Note: Descriptions are shown in the official language in which they were submitted.
WO 95132737 PCT/GB9~/01152
.
21 9~598
.,
~HARMACEUTICAL COMPOSITION
BACKGROIJND OF THE INVENTION
lbis invention relates to a method of making a ~ mrcl~AitiAln
comprising an inelusion complex of a ~-~y~,loL,.~I;/., or a LI~ y
aeeeptable derivative of a ~-cy~,lod~ and a sparingly water-soluble non-
steroidal anti-;l n~ y drug (NSAID), and to a ~
mr~ A'n eomprisimg an inelusion eomple~ of a ~-cy-~lod~,AL il- or a
derivative thereof and a sparingly water-soluble NSAID, in solid form whieh
is adapted to be dissolved in water to provide a elear or siightly opaque
solution for oral A.l...;.,;~llAI;....
Non-steroidal anti~ y drugs (NSAID's) are generally praetically
insoluble in water. The low solubility impedes the dissolution rate of the
drug in the ~_aLIuillt~ traet, resulting in slow absorption. ~ ..lly,
for most NSAlD's, peak plasma levels are usually reaehed only after one to
several kours after oral All,.,;.l~ depending on the solubility of the
drug. NSAlD's commonly formulated as tablets therefore suffer from two
dia~lv~ . (i) delayed onset of therapeutic action and (ii) local irritation
of the ~;_ L~U;IIt~ l mucosa due to prolonged localised contact of the drug
with the mucosa.
WO 95/32737 PCTIGB95/01152
21 90598
- 2 -
Attempts to solubilise NSAlD's via salt formation have been reported,
resulting in an improved absorption rate (see Reference 1). Several reports
have appeared on nomrl~ Y~ti~n of NSAlD's with cyclod~AL~ a in which the
complexes show significantly improved aqueous dissolution ..1,~ r~
(see References 2, ~, 4, 5, 6, 7). Apart from r~ of water
solubility, uy~lod~ALIhl fl 1~ has also been shown to increase the
rate and extent of NSAID adsorption after oral ~,1,.,;,1,~l.,,l,,,,l (see
References 2, 8). A further advantage of uy~,lOd~A~ omrl~Y~tinn is a
reduction in the UI~ LU~ Y commonly associated with orally au~ c~r :l
NSAlD's (see Reference 9).
Cyclodextrin inclusion complexes may be prepared on the basis of liquidstate, solid state or semi-solid state reaction between the Cu~u~Ju~ L~ (see
Reference 10). The first is ~f~"",~ l,rri by dissolving the cyclodextrin and
NSAID in a suitable solvent and ~ lly isolating the solid state
complex by crystallisation, ~vflJU.~lLiul~, spray drying or freeze drying. In
the solid state method, the two ~ may be optionally screened to
uniform particle size and thoroughly mixed whereafter they are ground in a
high energy mill with optional heating, screened and 1..""..~,~.,;,..1 (see
South African Patent No. 91/2282). In the semi-solid state, the two
..,.,1,.~,.,...1~ are Ifneaded in tne presence of small amounts of a suitable
solvent, and the complex so-formed, is oven dried, screened and
l,.""n", .1;~ d (see Reference 11).
In terms of ~ of the inclusion rnmrl~Y~tinn reaction, the particle
size and the water solubility of the final product, the freeze-drying and spray
drying methods represent the best methods of inclusion ~ l;fl.,
(Reference 10). lllese methods however are ~r~mnmi~-~lly ul~flLL~.Liv~ from
WO gs/32737 ~ ,S/01152
21 90598
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.
an industrial perspective. Owing to the ~ y~lCu~llclll;~dl nature of NSAlD's
it was found that the industrially simple and rrcmnmir~,lly attractive
kneading method provided a convenient process for the preparation of
NSAID-cyclodextrin complexes with the desired wa~er solubility
As stated above, various ~ l compositions containing inclusion
compounds or complexes of a iyulod~,ALill and a drug are known.
South African Patent No. 84/10042 to Janssen Pl IA~ 11 IA. I ~ I j ;l ~ N.V discloses
a ~ 1 composition comprising an inclusion compound of an
unstdble or sparingly water-soluble drug and a partially etherified ~3-
cyclodextrin of the formula
(j3 - CD) OR
in which the residues are hydroxyalkyl groups and in which part of the
residues R may optionally be alkyl groups, the ji3-~,lod~AI;ll ether having
a water-solubility of more than 1,8g in 100ml of water. The drug may be
a non-steroidal arlti-rheumatic agent. The partially etherified ~-~y~ dcAlfi~
is preferably lIYd1UA~LIIYI or lI~dIUAY~UIU~UYI ~-cyclodextrin
The inclusion compound is prepared by dissolving the partially etherified ~-
~:y~.lOd~ALlill in water and adding the drug. The ~ CnllllJUi~;liUII
may be formulated for oral :llllll;ll;~llrll;~lll
PCT WO/90/02141 to ~ustralian Commercial Research and D~lu~ t
Limited teaches inclusion complexes comprising amino ~yclodcAI;
derivatives in which at least one C2, C3 or C6 hydroxyl is substituted with -
NH" and a 11ll'.. IIIA. . .1l ;1 iilly active agent such as, fûr example, certain non-
steroidal anti-i"n~""~t~y drugs, e.g. in~lr~m~th~rin tolmetin, naproxen,
.
