Note: Descriptions are shown in the official language in which they were submitted.
132~97 6 ~
The pres~nt invention relates to azelastine-containing
medicaments with controlled release of the active substance
Azelastine is a phthalazinone derivative having the following
structural formula: Cl
.: .
¢~ ' ~,-,,,
~}~
~u~
The chemical designation is: 4-(4-chlorobenzyl)-2-(perhydro-
1-methylazepine-4-yl)-1-(2H)phthalazinone. Azelastine is
used in particular in asthma prophylaxis. Azelastine also
has anti-allergic and antihistaminic properties, see German
Patent No. 21 64 058.
One of the main disadvantages of using azelastine lies in the
side effect of tiredness. Many patients also report
drowziness, giddiness and the like. These side effects
develop in particular during the first days of azelastine `
therapy with the result that patients cannot operate vehicles
or machinery and that the general alertness of these patients
is greatly reduced.
:.:
It would therefore be highly desirable, and would be regarded
~s an important medical advance, if dosage forms of ~
az~lastine were available which did not cause tiredness as a -
side effect.
.'~,..
In the past the side effect was conventionally alleviated by
developing a combination preparation containing the tiredness -
causiny active substance and caffeine. The caffeine was
intended to antagonize the sedative property of the active
substance. This procedure cannot be applied in the case of
azelastine since the elimination half lives tl/2 ~tl/2 is the
time within which the serum level of the active substance in -~
the blood diminishes without further active substance intake
~Ib `
-- 1 -- ~
1325976
from a specific starting value to half this value) of
azelastine and caffeine differ very greatly from one another: --
the tl/2 of azelastine is 20 hours whereas the tl/2 of -
caffeine is only 3.5 hours. It is therefore to be expected
that, if azelastine and caffeine are administered together,
the effect of the caffeine will decrease after a certain -
time, whereby the sedative effect of the azelastine will once
more become apparent.
The conventional approach is then to delay the release of the
active substance - caffeine - in the dosage form so much that
a prolonged time of efficacy results. This procedure is, -
however, linked with the difficulty of adjusting the blood
level rates of the two active substances in vivo so that they
are as similar as possible. This is not possible, using
techniques presently available, because of the large
differences in the elimination values.
Azelastine has such an extremely unpleasant taste that, for
example, liquid azelastine formulations (for example juice)
are not taken or even refused by patients, in particular by
children. In accordance with the invention, however,
azelastine formulations are now possible with considerably
improved taste.
The present invention provides a drug formulation with the
active substance azelastine and a process for its preparation
whereby the sedative side effects of the azelastine are
extensively or completely suppressed.
According to the present invention there is provided a drug
formulation with controlled release of the active substance
containing conventional auxiliary substances and additives
and a sustained release component which is characterized in
that the active substance azelastine or its physiologically
acceptable salts are released in a controlled manner, that
0.001 to 800 parts by weight of sustained release components
are present in an amount of 1 part by weight of azelastine
- 2 - -
"~ ,,,,"~"~ :.,v" ",,"~,." "" ., .~, ", ", ~ ., , "
132597~ ~
calculated as base and that the release is 0.05 to 5 mg, for
example 0.05 mg to 3 mg or also 0.05 mg to 1 mg of
azelastine/hour the rate of release being determined in an
aqueous test solution having a pH of 1.0 and/or 6.8.
In one embodiment of the present invention the active
substance azelastine or its physiologically acceptable salts
(optionally with addition of other conventional auxiliary and i -
additional substances for controlled release) a) is coated
with one or more sustained release components, b) is bound to
a cation exchanger, c) is reacted with one or more
osmotically active substances and coated with a semi-
permeable membrane and a hole is bored into the membrane, d)
is embedded in one or more substance of the group of
digestible fats, indigestible fats or fat-like substances,
polymers or swelling agents, or is bound to these substances.
In another embodimen,t of the present invention the dosage
forms for the oral application containing 0.1 to 50 mg for
parenteral application, 0.1 to 500 mg and for dermal
application 5 to 5000 mg of azelastine active substance.
If the azelastine is present in the form of a salt, the above
mentioned amounts of azelastine which r~late to the base are
correspondingly increased due to the higher molecular weight
of the salt. The amounts quoted in the application with
reference to "azelastine" always relate to the base and must
be recalculated according to the increased molecular weight
when a salt is used.
The present invention also provides a process for the
preparation of a drug formulation with controlled release of
the active substance by incorporation of an active substance
in conventional auxiliary and ancillary substances and a
sustained release component which is characterized in that
azelastine or its physiologically acceptable salts are used
as the active substance to be released in a controlled manner
in the ratio of 1 part by weight of azelastine, calculated as
.~ .
- 3 -
132597~
base, to o.oo1 to 800 parts by weight of the sustained
release component whereby the azelastine is released at a
rate of 0.05 to 5 mg per hour the rate of release being
determined in an aqueous test solution having a pH of 1.0
and/or 6.8.
It was surprisingly found that it was not necessary to add
caffeine, either in sustained release or non-sustained
release form, in order to obtain a dosage form of azelastine
without the side effect of tiredness, but that it suffices to
delay the release of the active substance azelastine itself.
Thus, if the active substance azelastine is brought into a
dosage form which releases the active substance over a longer
period of time (and thereby effects a "retardation" of the ~-
active substance), it is found that patients treated with
this dosage form no longer experience the side effeat of
tiredness. This is particularly surprising since azelastine ~ -
is a substance with the already mentioned elimination half
life of 20 hours.
:' ' .: .:
To date, the process of sustained release has only been used - -
in pharmaceutical technology on substances with short half
lives, e.g. of up to a maximum of 10 hours. The sustained
release of an active substancs which ha~ a half life of 20
hours has to date been regarded by pharmaceutical saience
virtually as serving no useful purpose.
It is also surprising with these dosage forms that in the
case of their application the bitter taste hitherto~observed
does not occur some time after intake.
The invention thus relates to dosage forms with controlled
release of the active substance azelastine or of
physiologically acceptable salts of azelastine Suitable salts
are, for example, chloride, acetate, maleinate, lactate,
citrate, tartrate, gluconate, embonate.
i~25976
The :invention also provides is a process for the preparation
of dosage forms with controlled release of the active
substance azelastine or of physiologically acceptable salts
of a~ielastine.
The determination of the rate of release of the azelastine
between 0.05 and 5 mg per hour is carried out in an aqueous
test solution having a pH of 1.0 and/or 6.8. This test
solution is an aqueous solution having the defined pH values.
The adjustment of the pH values is carried out by adding acid
or a conventional buffer.
