blend for t~ Pttin~ or enrApsul~tion, at lOOug drug per 150mg excipient - dissolve 67g drug in lliter of water (i.e. 1% of water (1.067% of sollltion) on a weight basis) - slowly add this to lOOkg of a "direct compres~ion" grade of lactose monohydrate in a high-shear mixer-gr~n~llAt~-r - blend with 0.25kg lubri~nt (M~ )esi.l.~. stp~ratp) and 0.15kg Glidant (C~olloid~
Silica) - tablet filmco~t (optional) To make lOOkg of blend for t~hl~tting or en~ s~lAtion~ at lOOug drug per 150mg e~ripi~nt by way of a conr~ntrAt~:
- dissolve 67g drug in 0.1 liter of water - slowly add this to 9.8kg of a "direct compression" grade of lactose monohydrate and 0.2kg of acidifying agent (Sodium Dihydrogen Citrate) in a high-shear mixer-grAn~ tc)r~ followed by a fur~her 0.1 liter of water to rinse the co~t~inlo.r.c used, while mixing vigorously with a chopper speed of around 1500rpm and then raising the speed to around 3000rpm, for 10-20 minut~s total mixing time (i.e. a total of 2% of water (2.67%
of solution) is added on a weight basis relative to the amount of concentr~te) , wo g7/047SO Pcr/~. sr~
-sieve the resnlting crll~r~ t~ into a tumble-blender - blend with 88kg further lactose and 1.8kg Sodium Dihydrogen Citrate, then blend in 0.15kg Glidant (r~o~ 1 Silica) and Q25kg l~lb~ nt ~gnP~ II St~ t~) - tablet S film~o.~t (optional) To make unit doses of 75, 50, 25, 12.5 and 511g in 150mg ~Yciri~nt~ the amount of drug used in the above m~thotls is 50, 33.6, 16.8, 8.4 and 3.3g l~s~e~;Liv~ly.
Claims
1. A drug formulation process which comprises admixing carrier particles with a solution of drug in water in a quantity of 1-3% by weight of solution to total mix.
2. A process according to claim 1 wherein the carrier is a soluble or an insoluble directly compressible pharmaceutically acceptable excipient.
3. A process according to claim 2 wherein the carrier is a soluble excipient selected from anhydrous lactose, lactose monohydrate and mannitol.
4. A process according to claim 3 wherein the mixture further comprises an acidic or alkaline excipient to improve chemical stability of the drug in the formulation.5. A process according to any preceding claim which further comprises blending the mixture with further carrier and/or one or more additives selected from a disintegrant; an acidic or alkaline excipient to improve chemical stability of the drug in the formulation, a lubricant and a glidant 6. A process according to claim 5 wherein the mix is blended with further carrier in a weight ratio of 1/4 to 1/40.
7. A process according to any preceding claim wherein the mixture is formulated into a unit dose presentation.
8. A process according to any preceding claim for formulating [R-(Z)]-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydrochloride.
9. A pharmaceutical composition comprising a drug, obtainable by the process of any preceding claim.
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and [R-(Z)]-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydrochloride at a level of up to 0.1% by weight of drug to carrier, 0% volatile organic solvent and 0% binder.
11. A composition according to claim 10 wherein the carrier is a soluble or an insoluble directly compressible pharmaceutically acceptable excipient.
12. A composition according to claim 11 wherein the carrier is a soluble excipient selected from anhydrous lactose, lactose monohydrate and mannitol.
13. A composition according to any of claims 10 to 12 which also comprises one or more additives selected from a disintegrant; an acidic excipient to improve chemical stability of the drug in the formulation, a lubricant and a glidant 14. A composition according to claim 13 which comprises lactose monohydrate, sodium dihydrogen citrate, colloidal silica and magnesium stearate.
15. A composition according to any of claims 10 to 14 formulated into a unit dose presentation.
16. A method of treatment and/or prophylaxis of dementia, which method comprisesadministering to the patient [R-(Z)]-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydlochloride at a daily dose below 0.01mg/kg.
17. The use of [R-(Z)]-.alpha.-(methoyimino)-.alpha.-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydrochloride in the manufacture of a medicament for the treatment and/or prophylaxis of dementia at a daily dose below 0.01mg/kg.
18. A pharmaceutical composition for the treatment and/or prophylaxis of dementia which comprises [R-(z)]-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydrochloride at a unit dose suitable for administration at a daily dose below 0.01mg/kg, and a pharmaceutically acceptable carrier.