wo ss/32~37 ~ .ss5.~ 52
21 90598
- 4 -
ketoprofen and the like.
The complex is formed by forming a solution of the cyclodextrin in water
or other solYent, which solution is added to a solution of the drug in a
solvent, and thereafte} removing the solvent. The inclusion complex may be
formulated for oral A, l,,, ;,,; ~ ;""
European Patent Application No. 519 428 to Takeda Chemical Industries
teaches a ~ ;nAl romrncitinn comprising a slightly water-soluble
drug, a U~IOd~ALI;1I arld a water-soluble organic solvent in an amount of 071
to 10 percent by weight. The ~ , is prepared in powdered form and
is suitable for injection.
South African Patent No. 84/81 i6 to Chicsi rA.~ ;. i S.p.A. teaches
CU~ u~l~b obtained by 1.".,l.1 I;n" of piroxicam with a-~- or -type
~;y~ In~ in ratios comprised between 1:1 and 1:10 of piroxicam and
:y~,lOdl,AL ill~ ,L;~'y The complex may be formulated for oral
in the form of capsules, tablets, bags, syrups, solutions and
the like, including r rr.. ~ L tablets.
South African Patent No. 91/F~8~ to Chiesi FArrnAr~lltiri S.p.A. teaches a
process for preparing piroxicam-~_y.,lod~ALI;Il complexes wherein the
piroxicam and the cyclodextrin both in powder form are mixed together in
a solid state and optionally degassed; the mixture is co-ground in a high
energy mill with the grinding chamber saturated with steam; the product
obtained is dried under vacuum and screened to eliminate any a gregates.
Again the complex~roduced by this process may be formulated for oral
A,i.,,;" ~l,AI;nn for example in the form of tablets which have a much higher
W0 95/32737 r ~ . v 1152
21 9Q~98
.,
dissolution rate than commercial f~" " ",IAI If ~ containing piroxicam alone.
~Ithough many types of inclusion complexes of a ~:y~,lod~ and a non-
steroidal anti-;~ l y drug are known, there is always the need for a
new type of complex or l,ll~.lll~r~ ,.l ff~mroSitif~n containing such a
complex and a method for the production of such
SUMMA~Y OF THE IN-VENTION
According to a first aspect of the invention, tnere is provided a method of
making a ~ ".~ ;f", comprising as an actiYe ingredient an
inclusion complex of a ~ ,lod~.ALill or a 1,1,- ,.,=- . .,1;. ~lly acceptable
derivative of a ~ "v~lod~A~ . and a sparingly water-soluble non-steroidal
anti- '' y drug, the c"",l,.~ ;.... beirlg in solid form which is
adapted to be dissolved in water to provide a clear or slightly opaque
solution for orai ~1llll;ll~;l, ~;~l.l, which method includes the steps of:
(a) for~ning a paste from the ,i-cyclodextrin or the derivative thereof and the NSAID, with a wetting solution;
(b) mixing the paste with addition of further wetting solution if
necessary; and
(c) drying the product of step (b) to produce the inclusion complex
which dissolves in water to provide a clear or slightly opaque
solution.
W095132737 P~ 1152
2 1 90598
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. .
According to a seeond aspect of the invention, there is provided a
l)I,_.,.,~r, .lli. ,.1 n nmrncitinn produeed by the method described above.
ccording to a third aspect of the invention, there is provided a
o~ l comprising as an active ingredient an inclusion
complex of a !3-cyclodextrin or a 1)~ "~ ly acceptable derivative of
a ~ y.lo~ ,l.i.. and a sparingly water-soluble NSAID, the ~J~ o~iLiu~-
being in solid form which is adapted to be dissolved in wa~er to provide a
clear or slightly opaque solution for oral ;~,I",;";~I,r~;nn
Whenever any reference is made to a drug, there is meant the drug as well
as its 1.1,- ,~,,,.~,llir~ly acceptable salts
The l,I,,~ l rnmrncitinn in solid form may be in the foFm of a
powder, granule, tablet or saehet.
