DK173315B1

DK173315B1 - Delayed-release preparation for treating glaucoma

Info

Publication number: DK173315B1
Application number: DK608489A
Authority: DK
Inventors: Rajni Jani; Robert Gregg Harris
Original assignee: Alcon Lab Inc
Priority date: 1989-12-01
Filing date: 1989-12-01
Publication date: 2000-07-17
Also published as: DK608489D0; DK608489A

Description

DK 173315 B1DK 173315 B1

Den foreliggende opfindelse angår ophthalmiske præparater, der er anvendelige til regulering og sænkning af det intraokulare tryk (IOP) ved behandling af glaukom. Præparaterne ifølge opfindelsen er karakteriseret som langtidsvirkende (forsinket frigivelse) og er ved starten og forsat derefter komfortable for øjet. Specifikt vedrører opfm-5 delsen præparater med de ovennævnte egenskaber som blandt andet indeholder aktivt basestof og kationisk ionbytterharpiks (findelt) dispergeret i en vandig opløsning eller gel af en sur mucomimetisk polymer. Sådanne resulterende præparater i form af vandig gel eller hældbar væske er karakteriseret ved kontrollerede kationiske- anioniske indbyrdes indvirkninger, som ses at være ansvarlige for den resulterende komfort og egenska-10 beme med forsinket frigivelse.The present invention relates to ophthalmic compositions useful for controlling and lowering intraocular pressure (IOP) in the treatment of glaucoma. The compositions of the invention are characterized as long-lasting (delayed release) and are initially at first and then comfortably for the eye. Specifically, the invention relates to compositions having the above-mentioned properties which include, inter alia, active base substance and cationic ion exchange resin (finely divided) dispersed in an aqueous solution or gel of an acidic mucomimetic polymer. Such resultant preparations in the form of aqueous gel or pourable liquid are characterized by controlled cationic-anionic interactions which are seen to be responsible for the resulting comfort and delayed release properties.

IJ. Pharm. Sci., bind 60, nr. 9, september 1971, side 1343-1345 beskrives, at neomy-cinsulfat kan inkorporeres i en polymergel, uden at man går på kompromis med den sidstnævntes stabilitet, hvis det først absorberes på en særlig kationbytterharpiks og det resulterende neomycinsulfat-recinat derefter blandes med polymergelen. Det fremgår, 15 at gelerne, som beskrives deri, påtænkes til topisk hudpåføring.IJ. Pharm. Sci., Vol. 60, No. 9, September 1971, pages 1343-1345 disclose that neomyicinsulfate can be incorporated into a polymer gel without compromising the latter's stability if first absorbed on a particular cation exchange resin and the latter. resulting neomycin sulfate recinate is then mixed with the polymer gel. It will be appreciated that the gels described therein are intended for topical skin application.

Med opfindelsen anvises også behandlingsmetoder, der omfatter indgivelse af de beskrevne præparater ved indikation for behandling af okular hypertension og glaukom.The invention also provides treatment methods which include administration of the described compositions by indication for the treatment of ocular hypertension and glaucoma.

Betegnelsen "aktivt basestor betyder det aktive stof eller de aktive stoffer i de beskrevne præparater, som har den ønskede effekt på det intraokulare tryk, og som bærer eller er 20 i stand til at bære en positiv ladning under formuleringen af slutproduktet eller som formuleret i slutproduktformen. Således er betegnelsen aktivt basestof eller kationisk beskrivende for definitionen i beskrivelse og krav.The term "active base size" means the active substance (s) of the described compositions which have the desired effect on the intraocular pressure and which carry or are capable of carrying a positive charge during the formulation of the final product or as formulated in the final product form. Thus, the term active ingredient or cationic is descriptive of the definition in the specification and claims.