Dosage forms that may, for example, be considered are: -
sustained release tablets, sustained release capsules, ~ -
pellets, juices, implants, injections, plasters, aqueous or
oily suspensions, oily solutions, granulates, coated tablets, -
soft gelatine capsules, microcapsules.
The formulations of the invention may be obtained as follows:
1. Through binding of azelastine to physiologically
acceptable cation exchangers. The following may, for
example, be used as such cation exchangers:
Acrylic and methacrylic resins with exchangeable protons,
acid groups: C00 , e.g. AmberliteR IRP-64
:
Polystyrene resins with exchangeable Na+, acid groups: S03 ,
e.g. AmberliteR IRP-69 -
, ~ ": , ., , -, ,. - ' ~ ' ' . . : ~ ' . , . :
2~97~
The ion exchangers are acid ion exchangers. The maximum ratio of
az~lastlne: exchanger resin is about 1:1, the minimum ratio
about 1 part by weight of active substance to 800 parts of ion
exchanger resin For preference 1 to 400 parts by weight of ion
exchanger, are used for 1 part by weight of active substance, 1
to 100 parts by weight of ion exchanger bsing quite particularly
preferred.
The binding of the azelastine is effected by allowing an
azelastine solution to flow through a bed of the ion exchanger
in a column or by suspending the ion exchanger in a solution of
azelastine, filtering off after stirring and washing. The
charged ion exchanger is dried at temperatures up to about
50C. The charged ion exchanger particles are preferably also
provided ~ith a coating such as described for example in ~S-A-4 ~ -
221 776. One advantage of the additional coating consists
therein that the release rate of the active substance may be
altered and influQnces by the selection of the coating material.
The charged ion exchanger particle~ provided wlth a coating may
be dried with hot air at from 70C to 90C.
The charged ion exchanger particles may be filled into hard
gelatine capsules or a suspension may be prepared as a dosage
form with the aid of water and thickening agents, flavouring and
stabilizing agents and preservatives.
~ 132~976
2. Coating o-~ active ingredient particles, granulate or pellet
grains or azelastine-containing ta~lets with coatings of the
following substances, it also ~eing possible to use mixtures of
these coating substances: hydroxypropylmethyl cellulose
phthalate- or acetate succinate; cellulose-, starch-, as well as
polyvinyl acetate phthalate; carboxymethyl cellulose; polyvinyl
a~etate; methylcellulose phthalate, methylcellulose succinate,
methyl cellulose phthalate succinate as well as methyl cellulose
phthalic acid half ester; zein; ethyl cellulose as well as ethyl
cellulose succinate; shellac; gluten; ethylcarboxyethyl
cellulose; ethacrylate- maleic acid anhydride copolymer; maleic
acid anhydride vinyl methyl ether copolymer; styrol maleic acid ,~
copolymerizate; 2-ethylhexylacrylate maleic acid anhydride; ---;.-
crotonic acid vinyl acetate copolymer; glutaminic acid / :~ -
glutaminic acid ester copolymer; carboxymethylethyl cellulose
glycerine mono-octanoate; cellulose acetate succinate;
polyarginin; fats, oils, waxes, fatty alcohols; anionic ~ ~
polymerizates of methacrylic acid and methacrylic acid esters :: -
(EudragitRL, EudragitRS); copolymerizates of acrylic and
methacrylic acid esters with a low ammonium group
(EudragitRRS) content, as well as copolymers of acrylic and
methacrylic acid esters and trimethyl ammonium methacrylate
(EudragitRRL), copolymerizates of acrylic acid ethyl- and ;~
methacrylic acid methyl esters 70:30 (EudragitRNE 30 D), .
copolymeriza$es of acrylic acid, methacrylic acid ~s well as
their esters (ratio of the free carboxyl groups to the ester
: : .
groups ~or example 1:1~ (EudragitRL 30 D). ; .~
'';
1325976 :~-
.
The substances named may in addition contain conventional
softeners (e g di~utyl sebacate, citric and tartaric acid
esters, glycerine and glycerine esters, phthalic acid esters and ;
similar substances), it is also possi~le to add water-soluble
substances such as polyethylene glycols, polyvinylpyrrolidone,
copolymerisates of polyvinylpyrrolidone and polyvinyl acetate,
hydroxypropyl cellulose, hydroxypropylmethyl cellulose The ;
addition of solids such as talcum and~or magnesium stearate to
the coating is also possible
' ":
Organic acids (such as for example citric acid, tartaric acid, --
maleic, fumaric, ascorbic acid) may also be incorporated into
the pellet grains, granulate grains or tablets
, ~
Coating is effected by spraying solutlon~ in org-nlc solvents or
suspensions of the substances named in organic~solvents or
water, it also being pos~ible to :add further auxlllary
substances to optimize their proces~ablllty, 8uch~as for example
-::
surface-active substances, plgments
The ~praying is effected for example in a coating~drum or in
perforated drums or in an air suspension process (for example
Glatt WLSD5 fluidized air bed installation) ~ -
Coating may also take place using a coacervation process,
where~y so-called microcapsules ar- formed
~ ' ','' " ~
; '',., -
- 9 - 1 3 2 ~ 9 7 6 ` -~
Coating may also be effected by coagulation of aqueous
dispersions of the previously mentioned substances by mixing the
active substance with the dispersion and removing the water by ~ `
drying
' :,,.~ '.
Coated active substance particles and aoated granulates may be -
pressed into tablets, coated pellets may be filled into hard ;~-
gelatine capsules
.::
: ~ I ' :,,. ''
In coating the active substance particles or granulates which
contain active substance particles, more~coating substance is
generally used than in the case~of pel1-ts~since the surface
which must be covered is considerabl~y 1arg-r~than ln the case of
pellets
It is possible to use 0 001 to 800-pàrt- by w-lghtlof coating
substance for 1 part by w-lght of~a~t1v~sobstana-~ A w-iqht `~
ratio of 1 part of acti~ve ~ubstanc- and~0~005 to 500 parts by ~ `
weight of conting mater~al l~ preerr-d, 0 01 ~to 200 parts by
weight of coating material per 1~p ~ ~y~welght of actlve
substance being ~uite particolarly pr-f-rr~d ~Th- pplication of
the coating substances is effectod at~elevated;temperature, -~
preferably in a flow of air Air~ inl-t;temp-rature for example
70 to 90C; air outlet temperature~or,example~up~to 40C
:: : .. :
: : l
o
- 1325976
3 Coating of pressed disks, tablets, granulates aontaining the
azelast ne and one or more osmotically active substances, (e g
mannitol, sorbitol) with a semi-permeable membrane,~e g of 70
to 90 weight~ of cellulose acetate and hydroxypropylmethyl
cellulose (30 to 10 weight~J
~ ',
Osmotically active substances which may also be considered are
.:-...
