Note: Descriptions are shown in the official language in which they were submitted.
21 77721
WO 95/15155 PCT/EP9 1/03903
TASTE MASKED COMPOSITION CONTAINING A DRUG/POLYMER COMPLEX
The presenl invention relates to therapeutic agent/polymer matrix complexes
which have improved t. ste ~ a~Lli~Li~.
Many Ll~ ~r~ y active substances have an unpleasant taste or cause a
numbing effect when adl~ L~I~d by mouth to a patient.
Many Lll~la~ uLic a~llL/L~ol~ cl~mh;no~ nc are known but the therapeutic
âgent is coated with the polymer. The problem with such products is that Lhey are
liable to be broken when orally ~ r ~d by the patient, palLi~ulally when
chewed, thereby allowing the therapeutic agent to be in direct contact with the mouth,
thus the toste and/or numbing sensation of the therapeutic agent is no longer
effectively masked.
A further problem with Cv~01~ of methacrylic acid and methyl
methacrylate is Lhat when complexed with therapeutic agents the product formed
tends to be a gum.
One particular drug"~im ' yvl~ tu, is useful for treating the symptoms
associated with travel sickness. ~;...~..llr,' has a numbing taste.
A preferred fnrrn~ th~n of dilh~.hydlilla~r~ is in the form of a chewing gum or
a chewable tabiet which means that the ~u~ I coaLing techniques using
20 polymers such as anionic copolymers based on Illt:Llla.,-~liC acid and
m~L~ Lha~lylat~ (such as Eudragit), are ineffective in masking the numbing tastebecause the ~ .lLi~llàl polymer coated ' ' y,' complex is broken down
when chewed by the patient.
Another drug, paroxetine, is useful for the treatment of iPrr~.cci~m panic
25 disorders and obssessive ~ JUIi>i~. disorders. Paroxetine has an unplea~cant bitLer
tashe.
The present invention provides a therapeutic z~,~l.L/yOI~ ,I complex with
superior tash masking qualities and can be prepared as a powder which is more easily
formulahd with otherexcipients to form cu,,~. I r~... -1-~;....~
Accordingly, the present invention provides a chewable tash masked
r.... 1 ~ l " . C~ .g a Lh~ t;u~;~, agent (or drug) containing at least One basic
- group or atom optionally in the form of a salt which is reachd with a polymer
containing at least one acidic group to form a complex.
A preferred L~l~la~ agent is ~" ' ~lli-l~h or paroxetine.
The herm "basic group or atom" is understood to mean â group capable of
donating electrons. Such groups include optionally substituhd amino groups or
optionally substituted thio groups.
Suitable salts of therapeutic agents include acid addition salts which are
suiLably rl ~ v~ lly acceptable salts such as the hydrochloride hemi-hydrahe for
I
2l7772'
wo 95/1515~ r~ 903
paroxetine.
It should ~e ~ .l that in cases where the dru~ comprises two active
C~ i e- a basic one and an acidic one in the form of a salt, such as
d~ yl' which is the 8-chlorotheophylline salt of ~i~)}lc~ ydl~ c then the
S ter~n therapeutic agent in the form of a salt extends to both of tbese ~ F - ~Suitable polymers include pol~ l..t~," such as Eudragit L and S which
are copolymers of ' ~1;-, acid and methyl l~ yld~C and have a mean
molecular weight of about 135,000.
The term "acidic group" is understood to mean a group capable of receiving
10 electrons such as a carboxylic acid group.
The complexes of therapeutic agent (including salts thereof) with polymers
can be in different weight ratios. For paroxetine and dimenhydrinate, the complexes
are preferably in a weight ratio of therapeutic agent to polymer of 1:0.8 to 1:1.5.
Preferably the weight ratio is 1:1.
The ~ of complexes of tberapeutic agents (including salts thereof~
with polymers may suitably be ca~ied out by dissolving the polymer and the
therapeutic agent (including salts thereof) in suitable solvents, such as iso-propanol.
ethanol or diethyl ether, optionally at elevated ~ ulllrc such as 40C, then forexample adding a 1, ~ g solvent such as n-hexane om,v~l~o.~.~;l.& the solvent0 and triturating the residue with a suitable solvent such as acetone. The resulting
;~d complex is suitably filtered and dried.