Sådanne aktive basestoffer indbefatter alle for tiden kendte β-blokkere, der udviser den fordrede kationiske ladning og IOP-effekt. Typisk repræsenteres sådanne β-blokkere med 25 følgende generiske struktur, hvilken struktur også repræsenterer de β-blokerende aktive baseingredienser som indgår i den foreliggende opfindelse: DK 173315 B1 2 r R1 -0-CH2-CH(0H)-CH2NR2R3 (I) hvor RI er en substitueret eller usubstitueret cyklisk eller alifatisk rest, hvor cykliske rester indbefatter mono- og polycykliske strukturer, som kan indeholde et eller flere he-teroatomer valgt blandt C, N og O; R2 og R3 uafhængigt af hinanden er valgt blandt H 5 og substitueret eller usubstitueret alkyl. Med hensyn til strukturen I ovenfor inkorporeres følgende referencer heri ved henvisning: Annual Reports in Medicinal Chemistry 14, 81-87 (1979); J. Med. Chem. 1983, 26, 1570-1576; ibid., 1984, 27, 503-509; ibid., 1983, 26, 7-11; ibid., 1983, 26, 1561-1569; ibid., 1983, 1109-1112; ibid., 1983, 26, 950-957; ibid., 1983, 26, 649-657; og ibid., 1983, 26, 352357. Repræsentative for 10 sådanne aktive basisstoffer er betaxolol, timolol, befunolol, Iabetalol, propranolol, bupranolol, metaprolol, bunalol, esmalol, pindolol, carteolol, hepunolol, metipranolol, celiprolol, azotinolol (S-596), diacetolol, acebutolol, salbutamol, atenulol, isoxaprolol og lignende.Such active base substances include all currently known β-blockers which exhibit the required cationic charge and IOP effect. Typically, such β-blockers are represented by the following generic structure, which also represents the β-blocking active base ingredients included in the present invention: DK-173315 B1 2 r R1-O-CH2-CH (OH) -CH2NR2R3 (I) R 1 is a substituted or unsubstituted cyclic or aliphatic residue wherein cyclic residues include mono- and polycyclic structures which may contain one or more heteroatoms selected from C, N and O; R 2 and R 3 are independently selected from H 5 and substituted or unsubstituted alkyl. With respect to structure I, the following references are incorporated herein by reference: Annual Reports in Medicinal Chemistry 14, 81-87 (1979); J. Med. Chem. 1983, 26, 1570-1576; ibid., 1984, 27, 503-509; ibid., 1983, 26, 7-11; ibid., 1983, 26, 1561-1569; ibid., 1983, 1109-1112; ibid., 1983, 26, 950-957; ibid., 1983, 26, 649-657; and ibid., 1983, 26, 352357. Representative of such active ingredients are betaxolol, timolol, befunolol, Iabetalol, propranolol, bupranolol, metaprolol, bunalol, esmalol, pindolol, carteolol, hepunolol, metipranolol, celiprolol, azotrolol, azotrolol. ), diacetolol, acebutolol, salbutamol, atenulol, isoxaprolol and the like.

Definitionen af aktive basestoffer indbefatter også følgende klasser af lægemidler, som 15 anvendes ved behandling af okular hypertension og glaukom: pilocarpin, epinephrin, proepinephrin, norepinephrin, pronorepinephrin, clonidin og clonidin-derivater, f.eks. p-aminoclonidin og p-acetoamidocolinidin.The definition of active base substances also includes the following classes of drugs used in the treatment of ocular hypertension and glaucoma: pilocarpine, epinephrine, proepinephrine, norepinephrine, pronorepinephrine, clonidine and clonidine derivatives, e.g. p-aminoclonidine and p-acetoamidocolinidine.

Opsummerende defineres det ved den foreliggende opfindelse anvendte aktive basestof ved dets virkning til sænkning af det intraokulære tryk eller dets statiske kontrol deraf 20 og ved dets kationiske natur i et vandigt medium i pH-området ffa 3,0 til 8,5. De følgende patentpublikationer, som inkorporeres heri ved henvisning, demonstrerer yderligere på repræsentativ måde de ved den foreliggende opfindelse anvendte aktive basestoffer: US patentskrifteme nr. 4.252.984, 3.309.406, 3.619. 370, 3.655.663, 3.657.237, 4.012.444, 3.663.607, 3.836.671, 3.857.952, 3.202.660 og 2.774.789.In summary, the active base substance used in the present invention is defined by its action for lowering the intraocular pressure or its static control thereof and by its cationic nature in an aqueous medium in the pH range of ffa 3.0 to 8.5. The following patent publications incorporated herein by reference further demonstrate in a representative manner the active base materials used in the present invention: US Patent Nos. 4,252,984, 3,309,406, 3,619. 370, 3,655,663, 3,657,237, 4,012,444, 3,663,607, 3,836,671, 3,857,952, 3,202,660 and 2,774,789.

f.f.

3 DK 173315 B13 DK 173315 B1

De ophthalmiske præparater ifølge opfindelsen er i form af: vandfrie salte; hældbare, vandige dispersioner, og vandige geler. Præparaterne omfatter ved siden af konventionelle ingredienser, der giver f.eks. bakteriostatiske funktioner og funktioner til afbalancering af formuleringen, en kritisk polyanionisk polymer, en kationbytterharpiks og det 5 udvalgte aktive basestof. Sådanne vandfrie saltformer inkorporeres i salver eller faste okularindlæg, som danner kolloide geler in situ eller ved administration til ejet. Udførelsesformer i form af hældbar væske og gel påføres topisk til øjet. Det skal bemærkes, at sådanne udførelsesformer i form af væske eller gel, kan opnås ud fra den vandfrie form ved formulering med vand.The ophthalmic compositions of the invention are in the form of: anhydrous salts; pourable, aqueous dispersions, and aqueous gels. The compositions include, in addition to conventional ingredients, which provide e.g. bacteriostatic functions and functions for balancing the formulation, a critical polyanionic polymer, a cation exchange resin and the 5 active ingredients selected. Such anhydrous salt forms are incorporated into ointments or solid eyepieces which form colloidal gels in situ or by administration to the owner. Embodiments in the form of pourable liquid and gel are applied topically to the eye. It should be noted that such embodiments in the form of liquid or gel can be obtained from the anhydrous form by formulation with water.

