Note: Descriptions are shown in the official language in which they were submitted.
CA 02228048 1998-01-28
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
- 1 -
CONFIRMATION COPY
CA 02228048 1998-01-28
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.
- 2 -
CA 02228048 1998-01-28
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
CA 02228048 1998-01-28
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
CA 02228048 1998-01-28
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)
,
CA 02228048 1998-01-28
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.