Al~.ll~liivcly, such complexes may be prepared by suspending and mixing the
therapeutic agent (including salts thereof) and the polymer in water at ambient or
elevated . such as 25 to 60C, preferably 50C to 60C, for 5 to 24 hrs.
25 The resulting complex is suitably filtered and dried.
Complexes of tberapeutic agents (including salts thereof) and polymers may
be formulated into c~ , ' chewable dosage forms such as chewable tablets.
candies, chewing gums, or soft chewable gelatin capsules using techniques generally
known in the art or methods described or analogious to those described in the
30 exat~ples.
Preferably ' ' ~,' /poly.l.~. complexes may be in the form of chewing
gums or chewable tablets and ~UAC~ Oly~ complexes may be in the form of
chewable tablets or chewing gums.
The following examples are illustrative of the present invention.
Example 1
The Complex of D ' ~.' and Copolymer of Ir.~ l.,.ylic acid and
methyl ~ dl.l~ ' ' (CDC), was obtained by stepwise dissolving 10 g of Copolymer
(Eudragit L) and 10 g of d;lll~.l}l,~' ' in 100 ml of ;so~,lul ~1, which was heated
- 2-
2 ~ 7772 1
~VO 95/15155 PCT/EP94103903
to 40C until dissolved then 200 ml of ~-hexane were added to precipitate the
resulting product which was then filtered and dried.
The 16.8 g of CDC gave the following analytical results.
S Appearance : white powder
Numbing taste : absent
D ` ydli~ (HPLC assay) : 45.78 mg/100 mg of CDC.
Example 2
The Complex of D ' yd~ and Copolymer of methacrylic acid and
methyl .l.~ ' (CDC), was obtained by adding 1.5 kg of D ' ydlil.~t., and
1.5 kg of Copolymer (Eudragit L) to 22.5 Iitres of water, stirring at room t~ Lu(about 20C) for 5 hours, heating to 50C, stirring at 50C for 4 hours, cooling to
room l~ l,r~ r, stirring for 2 hours at room t~ p~ ulr" filtering and drying.
The 2.81 kg of CDC, gave the following analytical results:
Appearance : whitepowder
Numbingtaste : absent
D; ' yl' (~PLC assay) : 46.27 mg/100 mg of CDC
~5 Moi.hlre(K.F.) : ~.5491o
WO95/15155 2 1 77721 Pcr/EP941039~3 ~
Chewable Tablets
Ex.~4rnples 3 - 5
S The following were granulated and admixed in a ~,o~ iulldl manner and
formed into tablets of lSû mg (Example 3), 300 mg each (Example 4) and 600 mg
each (Example 5).
Example No.
3 4 5
Complex of Di~ ydlill~L~ and Copolymer of 50 100 200
.,lyliC acid and methyl I.~ lyld~ (CDC)(g)
st~rch (g) 12.5 25 50
Lactose (g) 15 30 60
Saccharin sodium (g) 5 10 20
Mint dry flavour (g) 5 10 20
Sorbitol (g) 58.5 117 234
Ammonium gly-,~ ' (g) 1.5 3 6
M. c,.~ ~: ,-- stearate(g) 2.5 5 10
Candies
Example 6
Complex of Dimenhydrinate and Copolymer of ~ yli~, acid 100
andmethyl ~- (CDC) (g)
Sucrûse (g) 1944
Liquid glucose (g) 1944
Mint navour (g) 12
--4--
~wo 9S/lSlSS 2 1 7 7 7 2 1 PCT/EP9.1/03903
The formula~ion of example No. 6 was prepared by heating the sucrose and
the liquid glucose dissolved in purified water, then drying the mass obt~ined and
dispersing in the mass the CDC and the mint flavour. The final dispe}sion was
5 pres5ed into candies of 4 g each.
Chewing Gums
Examples 7 & 8
Example No.