19. A method, use or composition according to claim 16, 17 or 18 wherein the daily dose is 0.003mg/kg or less.
20. A method, use or composition according to claim 19 wherein the daily dose is0.0001-0.003mg/kg.
21. A method, use or composition according to claim 20 wherein the daily dose is0.00035-0.003mg/kg.
22. A method, use or composition according to claim 20 wherein the daily dose is0.0007-0.003mg/kg.
23. A method, use or composition according to claim 20 wherein the daily dose is0.0001-0.0007mg/kg.
24. A method, use or composition according to claim 20 wherein the daily dose is0.00035-0.002mg/kg.
25. A method, use or composition according to claim 16, 17 or 18 wherein the compound is presented in a unit dose of 5, 12.5, 25,50 or 75µg, administered twice daily or, in the case of 50µg, once daily.
26. A pharmaceutical composition according to claim 9 as dependent on claim 8 oraccording to any of claims 10 to 15, in unit dose form selected from the range 5-125µg per unit dose.
27. A pharmaceutical composition according to claim 26 comprising 5, 12.5,25, 50 or 75µg per unit dose 28. A pharmaceutical composition according to claim 9, according to any of claims 10 to 15 or according to claim 26 or 27 for use as an active therapeutic substance.
29. A pharmaceutical composition according to claim 9 as dependent on claim 8, according to any of claims 10 to 15 or according to claim 26 or 27 for use in the treatment and/or prophylaxis of dementia.
30. A method of treatment and/or prophylaxis of dementia, which method comprisesadministering to the patient an effective amount of a composition according to claim 29.
31. Use of a pharmaceutical composition according to claim 29 in the manufacture of a medicament for the treatment and/or prophylaxis of dementia.
2. A process according to claim 1 wherein the carrier is a soluble or an insoluble directly compressible pharmaceutically acceptable excipient.
3. A process according to claim 2 wherein the carrier is a soluble excipient selected from anhydrous lactose, lactose monohydrate and mannitol.
4. A process according to claim 3 wherein the mixture further comprises an acidic or alkaline excipient to improve chemical stability of the drug in the formulation.5. A process according to any preceding claim which further comprises blending the mixture with further carrier and/or one or more additives selected from a disintegrant; an acidic or alkaline excipient to improve chemical stability of the drug in the formulation, a lubricant and a glidant 6. A process according to claim 5 wherein the mix is blended with further carrier in a weight ratio of 1/4 to 1/40.
7. A process according to any preceding claim wherein the mixture is formulated into a unit dose presentation.
8. A process according to any preceding claim for formulating [R-(Z)]-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydrochloride.
9. A pharmaceutical composition comprising a drug, obtainable by the process of any preceding claim.
10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and [R-(Z)]-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydrochloride at a level of up to 0.1% by weight of drug to carrier, 0% volatile organic solvent and 0% binder.
11. A composition according to claim 10 wherein the carrier is a soluble or an insoluble directly compressible pharmaceutically acceptable excipient.
12. A composition according to claim 11 wherein the carrier is a soluble excipient selected from anhydrous lactose, lactose monohydrate and mannitol.
13. A composition according to any of claims 10 to 12 which also comprises one or more additives selected from a disintegrant; an acidic excipient to improve chemical stability of the drug in the formulation, a lubricant and a glidant 14. A composition according to claim 13 which comprises lactose monohydrate, sodium dihydrogen citrate, colloidal silica and magnesium stearate.
15. A composition according to any of claims 10 to 14 formulated into a unit dose presentation.
16. A method of treatment and/or prophylaxis of dementia, which method comprisesadministering to the patient [R-(Z)]-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydlochloride at a daily dose below 0.01mg/kg.
17. The use of [R-(Z)]-.alpha.-(methoyimino)-.alpha.-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydrochloride in the manufacture of a medicament for the treatment and/or prophylaxis of dementia at a daily dose below 0.01mg/kg.
18. A pharmaceutical composition for the treatment and/or prophylaxis of dementia which comprises [R-(z)]-.alpha.-(methoxyimino)-.alpha.-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrile monohydrochloride at a unit dose suitable for administration at a daily dose below 0.01mg/kg, and a pharmaceutically acceptable carrier.