Examples of suitable ,~ yclo~l~AL il-~ or derivatives thereof include 13-
cyclodextrin, 2-llyLu~yplu~ y~ ill or methylated-~-
,lod~,Allill. The 2-lly~u~y~Jlu~yldLc~-B-~y~lOdc~uill preferably has adegree of ~I~hctitl~inn bet~veen 2 and 9, more prefeFably between 3.9 and i. I
2-llydlw~yulu~yl groups per B-uy~ludc.~llill moleeule.
Examples of suitable NSAID elasses inelude arylacetie acids, arylpropionic
acids, aminoaryl carboxylic acids and thiazine earboxarnides. Representative
NSAlDs include diclofenac sodium, naproxen, ibuprofen, mefenamic acid,
piroxicam, tenoxicara and Inrnnxir~nn
For NSAlD's, excluding the thiazine ~ r c, the ~ of the
WO gs/32737 ~ 52
2~ 90598
- 7 --
invention is preferably non-~rrt~ L.
Step (a) of the method may comprise mixing the ~-cyclodextrin or the
derivative thereof in powder form with the NSAID in powder form, and then
adding a suitable amount of the wetting solution to the powder mixture to
form the paste.
Alternatively, step (a) may comprise mixing the 13-l;y~,lud."~L1 1l~ or the
derivative thereof in powder form with a suitable amount of the wetting
solution to form a paste and then adding the NSAID in powder form or in
the form of an a~ueous suspension or solution in the wetting solution, with
mixing, to the paste.
rhe molar ratio of NSAID to ~-cyclodextrin or the derivative thereof is
preferably from 1:1 to 1:5, more preferably from 1:1 to 1:2,5.
The wetting solution may be selected from water, a lower alkanol, preferably
ethanol or propanol, or a mixture of water and a lower alkanol. When the
wetting solution contains water, it may optionally also contain an amount
of an aLkali such as sodium hydroxide.
In step (b), the mixing preferably continues for from 0,25 to 5 hours
inclusiYe. During this period, the wetting solution is preferably added
periodically to. maintain the paste-like ~,ulla;a~ "y of the mixture.
In step (c), the product of step (b) may be dried, for example, under vacuum
or in an oven at dLJ~Iu.~ L~ly 40C.
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21 90598
rhe method of the invention may include an additional step, after step (c)
of: ,.
(d) forming the product of step (c) into a suitable solid ~ A. ",Af. . ,~
form, optionally with the addition of ~IIIA,,,,A.. ,~I~.AIly acceptable
carriers or agents.
BR~EF DE:SCRIPTION OF THE DRAWINGS _
Figure I are differential scannirlg ~"llu~ ,.ly (DSC) I~ of (a)
naproxen (b) 2-llydlu~,ulu~yl~ p-~iy~lod~i~.uill, (c) nap}oxen/2-
,rdlV.~i~LJIUy,ylG~S_d p-U,y~ IOd~ 11.. I ;C physical mixture and (d)
rlaproxen/2-llydlu~lu~y' ' ,~-(;y~,lod~ ill kneaded complex from
Example 2;
Figure 2 are DSC Il' '"~'~C'A"'C of (a) ibuprofen (b) methylated ~-
~ ,lo~A~iul, (c) ibuprofen/methylated ~ lod~ "~: ~ ;c physica
mixture and (d) ibu~lurcl~/lu~,lllyl~ ;y~,lod~".LIill kneaded complex from
Example 3;
Figure 3 are DSC th~Afgr-rA.~ of (a) tenoxicam, (b) ~i-cyclodextrin, (c)
tenoxicarn/~-cyclodextrin ~1..;. ,,;".... :,;~ physical mixture, and (d)
tenoxicam/~-cyclodextrin kneaded complex from Example 7;
Figure 4 are fourier transform infra-red (FTIR) spectra of (a) diclofenac
sodium, (b) ~-cyclodextrin, (c) diclofenac sodium/~-uy~,lode,~ulll
,1~." l.,.",.. :.;C physical mixture, and (d) kneaded ir~clusion complex from
Example I - Peak A~ c~bu~ylatc stretch (I); aromatic stretch
(2,3);
Figure 5 are FTIR spectra of (a) naproxen, (b) 2-1lydlu~y~lu~Jyl
.. . . .... .. . ... _ .. .... , ..... . . . .. . . _ .. .
wo 9~132737 Pf~T/GB95,fO1152
2 ~ 93598
g
~.,lod..ALIil~, (c) naproxen/2-lly~uAyululJyl....l-fj3-~y~,lou~ALlill ~l.,;-',;..,,.-:,;.
physical mixture, and (d) Aneaded inclusion complex from Exarnple 2 - Peak
""". .,1~ carboxyl stretch (1,2); aromatic stretch (3,4); and
Figure 6 are F~IR spectra of (a) piroxicam, (b) 2-hlfdluAy~lu,uyldLGd f3-
cyclodextrin, (c) piroxicaml2-hydloAy"lu~ylated-~-cyclodextrin
~I,,i,ll;.llll..,iC physical mixture, and (d) kneaded inclusion complex from
Example 6 - Peak A~;f~"",...;~ Amide carbonyl (I); pyridine ring (2);
secondary amine (3); aromatic stretch (4).