organic and inorganic compounds or soluble substances which
generate an osmotic pressure gradient as compared to the outer
liq~id via the semi-permeable wall Osmotically active agents or
osmotically active compounds compris- magne-lU- sulphate, ~`
magnesium chloride, sodium chloride, lithium chloride, potassium ;
sulphate, potassium hydrogen phosphate,~ur-a, saccharose and the
like Other osmotically active ag-nts are known from US patents
Nos 3 854 770, 4 077 407 and 4 235 236 ;
Semi-permeable materials which are known as;polym-rs for osmosls
and reverse osmosis are, for exampl~ aellulos-~aaylate, ~ s
cellulose diacylate, cellulose trlacylat-, c-llulo9- acetat-,
cellulo~e diacetate~ cellulo e trlacètat~ glucan acetate,
acetaldehyde dimethyl acetate, cellulose acetate ethyl ~ -;`
carbamate, polyamide, polyurethano,~sulphonat-d~polystyrene,- -
cellulose acetate phthal~ate, cell~ulo~e-~acetate~-ethyI carbamate,
cellulose acetate succinate, cellulose acetate~dimqthylamino ~
ac0tate, cellulose acetate chloraoetate,~ cell~ulose~dipalmitate,
cellulose dioctanoate, aellulose dicaprylat-,~cel~l~ulose
- ~- 132~976 ~:
dipentanate, cellulose acetate valerate, cellulose
acetate-p-toluene sulphonate, cellulose acetate butyrate, ethyl ~;~
cellulose, selectively permeable polymers which are formed by
joint precipitation of a polycation and a polyanion as set out
in US patents Nos 3,173,876, 3,276,586, 3,541,005, 3,541,006 -~
and 3,546,142 Coatings of this type in semi-permeable membranes
may for example also be effected according to DE-A-33 10 081 or
DE-A-33 10 096
,
The proportion o osmotically active substance aan be from 10 to
800 parts by weight, preferably 20 to 600, 50 to 400 parts by
weight based on 1 part by weight of azeiastine being quite
particularly preferred The amount of coating substances applied ~ ;
is such that the semi-permeable membrane is 50 to 500Jum! ~
-. :. .
preferably 100 to 300~um thick
' ", ~:,
The processing of the active substanae and the osmotically ~ -
active substances may be effected bet~ween room t-mperature and ~-
80C To ad~ust the relea~e rate a hol~ ~s for example bored
in the membrane wall for exu~ple with the aid of ~ laser beam so
:. :.::: .
that after addition of the tablets prepared therefrom to an
aqueous liquid the active substance mày be dissolved or
suspended by entering liquid and pressed out through the hole
:.: -:
The application of th- semi-permeable~layer is ff-cted for
example at an air inlet temperature of 70 - 90C ~-
: . . -
',' '''`.:
' .' ~
, : .. :
~,.
.~
: :'
132~976
,~ ., .
The semi-permeable membrane may optionally also contain a
microporous layer or microporous substances may be incorporated
in the connection German Offenlegungsschrift 33 10 081, for
example pages 7 - 17)
Materials which are suitable for the preparation of the
microporous layer comprise for example polycar~onates of linear ~;
polyesters of carbonic acid in which carbonate groups recur in
the polymer chain, microporous materials which have been
prepared by phosgenation of a dihydroxy-aromatic compound such
as bisphenol, a microporous polyvinyl chloride, microporous
polyamides such as polyhexamethylene adlpamide, microporous
modacrylic polymers including those formed;from poly~inyl --
chloride and acrylonitrile, microporous styrene acrylic monomers
and their copolymers, porous polysulphones charaoterized by
diphenylene sulphone in a linear ahain, halogeDat-d
polyvinylides, polychloroether, acetal polymers, polyesters
prepared by esterification of a dicarboxylic scid or an `-~
anhydride with an alkylene polyol,~ polyalkyl-n- ~ulphides,
phenolic polymers, polyesters, microporous polysaccharides with
~ ~ !
substituted anhydroglucose units having a decreasing
permeability for water and biological fluids, asymmetric porous
polymers, cro~s-linked olefine poiymers, hydrophobic or _
hydrophilic microporous low denslty homopolymers, copolymers or
interpolymers as well as materials which are described in the US
patents Nos 3 595 752, 3 643 178, 3 654 066,;3 709 774, 3 718
_ 3_ 132~976 `::~ -
532, 3 ~03 601, 3 852 224, 3 852 388 and 3 853 601; in British
patent 1 126 849 and in Chemical Abstracts Volume 71, 427f,
22573f, 1969.
~ '
Other microporous materials for the preparation of the
microporous layer include polyurethane, cross-linked :
chain-extending polyurethanes, polyimides, polybenzimidazoles, :~
collodium, regenerated proteins, semi-solid cross-linked : `
polyvinyl pyrrolidone, microporous mater;als which have been : :
prepared by diffusion of poly-valent cations in polyelectrolyte ~:
salt water, microporous derivativee of polystyrene such as . .
sodium polystyrene sulphonate, polyvinylbenzyl trimethyl ::
ammonium chloride, microporous c-llulose acylates and similar :.
microporous polymers are known from US patents Nos. 3 524 753, ;:-~
3 565 259, 3 276 589, 3 541 055, 3 541 006, 3 546 142, .~.
, ~,:; .
3 615 024, 3 646 178 and 3 852 224. .
.-
The pore forming agent~ suitable for the prep~r~tloh of the ~:
microporous layer in the coating compris- solids and pore
forming liquids. The term pore forming geDts as u-ed here also . ~
comprises substances`which form micro passages and the range of ::
.....
the pore formers can lead to both types. The expression pore : ~-
::-, :
forming liquids within the~scopQ of this descrption comprises
semisolid and viscous liquids. The pore formers can be inorganic ; :
or organic and the layer forming polymer generally aontains 5 to ~-. -
70 weight~ of pore forming agent, in particular 20 to 50
, ' ';,
.. ..
,: .:
. .
, ., ::
-~: ',
.....