19. A method, use or composition according to claim 16, 17 or 18 wherein the daily dose is 0.003mg/kg or less.
20. A method, use or composition according to claim 19 wherein the daily dose is0.0001-0.003mg/kg.
21. A method, use or composition according to claim 20 wherein the daily dose is0.00035-0.003mg/kg.
22. A method, use or composition according to claim 20 wherein the daily dose is0.0007-0.003mg/kg.
23. A method, use or composition according to claim 20 wherein the daily dose is0.0001-0.0007mg/kg.
24. A method, use or composition according to claim 20 wherein the daily dose is0.00035-0.002mg/kg.
25. A method, use or composition according to claim 16, 17 or 18 wherein the compound is presented in a unit dose of 5, 12.5, 25,50 or 75µg, administered twice daily or, in the case of 50µg, once daily.
26. A pharmaceutical composition according to claim 9 as dependent on claim 8 oraccording to any of claims 10 to 15, in unit dose form selected from the range 5-125µg per unit dose.
27. A pharmaceutical composition according to claim 26 comprising 5, 12.5,25, 50 or 75µg per unit dose 28. A pharmaceutical composition according to claim 9, according to any of claims 10 to 15 or according to claim 26 or 27 for use as an active therapeutic substance.
29. A pharmaceutical composition according to claim 9 as dependent on claim 8, according to any of claims 10 to 15 or according to claim 26 or 27 for use in the treatment and/or prophylaxis of dementia.
30. A method of treatment and/or prophylaxis of dementia, which method comprisesadministering to the patient an effective amount of a composition according to claim 29.
31. Use of a pharmaceutical composition according to claim 29 in the manufacture of a medicament for the treatment and/or prophylaxis of dementia.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9515624.6A GB9515624D0 (en) | 1995-07-29 | 1995-07-29 | Novel process |
| GB9515624.6 | 1995-07-29 | ||
| GBGB9606684.0A GB9606684D0 (en) | 1996-03-29 | 1996-03-29 | Novel process |
| GB9606684.0 | 1996-03-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2228048A1 true CA2228048A1 (en) | 1997-02-13 |
Family
ID=26307485
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002228048A Abandoned CA2228048A1 (en) | 1995-07-29 | 1996-07-29 | Process for preparing solid dosage forms of very low-dose drugs |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP0841902A2 (en) |
| JP (1) | JPH11510493A (en) |
| KR (1) | KR19990035972A (en) |
| CN (1) | CN1196677A (en) |
| AP (1) | AP858A (en) |
| AR (1) | AR004178A1 (en) |
| AU (1) | AU716961B2 (en) |
| BG (1) | BG102266A (en) |
| BR (1) | BR9609804A (en) |
| CA (1) | CA2228048A1 (en) |
| CZ (1) | CZ24798A3 (en) |
| DZ (1) | DZ2077A1 (en) |
| EA (2) | EA000740B1 (en) |
| HU (1) | HUP9900521A3 (en) |
| IL (1) | IL122897A0 (en) |
| MA (1) | MA23953A1 (en) |
| MX (1) | MX9800809A (en) |
| NO (1) | NO980384L (en) |
| NZ (1) | NZ315632A (en) |
| OA (1) | OA10659A (en) |
| PL (1) | PL325242A1 (en) |
| SK (1) | SK11098A3 (en) |
| TR (1) | TR199800156T1 (en) |
| UY (1) | UY24297A1 (en) |
| WO (1) | WO1997004750A2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9619074D0 (en) * | 1996-09-12 | 1996-10-23 | Smithkline Beecham Plc | Composition |
| WO1999045924A1 (en) | 1998-03-11 | 1999-09-16 | Smithkline Beecham Plc | Composition |
| FR2796840B1 (en) * | 1999-07-26 | 2003-06-20 | Ethypharm Lab Prod Ethiques | LOW-DOSE TABLETS AND METHOD OF PREPARATION |
| DE60114467T2 (en) | 2000-12-14 | 2006-07-20 | Ortho-Mcneil Pharmaceutical, Inc. | PREPARATIONS CONTAINS A STEROID HORMONE AND A STABILIZER OF NON-CRYSTALLINE FORM |
