CA2274910C - Flat medicament preparation for the application and release of buprenorphine or a pharmacologically comparable substance in the buccal cavity, and method of producing the same - Google Patents
Flat medicament preparation for the application and release of buprenorphine or a pharmacologically comparable substance in the buccal cavity, and method of producing the same Download PDFInfo
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- CA2274910C CA2274910C CA002274910A CA2274910A CA2274910C CA 2274910 C CA2274910 C CA 2274910C CA 002274910 A CA002274910 A CA 002274910A CA 2274910 A CA2274910 A CA 2274910A CA 2274910 C CA2274910 C CA 2274910C
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- active substance
- pharmaceutical preparation
- preparation according
- shaped
- buprenorphine
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
Abstract
A solid pharmaceutical preparation, disintegratable in aqueous media, with a flat, foil-shaped, paper-shaped or wafer-shaped administration form, for application and release of active substances in the oral cavity is charac-terized by a content of buprenophine, of an active substance pharmacologically comparable to buprenorphine, or of a therapeutically suitable salt of buprenorphine or the pharmacologically comparable active substance.
Description
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.
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.
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-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 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.
'!.'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.
'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, 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 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 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 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.
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-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 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.
'!.'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.
'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, 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 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 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 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.
Claims (13)
1. A buccal pharmaceutical preparation for treating acute conditions of pain or for addiction therapy, comprising as active substance buprenorphine, morphine, dihydromorphine derivatives, substances from the methadone or fentanyl groups as such or a therapeutically suitable salt thereof, 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, for rapid active substance transfer through short diffusion paths, while having a large surface appropriate to an effective dose, the said administration form having a non-mucoadhesive outer layer, opposed to the mucoadhesive surface, which outer layer has a lower permeability to the active substance.
2. The pharmaceutical preparation according to claim 1, characterized by a two-or multi-layered structure having a mucoadhesive active substance-containing layer based on water-soluble, film-forming polymers for rapid active substance uptake through short diffusion paths.
3. The pharmaceutical preparation according to claim 1 or 2, characterized by a single-dose buprenorphine content of 0.1-1 mg.
4. The pharmaceutical preparation according to any one of claims 1 to 3, characterized in that it is equipped with bioadhesive or mucoadhesive properties by the addition of an adhesionpromoting auxiliary substance or auxiliary substance mixture.
5. The pharmaceutical preparation according to claim 4, characterized in that as a further active substance an opiate or a partial opiate antagonist is present.
6. The pharmaceutical preparation according to claim 5, characterized in that the further active substance is selected from the group consisting of nalbuphine, naloxone or naltrexone.
7. The pharmaceutical preparation according to any one of claims 1 to 6, characterized in that it is present as an undivided, sheet-shaped or tape-shaped material, from which it is possible to separate dosage units for the purpose of application.
8. The pharmaceutical preparation according to any one of claims 1 to 7, characterized in that it is present predivided into doses.
9. The pharmaceutical preparation according to any one of claims 1 to 8, characterized in that, per dosage unit, it has a content of active substance which is suitable for analgesia.
10. The pharmaceutical preparation according to any one of claims 1 to 9, characterized in that, per dosage unit, it has a content of active substance which is suitable for opiate or cocaine substitution therapy.
11. A method of producing a pharmaceutical preparation according to any one of claims 1 to 10, characterized in that in a first step at least one active substance, together with a water-soluble polymer capable of film-formation, is dissolved in a suitable, hydrophilic solvent, optionally in presence of further dissolved or suspended auxiliary agents, that in a second step the solution or suspension is applied, in a continuous process and with even thickness, to a tape or a process sheet or foil, where, in a third step, it is largely freed from the solvent, thereby forming a sheet-shaped or tape-shaped starting material, wherefrom, in a forth step, the dosage or multidosage units are separated by cutting or punching.
12. A method of producing a pharmaceutical preparation according to any one of claims 1 to 10, characterized in that in a first step at least one active substance, together with a water-soluble, thermoplastic polymer capable of film-formation, is formed, under action of heat and/or pressure, and optionally in presence of further auxiliary substances, into a sheet-shaped ar tape-shaped starting material, from which starting material the dosage or multidosage units are separated by cutting or punching.
