SI8712284A - Preparations for nasal application and procedures for their production. - Google Patents

Abstract

Sistemska absorpcija je po intranazalnem dajanju določenih zdravil, še posebno farmakološko aktivnih polipeptidov, izboljšana v prisotnosti fosfolipidov, kot je fosfalidilholin (lecitin), prednostno zmešan z rastlinskim oljem,Systemic absorption is after intranasal administration certain medicines, especially pharmacological ones of active polypeptides, enhanced in the presence of phospholipids, such as phosphalidylcholine (lecithin), preferably mixed with vegetable oil,

Description

PREPARATI ZA NAZAIITU UPOTREBU I P03TUP;£ ZA NJIHOVO DOBIJANJEPREPARATION FOR OWN USE AND P03TUP; £ TO OBTAIN THEM

1. Oblast tehnike1. Field of technology

Ovaj pronalazak se odnosi na nove farmaceutske preparate podešene za intranazalnu upotrebu i na postupak za njihovo pripremanje.The present invention relates to novel pharmaceutical preparations adapted for intranasal use and to a process for their preparation.

2. Definisan tehnički problem2. Technical problem defined

Zadatak ovog pronalaska je da obezbedi preparat za intranazalnu upotrebu sa poboljšanom apsorbcijom, koji obuhvata najmanje jedan fosfolipid i postupak zn dobijanje ovog preparata.It is an object of the present invention to provide a preparation for intranasal use with enhanced absorption, comprising at least one phospholipid and a process for the preparation of this preparation.

3. Stanje tehnike3. State of the art

Lok je neagresivno lečenje, kao što je oralno ili rektalno davanje loka najpogodnije za pacijenta, parenteralno davanje leka se uzima kao najefikasnije. ITaiOČito se-,i lekovi koji su nedelotvorni ili su slabo apsorbovani u želudačno-crevnom traktu i lekovi koji su podvrgnuti ckstenzivnom poeetku hepatiekog metabolizma koji prati oralno davanje leka, uobičajeno daju parentcralno.Lok is a non-aggressive treatment, such as oral or rectal administration of the bow is most appropriate for the patient, parenteral administration of the drug is considered to be most effective. However, drugs that are ineffective or poorly absorbed in the gastrointestinal tract and drugs that undergo the extensive onset of hepatic metabolism that accompanies oral administration are usually parenteral.

Razumljive su nepogodnosti vezane za parenteralno davanjc leka, kao što je potreba za stcrilnošču opreme, bol i nadrašaj izazvani učestanim davanjem injekcija i potenci jalni rizik od infekcije. Za tu svrhu tražena su alternativna sredstva za pružanje leka, jednaka parcnteralnom davanju leka koja u odred.jenom smislu onemogucavaju ovaj pocetni metabolizem. Način leoenja koje obeeava takvu moguenost je davanje leka nazalnim putem. Ipak, kao i u.The disadvantages associated with parenteral administration of the drug are understandable, such as the need for infirmity of the equipment, pain and irritation caused by frequent injections and the potential risk of infection. For this purpose, alternative means of drug delivery were sought, equivalent to the partial administration of the drug, which in a sense impeded this initial metabolism. The way of healing that promises such a possibility is to administer the medicine by nasal route. Still, as in.

slučaju drugih postupaka neagresivnog ločenja, hioupotrehljivost leka nakon intranazalnog davanja je najčežee ncpredvidiva, i zavisi od inter alia hemijske prirode leka.in the case of other non-aggressive separation methods, the hyo-immunity of the drug after intranasal administration is most often unpredictable, and depends, inter alia, on the chemical nature of the drug.

Poznato je da progesteron i propranolol apsorbovani u nazalnoj šupljini donckle obezbedjuju nivoe krvi skoro jednske intravenoznom načinu leč enja.Progesterone and propranolol absorbed in the nasal cavity are known to provide blood levels almost equal to the intravenous route of treatment.

Poznati su i drugi primeri intranazalnih upotreba farmaceutski aktivnih sredstava sa molekularnim težinama do oko 1 kD, na primer, sastavi koji sadržavaju alkaloide ergopeptida rastvorene u vodnom rastvoru etanola koji su dati kao aerosoli (Švajcarski patent No. 636,011), soli farmaceutski aktivnih amina sa masnim kiselinama (Kanadski patent No. 988,852) i katehdlamin suspendovan u masno j kiselini (ili esteru) emulgovan sa polioksietilenom (Evropska patentna prijava No. 160,501).Other examples of intranasal use of pharmaceutically active agents with molecular weights up to about 1 kD are known, for example, compositions containing ergopeptide alkaloids dissolved in an aqueous solution of ethanol given as aerosols (Swiss Patent No. 636,011), salts of pharmaceutically active amines with fatty acids (Canadian Patent No. 988,852) and catechdlamine suspended in fatty acid (or ester) emulsified with polyoxyethylene (European Patent Application No. 160,501).