DESCE~IPTION OF EMBODI:ME~TS
The crux of the invention is a method of maAing a l~l,- ,., ..,,lf. l
;l ,.", comprising an inclusion complex of a ~3-f~yulod~ALIi~l (BCD) or
a ~ y acceptable derivative of a BCD and a sparingly water-
soluble NSAID in solid form, which is adapted to be dissolved in water to
provide a clear or slightly opaque solution for oral ,./Il,l;l.;~l~rl;l.l~ wllich hds
therapeutic advantages as set out in more detail below.
The method of NSAID-BCD f....,l.lf~ ", is based on a semi-solid
preparation.
In a fust stage, the NSAID and ~ ,lod~,ALI;.I, both in a uniform finelydivided powder state, af e mixed together in a powder mixer. The particle
size of the NSAID and "y' lOdGAL ill is preferably less than Z50 micron. The
molar ratio of NSAID to cyclodextrin is between 1:1 and 1:5, but preferably
between 1:1 and 1:2,5.
wo95/32737 2 1 90598 ~ 52
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In a second stage the powder mixture is triturated with appropriate aliquots
of a wetting solution to obtain a paste-like colla;a~ Vigorous mixing is
continued for 0,25 to 5 hours mAint~inin~ the paste-like consistency by
periodic addition of wetting solution. The said wetting solution may be
selected from water, a lower alkanoi, preferably ethanol or propanol, or a
mixture of water and a lower alkanol.
When the wetting soluhon contains water, it may optional~y contain an
aikaii, preferably sodium hydroxide. The alka~i serves two purposes: firstly.
it causes ionisation of the NSAID resulting in improved wettability and
solubility of the NSAID, and secondly, it enhances the solubility of the
Atl ;11 Togetiler these factors appear to result in more rapid
r~ during the kneading process.
On the other hand, ionisation of NSAlD's has been shown to reduce the
degree of cyclodextrin 1l~ in solutiorL However, it has been
reported from solution studies that cyclodextrin rnmrlPY~ltirn of ionised
NSAlD's can result in much larger totai NSAID cnlllhili~tirln i.e.
50lllhili~tinn of the NSAID both due to ~,1"~ l;r"~ and ionisation, than
if either method were used individually (See Reference 1~). Thus, the
combined use of ~,yClOd~,~L;II ~ together with salt fomlation of
relevant NSAlD's provides for a readily soluble fomm of the NSAID via
technically simple m~-thr,~lrgy
In an altemative procedure, the NSAID is generally added with mixing toa paste prepared by mixing the cyclodextrin with appropnate aliquots of
water which may optionally contain an alkali, preferably sodium
hydroxide. The NSAID may be added as a dry powder or suspended or
_ _ , .. ... .. . .. .. . . ..... . ..
WO 95132737 PCTJGB95/01152
21 90598
1,
dissolved in a solution which may contain up to 100 percent v/v of a lower
alkanol, preferably ethanol or propanol Mixing is continued according to
the second stage as descnbed above.
In a third stage tne product obtained is dried either under vacuum and/or in
an oven at 40C. The dried product is passed through a 30 mesh screen and
mixed in a powder mixer.
The final product is Clldldl,t~ c~ by small particle siæ with significantly
enhanced water solubility relative to the pure NSAID. It consists of a
NSAlD-cyclodextrin molecular inclusion complex. Evidence for the said
complex may be d~ lul~ ,d by differential scanning . ~ , ;( (DSC)
and fourier transform infrared (FTIR) ~ ,llvaculJic arlalyses.
The solubility ~ ~Lcl;~lic~ of NSAlD-~,y~,lOd~,ALill complexes according
to the invention permit the J~ of orally d~ c,~
.",.,I.~,~;I;I",~havinganti-;.~ ,.,..,-l..,y,analgesicamd~ ,."~ activity.
The said r.,, ." ~ have significant advantages over col~ iull~l oral
NSAID treatments. Because the drug is a.L~ t, l~ in tne dissolved state,
the problem of slow NSAID dissolution rate is effectively overcome.
CU~I~C~ .,IILIY, the time to reach peak plasma ~ ..,.,./;""~ may be
Si~llir~ -ly reduced resulting in a more rapid onset of therapeutic action.
