Note: Descriptions are shown in the official language in which they were submitted.
CA 02274910 1999-06-14
Flat pharmaceutical preparation for application and release
of buprenorphine or of a pharmacologically comparable
substance in the oral cavity, and process for the
production thereof
The present invention relates to a pharmaceutical
preparation for application of buprenorphine or
pharmacologically comparable active substances in the
region of the oral cavity, respectively the oral mucosa.
More particularly, it relates to a preparation that is
adapted to be flat and in the form of a foil-, paper- or
wafer-shaped administration form.
Flat active substance carriers have already been developed
and produced for various purposes. DE-OS 27 46 414 can be
regarded as fundamental to this administration form, said
document describing a foil-type tape of active substance,
binder and further active substances, with a direct
relation existing, by reason of the homogeneous thickness,
density and width, between a unit of length of the tape and
the dose of active substance contained therein. The
advantages of the continuous dosage property have been
recognized also by other applicants and have been described
in specific individual variants. Thus, DE-PS 36 30 603
claims a flat-shaped carrier material, for example in the
form of a separating layer, with an active substance-
containing coating, the latter being peelable, in doses,
off the carrier material after having been previously
separated into dosage units.
The practicability of the flat format in general and the
advantages afforded in the manufacture of the adminis-
tration form and in the dosing when employing such
administration form have been recognized in the prior art.
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Moreover, further advantages of such administration forms
can be derived such as the fact that, relative to the
weight of the administration form, a relatively large
surface may be printed on the said administration form,
thereby making it possible to increase intake safety, as
well as affording the possibility of discrete intake
without any liquid being available.
Despite these obvious advantages, such flat administration
forms have hitherto hardly been successful. Obviously, the
advantage as compared to conventional administration forms
does not suffice for many manufacturers of pharmaceutics to
develop products of this type comprising the usual active
ingredients and to pursue the legal drug approval thereof.
Moreover, existing production machinery and existing know-
how cannot be made use of for these novel products; this
means that the necessity of large investments would arise.
Despite the above-described advantages of flat, film- or
paper-like administration forms, the therapeutic and/or
economic advantage in administration of common active
substances which are also perorally applicable is
apparently not great enough as compared to conventional
tablets to justify the costs of switching over to these
administration forms.
One of the substances that are little suitable for peroral
administration is buprenorphine, an opiate which has been
successfully used in the therapy of pain for years. After
peroral application it is hardly bioavalable, i.e. it
appears in the blood circulation only to the vary small
extent of a few percent of the dose taken (McQuay & Moore,
in: Bupenorphine, ad. Cowan & Lewis, New York 1995).
Presumably, the reason for the lack in bioavailability lies
in the extensive decomposition of the substance during the
first liver passage following gastrointestinal absorption
("first-pass effect°). A possibility of avoiding the first-
CA 02274910 1999-06-14
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pass effect in oral administration is to bring the active
substance to absorption already on the oral mucosa. In
order to enter the central systemic circulation, an active
substance which enters into the blood via the oral mucosa
does not have to first pass the portal system and thus, in
concentrated form, the liver, which metabolizes the active
substance. A prerequisite for buccal or sublingual
application, however, is a sufficient permeability of the
oral mucosa to the active substance, taking into
consideration the required dose. Permeability in turn
depends to a large extant on the physicochemical properties
of the active substance. Since buprenorphine is effective
in very small doses, and since it has the required
physicochemical characteristics, buccal or sublingual
application is very attractive.
In fact, apart from injectable administration forms there
are - at least in Germany - no commercially available
peroral administration forms, but only so-called sublingual
tablets, which comprise buprenorphine (Temgesic~ sub-
lingual). It is true that such tablets take into account
the fact that sublingual application of the active
substance is preferable to peroral administration - even
though they do so above all by way of their intake
directions as only these suggest the sublingual
administration, not the tablet itself. However, they offer
a vehicle which has considerable drawbacks for this purpose
of application. Among these disadvantages is, firstly, the
not inconsiderable disintegration time, which in the case
of pressed tablets is at least several minutes even under
favorable conditions, and in the case of the commercially
available tablets is typically about 5 to 10 minutes. For
patients suffering from severe, acute pain this
disintegration time results in an unwanted delay of the
onset of action; in a substitution or withdrawal therapy,
however, this puts a strain on the medicinal personnel with
CA 02274910 2004-02-26
respect >ra the time requixed for ad~ui,nigtratiaa, since the
persoasao7. must supervise that the tablets ors used as
d~.raCted and antst prevent proper s~oval of tte hon-
clisiateQraCed tsxblet frcma the mouth. I~rtb,er disadvanta,las
of the tablet are the fareigr~ body ee~ns$tion occurring
dazria~ the dis~.~ategratioai time, but a*so tho great
vaz~fabxlity is the extent of subliagua* absorption, oPhich
ie caused by the active substance duriaQ or after
di.sintreQratioa of the tablet having for the most part np
direct contact with the ora* mueasa, bat baiaQ released
into the sa2iva; the saliva, hoara~rer, cars be reta3.aad is
the oral cavity for a very variable time, which is more or
less haphazard, before being swa*~,a9aed.