U poslednjim decenijama, razvijene su r_azličite vrste (uglavnom sintetičke) polipoptidskih lekova. Generalno, polipeptidi su bili davgni parenteralno zbog nckompletnc apsorbcije i probavne nestabilnosti u probavnom traktu.In recent decades, _a variety of (mostly synthetic) polyoptid drugs have been developed. Generally, polypeptides have been elongated parenterally due to incomplete absorption and digestive instability in the gastrointestinal tract.

Ovo je verovatno razlog zbog čega jc u po j edinim študijama zadnjih godina, bila intenzivirana nazalna upotreba polipeptida. Pronadjeno je da, dok neki manji polipeptidi (do ©ko 10 ostataka amino kiseline) mogu biti relativno dobro apsorbovani intranazalno iz jednostavnih vodnih preparata, generalno nazalna bioupotrebljivost večih polipeptida postaje i nekompletna i nestabilna, i to se pojačava sa povečanjem molekularne težine (vidi L. Illum: Archiv for Pharmaci og Chemi 94 (1987), 127-135).This is probably the reason why nasal use of polypeptides has been intensified in recent studies in recent years. It has been found that while some smaller polypeptides (up to 10 amino acid residues) can be relatively well absorbed intranasally from simple aqueous preparations, generally the nasal bioavailability of larger polypeptides becomes incomplete and unstable, and this is enhanced with increasing molecular weight (see L Illum: Archiv for Pharmaci og Chemi 94 (1987), 127-135.

U cilju prevazilaženja uočenih nedostataka sa nazalnom upotrebom sastava koji sadržavaju veče polipeptido, pronadjena su dodatno udružena različita biokompatibilna sredstva koja poboljšavaju apsorbciju, ili takozvani pojačivači.In order to overcome the perceived disadvantages with nasal use of compositions containing evening polypeptides, additional combined biocompatible absorption enhancers or so-called enhancers have been found.

U tom pogledu, cilj je postignut u Evropskoj patentnoj prijavi No. 111,841, u' kojoj je prikazan efekat poboljšanja apsorbcije žuene kiseline i u U.S. Patentu Iio. 4,476, 116, upotrebom helatnog reagensa kao što je EDTA.In this respect, the objective was achieved in European patent application No. 111,841, which shows the effect of improving the absorption of bile acid and in U.S. Pat. Patent Iio. No. 4,476, 116, using a chelating reagent such as EDTA.

Preparati za nazalnu upotrebu prilagodjeni za insulinsko davanje, prirodno če biti poželjniji kod insulinskih zavisnika - .dijabetičara, u odnosu na tre.nutno raspoložive preparate za parenteralnu upotrebu, jer obezbedjuju da je insulin apsorbovan sa srazmerno® delotvornošču i konstantnom veličinom kroz nazalnu šupljinu. Pronadjeno su mnogobrojne vrste sredstava, uglavnom surfaktanti, koji pojačavaju apsorbciju takvih preparata.Nasal preparations adapted for insulin administration will naturally be more desirable for insulin-dependent diabetic subjects than currently available parenteral preparations as they ensure that insulin is absorbed at a commensurate effectiveness and constant size through the nasal cavity. Numerous types of agents have been found, mainly surfactants, which enhance the absorption of such preparations.

Jonski, kao i nejonski surfaktant pojačivači, kao što su soli žučne kiseline i polioksietilen višeg alkoholnog etera su obelodanjeni u Britanskom patentu Ho. 1,527,605 dok je upotrebg. specifičnog polioksietilen višek alkoholnog etera, odnosno polioksietilcn-9 lauril etera opisana u: R. Salzman ct al., Nova Engleska J. od i.Ied. 312 (1935), 1073-1034. Drugi pojačavači, na primer, sloli taurodihidrofusidik kiseline su obelodanjeni u U.S. Patentu Ko. 4,548,922.Ionic as well as non-ionic surfactant enhancers such as bile salts and polyoxyethylene of higher alcohol ether have been disclosed in British Patent Ho. 1,527,605 while the use of. the specific polyoxyethylene excess alcohol ether, namely polyoxyethylcn-9 lauryl ether described in: R. Salzman et al., New England J. of i.Ied. 312 (1935), 1073-1034. Other enhancers, for example, taurodihydrofusidic acid salts have been disclosed in U.S. Pat. To the patent of Ko. 4,548,922.