10 Præparaterne ifølge opfindelsen udviser forsinket frigivelse af den det aktive basestof og er komfortable ved topisk administration til øjet. Det skal bemærkes, at der sædvanligvis fremkommer en stikkende følelse, når det aktive basestof som identificeret ovenfor indgives i ren form. Således er opnåelsen af såvel komfort som forsinket frigivelse et uventet resultat og muliggør indgivelse af en klasse af forbindelser, som ellers ikke 15 kunne komme i betragtning.The compositions of the invention exhibit delayed release of the active base substance and are comfortable in topical administration to the eye. It should be noted that a tingling sensation usually arises when the active base substance as identified above is administered in pure form. Thus, the attainment of both comfort and delayed release is an unexpected result and enables the administration of a class of compounds which would otherwise not be considered.

Polvanionisk poIvmerbestanddeLPolvanionic Polymer Ingredient

De højmolekylære, polyanioniske polymerer, der kan anvendes ved den foreliggende opfindelse, har en molekylvægt fra ca. 50.000 til ca. 6 millioner. Polymererne er karakteriseret ved at have carboxylsyrefunktionelle grupper og indeholder fortrinsvis fra 2 til 20 7 carbonatomer pr. funktionel gruppe. De geler, der dannes under fremstillingen af den ophthalmiske polymerdispersion, har en viskositet fra ca. 1000 til ca. 300.000 cps. Ved siden af de ovennævnte indbyrdes indvirkninger mellem aktiv basestof og polymer (anionisk-kationisk) fortykker de højmolekylære polymerer, der anvendes i præparaterne ifølge opfindelsen, præparaterne til tilvejebringelse af en gel og de giver en særlig 25 type rheologi, dvs. plastisk viskositet, som kan være forklaringen på den forsinkede frigivelse og komfort, der opnås med de færdige præparater. Sådanne præparater ligger i pH-området fra 3,0 til 8,5.The high molecular weight polyanionic polymers which can be used in the present invention have a molecular weight of approx. 50,000 to approx. 6 million. The polymers are characterized by having carboxylic acid functional groups and preferably contain from 2 to 20 7 carbon atoms per minute. functional group. The gels formed during the preparation of the ophthalmic polymer dispersion have a viscosity of approx. 1000 to approx. 300,000 cps. In addition to the aforementioned interactions between active base substance and polymer (anionic-cationic), the high molecular weight polymers used in the compositions of the invention thicken the compositions to provide a gel and provide a particular type of rheology, ie. plastic viscosity, which may be the explanation for the delayed release and comfort achieved with the finished preparations. Such preparations range in the pH range from 3.0 to 8.5.

DK 173315 B1 4DK 173315 B1 4

Udførelsesformer i form af hældbar væske (indgivet som dråber til øjet) ifølge opfindelsen har en viskositet fra ca. 1 til ca. 20.000 cps. pH-fordringen er den samme som nævnt ovenfor for de gelformige slutprodukter, dvs. pH 3,0-8,5.Embodiments in the form of pourable liquid (administered as drops to the eye) according to the invention have a viscosity of approx. 1 to approx. 20,000 cps. The pH requirement is the same as mentioned above for the gel-shaped end products, i.e. pH 3.0-8.5.

Den tredje farmaceutiske form ifølge opfindelsen, den vandfrie saltform, afledes af et 5 salt af polycarboxylsyrepolymeren og det aktive basestof. (Tilstedeværelsen af den kationiske ion- bytterharpiks bidrager også til saltdannelsen, naturen af ionbytterharpik-sen i alle udførelsesfonneme for opfindelsen de- fineres nedenfor). Sådanne salte kan formuleres eller rekon- stitueres til vandige geler og hældbare dispersioner som beskrevet ovenfor ved tilsætning af vand, eller de kan formuleres som okularindlæg i 10 overensstemmelse med kendt teknologi og kendte former, eller de kan kombineres med et olievehikel til dannelse af en ophthalmisk salve. Alle sådanne færdige ophthalmiske farmaceutiske former beskrives fuldt ud i det følgende.The third pharmaceutical form of the invention, the anhydrous salt form, is derived from a salt of the polycarboxylic acid polymer and the active base substance. (The presence of the cationic ion exchange resin also contributes to salt formation, the nature of the ion exchange resin in all embodiments of the invention is defined below). Such salts may be formulated or reconstituted into aqueous gels and pourable dispersions as described above by the addition of water, or they may be formulated as ocular inserts according to known technology and known forms, or they may be combined with an oil vehicle to form an ophthalmic ointment. All such finished ophthalmic pharmaceutical forms are fully described in the following.