13. The method of producing a pharmaceutical preparation according to claim 11 or 12, characterized in that a plurality of simultaneously or subsequently prepared, sheet-shaped or tape-shaped starting materials are combined to form a multilayered material, from which the dosage or multidosage units are separated.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19652188A DE19652188C2 (en) | 1996-12-16 | 1996-12-16 | Flat drug preparation for application and release of buprenorphine or a pharmacologically comparable substance in the oral cavity and process for its preparation |
| DE19652188.2 | 1996-12-16 | ||
| PCT/EP1997/006369 WO1998026780A2 (en) | 1996-12-16 | 1997-11-14 | Flat medicament preparation for the application and release of buprenorphine or a pharmacologically comparable substance in the buccal cavity, and method of producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2274910A1 CA2274910A1 (en) | 1998-06-25 |
| CA2274910C true CA2274910C (en) | 2005-07-05 |
Family
ID=7814805
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002274910A Expired - Lifetime CA2274910C (en) | 1996-12-16 | 1997-11-14 | Flat medicament preparation for the application and release of buprenorphine or a pharmacologically comparable substance in the buccal cavity, and method of producing the same |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0949925B1 (en) |
| JP (2) | JP2001506640A (en) |
| KR (1) | KR100514306B1 (en) |
| AT (1) | ATE257381T1 (en) |
| AU (1) | AU741362B2 (en) |
| CA (1) | CA2274910C (en) |
| DE (2) | DE19652188C2 (en) |
| DK (1) | DK0949925T3 (en) |
| ES (1) | ES2214649T3 (en) |
| NO (1) | NO992907L (en) |
| PT (1) | PT949925E (en) |
| WO (1) | WO1998026780A2 (en) |
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| US8900497B2 (en) | 2001-10-12 | 2014-12-02 | Monosol Rx, Llc | Process for making a film having a substantially uniform distribution of components |
| US8900498B2 (en) | 2001-10-12 | 2014-12-02 | Monosol Rx, Llc | Process for manufacturing a resulting multi-layer pharmaceutical film |
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| US9101625B2 (en) | 2006-08-30 | 2015-08-11 | Purdue Pharma L.P. | Buprenorphine-wafer for drug substitution therapy |
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| US5968547A (en) | 1997-02-24 | 1999-10-19 | Euro-Celtique, S.A. | Method of providing sustained analgesia with buprenorphine |
| SE9803240D0 (en) | 1998-09-24 | 1998-09-24 | Diabact Ab | A pharmaceutical composition having a rapid action |
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| WO2004050008A1 (en) | 2002-12-02 | 2004-06-17 | Kyukyu Pharmaceutical Co., Ltd. | Process for producing edible orally administered agent of laminate film form and compression bonding apparatus |
| DE10338544B4 (en) * | 2003-08-19 | 2017-08-31 | Janssen Pharmaceutica N.V. | Buccal formulations of galanthamine and their applications |
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| DE102004045599A1 (en) * | 2004-09-17 | 2006-03-23 | Grünenthal GmbH | System for the sequential, transdermal administration of systemically active substances |
| DE102005007859A1 (en) * | 2005-02-21 | 2006-08-24 | Lts Lohmann Therapie-Systeme Ag | Procedures for a combination drug treatment, as well as suitable drug combinations |
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| EP1810669A1 (en) * | 2006-01-19 | 2007-07-25 | Holger Lars Hermann | Application form for burprenorphine |
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| AU2011224107B2 (en) * | 2006-08-30 | 2012-01-19 | Euro-Celtique S.A. | Buprenophine-wafer for drug substitution therapy |
| CN101631549B (en) | 2007-03-15 | 2012-08-22 | 东洋纺织株式会社 | Process for production of buprenorphine pharmaceutical preparation to be applied to mouth mucosa |
| CA2728912C (en) * | 2008-06-23 | 2018-04-10 | Biodelivery Sciences International, Inc. | Multidirectional mucosal delivery devices and methods of use |
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-
1996
- 1996-12-16 DE DE19652188A patent/DE19652188C2/en not_active Expired - Lifetime
-
1997
- 1997-11-14 EP EP97952767A patent/EP0949925B1/en not_active Expired - Lifetime
- 1997-11-14 KR KR10-1999-7005306A patent/KR100514306B1/en not_active IP Right Cessation
- 1997-11-14 AU AU56532/98A patent/AU741362B2/en not_active Expired
- 1997-11-14 JP JP52722398A patent/JP2001506640A/en active Pending
- 1997-11-14 ES ES97952767T patent/ES2214649T3/en not_active Expired - Lifetime
- 1997-11-14 PT PT97952767T patent/PT949925E/en unknown
- 1997-11-14 DE DE59711194T patent/DE59711194D1/en not_active Expired - Lifetime
- 1997-11-14 AT AT97952767T patent/ATE257381T1/en active
- 1997-11-14 CA CA002274910A patent/CA2274910C/en not_active Expired - Lifetime
- 1997-11-14 WO PCT/EP1997/006369 patent/WO1998026780A2/en active IP Right Grant
- 1997-11-14 DK DK97952767T patent/DK0949925T3/en active
-
1999
- 1999-06-14 NO NO992907A patent/NO992907L/en not_active Application Discontinuation
-
2009
- 2009-06-17 JP JP2009144244A patent/JP2009242415A/en active Pending
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Also Published As
| Publication number | Publication date |
|---|---|
| WO1998026780A2 (en) | 1998-06-25 |
| JP2009242415A (en) | 2009-10-22 |
| NO992907D0 (en) | 1999-06-14 |
| PT949925E (en) | 2004-05-31 |
| DK0949925T3 (en) | 2004-04-05 |
| WO1998026780A3 (en) | 1998-08-27 |
| JP2001506640A (en) | 2001-05-22 |
| AU5653298A (en) | 1998-07-15 |
| KR100514306B1 (en) | 2005-09-13 |
| EP0949925A2 (en) | 1999-10-20 |
| KR20000057566A (en) | 2000-09-25 |
| DE59711194D1 (en) | 2004-02-12 |
| DE19652188A1 (en) | 1998-06-18 |
| AU741362B2 (en) | 2001-11-29 |
| ATE257381T1 (en) | 2004-01-15 |
| NO992907L (en) | 1999-06-14 |
| ES2214649T3 (en) | 2004-09-16 |
| DE19652188C2 (en) | 2002-02-14 |
| CA2274910A1 (en) | 1998-06-25 |
| EP0949925B1 (en) | 2004-01-07 |
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