Local gastric irritation due to prolonged contact of the NSAID with the
~ aat~ Lillal mucosa is avoided owing to the widespread dispersion of the
drug when adlllill~ lcd according to the invention. Palatable 1.l....l,.,~;l;..,.~
of the complexes may be simply prepared by mixture of the complex powder
with suitable water soluble powder excipients which may include a diluent
such as sorbitol or lactose. sweeteners and flavours. The ~mr~citi(7n may
-
W095/32737 PCT/GB95101152
21 905q8
- 12 -
be in the form of a powder for Ic~,ULIaLiLULiUII or a soluble tablet, both
intended for rapid dissolution in water prior to oral ~ n-~ The said
rf~nnr~citinn~ are readily soluble in at least lOOml tap water at room
.Lu c In order that the invention may be more fully understood the
following examples relatirlg to the preparation of NSAlD-~:yclod~.A~
complexes, their.,ll ~ ll and ~ c ~ l ct~mrocitil~n~ are g;ven
In the examples which follow. the following cl-nnro..n~ are designated as
indicated:
Diclofenac sodium - (I)
Naproxen ~ (II)
Ibuproferl ~ (III)
Mefen2mic acid - (IV)
Piroxicam - (V)
Tenoxicarn - (VI)
r,nrnn~in~rn - (VII)
~ yl lod~.LIill - (BCD)
2-ll~UAy,ulu~yl.lLcd ~-cy~,lod~,Atlill - (HPB)
Methylated-~-cyclodextrin ~ (MBC)
EXAMPLE I ~ ~
BCD and I are passed through 60 mesh screen. BCD (15,6g) is vigorously
mixed with deiorlised water (6ml) to produce a uniform paste. I (4,4g) is
slowly added with mixing. Vigorous rnixing is continued for 0_5 hour
ensuring a uniform paste-like Culla;aL~,ll.,y throughout the operation. The
mixture is oven dried at 40C. Tbe dried mass is crushed and passed
-
cl
WO 9s/32737 Y~ . c1152
2 1 93598
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through 30 mesh screen. The powder is hr~mrlgrni~e~ in a powder mixer for
10 minutes. The product contains 21,6 percent m/m I with arl equilibrium
water solubility of 3864mg/lOOml as detetmined by HPLC.
EXAMPLE 2
To 6,0g HPB in a mortar, 474ml of a IN sodium hydroxide solution is added
with vigorous mixing to produce a paste. 11 (I,Og) is passed through a 60
mesh screen and added gradually to the paste with vigorous mixing. The
mixture is kneaded for I hour with ~,.u~.i...~, addition of small aliquots of
deionised water to maintain a paste-like L,Ulla;~ . The mixture is oven
dried at 40C. The dried mass is crushed and passed through 30 mesh
screen. The powder is llull~ d in a powder mixer for 10 minutes. The
product contains 13,7 percent m/m Il with an ~.l";I;l,l ;"", water solubility of460mg/lOOml as determined by HPLC.
EX.~MPLE 3
To 2,~g MBC in a mortar, 3m~ propan-l-ol containing 0,4g 111 is gradually
added with vigorous mixing. The mixture is vigorously kneaded for 0,~
hour with appropriate addition of small aliquots of neat propan-l-ol to
maintain a paste-like L~Ullai:~L~ . ThG mixture is dried under vacuum at
40C. The dried mass is crushed and passed through a 30 mesh screen. The
powder is 11~ rrl in a powder mixer for 10 minutes. The product
contains 12,4 percent m/m 11I with an eqllilibri~lnn water solubility of
400mg/lOOml as determined by HPLC.
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EXAMPLE 4
To 6,3g HPB in a mortar, 5ml of a IN sodium hydroxide solution is addedwith vigorous mixing to produce a paste. lrl (I,Og) is passed through a 60
mesh screen and added gradually to the paste with vigorous mixing. The
mixture is kneaded for I hour with appropriate addition of small aliquots of
deionised water to maintain a paste-like culla;au,lll,y. The mixture is dried
at 40C. The dried mass is crushed and passed through a 30 mesh screen.
The powder is llulllO~ a~;l in a powder mixer for 10 minutes The product
contains 13,1 percent m/m III with an equilibrium water solubility of
1300mg/lOOml as determined by HPLC.