It is thus the object of the preeeat iriveistioa to crate
pharmaceutical preparatic~xs based on, sad having .the . ..
~eneacal advaatatles of, flat, film~like.ar paper-like active
substsace aarriers.~ch by xeascu of the oo~j,l4atica pith
a apgaial active substance have additioaa~. economical
and/or therapeutical advaataQes, apart frown those msationsd
above, over pharmacastical prBparatiana of the same aCtiva
suhstaaae based oa cpaventional. adtnfaistratfoa farms such
as tablets. Ia addition. a.t is llf~c~ri.se na object of the
i.nveation to pravi8e na ac~iriist7ratioa farm for
bupre~aarphiae that re*eases the aciri9e substance 3a the
ora* cavity ~hila root havxa~ the disadvantages described is
the prior art.
In one embodiment, the present invetxtion provides a buccal pharmaceutical
preparation for treating acute conditions of pain or for addiction therapy,
comprising as active substance buprenorphine or a pharmacologically
comparable substance as such or as a thexapeutieally suitable salt,
characterized by a wafer-shaped administration form, disintegratable in
the aqueous medium of the oral cavity, which has a mucoadhesive, active
substance containing layer based on water-soluble, film-forming polymers
of small thickness, for rapid active substance transfer through short
diffusion paths, while having a large surface appropriate to the effective
dose.
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'!.'he ob~sct is achi~d is accordaace..with the fvrxt~tss of
the cisfma by provid3.sey as admsaiatration form oa the basin
of a fZaty foil-, pier- or safer-like active subst~ce
carrier, which asb~atfoti form conCairig as active
substaaea buproaorphine, respectzvc.ly one of its
t~serapant3ea7,lx aCCOptabla salts, or a thertxyeistically
coa~tarable actsve sabataaoe. As will be eo~laiae8 is ty,e
fol.l,cro~irr~., the achoinistration form of .the preSeat invent;on is
by far s~srfor to a coavuationai a~ai~strats.ca fog for
adm3afstexi~ ~~i7?lsilae - hbth fi~ams the eGOnoaeical is
well as the tlasrupawtica7, poa.Rt of ~-iar - asad it is
espeoia,lly Sultal~le, ou the vne ht~und, for anxvlQesia ~La
arses of acute coadxt3ox~ of paip, and. ~ the other ~d.
for the therapyaf opiate or coraiae addxotiori in the sense
o! a substituti~ therapy or s witbdraeral ~~gram.
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'The phat~tacerltic~dl preperatxoa Of the pi'eserit invetltion cair,
upva applivativn. be bx'ou~ht into direct contact.with the
oral Qtucosa~,. Due -to the flat dea3~, iaane81ate1y afber
appl~.cata.oa about half of the surface of the adm,iaistratioa
foam, orhic~a is large ar~ywrsy, is located directly oa the
mucosa. The bupranorphilxe released thus eaaovaters two
factors paxtioularly favorable far entry into the body,
~7.y a shos't diffusion path sad ~ a lax'ge diffusion area.