Den ovennævnte betegnelse "plastisk viskositet" angiver for et materiale, at det ikke flyder mærkbart, før en vis kraft eller trykværdi overskrides; denne kraft eller dette tryk 15 betegnes som flydegrænsen. Uden noget ønske om at binde sig til en bestemt teori antages det, at den forøgede aktivitetsvarighed hos præparaterne ifølge opfindelsen er i delvis relation til flydegrænsen. Præparaterne ifølge opfindelsen udviser en unik reaktion på forskydningskræfter. Når flydegrænsen overskrides, ændres gelstrukturen temporært og tillader gelen at flyde. I øjet tilskrives denne mekanisme partielt til blinkning 20 med øjenlåget. Når spændingen fjernes (øjenlåget hviler) genetableres gelens struktur partielt. Andre faktorer, som forklarer varigheden af præparaterne ifølge opfindelsen er i relation til ioniske indbyrdes indvirkninger, og en frigørelsesmekanisme som forklares ved en dynamisk ligevægt, der involverer normal tåreproduktion og fortrængning af aktivt basestofkationer med kationer, der er til stede i tårerne. Denne mekanisme næv-25 nes igen nedenfor.The above term "plastic viscosity" indicates to a material that it does not flow appreciably until a certain force or pressure value is exceeded; this force or pressure 15 is referred to as the flow limit. Without any desire to bind to a particular theory, it is believed that the increased activity duration of the compositions of the invention is in part related to the flow limit. The compositions of the invention exhibit a unique response to shear forces. When the flow limit is exceeded, the gel structure changes temporarily and allows the gel to flow. To the eye, this mechanism is partially attributed to blinking 20 with the eyelid. When the tension is removed (the eyelid rests), the structure of the gel is partially restored. Other factors explaining the duration of the compositions of the invention are in relation to ionic interactions, and a release mechanism explained by a dynamic equilibrium involving normal tear production and displacement of active base cations with cations present in the tears. This mechanism is mentioned again below.

Velegnede polymerer, der er anvendelige ved den foreliggende opfindelse, er carboxyl-vinylpolymerer. Foretrukne polymerer af denne klasse indbefatter de såkaldte carbo- 5 DK 173315 B1 merer, der leveres under handelsenavnet Carbopol af B. F. Goodrich Company, og ethylen-maleinsyreanhydrid-polymermateriale, der leveres under handelsnavnet EMA af Monsanto Company. De kendte og let tilgængelige polymerer Carbopol 934 og 940 er særligt foretrukne. Polymererne anvendes i de vandige gelpræparater i en koncen-5 tration op til 8 vægt%, hældbare væskepræparater omfatter 0,05 til 2,0 vægt% polymer.Suitable polymers useful in the present invention are carboxyl-vinyl polymers. Preferred polymers of this class include the so-called carbopolymers supplied under the trade name Carbopol by B. F. Goodrich Company, and ethylene-maleic anhydride polymer material supplied under the trade name EMA by Monsanto Company. The known and readily available polymers Carbopol 934 and 940 are particularly preferred. The polymers are used in the aqueous gel compositions at a concentration up to 8% by weight, pourable liquid compositions comprise 0.05 to 2.0% by weight polymer.

Aktivt basestofActive base substance

De foretrukne aktive basestoffer ved den foreliggende opfindelse er dem, der er beskrevet ovenfor. De mest foretrukne aktive basestoffer er betaxolol og timolol. Det aktive base- stof i udførelsesformeme som gel eller hældbar væske er til stede i en koncentra-10 tion fra ca. 0,01 til 4,0 vægt% og det mest foretrukne område er fra 0,10 til 1,0 vægt%.The preferred active base substances of the present invention are those described above. The most preferred active base substances are betaxolol and timolol. The active base substance in the embodiments as gel or pourable liquid is present at a concentration of about 10%. 0.01 to 4.0% by weight and the most preferred range is from 0.10 to 1.0% by weight.

IonbvtterharpiksIonbvtterharpiks

Den kationiske harpiksbestanddel i præparaterne ifølge opfindelsen giver et yderligere middel til forsinket frigivelse af det aktive basestof og ses at være nødvendig for den indledende og forlængede komfort. Sådanne harpikser er karakteriseret som enten kraf-15 tigt sure, såsom dem der har en sulfonsyrefunktionalitet, eller svagt sure kationbyttere, såsom dem der har en carboxylsyrefunktionalitet. Harpiksen må være inkorporeret som et findelt pulver, dvs. 95 % af de resulterende kugleformede partikler må have en diameter mindre end 20,0 μτη. Frigi- velsen af den aktive basis, som holdes af kationbytterhar-piksen, og den anioniske polymer opnås, når ioner, der er naturligt til stede i tårevæ-20 sken, hovedsageligt natrium og kalium, konkurrerer med det bundne aktive basestof om steder på polymervehiklet og ionbytterharpiksen. Frigivet på denne måde præsenteres øjeoverfladen for det aktive basestof til transport til receptorstederne.The cationic resin component of the compositions of the invention provides a further means of delayed release of the active base substance and is seen to be necessary for the initial and extended comfort. Such resins are characterized as either highly acidic, such as those having a sulfonic acid functionality, or weakly acidic cation exchangers such as those having a carboxylic acid functionality. The resin must be incorporated as a finely divided powder, ie. 95% of the resulting spherical particles must have a diameter less than 20.0 μτη. The release of the active base held by the cation exchange resin and the anionic polymer is achieved when ions naturally present in the tear fluid, mainly sodium and potassium, compete with the bound active base substance at sites on the polymer wrap. and the ion exchange resin. Released in this way, the eye surface of the active base substance for transport to the receptor sites is presented.