EXAMPLE ~
To 5,7g HPB in a mortar, 4ml of a IN sodium hydroxide solution is addedwith vigorous mixirlg to produce a paste. IV (I,Og) is passed through a 60
mesh screen and added gradually to the paste with vigorous mixing. The
mixture is kneaded for I hour with appropriate addition of small aliquots of
deionised water to maintain a paste-like Culla;a~ ,y. The mixture is oven
dried at 40C. The dried mass is crushed and passed through a 30 mesh
screen. The powder is l~ 1 in a powder mixer for 10 minutes. The
product contains 14,0 percent mlm IV with an Pqllilihri~lrn water solubility
of 430mg/lOOrnl as determined by HPLC
EXAMPLE 6 ~:
HPB (24,0g) and V (2,9g) are passed through 60 mesh screen and tumble
mixed for 10 minutes. A 50 percent vlv ,olution of etharlol in deionised
w0 ss/32737 r
21 905q8
- 15 -
water (14ml) is gradually added to the mixture witb vigorous mixing to
produce a uniform paste. VigorouS mixing is continued for 0,3 hours
ensuring a uniform paste-like ~ L~llcy throughout the operation. The
mixture is oven dried at 40C under vacuum. The dried mass is crushed and
passed through 30 mesh screen. The powder is h~,,.o~ cd in a powder
mixer for 10 minutes. The product contains 9,6 percent mlm V with an
eq~lilihri-lm water solubility of 120mg/lOOml as determined by HPLC.
EXAMPLE 7
To 8,7g BCD in a mortar, 7ml deionised water is gradually added with
vigorous mixing to produce a paste. Vl (1,3g) is passed through a 60 mesh
screen arld added gradually to the paste with vigorous mixirlg. The mixture
is kneaded for 0,25 hours The mixture is oven dried at 40C. The dried
mass is crushed arld passed through 30 mesh screen. The powder is
J in a powder mixer for 10 minutes. The product contains 22,0
percent mlm Vl with an ~q~lilihri~lm water solubiiity of 14mgllOOml as
determined by HPLC.
E2~AMPLE 8
HPB (2,4g) and Vll (0,64g) are passed through 60 mesh screen and tumblemixed for 10 minutes. Deionised water (1-2ml) is gradually added to the
mixture with vigorous mixing to produce a uniform paste. Vigorous mixing
is continued for 0,3 hours erlsuring a urliform paste-like consistency
throughout the operation. The mixture is oven dried at 40C under vacuum.
The dried mass is crushed and passed through 30 mesh screen. The powder
is h~ l in a powder mixer for 10 minutes. The product contains
wo 95/32737 . ~ .. ~ 1 152
21 905q~ --
- 16 -
2079 percent m/m VII with an ~ ilihrillm water solubility of 14,6mg/lOOml
as determined by HPLC.
EXAMPLE 9
HPB ~21,0g) and IV (2,41g) are passed through a 60 mesh screen and
tumble mixed. Deionised water (lOml) is added with vigorous mixing to
produce a paste. The mixture is kneaded for 30 minutes with appropriate
addition of small aliquots of deionised water to maintain a paste-like
consistency. The mixture is vacuum dried at 40C. The dried mass is
crushed and passed through a 30 mesh screen. The powder is homogenised
in a powder mixer for 10 minutes. The product contains 10,3 percent m/m
IV.
EXAMPLE 10
According to the procedure of Example 1, 2,2g naproxen sodium and 19,8gBCD were used to form a complex containing 10% m/m naproxen sodium.
PEIYSICO-CHEMICAL CHARACTERISATION OF NSAID
rNCLUSlON COMPLEXES
Table I shows the aqueous solubility of the pure NSAID's ~1, III and V) as
their St~ y~ d~ inclusion complexes prepared by kneading
and spray drying. It has been shown that inclusion complexes prepared by
spray drying represent the best examples in terms of ~ of
and highest water solubility (Reference 10). From the table
it is evident that the solubility of the complexes prepared according to the
,, , _ . .. .... . . .. .. ..
, ~.~, . 1 152
Wo 95/32737 rc~l
2~ 905~8
- 11 - '
invention compare faYourably with the spray dried complexes indicating tbat
acceptable inclusion rrl",l.l. Al;.,l, has taken place,
Table I Comparison of the aqueous solubility of NSAID complexes
prepared by kneading and spray drying,
'b.' Aqueous Solubility* (mg/lOOml)
Compou~d Kneaded Complex~* Spray Dried Complex
l-BCD 3864 451?
III-HPB 1302 3967
V-HPB 120 1~6
'~ Determ~ned by ~PLC
** Complex from ~u~ ,ly described examplQ
Differential Scanning Calorimetry (DSC) is the lI~IIICIII~ of the rate of
heat evolved or absorbed by a sample durirlg a ~ ll,u~ Lulc program, The
tecbnique may be used to ~ inclusion ~ "l~ I in cases where
the melting point of the included molecule is below the therrnal rlP~A~i~tir~n
r~mge of the cyclodextrin (i,e, < 2'iO~C), Evidence for inclusion
c."..~ may be obtained from a diminished and/or shifted thermal
event uullc~u~ling to the melting point of the included guest relative to the
pure substance. Compared to the pure NSAID or simple ,l.. ;.l,;.. l,;c
NSAID/cyclodextrin mixtures, I~,UlC~ lL_~ivc DSC 11.. IIllO~lAllli of the
UUllC~lUlalillg kneaded inclusion complexes taken from Examples 7, 3 and
7 show a diminished thermal event ,UII~;~jUUlld;ll~ to the melting point of theNSAID as sho~vn in Figures I to 3 IQ~,Li~ly.