: ''~ ' `
~ 1325976
~eight~ The term pore forming agent, as applied both to solids
and to liquids comprises substances which can be dissolved,
extracted or leached out of liquid present in the coating used
from the precursor of the microporous membrane with the
formation of an effective, open cellular microporous layer The
pore forming solids have a particle size of about 0 1 to 200 um
and comprise alkali salts such as lithium carbonate, sodium
chloride, sodium bromide, potassium chloride, pota~sium
sulphate, potassium phosphate, sodlum acetat~, sodium citrate
. .
and the like Organic compounds s~ch as saccharide~ including -~
the sugars saccharose, glucose, fructose, mannitol J mannose,
..~ . .
galactose, sorbitol and the like One may
also employ soluble polymers such as carbowaxes, Carbopol and
the like The pore forming agents also comprise~diols, polyols,
poly-valent alcohols, polyalkyIene glycols~, polyglycols, poly(~-
~) alkylene diols and the like
4 Embedding of azelastine activ- substance or~ binding to the
following substances or mixtures of these~5ubstances
. .
digestible fat~, such as
triglycerides of saturated fatty acids CgH16o2~to
C1gH36O2 and mixturQs thereof,~peanut oil and~hydrated
peanut oil, castor oil and hydrated;castor;oi~l~ olive oll,
sesame oil, cottonseed oil and~hydrogenated~cottonseed oil, -~
corn oil, wheat germ oil, sunflowQr seed~ oi;l, ¢od liver oil,
mixtures of mono-, di- and triQst-rs of palmltlc and stearic
: ,
:
,~ 132~976
~ ~:
acid with glycerine, glycerine triolsate, diglycol stearate,
stearic acid
', "
Indigestible fats or fat-like substanees, for example esters
of aliphatic saturated or unsaturated fatty aeids (2 to 22
carbon atoms, in partieular 10 to 18 earbon atoms) with ~- -
monovalent aliphatie aleohols (1 to 20 earbon atoms), `
carnauba wax, beeswax, fatty aleohols (straight ehain or
branehed) of ehain length C8H170H to C30H61H~ in
particular c12H25oH to C24H49H
Polymers such as ~ --
- . .~
polyvinyl aleohol, poIyvinyl ehloride,~polyaerylie aeid - ~
.: ,....
(CarbopolR~; anionie polymerisat of methaerylie aeid and
methacrylie aeid esters (EudragitRL, EudragitR8), ; i
acrylic and msthaerylie aeid eat-r~Copoiym~-riSAtsS with `-;-
trimethyl ammonium msthaerylats (Eudrag~lt~ L,~
EudragitRRS). ; .,.~".'
Copolymerisatss of ethyl aerylatss and methyl methaerylates
(EudragitRNE 30 D), as well as of aerylie aeid, ~ `
methaerylic aeid as well as esters thsrsof Iratio of free
carboxyl groups to ester groups~ EudragitRL 30 D),
polyethylene, polyglyeolie aeid,~polyhydroxybutyrie aeid,
polylaetie aeid, eopolymers of~laetie aeid and~glyeollie
acid (manufaeturer ~oehringer~Ingelheim), eopolymers of
: .
~ ~ ~ .",,,",
.:
132~976 :~
~ ,.
lactic acid and ethylene oxide, eopolymers of glycollic acid
and ethylene oxide, copolymers of laatie aeid and
hydroxyhutyrie aeid, hydroxypropylmethyl eellulose-
phthalate or -acetate sueeinate; eellulose aeetate
phthalate, starch acetate phthalate as well as polyvinyl
acetate phthalate; carboxymethyl eellulose; methylcellulose ` -
phthalate, -sueeinate, -phthalate sueainate, m~thyl -~
cellulose phthallc aeld half ester; z-in; ethyl eellulose;
shellac, gluten; ethylearboxyethyl eellulose;~thaerylate
maleic acid anhydride eopolymer; maleic ~acld anhydride vinyl ~ -
......
methyl ether eopolymer; styrene maleia aeid eopolymerisate; `
2-ethylhexyl aerylate maleie aeid~anhydride;~esotonic acid
vinyl acetate eopolymer, glutamin~ie;aeid j~glutaminie aeid
ester copolymer; carboxymethyl c-llu~los~glycerine ~; -
mono-octanoate; eellulose aeetate soeeinate;~polyarginine;
cross-linked alginate; aross-linked gélat;ne~
Swelling agent~ sueh a~ methyl ~cellulo~ hydroxypropyl
cellulose, hydroxypropyl -ethyl~eel~lulo-e ~(Pharmaeoat,
Methocel E - propylene glyaol~ether~of~methyl~eellulose),~
alginie acid and their salts~(~Na~ Ca-salt, also mixtures of
sodium alginate and ealeium salt8~ueh~a~ CaNP04~, starch,
carboxymethyl stareh, ear~oxy-ethyi;eellu`lo5e~and their
salts (e g Na-salts), galaeto~mannaD~,~gum~arabie, karaya
rubber, ghatti gum, agar-agar,~earrageen,~xanthan rubber,
guar rubber and its derivatives~ earob b~an fleur, propylene
glycol alginate, pectin, tragàeanbh ~
1325976
7 : .
. ':
In the case of these sustained release components 1 to 800 parts
by weight of sustained release components are used per 1 part by
weight of azelastine, preferably 1 5 to 600 parts by weight, 2 0 -~
to 400 parts by weight being quite particularly preferred The
preparation of these formulations is effected at temperatures
between 18C and 80C
This dosage form may be prepared as follows
: ,, .
a) by dissolving or dispersing azelastln-~or~its salts in the `~;
.., .. ~
fats or fat-like substances~ment~ioned~or~in mixtures ~`-
thereof, also by melting the substanc-s~mentioned with
subsequent cooling, pulverlsing,~possibly~addi~ng other
substances such a~, for example, th~ two above mentioned ;~
substances that are water soluble~or~-wel~ in water and
pressing into tablet~ The coollng ;of the ;~molten materiai
and pulverising can al~o :be comblned ln on- ~tep by b~
dispersing the melt in aold water or ubj~ctinq it to spray
solidification
When the above mentioned oils~are used-~as sust~ined release
agents azelastine or its salt~is~di8~sQlved or~`suspended in ; . .
oil and, possibly fter addition;of~up to~2~ of ammonium
monostearate, filled lnto ampoules~and subsequently
sterilized or homogenized and f~ d~lnto~bottles optionally ~ ~
after addition of flavoori~ngs~anci/or~sed~imentation ~ -
: ~ ;
132~976 :~
retardants such as highly disperse silicon dioxide (e g
AerosilR)
b) ~y mixing azelastine with the fats, polymers or swelling
agents referred to or mixtures of these substances, also
with the application of heat, and pressing the mixtures, ;
optionally after the addition of further auxlliary
substances, into tablets or forming them into pellets
,'-''~ ~
c) ~y mixing azelastine or solutions of the f-ts or polymers
referred to in water or organic solvents, such as for
example ethanol, ethyl acetate, acetone or isopropanol, ;- ~-
optionally mixing with carrier materials such as celluloses,
as well as subsequent evaporation off of the solvents and -
mixing the smbedded activ- substanc-~obtain-d with ;~
additional auxiliary substances~ant processing into shapes
such as, for example, tablet8 or pellet8
~:
. :,.
d) by moistening of a mixture of azelastine and the mentioned -
swelling agents with organic ~olvents such as thanol, ethyl
acetate, acetone or isopropanol, possibly with addition of
binding agents such as polyvinyl pyrrolidon- or copolymers
of polyvinyl pyrrolidone and polyv nyl~acetat-, granulating
the mixture obtalned, th-n drying, optionally adding further
auxiliary substances and pressing th-~ixture into tablets
'
- ,' :'".