- Enhver kationisk ionbytterharpiks af farmaceutisk kvalitet er velegnet til formuleringen, og de kan anvendes enten på hydrogenformen eller på natriumformen. Sådanne harpikser DK 173315 B1 6 er let tilgængelige f.eks. fra Rohm & Haas under handelsnavnet AMBER- LITE og fra Dow Chemical Company under handelsnavnet DOWEX.Any pharmaceutical grade cationic ion exchange resin is suitable for the formulation and can be used either in the hydrogen form or in the sodium form. Such resins DK 173315 B1 6 are readily available e.g. from Rohm & Haas under the trade name AMBERLITE and from the Dow Chemical Company under the trade name DOWEX.

Ionbytterharpiksbestanddelen er til stede i formuleringerne ifølge opfindelsen i en koncentration på fra 0,05 til 10,0 vægt%. Den gennemsnitlige partikelstørrelsesdiameter for 5 harpiksen ligger fra 1 til 20 fim.The ion exchange resin component is present in the formulations of the invention at a concentration of 0.05 to 10.0% by weight. The average particle size diameter of the resin ranges from 1 to 20 µm.

Harpiksens partikelstørrelse er kritisk, både med hensyn til virkningsmåden og komforten. I typiske tilfælde ligger den gennemsnitlige partikelstørrelse hos de i handlen tilgængelige former af det valgte ionbyttermateriale på ca. 40 til 150 fim. Sådanne partikler kan mest hensigtsmæssigt reduceres til et partikelstørrelsesområde på ca. 1,0 til 25 μπν 10 ved kugleformaling i overensstemmelse med kendt teknik.The particle size of the resin is critical, both in terms of operation and comfort. In typical cases, the average particle size of the commercially available forms of the selected ion exchange material is approx. 40 to 150 µm. Such particles can most conveniently be reduced to a particle size range of approx. 1.0 to 25 μπν 10 by ball milling according to prior art.

Andre bestanddeleOther constituents

Antimikrobiel konserveringsmiddel:Antimicrobial preservative:

Ophthalmiske produkter emballeres typisk i multidosisform. Konserveringsmidler behøves derfor for at forhindre mikrobiel forurening under anvendelse. Velegende konser-15 veringsmidler indbefatter: benzalkoniumchlorid, thimerosal, chlorbutanol, methylpara-ben, propylparaben, phenethylalkohol, dinatriumedetat, sorbinsyre, onamer M eller andre midler, der er kendt blandt fagfolk. Typisk anvendes sådanne konserveringsmidler i en koncentration fra 0,001 til 1,0 vægt%.Ophthalmic products are typically packaged in multi-dose form. Preservatives are therefore needed to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenethyl alcohol, disodium edetate, sorbic acid, onamer M or other agents known to those skilled in the art. Typically, such preservatives are used at a concentration of 0.001 to 1.0% by weight.

lonicitetsmidler: 20 Produktets tonicitet eller osmolalitet kan indstilles til enten hypotonisk, isotonisk eller hypertonisk i forhold til normale tårer ved anvendelse af inden for fagområdet konventionelle materialer. Sådanne tonicitetsmidler er imidlertid begrænset til ikke-ioniske forbindelser og ligger typisk, når de anvendes, i området fra 0,0 til 10 vægt% af slutpro- DK 173315 B1 7 duktet. Ikke-ioniske midler indbefatter repræsentativt mannitol, dextrose, glycerol og propylenglycol, idet deres tilstedeværelse i den endelige produktform imidlertid er valgfri.lonitic agents: 20 The tonicity or osmolality of the product can be set to either hypotonic, isotonic or hypertonic compared to normal tears using conventional materials within the art. However, such tonicity agents are limited to nonionic compounds and typically, when used, range from 0.0 to 10% by weight of the final product. Nonionic agents include representative mannitol, dextrose, glycerol and propylene glycol, however, their presence in the final product form is optional.