.. Thxa reduces .the:portiaa of.bupteaorpb~'that is
. : swa~.lo~yv~ed, v~rhich xa the ca~aa of . many othez' active aQeata
,wonsid not be a pastivular 'prola~.mn. v~r. v~ath
bupreaorpblas, ewal~.avPiag of the active substance should be
avoide8 i~ possible, or ab~ovld be xe$uced siace. for the
above mentioned reasons, ~allaorod bupreaorph3ae ~s
iaaffevtive. eves fps th4 ease o! the moat simpia em~odfmeat
accordiaQ to the iavaation, sad given a dtai~ateQratioas tiaoa
o~ a few minutes folloariag ~pplioa,t~.ms or fellawiag
introduction iat4 aqueous media, the super~.ority of a
?yupres~arphine-coataiaa.ag film over a buprcaorphiae-
ovntaix~iag tablet mill thus beacme ovident_
~n impxorad ooataat of the pharmaceutical Dreparatioa with
the oral muaosa caa be a.ehieved through selectiag avgiliasy
substaaaBS. It is kaowxa of certain orall5r applicable
auxiliary assets which are co~oaly used is phaaoaceutfes
that they knave mncoadhesS,ve propax't3e8. Examglea for such
mucoadhesive subataaces are polyacrylic acid, aarbv~-
methylesllulo~ae, tragacaath, alginic acid, gelatin,
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h~o~etbylCallulose, methylcellulose and slum Arabic. xa
addition, it is 'known of various aoa-sauaosdbesive
substances that is certain m'Lxiag ratios xhel. dovalap
mucvadhes~.~re properties tvo. ha ale for such a mixture
xs glycerol moaoo7.eate/water is a ratio of 84:16 (8agstraat
at al., Fhara_ Tech. ~rnr. 9 [1995), No. 2, pa,~s i4-17)-
xn the case that mucoadhesiva ~avxilsary sukrstaata3a are
uaedr ft is'prefarablo for the adm3n3atration form of the
.pharma.ceut~.cal nraparatiou, aaaora3iag to the iaveatioa to
have a tvfo-layer os mufti-layer structure. It Can thereby
be prevented that the preparation canylutixrateg various
parts of the muaosa with each other, a~hi.ch woula3 lead to
seasattioris o~ ooxsa~.dgrable disc4~ort durxl~g app~.scatioa.
zn addition, i.t ig ~.n such a case preferable for tho
admfaistra3tion fog to have a structure the aon-
mucoadhesive 7~a~rer of which has a permeability to the
.actyv~ substance arhich is relatively smaller that that of
the mucQadhesfve layer, ~.t thereby being possible to
prereat thane active substance losses occur dtia to active
sulsstaxace being released into the saliva ixastead of to the
msaeosa.
Fhasmaceutical prepasati~s accordiaQ to the pregeat
xaveatioa are also those cvataiaing, sprxrt fx~cm~ the active
substance bu7prsnorphiae or an active substa:sca
pharmacolog~.cally aamparabla therata. one or pore further
active substaszces . Such a prepara.txva can be advarataQ$ous
~.n sewe:ral respects. Oa the one hand 3t is a recognised
xa~thod far t~atiny several syaaptoms or conditions
occurring simsiltsttleat~a~.y to admiaiater a fixed active
subatAnca caombinaLiaya 3a a majdiazasmaat. 'ho taxis esid, 3,t fs
possible to a.ncorporate any therapeut~.cally appropriate
active substances into Che preparation wacotQ the
pxeseat iaveatioa. Oa tho other hand, the cambinat3on, as
according t4 the savaab.Cioa, of as opiate active substaaee
CA 02274910 2004-02-26
with asaother ~tubstaltce that se capable of reduciag the
g~pecific rie7ts of dpxate adtai.x~,~.stratioa ie especially
usetu~. aad ad~o~aatagaous.
Thus - possibly partial - opiate antagonists, eucb as, fpr
exaaxple, ssslbuph3aa, naloxoae or naltrexone, caa be
oo~biaed xith the opiate aot~.'i1e sabstaace~, which rssnlts is
the szak of addictso~n or habstuatioa 3.avolved i.a the
xepeatad admi.~nfstrat~.on of the preparat3.oa beirag $hed
by reason of the fast that the dc~ae caaaot be ~.xiareased
without at the same Gim~ accept~.ng as .iacz~e~a~~ of the
anteyoaisbic affect _ The success o~ this strategy vrill
depend on the select~.cn of a aaitabie antagemigt as well as
the selection pf they dose ratio.
shaugh bupr~rph.~ae ~- optioa~ally is the for~u of oae of its
therarpeuticalay acceptable salty - s~s the most preferred
aat~,Ya substaszce, the iaveatioa also relates to such actf~
substances as are phaxmacologica~.7.y similar ox .cosnpnrable .