| JP2007532511A (en) * | 2004-04-09 | 2007-11-15 | スミスクライン ビーチャム コーポレーション | Low dose medicine |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4489026A (en) * | 1982-09-07 | 1984-12-18 | The Upjohn Company | Process for preparing solid unit dosage forms of ultra-low dose drugs |
| JPS5970614A (en) * | 1982-10-14 | 1984-04-21 | Asahi Chem Ind Co Ltd | Wet solid pharmaceutical preparation of very small amount of main drug |
| US4898736A (en) * | 1988-03-09 | 1990-02-06 | Merck & Co., Inc. | Method for tablet preparation |
| ATE269330T1 (en) * | 1989-04-13 | 2004-07-15 | Beecham Group Plc | CHEMICAL COMPOUNDS |
| ZA939565B (en) * | 1993-12-21 | 1994-08-11 | Applied Analytical Ind Inc | Method for preparing low dose pharmaceutical products. |
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1996
- 1996-07-25 AR ARP960103748A patent/AR004178A1/en not_active Application Discontinuation
- 1996-07-26 UY UY24297A patent/UY24297A1/en not_active IP Right Cessation
- 1996-07-26 MA MA24329A patent/MA23953A1/en unknown
- 1996-07-27 DZ DZ960121A patent/DZ2077A1/en active
- 1996-07-29 CN CN96197054A patent/CN1196677A/en active Pending
- 1996-07-29 KR KR1019980700633A patent/KR19990035972A/en not_active Application Discontinuation
- 1996-07-29 EP EP96927621A patent/EP0841902A2/en not_active Withdrawn
- 1996-07-29 CA CA002228048A patent/CA2228048A1/en not_active Abandoned
- 1996-07-29 HU HU9900521A patent/HUP9900521A3/en unknown
- 1996-07-29 EA EA199800179A patent/EA000740B1/en not_active IP Right Cessation
- 1996-07-29 IL IL12289796A patent/IL122897A0/en unknown
- 1996-07-29 JP JP9507243A patent/JPH11510493A/en active Pending
- 1996-07-29 WO PCT/EP1996/003326 patent/WO1997004750A2/en not_active Application Discontinuation
- 1996-07-29 AP APAP/P/1998/001170A patent/AP858A/en active
- 1996-07-29 TR TR1998/00156T patent/TR199800156T1/en unknown
- 1996-07-29 PL PL96325242A patent/PL325242A1/en unknown
- 1996-07-29 SK SK110-98A patent/SK11098A3/en unknown
- 1996-07-29 AU AU67384/96A patent/AU716961B2/en not_active Ceased
- 1996-07-29 CZ CZ98247A patent/CZ24798A3/en unknown
- 1996-07-29 NZ NZ315632A patent/NZ315632A/en unknown
- 1996-07-29 BR BR9609804A patent/BR9609804A/en not_active Application Discontinuation
- 1996-07-29 EA EA199901055A patent/EA199901055A1/en unknown
- 1996-07-29 MX MX9800809A patent/MX9800809A/en unknown
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1998
- 1998-01-28 NO NO980384A patent/NO980384L/en unknown
- 1998-01-28 OA OA9800013A patent/OA10659A/en unknown
- 1998-02-20 BG BG102266A patent/BG102266A/en unknown
Also Published As
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| AP9801170A0 (en) | 1998-01-31 |
| MA23953A1 (en) | 1997-04-01 |
| NZ315632A (en) | 1999-11-29 |
| EP0841902A2 (en) | 1998-05-20 |
| UY24297A1 (en) | 1997-01-23 |
| CN1196677A (en) | 1998-10-21 |
| AU6738496A (en) | 1997-02-26 |
| EA199800179A1 (en) | 1998-10-29 |
| NO980384L (en) | 1998-03-26 |
| BG102266A (en) | 1998-10-30 |
| SK11098A3 (en) | 1998-07-08 |
| TR199800156T1 (en) | 1998-04-21 |
| MX9800809A (en) | 1998-04-30 |
| EA199901055A1 (en) | 2000-06-26 |
| IL122897A0 (en) | 1998-08-16 |
| PL325242A1 (en) | 1998-07-06 |
| WO1997004750A3 (en) | 1997-03-27 |
| AU716961B2 (en) | 2000-03-09 |
| AR004178A1 (en) | 1998-11-04 |
| JPH11510493A (en) | 1999-09-14 |
| BR9609804A (en) | 1999-07-06 |
| AP858A (en) | 2000-07-12 |
| KR19990035972A (en) | 1999-05-25 |
| EA000740B1 (en) | 2000-02-28 |
| CZ24798A3 (en) | 1998-06-17 |
| WO1997004750A2 (en) | 1997-02-13 |
| NO980384D0 (en) | 1998-01-28 |
| OA10659A (en) | 2002-09-18 |
| HUP9900521A2 (en) | 1999-06-28 |
| DZ2077A1 (en) | 2002-07-22 |
| HUP9900521A3 (en) | 2001-04-28 |
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