.': ~ '"
- ~ - 132597~ -
e) by mixing azelastine with a solution of nntural or synthetic ~-~
resins such as shellac or polyvinyl acetate in polyethyl
glycol having a molecular weight of 200 to 1500, optionally ;-
adding further auxiliary substances such as for example ;
stearates or swelling agents and encapsulating the material
obtained into soft or hard gelatlne capsules
. '''"' '
Generally speaking, the preparatlon of the drug formulations i8
effected in a manner kno~n per se, the known and colventional
pharmaceutical auxiliary substanc-s b-ing u~ed in addition to
the sustained release components as well ~s ot~h-r conventionnl
carrier and diluting agents, wher-by the ~uxiliary $ubstances
mentioned as sustained releas- compon-nts may also fulfill other
functions, for example as demoulding ag-nts or as disintegrating ~ `
agents
Carrier and auxiliary substances of thls~typ- may~or example be
those which are recommendsd or li~ted as~ ;auxili~ary substances
for pharmacy, cosmetics and related~l-ld~iln the followlng ` '
~ !
literature references allmann~ Encyklop--dle der technischen
Chemie, volume 4 (1953), pages 1 to~39; Journal of ,
Pharmaceutical Sciences, volume 52-~(19~63~ pag-s~91~8 t seq ; ~ -
H v Czetsch-Lindenwald, HilfsstofE-~fu-r Pharm-z~-~und
angrenzende Gebiete; Pharm Ind I~suei~2,-~1961,~page~ 72 et
seq ; Dr H P Fiedler, Lexikon der Hiif~stoffe fuer Pharmazie,
Kosmetik und angrenzende Gebiete,~2nd~edition, Editio Cantor,
~, :,. .
Aulendorf in Wuerttemberg 1981
~ ~ , ''- ',
: .
:,. . ~.
,~ 1325976
Examples of conventional auxlliary substances, carrier
substances and diluting agents are gelatine, natural sugars such
as raw sugar or lactose, lecithin, pectin, starch (e g corn
starch), as well as starch derivatives, cyclodextrines and
cyclodextrine derivatives, polyvinyl pyrrolldone, gelatine, gum ~
arabic, alginic acid, tylose, talcum, lycopodium, silica gel - -
(e g colloidal), laevulose, tragacanth, sodium ahloride,
stearate, magnesium and calcium salts of fatty acid- with 12 to
22 carbon atoms, in particular the saturat-d acld (- g
stearates), polyethylen- glycol wlth a m-an molecular weiqht
between 200 and 20,000, preferably between 200~and~5,000, in
particular between 200 and 1,000, or th-ir mixtur-s and/or
polymerisates of vinyl pyrrolidone and/or mix-d~polymerisates of
vinyl pyrrolidone and vinyl acetate, e~ters of~aliphatic
saturated or unsaturated fatty acids ~(~2~to 2Z carbon atoms, in
particular 10 to 18 carbon atoms) with -onova~l-nt;~41iphatic
alcohols (1 to 20 carbon atoms) or poly-val-nt~alcohol such as
glycols, glycerine, diethylene glycol, pent~-rythr~itol,
sorbitol, mannitol, etc which may optionally~also be
etherified, benzyl benzoate, dioxolan-s,~ glyc-rol~formals,
tetrahydrofurfuryl alcohol, polyglycol :ethers with C1 to C12
alcohols, dimethylacetamide, lactamid-s~,;lactat-s,~ethyl
carbonates, silicones (in particular modium ~viscouJ polydimethyl
siloxanes), calcium carbonate, sodi~um~carbonate,~calcium
phDsphate, sodium phosphate, magn-sium carbonat-,~gum arabio,
alginic acid, stearAtes, fats and simllarly acting~substances -
: ' ~ , ' ;.--
: : ~ ~ ''.,''
~, 132~976
In addition, the dosage forms may contain surface a~tive
substances that are active at the interface Some examples that
may be mentioned are alkali soaps such as alkali salts of
high~r fatty acids (e g Na-palmitate, Na-stearate) or their
derivatives (e g Na-ricinoleate sulphate); sulphurated ~
compounds or sulphonated compounds which are formed by reaction -~ ;
of higher fatty alcohol8 with 8ulphurlc ac~d or chlorosulphonic ;~
acid and are usQd, for example, as sodium salts (e.g. sodium
lauryl sulphate, sodium acetyl sulphate, sadium 8;t-aryl -;
sulphate, sodium acetyl sulphonate); salts of the;gallic acids;
saponins; quaternary ammonium compounds ~partial fatty acid
esters of sorbitan; partial fatty acid est~-rs~;and~fatty acid
esters of polyoxyethylene sorbitans; sorbitol e~ther of ~;
polyoxyethylene; fatty acid esters of polyoxy-thyl-ne; fatty
alcohol ethers of polyoxyethylene; Eatty;acid~-sters of
saccharose; fatty acid esters of polyglya-ro~ prot-ins,
lecithins
The dosage forms may also contain aellulo~--, in particular if
it is intended to prepare compres~ed~shapes These~may be
purified cellulose (e g commercially~available s~ElcemaR) or
microcrystalline celluloses as for~exampl~;sold~com-ercially -~
under the name of AvicelR It is, howeveD~,~ also possible to
use other filling agents having the functlon of binding agents
such as calcium hydrogen phosphate, l~ctose, starches (e g
: .,
.j .
l~ 132~976
~ ..
potato starch, corn starch, modified starches such ~s Starch ST
1500/Colorcon), glucose, mannitol, saccharose.
The dosage forms may in addition contain sedimentation
retardants such as for example highly disperse silicic acids
having a surface of 50 to 500 m2/g, in particular 100 to 400
m2/g (determined using the 8ET method). These are available
commercially for example under the name AerosilR.
:`
It may in addition be appropriate to use demoulding agents in
the dosage forms. Those that may be mentioned are: talcum or
siliconized talcum, calcium- and magnesium~stea~rate, stearic
acid, paraffin, hydrated fats and oils, silicon oil~emulsion.
.
Other auxiliary substances that may~be used are substances that
effect disintegration (so called disintegr-nt-)~such as~
cross-linked polyvinyl pyrrolidone, so~ium carboxymethyl starch,
sodium carboxymethyl cellulcsR, formald-hyd- gelatlne, - -
formaldehyde casein, polyacryllc acid ~nd ultra-amylopectin.