_ _ . . . . .
WO 9S/32737 P~ 'C I I52
219~q~ --
. .
Fourier transform infrared (FTIR) ~ u~OI~r is particularly useful in the
. " ;`';;..A. of NSAlD/cyclodextrin inclusion complexes owing to the
well separated carbonyl band (1680-173ûcm ') or the corresponding ionised
carboxylate band (1550-1650cm ') presenl in most NSAlD's which generally
undergoes a frequency shift and/or a reduction in intensity upon inclusion
cu~llulcAd~iull. The former effect is principally due to disruption of
int~rrnr)lreul~r (.NSAID-NS~ID) hydrogen bonds whereas the latter effect is
due to vibrational restrictions imposed on the guest molecule in the
uyclo~LIill cavity. Additionally, reduced intensity of bands ~ullcaAJulldillg
to aromatic -C=C- stretching modes (1460-1650 and 680-850cm l) may also
be used as evidence for inclusion ~ ;"l, RclJIcacll~dlivc FTIR
spectra of kneaded complexes from Examples 1, 2 and 6 show the aboYe
phenomena relative to the pure NSAID or the cullc uulldlllg ct~irhillrr~ trir
NSAlD/uy~,lOd~,Auill physical mixture as illustrated in Figures 4 to 6
Ic,~ ,Liv~ . In the case of Example 2, it is cul~ alJI~ that salt formation
has taken place with the NSAID carboxyl, in which case the earbonyl group
frequency would shift to a shorter ~a~ lulllb~ of the
buAyl_~., anion. However, the ..~ l;r band of the carbonyl or its
Cull~uulllillg C~UUAYI.~h are diminished as shown in Figure 5.
P~IARMACEUTICAL COMPOSITIONS
EXAMPLE I1
The following r..",,.~l~l;",, was used to prepare readily soluble tablets
produeing a pleasant tasting clear solution when added to 100ml tap water:
Kneaded l-BCD complex from Example I was mixed with all other
~...,.,1.~..,..,l~ for 10 minutes, screened through a 30 mesh screen and further
5/01152
WO 95132737 PCr/GB9
21 ~0598
- 19 -
. .
mixed for a suitable time period. The mixture obtained was formed into
oval shaped tablets with high surface area The unit ~nmrncition of each
tablet is as follows:
Kneaded l-BCD complex 120 mg
PEC 6000 5 mg
Spray dried natural orange flavour 30 mg
Sodium cyclamate 30 mg
Sodium saccharin 15 mg
Sorbitol 300 m~
Total: 500 mg
The tablets have a hardness of about 30 N and dissoive vith swirling in a
time of 3 minules.
EXAMPLE 12
The following r.~"~ "~ was used to prepare a readily soluble powder
producing a pleasarlt tasting clear solution when added to lOOml tap water:
Kneaded Il-HPB complex from Example 2 waS mixed with all othe~
col.lLuul.~ for 10 minutes, screened through a 30 mesh screen and further
mixed for a suitable time period. The mixture obtained was packed into
sachets. The unit ~ , of each sachet is as follows:
wo 95/32737 ' ~ ,5, ~ 1 152
2 ~ 90598
- 20 -
Kneaded ~I-HPB complex 1465 mg
Sucrose 3365 mg
Spray dried natural cherry flavour 90 mg
Sodium cyclamate 40 mg
Sodium saccharin 40 m~
Total: 5000 mg
=
EXAMPLE 13
The following ro",. ~ .,. was used to prepare a readily soluble powder
prvducing a pleasant tasting slightly opaque solution when added to lOOml
tap water: Kneaded III-HPB complex from Example 4 was mixed with all
other ~ for 10 minutes, screened through a 30 rnesh screen and
further mixed for a suitable time period. The mixture obtained was packed
into sachets. The unit ~ of each sachet is as follows:
Kneaded III-HPB complex 1524 mg
Spray dried natural cherry flavour 90 mg
Sodium saccharin 115 m~
Total : 1729 mg
EXAMPLE 14
The following r~."""l~ " was used to prepare a readily solubl~ powder
producing a pleasant tasting slightly opaque solution when added to lOOml
tap water: Kneaded V-HPB complex from Example 6 was mixed with all
other (,:.,,,l~v, ,l~ for 10 minutes, screened through a 30 mesh screen and
w09sl32737 r~ ll52
2~ q3S98
- 21 -
.