Formulering 5 Præparaterne formuleres i tre grundliggende tilstande: 1) geler, 2) hældbare væsker og 3) vandfrie salte: 1) fistelFormulation 5 The preparations are formulated in three basic conditions: 1) gels, 2) pourable liquids and 3) anhydrous salts: 1) fistula

Den kationiske ionbytterharpiksbestanddel dispergeres i vand. Det aktive basestof tilsættes derefter under omrøring. Derefter tilsættes den polyanioniske polymer-10 bestanddel. Det resulterende produkt har en viskositet, der ligger fra 1000 til 300.000 cps i afhængighed af koncentrationen af anionisk polymer. Den resulterende pH-værdi er 3,0 til 8,5, hvilket kan justeres om nødvendigt med HC1 og NaOH.The cationic ion exchange resin component is dispersed in water. The active base substance is then added with stirring. Then, the polyanionic polymer component is added. The resulting product has a viscosity ranging from 1000 to 300,000 cps depending on the concentration of anionic polymer. The resulting pH is 3.0 to 8.5, which can be adjusted if necessary with HCl and NaOH.

2) Hældbare væsker2) Pourable liquids

Den kationiske ionbytterkomponent dispergeres i 10 til 50 rumfangs % af det samle-15 de vand i formuleringen og derefter dispergeres og/eller opløses det aktive basestof under omrøring. Den polyanioniske polymer, i form af en vandig dispersion, tilsættes, indtil den ønskede pH-værdi hos produktet er opnået. Produktets pH-værdi kan indstilles til den ønskede værdi ved varierende forhold mellem aktivt basestof/poly-mer/harpiks. Om ønsket kan produktets endelige pH-værdi indstilles ved tilsætning 20 af enten NaOH eller HC1. De foretrukne pH-områder for ophthalmiske præparater er fra 3,0 til 8,5. Slutproduktet er en dispersion, der kan kræve blanding under høj energi for at bryde enhver agglomeration til opnåelse af ensartethed. Andre formuleringsbestanddele tilsættes derefter under omrøring. Det resulterende produkt har en viskositet, der ligger fra 1,0 til 20.000 cps i afhængighed af koncentrationen af 25 anionisk polymer.The cationic ion exchange component is dispersed in 10 to 50% by volume of the collected water in the formulation and then dispersed and / or dissolved in the active base substance with stirring. The polyanionic polymer, in the form of an aqueous dispersion, is added until the desired pH of the product is obtained. The pH of the product can be adjusted to the desired value at varying ratios of active base / polymer / resin. If desired, the final pH of the product can be adjusted by the addition of either NaOH or HCl. The preferred pH ranges for ophthalmic preparations are from 3.0 to 8.5. The final product is a dispersion that may require high energy mixing to break any agglomeration to achieve uniformity. Other formulation ingredients are then added with stirring. The resulting product has a viscosity ranging from 1.0 to 20,000 cps depending on the concentration of 25 anionic polymer.

te · DK 173315 B1 8 3) Vandfrie saltete · DK 173315 B1 8 3) Anhydrous salts

Det aktive basestof, ionbytterharpiksen og den polyanioniske polymer kombineres i vand og efter blanding lyofiliseres til et pulver. Fyldstoffer, såsom mannitol og andre materialer kan tilsættes for at lette fryse/tørre-behandlingen i overensstemmel-5 se med for fagfolk velkendte metoder. De på denne måde fremstillede vandfrie salte kan derefter formuleres eller restitueres til vandige geler og væsker eller de kan formuleres og formes som okularindlæg. Det Iyofiliserede pulver kan også kombineres med et ikke-vandigt vehikel til dannelse af en ophthalmisk salve.The active base substance, the ion exchange resin and the polyanionic polymer are combined in water and, after mixing, lyophilized to a powder. Fillers such as mannitol and other materials may be added to facilitate the freeze / dry treatment in accordance with methods well known to those skilled in the art. The anhydrous salts thus prepared can then be formulated or restored to aqueous gels and liquids or they can be formulated and formed as eyepiece inserts. The lyophilized powder can also be combined with a non-aqueous vehicle to form an ophthalmic ointment.

Sådanne udførelsesformer for opfindelsen i form af vandfrie salte kan også fremstil-10 les ved at ekstrahere den oprindelige vandige dispersion med et organisk opløsnings middel , såsom ethanol, chloroform, benzen eller lignende og afdampe det organiske opløsningsmiddel til fremstilling af det ønskede saltkompleks. Det resulterende produkt er i det væsentlige ækvivalent med det ovenfor beskrevne Iyofiliserede produkt.Such embodiments of the invention in the form of anhydrous salts can also be prepared by extracting the original aqueous dispersion with an organic solvent such as ethanol, chloroform, benzene or the like and evaporating the organic solvent to produce the desired salt complex. The resulting product is substantially equivalent to the lyophilized product described above.

15 Anvendelighed15 Applicability

De ophthalmiske præparater ifølge opfindelsen indgives til øjnene som geler, hældbare væsker (øjendråber) og i form af salver og okularindlæg, hvor sidstnævnte klassifikationer formuleres ud fra vandfrie salte. Alle sådanne præparater formuleres til at kontrollere frigivelsen af det aktive basestof ved administration til øjet og for derved at give en 20 effekt med forsinket frigivelse. Typisk behøves en sådan administration en eller to gange om dagen. Den nøjagtige doseringsplan overlades til klinikerens rutine.The ophthalmic compositions of the invention are administered to the eyes as gels, pourable fluids (eye drops) and in the form of ointments and ocular inserts, wherein the latter classifications are formulated from anhydrous salts. All such preparations are formulated to control the release of the active base substance by administration to the eye, thereby providing a delayed release effect. Typically, such administration is needed once or twice a day. The exact dosing schedule is left to the clinician's routine.