Complex of D;.. ,.,.~ d~ t., and Copolymer of 50 100
methacrylic acid and methyl methacrylate (CDC) (g)
Gum base (g) 495 4g5
Sorbitol (g) 637.5 587.5
Mint oil (g) 10.7 10.7
Menthol (g) 16.5 16.5
Aspartame (g) 7.6 7.6
r~,, stearaoe (g) 12.7 22.7
Milled gum base is mixed with sorbitol (ca 40% of total amount), menthol (ca
90% of total amount) and aspartame (ca 25% of total amount). The blend is wettedwith purified water, kneeded, granulated and then dried at about 40C. The driedgranules are mixed with CDC, mint oil, ~" stearate and the remaining
15 amounts of sorbitol, menthol and aspartame. This final mixture is pressed into
chewing gums of 1230 mg each. The chewing gums can be film coated by
.,~,..~. I film coating procedures.
-5-
WO 95115155 2 1 7 7 7 ~ 1 PCTIEP9 U03903
Soft Chewable Gelabn Capsule
Example ~
Complex of D;.lle..l.yl' and Copolymer of ~ a~lylic acid 100
and methyl ' yl, .~ (CDC) (g)
Gelatin (g) ` 900
Glycerol (g) 345
Saccharin sodium (g) 5
Orange flavour (g) 50
Purified water (g) 450
The r, of the Example 11 is prepared by dissolving the gelatin and glycerol
in the purified water heated to 70C and then, after cooling to 50C, adding thesaccharin sodium, the orange flavour and the CDC. The mass obtained is continually
stirred, and processed with a c~ ".Londl rotary-die process, to obtain soft chewable
10 gelatin capsules of 1850 mg each.
The soft gelatin capsules are then dried at 20C and 20% relative humidity for
five days.
Example 10
The Complex of paroxetine and Copolymer of Ill~,L~àwylic acid and methyl
Ill~.~a~lylat~ (CPC), was obtained by mixing a solution of 3g of Copolymer (Eudragit
L) in 150 ml of ethanol with a solution of 3 g of paroxetine base in 100ml of diethyl
ether and stirring at room ~ . r for 12 hours. The solvent was then evaporated
under vacuum and the residue was triturated with acetone. The precipitate was
20 collected by suction filtration, washed with acetone and dried.
The 4.6 g of CPC gave the following analytical results.
Appearance : white powder
Bitter taste : absent
Melting point : 215-230C
Paroxetine (HPLC assay) : 42.50mg/lOOmg of CPC
Loss on drying : 0.4%
- 6 -
~wo ss/lslsS 2 1 7 7 7 2 1 r~ A~903
Example 11
The Complex of paroxetine and Copolymer of methacrylic acid and methyl
ldt~ (CPC), was obtained by adding lOg of paroxetine hydrochloride
, 5 I~ dl~, lOg of Copolimer (Eudragit L) and 2.3g of sodium hydrogen carbonate
to 300 ml of water, The mixture was stirred at room t~.a~ Lu-~ for 12 hours, heated
to 60C and stirred at 60C for 12 hours. After cooling to room t~ , the
precipitate was collected by suction filtration, washed with water and dried.
The 18 g of CPC gave the following analytical results.
Appearance : off-white powder
Bitter taste : absent
Melting point : 195-235C
Paroxetine (HPLC assay) : 43.53mg/lOOmg of CPC
Moisture (K.F) : 6.3%
Chewable tablets
Examples 12,13 & 14
E~:ample No.
12 13 14
Complex of paroxetine
and Copolymer of
methacrylic acid and
methyl 1.l~ laL~
(CPC) (g) 23 46 69
r,~ starch (g) 5 10 15
Aspartame (g) 10 10 10
Strawberry dry flavour (g) 50 50 50
Sorbitol (g) 409 381 353
r~ ~ stearate (g) 3 3 3
CDC aad pl~ starch are mixed, wetted with purified water,
kneeded, granulated and then dried at about 40C. The dried granules are mixed with
sorbitol, lactose, saccharin sodium"~m. r onillm gly. ~ , mint dried aroma and
~ stearate, then the final mixture is pressed into tablets of 150 mg, 300 mg
or 600 mg.
- 7 -
wo gsllSlss 2 1 7 7 7 2 1 PCTII~P9 1/03903 ~
Bi~y ;~ ' Studies
In a cross-over single dose study on 12 healthy volunteers, chewable tablets
50 mg ( ~ e to 100 mg of complexed dil~ ydlillG~ were ~Pr~nctr~tpd to be bio-equivalent to swallow soft gelatin capsules (50 mg) of non-complexed
product.