further mixed for a suitable time period. The mixture obtained was packed
into sachets. The unit cnnnrn~iti~n of each sachet is as follows:
Kneaded V-HPB complex 210 mg
Spray dried natural orange flavour 5 mg
Sodium saccharin 15 mg
Sodium cyclarnate 30 mg
Spray dried lactose ~mg
Total: 2000 mg
E~AMPLE 15
The following fnrn~ tinn was used to prepare a readily soluble powder
producmg a pleasant tasting slightly opaque solution when added to lOOml
tap water: Kneaded IV-HPB complex from Example 9 was mixed with the
other component for 10 minutes, screened through a 30 mesh screen and
further mixed for a suitable time period. The mixture obtained was packed
into sachets. The unit ~ o~ of each sachet is as follows:
Kneaded IV-HPB complex 2,425 g
Trusil cherry flavour 0~050 ~
Total 2,475 g
EXAMPLE 16
The following r.., ~ , was used to prepare a readily soluble powder
, . . .... . . .. . .
Wo ssl32737 P~l,~,~ ilS2
21 90598
- 22
producing a pleasant tasting slightly opaque solution when added to 100ml
tap water: Kneaded naproxen sodiurn-BCD complex from Example 10 was
mixed with the other ~ yull~llb for 10 minutes, screened through a 30
mesh screen and further mixed for a suitable time period. The mixture
obtained was packed intû sachets The unit rrmrncitinn of each sachel is as
followS:
Kneaded naproxen sodium-BCD complex 2,20g
Passion fruit flavour 0,07sg
Sodiurn cyclamate 0~005
Total 2,280g
R~FERENCES
1. Ceppi Monti, N. et al Activity and phs~rm~rnkin~tirs of a New Oral
Dosage Form of Soluble Ibuprofen, ~r7n.-imitt~1 Forschung 1992, 42
(1), Nr. 4, 556-559.
2. Chow, D.D. and Karara, A.H. ('1~ i".~ , dissolution and
bioavailability in rats of ibuprofen-~-~y.,lodcALll~l complex system.
T"l~ ..,,.l Journal of Fll~ 1986, 28, 95-101.
3. Erden, N. and Çelebi, N. A study of the inclusion complex of
naproxen with l3-cyclodextrin. T ~ l Journal of
1988, 48, 83-89.
4. R~rl~n~ . T. et al. Interaction of NSA with cyclodextrins and
lly~LuAyyluyyl ~ ,lod.,AI;I. derivatives. Tnt~rn~tinn~l Journal of
. _ . ... . . . .. .. . .. . ... . .. ... ... . ... . . ..
wo 9~13273~ P~ 52
2 1 90598
- 23 -
r l, 1 9 9 1, 7 4, 8 5 9 3
5. Senel, S. et al. Preparation and I~ ;aLiull of the Tenoxicam/~-
Cyclodextrin Complex. Journal of Inclusion Phenomena and
Molecular Recognition in Chemistr~ 1992, 14, 171-179.
6. Zecchi, V. et al. Control of NSAID Dissolution by ~-Cyclodextrin
('.nmrlrYslti~ln. Pl,~ Acta Helvetia 1988, 63, Nr. I l, 299-
302.
7. Kurozumi, M. et al. Inclusion ('r,mro~nrC of Non-Steroidal
A - n y and Other Slightly Water Soluble Drugs vith a-
and ,B-Cy~,lod~ ills in Powdered Form. Chemical and
pl,,""~ ,-1 Bulletin 1975, 23, 3062-3068.
8. Acerbi, D. et al. Rapid oral absorption profile of Piroxicam from its
3-Cyclûdextrin Complex. Drug l.~ .l 1990, 2 (Suppl. 4), 50-
55.
9. Otero Espinar, F.J. et al. Reduction in the ulcerogenicity of
naproxen by r"mri~YI-ti~-n with 13-Cyc~odextrin. Tntrm~til~n~l Journal
of Fl, ", - ~ 1991, 70, 35-41.
10. Blanco, J. et al. Influence of method of preparation on inclusion
complexes of naproxen with different cyrlr~ irYtrinc Drug
D~,v~lv~ and Industrial Pharmacy 1991, 17, 943-957.
I l. Toricelli, C., Martini, A., Muggetti, L., Eli, M. and De Ponti, R.
... . . . .
WO gsl3Z737 PCTIGB9510115~
2 1 90598 ~
- 24 -
r~ 1 lournal of Pl~ 1991~ 75, 147-153,
IZ. Loftsson, T. et al, Cyclodextrin f`l.,,,~ ;.," o~ NS~lDs:
Plly ~ , European lournal of PI ~ ~ " " ~
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