. : : :' '- -
To prepare solutions and suspensions~ it is for example possible --
:
to use water or physiologically acceptable~organic solvenis, for
example ethanol, 1,2-propylen- glyccl~ polyglyccl9 and deriva- -~
tives thereof. For injectable solut~ions or~suspensions it is for --~
example possible to use non-toxic parenterally tolerated
diluting agents or solvents, such~as for example~
,,:
: :
,, 132~976 ~ ~
water, 1,3-butane diol, ethanol, 1,2-propylene glycol,
polyglycol - water mixtures, Ringer's solution, isotonic salt
sol~tion ~ -
`, "'.
Moreover the addition of stabilizers, colourants, antioxidants
and complex formers (for example ethylenediaminetetra-acetic
acid) and similsr agents is po sible _~ well as the addition of
acids such as citric acid, tartAric acld, mal-ic acld, fumaric
acid
Antioxidants that may for exampl- be used~are sodlum
metabisulphite, cystein, ascorbic acid and their~esters (for ~ -
example palmitate), flavonoids, gall;ic acid,~gallic acid alkyl
esters, butylhydroxyanisol, nordihydroguaiacic~acid, tocopherols
as well as tocopherols ~ synergists (~ubstances~whlch bind heavy
metals by complex formation, for example lecibhin,;ascorbia~
acid, citric acid, phosphoric acid) ~ ~ ;
. :, . .
Conserving agents that may~be u~ed ar- for~exampl~e sorbic aaid,~
p-hydroxybenzoic acid ester (e g low-r alkyl;~e-ters), benzoic
acid, sodium benzoate, trichloroisobutyl alcohol~ phenol,
cresol, benzethonium chloride and ~formalin d-rivatlves~
Plasticizing agents that may be oonsidèréd as~aoating substances
: : : : .: ,.:
are
1~2~97~
~t
-- a~ --
citric and tartaric acid esters (acetyltriethyl-, acetyl-,
tributyl-, tributyl-, triethyl-citrate);
glycerine and glycerine esters (glycerine diacetate, -
triacetate, acetylated monoglycerides, castor oil);
phthalic acid esters (dibutyl-, diamyl-, diethyl-, dimethyl-, -
dipropyl-, D~(2-methoxy- or ethoxyethyl)-phthalate, ethyl
phthalyl- and butylphthalylethyl- and butylglycolate)
alcohols (propylene glycol, polyethylene glycol of various chain
lengths), adipates (diethyl-, di(2-methoxy- or ethoxy
ethyl)adipate); benzophenone; diethyl- and dibutyl sebacate, -
succinate, -tartrate; - -
diethylene glycol dipropionate; ethylene~glycol diacetate,
-dibutyrate, -diproprionate; tributylphosphate, tributyrin;
polyethylene glycol sorbitane mono-oleate; sorbitane
- .
mono-oleate ~ -
To apply the sustained release components or coating substances
.
it is possible to use solvents which may or example be aqueous
~ ::
solvents, alcohols, ketones, e~ters, ethers, aliph~tic
hydrocarbons, halogenated solvents, cycloaliphatia, aromatic or
heterocyclic solvents or mixtures thereof Typical solvents are
''~'..-
inter alia acetone, diacetone-alcohol, methanol, ethanol, ~
isopropyl alcohol, butyl alcohol, me,thylacetat~, ethyl acetate, -
isopropyl acetate, n-butyl acetats, methylisobutyl ketone,
methyl propyl ketone, n-hexane, n-h-ptan-,~ethyl glycol
monoethyl ether, ethylene glycol monoethyl~acetat-, methylene
.:
, - ,, .
~ ~ ',,'.
' ~ '
' ,''',',,', 1',~ "". ~ ' " ,~ "'""~
~ 132~976
. .
dichloride, ethylene dichloride, propylene dichloride, carbon
tetrachloride, nitroethane, nitropropane, tetrachloroethane,
ethyl ether, isopropyl ether, cyclohexane, cyclo-octane,
benzene, toluene, naphtha, 1,4-dioxan, tetrahydrofuran,
diethylene glycol dimethyl ether, water and mixtures thereof
such as acetone and water, acetone and methanol, acetone and
ethyl alcohol, methylene dichloride and methanol and ethylene
dichloride and methanol and well as mixtures thereof. These
solvents are removed again in the course of the coating process.
Independent of the process of preparation the dosage forms of
the invention are charactçrized in that they release the active
substance azelastine or its physiologically acceptable salts at
a release rate between 0.05 and 5 mg per hour to the body fluids
or allow it to pass therein.
Dosage data relate in each case to azelastine as base; if
azelastine salts are used, a conversion must be made according
to the molecular weight.
' :' ,
The amounts of azelastine active substance in the formulations
of the invention are
a) for dosage forms to be used orally
0.1 mg to 50 mg, preferably
0.2 mg to 30 mg, in particular
0.5 mg to 20 mg of azelastine active substance.
~ ~' '' ' ;
132597~ ;
The individual doses mentioned may be used 1-5, preferably
1-3, in particular 1-2 times daily.
b) in the case of dosage forms to be used parenterally ~
(intraveously, intramuscularly, subcutaneously, ~-
intraperitoneally):
0.1 mg to 500 mg, preferably
0.2 mg to 400 mg, in particular
0 5 to 250 mg of azelastine active substance. ;-
The single doses mentioned may be administered once monthly
(for example for implants to be applied subcutaneously) up ~-
to 3 times daily, preferably once monthly to twice daily, in
particular once monthly to once daily.
c) in the case of dosage forms to be used dermally (e.g.
plasters)
5 mg to 5000 mg, pref~rably
10 mg to 3000 mg, in particuIar
30 mg to 2000 mg of azel-astine active substance.
The single doses mentioned may be administered onc~ daily to -~
once monthly, preferably once every 3 days to ance every 3
weeks, in particularly weekly to every 2 weeks.
: . '
Particularly preferred sustained release components are: ;
'.
~ ~ -
~32~976
~ :,
a) cation exchangers
Sedium poly(styrol, divinylbenzene)sulphonate (e.g.
AmberliteR IRP 69) 3 to 10 parts of AmberliteR IRP 69
are for example used per 1 part of azelastine (base). ~
~'. ', -
b) Coating substances
~ydroxypropylmethyl cellulose phthalate
1.5 to 3 part~ of hydroxypropyl methyl cellulose phthalate
55 are used per 1 part of azelastine.
Ethyl cellulose -
0.1 per 1 part of ethyl cellulose are used per 1 part of
azelastine.