Følgende eksempler illustrerer men begrænser ikke de sammensætningsmæssige, metodemæssige og behandlingsmæssige aspekter af den foreliggende opfindelse.The following examples illustrate but do not limit the compositional, methodological and therapeutic aspects of the present invention.

DK 173315 B1 9DK 173315 B1 9

Fremstilling af fri base af betaxolol ud fra betaxolol-hvdrochloridPreparation of free base of betaxolol from betaxolol hydrochloride

Betaxolol-hydrochlorid er beskrevet i US patentskrift nr. 4.252.984 og er tilgængelig i handlen.Betaxolol hydrochloride is described in U.S. Patent No. 4,252,984 and is commercially available.

5 Betaxolol-hydrochlorid (0,88 mol) opløses i vand og opløsningen afkøles i et isbad. Til denne opløsning sættes en opløsning af natriumhydroxid (0,97 mol) i vand portionsvis for at gøre blandingen basisk mens den omrøres kraftigt. På dette tidspunkt er blandingens pH-værdi ca. 9,6. Det resulterende faste hvide stof opsamles ved filtrering og vaskes med et stort rumfang vand.5 Betaxolol hydrochloride (0.88 mol) is dissolved in water and the solution is cooled in an ice bath. To this solution is added a solution of sodium hydroxide (0.97 mol) in water portionwise to make the mixture basic while stirring vigorously. At this point, the pH of the mixture is approx. 9.6. The resulting white solid is collected by filtration and washed with a large volume of water.

10 Efter presning/tørring i filtertragten gensuspenderes det semitørre faste stof i et stort rumfang vand og omrøres i 1-2 timer. Det hvide fast stof opsamles ved filtrering og vaskes med et stort rumfang vand for at give den saltfrie betaxolol som fri base, som tørres under vakuum.After pressing / drying in the filter funnel, the semi-dry solid is resuspended in a large volume of water and stirred for 1-2 hours. The white solid is collected by filtration and washed with a large volume of water to give the salt-free betaxolol as a free base which is dried under vacuum.

Eksempel 2 15 Produktsammensætning A (vægt%l B (vægt%) £jfvægt%)Example 2 Product Composition A (wt% l B (wt%) £ wt%)

Betaxolol 0,50 0,25 1,0 CARBOPOL-934 P (Carbomer) 0,25 0,15 0,35Betaxolol 0.50 0.25 1.0 CARBOPOL-934 P (Carbomer) 0.25 0.15 0.35

Natrium-poly(styren/divmyl- 20 benzen)-sulfonat 0,25 0,125 0,50Sodium poly (styrene / divmylbenzene) sulfonate 0.25 0.125 0.50

Benzalkoniumchlorid 0,01 0,01 0,01Benzalkonium chloride 0.01 0.01 0.01

Mannitol 5,0 5,0 5,0Mannitol 5.0 5.0 5.0

Vand q.s. 100% DK 173315 B1 10Water q.s. 100% DK 173315 B1 10

FremgangsmådeCourse of action

Findelt Amberlite IRP-69 harpiks, et natrium-poIy-(styren/divinylbenzen)-sulfonat og betaxololet blandes i 50% af det samlede rumfang af vandbestanddelen til dannelse af en ensartet dispersion. Carbopol-934P tilsættes langsomt som en vandig dispersion.Finely divided Amberlite IRP-69 resin, a sodium poly (styrene / divinylbenzene) sulfonate, and the betaxolol are mixed in 50% of the total volume of the water component to form a uniform dispersion. Carbopol-934P is slowly added as an aqueous dispersion.

5 Blandingen homogeniseres ved høj hastighed. De øvrige bestanddele tilsættes som vandige opløsninger. Slutrumfanget tilvejebringes ved tilsætning af vand. De resulterende produkter. A, B og C, er hvide ensartede suspensioner.5 The mixture is homogenized at high speed. The other ingredients are added as aqueous solutions. The final volume is provided by the addition of water. The resulting products. A, B and C are white uniform suspensions.

Eksempel 3Example 3

Produktsammensætning 10 A (vægt%VB (vægt%) C (vægt%)Product composition 10 A (wt% VB (wt%) C (wt%)

Betaxolol-base 0,50 0,25 1,0Betaxolol Base 0.50 0.25 1.0

Poly(styren/divinyl)- benzen)-sulfonsyre 0,25 0,125 0,5Poly (styrene / divinyl) - benzene) sulfonic acid 0.25 0.125 0.5

Carbopol-934P 0,20 0,1 0,35 15 Benzalkoniumchlorid 0,01 0,01 0,01Carbopol-934P 0.20 0.1 0.35 Benzalkonium chloride 0.01 0.01 0.01

Mannitol 5,0 5,0 5,0Mannitol 5.0 5.0 5.0

Vand q.s. 100%Water q.s. 100%

FremgangsmådeCourse of action

Opløsningerne A, B og C fra eksempel 3 fremstilles ved at følge fremgangsmåden i 20 eksempel 2. De resulterende produkter er hvide eller smudsighvide ensartede suspensioner med pH mellem 5,5 og 6,5.The solutions A, B and C of Example 3 are prepared following the procedure of Example 2. The resulting products are white or sooty white uniform suspensions with pH between 5.5 and 6.5.