to b~prer,~orphiae~ ace the advantages of the isiveat~foa
desar~.bed herefa also apply is these cases, thou~b, to
di~fesaat extaat. Fuxthar auibsble active substaaoas, which
are also described hereia as hea.rg "pharmaco7.ogi~aally
similar or comparable°, are, is particular, those
substances heloagillQ tQ the opiates ox oplDidB ~~11C(~ mBl~i
of these adt only exhibit pharmaeedynamic but also
pharmacokiaat3.c s~.milsra.tias to buprenorphiae, that fs a
relat3~Pely low dose, Qaod capacity for permeating
braces, arid a high fi~8t-pass e~foct_ Paxt~.C~larly
prefersad are moxphfae derivat Lvaa or dit~ydrn~~orphina
derivatives as well ae snbatsncea from the methadone sad
featanyl 9'ro'ap~
Iu orslar not to prompts air proper apyJ.a.catioh or one
that dose sot ooaform to the intended use, pha~s~-autical
QraparatiOtas t~oGord~"ag to the iaveat~.pa rorill typically be
present predivided into doses a~ separated from each other
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3n a ~auitabla paclsaQa, so that when Femvviug a dcsayo unit
it v~3.11 ba possible to remove only one unit at a tiara, such
as is the case of a blister pack, rebate each dosage unit is
sealed iadi'rridual~.Y is a deep-dratva cup. Within programs
fox treatment of opiate yr cocaine addictiaa at nay,
haspever, also be useful to supply physiciarxs ovho are
providing tlxe medical care, for exam,~pla. rotith preparations
in the foxes of~packaQx~ units wherein sa3d~praparatioas
a7re presexst as undivided sheet-J.ike or type-like material,
from which tlxe dosage units can he separated for the
purpose of application. This facilitates mesa appllcat3,ou
and affords the pbysi.oians who are admiaisterin~ the
preparations the possibility o~ sepnratiaQ frown one wad the
same material various dogagw ux~ts is accordance with the
given doaaQe reQttarem~eata .
Since the pharmaceutical preparation according to the
present iaventiaas is enacted to exhibit .increased bio-
availability as cos~ared to lmo~n preparatiox~s. it ~r3~.x1
possibly be necessary to adjust tk~e 8oaaga. In the case of
buprenorph3ne the individual analgesic do8e will be abp~,~,t
0.1 to 7. mgr in addzetivn or substitution therapy, hawavar,
this value might be considerably higher.
Iu accordaxaae with the inventive ttse manufacture of the
pharmaceutical preparation is performed a.~a sevexal st$pg,
For pz~eparin~ the w~ab-shaped startxnQ material .- from sohf.ch
ult3.mate3y either individual doses or entire packaging
units will be separated by cutt~.r~ or psaachinQ - two basic
process variaata era suitable. The first group of processes
faaludes those v~here a tape, or a process sheet or foil, is
evexily coated with aqueotie or svlveiat-cantairi~1i~ liquids
being in part of l~i.ghar vf$ooafty, and r~here this ~.s
subsequently subjectod to a drying process. To this sad,
fist, a coating mass is prepared, ~pr which purpose at
least vas water-soluble polyxaex c~geb~,g of t~,r~,i.ag a film,
the aatxve substaace(s) wad a suitable, vaporizable liQUid
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La
moat be intimately mixed. =f rewired it xs possible to
iacorgoxate further a~txxliary subatanaes such es
dssiate~rat~-on-modifying polymers, softeara7rs, fi7.lers,
texture-provsdiaQ sul~letaa~ces. ps~ats, dyes, taste
corrige4~ts~ salubilizexs, substa~es far ad3ust~.:nQ the p7At,
;smoothiaff agents, duxliag aQeats, disiategre.ti.oa
promoters, etc. .~ an altexxsative; the web-like startiasx
material may be made ~by tharm~a~plestic fea~rm3.~, i.e. without
the aid of liquids. Suitable processes.are, later ells, at~y
hot-malt coating methods as mall as a.~ e5etruaioa methods.
Ag a preraQuisite, the golymer or polymer myxtu~ capab7.a
op film-formetioa must fa this oars be thsr~aplasCically
foxmable. The rertaired iagre8ieats are miyced sad, under
actiosz of pressure ahd/or heat, formed by ~xtrud3.ag,
blowing ox by coating of tapes, sheets or foils, sad, after
solidif~.catit~n, transferred far fuz~Gher proaassa.ng.
Suitable fcr the manufacture 4E prepare~tjLone accordiaQ to
the present s.avention that have a mu7.tx-lnyar atraaturs tears
correapond~,ugrly modified methods, it bei~ syrrdlavaat
avhether several ~oeb-shsge~d natoriale are sisnaltaaaausly or
subsaqueatly produced and ca~biaod.