:
Eudragit resins for example EudragitRRS
0 01 per 0.1 part of EudragitRRS per 1 part of azelastine.
c) Semi-permeable layers with osmotically acting active
substance containing core and outlet openings:
Coating with 100 to 300 ~m thick layer of 82S cellulose
acetate and 18 S hydroxypropyl methyl cellulose.
d~ Embedding substances
'' " ~
132~976
Hydrocolloidal, e g. hydroxypropyl methyl cellulose: 2 to 10
parts of hydrocolloid per 1 part of azelastine.
:,
EudragitRRS:
10 to 15 parts of EudragitRRS per 1 part of azelastine.
Glycerineditripalmito stearate (e.g. Precirol Ato 5)
1 to 10 parts of Precirol Ato 5 per 1 part of azelastine.
` :" '
The requisite release of active substance of 0.05 to 5 mg per
hour occurs within the desired range through the parameters set
out in the process claim in conjunction with the corresponding
detai 15 in the description. Should it be desired to aahieve a
specific release rate within this range it is possible, for
~xample, to proceed as follows:
., '
1. The preparation of the coating or embedding of the active
substance in the described manner.
' :'
2 Testing of the release of active substance from the dosage
_ .
form using 0.1 N HCl (2 hours) and'phosphate buffer pH 6.8
~subsequently) as release medium.
3 a) Should too much substance be released: -
,- ~
' '' ''.',:
1325976
~ .
~" ..
Increase of the proportion of the sustained release
component and/or reduction of the proportion of
water-coluble auxiliary substances. Reduction of the
proportion of osmotically active substance.
-.
b) Should too little substance be released:
Reduction of the proportion of the sustained release
component and/or increase of the proportion of water
soluble auxiliary substances. Increase of the
proportion of osmotically active substance.
In general it is aimed to achieve a release rate of 1 mg of
azelastine per hour.
.
Exam~le 1: ~
____ ____ :
100 g of azelastine hydrochloride are mixed with 960 g of
hydroxypropyl methyl cellulose [visco~ity of a 2~ aqueous
so l ution: 4000 cP ( commercial product: e.g. Methocel K4M
Premium)], 1320 g of spray-dried lactose and 20 g of magnesium ~`
stearate and the mixture pressed into tablets weighing 120 mg,
having a diameter of 6 mm and a radius of curvature of 6 mm.
In conjunction thereto the tablets may be provided in a
conventional procedure with A gastric juice-soluble or gastric
juice permeable or gastric juice-resistant film coating.
- .' ~ . u ~: ,r
132~976 -:
~o ~ -
~ .:. . .
To produce a gastric juice-resistant coating, 1000 g of tablets
are sprayed with about 1000 g of the following suspension, for
example in a coating drum:
`':, ,'', :,'
63 g of cellulose acetate phthalate are dissolved in 480 g of ~ -
acetone. To this solution are added 21 g of phthalic acid
diethyl ester, 30 g of dicloromethane and 131 g of methanol. 4.4
g of titanium dioxide are suspended homogenously in the solution ;
ohtained
' ".^ .
The spraying is carried out in discontinuous manner with heated
air being blown in between the spraying phases for drying
: . . - ~:,.
purposes. ~
,;'~,
One sustained release tablet contains 5 mg of azelastine
hydrochloride. -
Exam~le_2
12 g of azelastine hydrochloride, 20 g of EudragitRRS PM, 250
g of talcum and 200 g of lactose are mixed and ths mixture
. . .
moiste~ed with about 140 g of a mixturs of 12.7 g of glycerine :
triacetate (commercial name for exampls Triacetin) and 127.3 g
of EudragitR RS 12.5. The moist mass i granulated ln a
con~entional manner through a sieve of mesh size 1 mm and ~ --
- ~.
sprayed, after drying at room temperature, in the coating drum
onto a mixture of 909 g of EudragitRRS 12.5 and 91 g of ;-
.,:
.- :,-:-.
132~976
Triacetin using a spray gun. The dried granulate so obtained
is pressed into biconvex tablets weighing 300 mg each and
having a diameter of 10 without addition of further
auxiliary substances.
One tablet contains 5 mg of azelastine hydrochloride in
sustained release formulation.
Example_3:
50 g of azelastine HCl are mixed with 100 g of tartaric acid,
250 g of lactose, 10 g of microcrystalline cellulose (Avicel*
PH 101) and 7 g of hydroxypropyl cellulose [viscosity of the
5% solution: 75 to 150 cps (e.g. trade mark: Klucel LF)] and ~'~
the mixture made up into a paste with 60 g of a 6.25% aqueous
~olution of hydroxypropyl cellulose (viscosity of the 5%
aqueous solution: 75 to 150 cps (e.g. trade mark Xlucel LF)).
The moist mas~ i~ pressed through a perforated plate of a
hole diameter of 1 mm and the resulting strands are divided
~: .
and rounded in the conventional manner by treatment on a
spheronizer di~c. The pellets obtained are dried and sieved.
300 g of pellets of the sieve ~ractlon 800 to 1200 ~m are
coated in the conventional manner with a solution of 42.5 g ;
of ethyl cellulose (trade mark: Ethocel* Type N 22), and 37.5
g o~ polyethylene glycol 1500 (trade mark e.g. Carbowax 1540)
in 720 g of chloroform through spraying in a fluidized bed
apparatus.
* Trade mark ~ -;
- 31 -
- 1325976
~a
3~
50 g of the above obtained coated pellets are filled into size 3
hard gelatine capsules.
: ''
One hard gelatine capsule contains 4 4 mg of azelastine
hydrochloride in sustained release formulation.
.:';
E__m~le_4:
The preparation of the dosage forms of the invention is effected
by mea~s of embedding in swelling agents:
, ,:
The following substances are mixed: ~-
(amounts in grams) -~
~''~'"'
Mixture -
1 2 3
. .
Azelastine hydrochloride 50 50 50
: .:. ~,
~ydroxypropyl methyl cellulose
(- Methocel K 4 M) 480 192 96
'' ~
Lactose 660 948 1044 :: .
Magnesium st~arate 10 10 10
,.. . .
The mixtures are pressed on a tablet press into planar tablets
each weighing 120 mg and having a diameter of 6 mm. --
: . - .
~ fK
. . .
... ...
- .,. ., .. ,. ,, ;;,: -, ~: " ,.: .. . ~. -: . ,, ~ . : .: .:. .:: . : . - .
33 ~32~97 ~
3~
The thickness in mm is 3.25 3.15 3.05
sreaking strength (N) 47 48 50
(Heberlein breaking
strength tester) ::
One tablet contains 5 mg of azelastine HCl. :
The release of active substance in the ~pparatus of USP XXI
(dissolution tester apparatus 2, dissolution medium: 500 mg 0.1 ::;
N HCl, speed of rotation 120 rpm) is the following (rele~se of
active substance quoted in S):
Mixture :
1 2 3
After 5 mins 4 31 50
60 mins 20 76 100
120 mins 36 96
180 mins 55
240 mins 74
300 mins 86
360 mins 93
_. :. .:
Exam~le 5 : .