Ved at følge fremgangsmåden i eksempel 2 og 3 opnås der i det væsentlige ækvivalente resultater, når betaxolol-bestanddelen erstattes med en ækvivalent mængde af timolol eller med en hvilken som helst af de respektive tidligere identificerede β-blokkere og andre eksempler på aktivt basestof.Following the procedure of Examples 2 and 3, substantially equivalent results are obtained when the betaxolol component is replaced by an equivalent amount of timolol or by any of the respective previously identified β-blockers and other examples of active base substance.

11 DK 173315 B111 DK 173315 B1

Den foreliggende opfindelse er beskrevet her med henvisning til visse foretrukne udførelsesformer. Da imidlertid nærliggende varianter heraf vil være tydelige for fagfolk, 5 skal opfindelsen ikke betragtes som begrænset dertil.The present invention is described herein with reference to certain preferred embodiments. However, as obvious variations thereof will be apparent to those skilled in the art, the invention is not to be construed as being limited thereto.

Claims

1. Delayed-release ophthalmic pharmaceutical composition for controlling and lowering the intraocular pressure, characterized in that it comprises an active base substance 5 effective to reduce the intraocular pressure, an anionic mucomimetic polymer and a cation exchange resin.

Composition according to claim 1, characterized in that the composition is an aqueous dispersion.

A delayed-release ophthalmic pharmaceutical composition for controlling and lowering the intraocular pressure of claim 1 comprising an aqueous dispersion of the active base substance, an anionic mucomimetic polymer and a finely divided cation exchange resin.

Composition according to any one of claims 1-3, characterized in that the active base substance is betaxolol.

Composition according to any one of claims 1-3, characterized in that the active base substance is timolol.

Composition according to any one of claims 1-3, characterized in that the active base substance is selected from pilocarpine, epinephrine, proepinephrine, norepinephrine, pronorepinephrine, clonidine, p-aminoclonidine, p-acetoamidoclonidine or a B-block selected from betaxolol, timolol, acebutolol, alprenolol, atenolol, bevantolol, bucomolol, 20 bupranolol, butidrin, bunitolol, bunolol, butocrolol, butamine, carazolol, carteolol, exaprolol, indenolol, iprocrolol, labetolol, mepolol, mepolol , nifenalol, oxprenolol, pamatolol, paragolol, penbutolol, pindolol, practolol, procinolol, pronethalol, propranolol, sotalol, tazolol, tiprenolol, tolamolol, DK 173315 B1 toliprolol, befunolol, esmalolol, hepunolol, isoxaprolol.

A composition according to claim 1 in the form of a sustained-release ophthalmic pharmaceutical composition in the form of an aqueous gel, a pourable aqueous dispersion or anhydrous salt for controlling and lowering the intraocular pressure, characterized in that it comprises a therapeutically effective amount of a β-blocker of the formula R, -O-CH 2 -CH (OH) -CH 2 -NR 2 R 3 wherein R 1 is a substituted or unsubstituted cyclic or aliphatic residue and R 2 and R 3 are independently selected from hydrogen and substituted or unsubstituted alkyl An amount of an anionic mucomimetic polymer having functional carboxylic acid groups comprising 2 to 7 carbon atoms per functional group and having a molecular weight of 50,000 to 6 million such that the composition in the form of an aqueous gel or pourable aqueous dispersion has a viscosity of from 1 to 20,000 cps, and a particulate cation exchange resin at a concentration of 0.05 to 10.0 weight %, which has a pH between about 3.0 and 8.5.

Composition according to claim 7, characterized in that the particulate cation exchange resin is in the form of a finely divided powder, which powder consists of spherical particles.

Composition according to claim 7 or 8, characterized in that the cation exchange resin is sodium poly (styrene / divinylbenzene) sulfonic acid and that the fl blocker is betaxolol.

Preparation according to any one of claims 7-9, characterized in that the β-blocker is present at a concentration of approx. 0.25 wt%, the anionic mucomimetic polymer is present at a concentration of approx. 0.20 wt% and the cation exchange resin is present at a concentration of approx. 0.25% by weight.

A composition according to any one of the preceding claims, wherein the cation exchange resin consists of particles ranging in size from 1.0 to 25 µπι.

A composition according to any one of claims 1-10 for use in the manufacture of a medicament for controlling and lowering the intraocular pressure. ; f i I