____ ____ :::'
100 g of azelastine hydrochloride, 200 g of tartaric acid, 500 g :
of lactose and 700 g of microcrystalline cellulose are mixed and
made up into a paste with a~out 700 g of purified water. The .
- : :
132~97~
_ 3~ _
moist mass is pressed through a perforated plate of hole
diameter 1 mm and the resulting strands are divided and rounded -
in 2L eonventional manner on a spheronizer disc. The pellets
obtained are dried and sieved.
1000 g of the pellets of sieve fraction 800 to 1250 pm are
sprayed with a suspension which is prepared as follows:
0 6 g of Polysorbate 80 are dissolved in 190 g of purified water
and 40 g of triethyl citrate are emulsified in the solution. 800
g of a 30~ aqueous dispersion of a copolymerizate of a~rylates ~-~
and methacrylates with a low trimethylammonium ethacrylate -~ ~ -
chloride (- EudragitRRS 30 D) content are added to the
emulsion obtained and stirred for about 10 minutes.
109.2 9 of talcum and 0.2 g of silicon anti foaming oil ;;
(Simethicone) are suspended in 860 g of purified water. This
suspension is stirred into the above obtained dispersion.
' ' ~ '"
Tne coating of the lacquering suspension so obtained onto the
pellets is effected in a conventional manner, for example using
a fluidized bed spray granulator with an inlet air temperature
of 40-50C and a maximum outlet air temperature of 40C. The
drying of the pellets is effected under the same conditions.
. :`'~ '
I r~ mdr~
:
132~976
3~
~ _
The above mentioned lacquer suspension is sprayed on until the
total ~eight of the dried pellets is equal to 1042 g.
:' .: ' .
The lacquered pallets are filled in amounts of 78.1 mg into size
3 hard gelatine capsules. One hard gelatine capsule contains 5
mg of azelastine hydrochloride in sustained release formulation.
The release of the active substance from a capsule in the
apparatus of USP XXI (dissolution tester, apparatus 2,
dissolution medium: 500 ml of 0.1 N HCl, rotation speed: 120
rpm) is:
: .
After 1 hour 3 0 mg ~ 60
After 2 hours 4.5 mg ~ 90 ~
The release of active substance i5 thu~ 3 mg per hour.
Exarn~le_6
The procedure of Example 5 is followed, except that the lacquer
suspension described in Example 5 is sprayed on until the total
~eight of the dried pellets is 1127 g. The lacquered pellets are
t'nen filled in amounts of 84.5 mg into size 3 hard gelatine
capsules~ One hard gelatine capsule contains 5 mg of azelastine
hydrochloride in sustained release formulation. The release of
the active substance from a ~apsule in the apparat~s of ~SP XXI
is (conditions of the test as in Example 5~:
132~976
~ , .
.~ , ~ .
,
After 1 hour 0.25 mg - 5
After 2 hours 0.50 mg ~ 10 ~ ~
The release of active su~stance is thus 0.25 mg per hour. --
Exam~le 7 ~ :
The procedure of Example 6 is followed.
. -::
If the pellets obtained in Example 6 are filled in amounts of :~.
16.9 mg into size 3 hard gelatine capsules, one hard gelatine .-
capsule contains 1 mg of azelastine hydrochloride in sustained
release formulation. The release of the active substance from a .:-
capsule in the apparatus of USP XXI (conditions for the test as ..
in Example 5) is: -
: .:
After 1 hour 0.05 mg ~ 5
After 2 hours 0.10 mg ~ 10 *
!`~ '
': '
The release of active substance lS thus 0.05 mg per hour.
: ' '; " .
':
-
i32~97 ~
Example:8
Capsules containing 6 mg of azelastine or suspensioncontaining 6 mg of azelastine in 5 ml, in each case Iinked to
an intensely acid cation exchanger 8.48 g of azelastine
hydrochloride are dissolved in 4 litres of purified water.
71.5 g of styrene sulphonic acid-divinyl benzene copolymer
(degree of cross-linking 8%) (commercial product, for
example, AmberliteR IR 120) are suspended in the solution and
the suspension is stirred for 3 hours. The suspension is
then filtered through a glass filter funnel and the filter
cake obtained is washed twice with purified water, using 300
ml each time. The wash water is properly filtered with
suction.
5 g of gelatin (isoelectric point 6-7.6, molecular weight
25,0009 to 35,000) (commercial product: Belito R Collagel,
Deutsch Gelatinefabriken, Eberbach/Neckar) are dissolved in a -
solution of 5 g of l-N-hydrochloirc acid in 800 g of purified
water in a beaker. The above-mentioned filter cake is
suspended in the solution and the suspension is stirred for 1
hour. The suspension is then filtered through a glass filter
funnel and the filter cake obtained is washed twice, using
200 ml of purified water each time. The wa~h water is
filtered with suction.
The filter cake is dried at 60C. The dried product is drawn
off in batches of 63 mg into hard gelatin capsules of size 4.
One hand gelatin capsule contains 6 mg of azelastine linked
to intensely acid cation exchanger.
A juice containing 6 mg of azelastine linked to cation
exchanger in 5 ml is obtained in the followiny manner:
7.4 kg of purified water are heated to a temperature of 90 to
~50C and 0.002 kg of propyl-4-hydroxy-benzoate and 0.013 kg
of methyl-4-hydroxy-benzoate are dissolved therein. 0.020 kg
of hydroxy-ethyl cellulose (average degree of
_ ~ _ , :
37
132~976
polymerization:250) and 3.0 kg of saccharose are dissolved in ~ -
the solution cooled to 70C.
On cooling to 25C 3 g of raspberry aroma and 0.2 kg of ~;
modified starch (Starch 1500 R Colorcon) are dissolved and
suspended while stirring. 124 g of dried ion exchanger ~
loaded azelastin2 are stirred into the suspension. The ~ -
suspension is subsequently replenished to 11 kg
(corresponding to 10 litres). - -~
The release of the active substance from one capsule or 5 ml
of suspension in the apparatus of the USP XXI (dissolution
tester, apparatus 2, dissolution medium 500 ml of sodium :
chloride 0.8%, speed of rotation:lOO rpm) is after l hour -
25%, 2 hours - 40%, 3 hours - 50%, 4 hours - 58%. 5 hours - -
65~, 6 hours - 69%, 7 hours - 72% and 8 hours - 75%.
'",`''' ':
The dissolution medium is restored every hour. The values
obtained for the release are added up.
' ~'.
,':
.' .:
., .
_ 3~ _ ~
' ~ :