Hemi^ske strukture do sada poznatih pojačavača znatnijc odstupaju od poznatih sastojaka celi jskih., membrana, ukLjučujuči ove nazalnih šupljina. Ovo svojstvo može objasniti njihovu opštu sklonost da uzrokuju nazalni nadražaj ili čak, stalnu ozledu nazalne membrane, naročito za vreme dugotrajnog lečenja. Na osnovu ovoga saznanja mogli su biti razmotreni pojačavači srodniji drugim fiziološki dobijenim surfaktantima, kao što su fosfolipidi. Ipak, u skladu sa podatkom obelodanjenim u Britanskom patentu No. 1,527,605 (supra) fosfolipidi u dugom lancu smeše lecitina nemaju pospešujuči efekat apsorbcije u insulinskom sadržaju u preparatima za nazalnu upotrebu.The chemical structures of the enhancers known so far deviate significantly from the known constituents of whole membranes, including these nasal cavities. This property may explain their general tendency to cause nasal irritation or even, permanent injury to the nasal membrane, especially during long-term treatment. Based on this knowledge, enhancers more similar to other physiologically derived surfactants, such as phospholipids, could be considered. However, according to the information disclosed in British Pat. 1,527,605 (supra) phospholipids in the long-chain lecithin mixture do not have the accelerating effect of absorption on insulin content in preparations for nasal use.

Izvanredno je saznanje da srednjih dužina, lanca fosfatdilholini i fosfatidiletanolamini znatno poboljšavaju intranazalnu apsorbciju farmaceutski aktivnih jedinjenja, naročito polipeptida, bez štetnosti ili nadražaja nazalne sluzokože. Intranazalna apsorbcija je dalje poboljšana preparatima u kojima je masno ulje, na primer, biIt is remarkable that medium-chain, phosphatidylcholine, and phosphatidylethanolamine amines significantly improve the intranasal absorption of pharmaceutically active compounds, especially polypeptides, without damaging or irritating the nasal mucosa. Intranasal absorption is further enhanced by preparations in which the fatty oil, for example, is bi

Ijno ulje izmešano sa fosfolipidom.Edible oil mixed with phospholipid.

4. Opis rešenja tehničkog problema4. Description of the solution to the technical problem

U skladu sa svojim prvim aspektom, ovaj pronalazak tr ba da obezbedi preparat za intranazalno lečenje koje obu hvata farmaceutski aktivno sredstvo i sistem poboljšavanja apsorbcije koji obuhvata najmanje jedan fosfolipid o pšte formule IIn accordance with its first aspect, the present invention is to provide an intranasal treatment composition comprising a pharmaceutically active agent and an absorption enhancement system comprising at least one phospholipid of the general Formula I

H-CK-OR’H-CK-OR '

II

CH-OR (I)CH-OR (I)

II

H-CK-O-P(O) (OH)-OR* u kojoj su R’ i R isti ili različiti i svaki je odabran iz grupe koja se sastoji od vodonika, alkila, alkenila, alkilkarbonila, alkenilkarbonila i alkadienila-, olkatri enila- ili alkatetraenilkarbonila sadržavajuči do ukupno atoma kabbona, pod uslovom da ni R’ ni r» nisu vodoni i R ‘ predstavlja hidrofilni deo izdvojen iz grupe koja se sastoji od 2-(trimetilamonio)etila, 2-aminoetila, 2-karboksi-2-aminoetila, 2,3-dihidroksipropila i pentahi droksicikloheksila, odnosno sadrži fosfatidil derivate holina (lecitina), etnolamina, glicerola, serina i inozita. Neobavezno, ali poželjno, sistem za poboljsavanjc apsorbcije, takodje obuhvata masno ulje u smeši sa fosfolipidima.H-CK-OP (O) (OH) -OR * in which R 'and R are the same or different and each is selected from the group consisting of hydrogen, alkyl, alkenyl, alkylcarbonyl, alkenylcarbonyl, and alkadienyl-, enalkyl enyl- or alkatetraenylcarbonyl containing up to a total of carbon atoms, provided that neither R 'nor r' is hydrogen and R 'represents a hydrophilic moiety separated from the group consisting of 2- (trimethylammonio) ethyl, 2-aminoethyl, 2-carboxy-2-aminoethyl , 2,3-dihydroxypropyl and pentachy droxycyclohexyl, respectively, containing phosphatidyl derivatives of choline (lecithin), ethnolamine, glycerol, serine and inositol. Optionally, but preferably, an absorption enhancement system also comprises fatty oil in admixture with phospholipids.

U skladu sa drugim aspektom, ovaj pronalazak treba da obezbedi postupak za pripremanje preparata za intranazalnu upotrebu, čiji metod obuhvata disperziju najmanje jednog fosfolipida opšte formule I, neobavezno, ali poželjno, izmešanog sa masnim uljem, u čvrstom ili tečnom razredjivaču zajedno sa farmaceutski aktivnim sredstvom, ili u rastvoru ili u prahastom stanju, čiji razredjivaČ može neobavezno obuhvatati pomočno pH-puferovanje, zaštitu i sredstva koja kontrolišu osmotski pritisak.In accordance with another aspect, the present invention is to provide a process for the preparation of preparations for intranasal use, the method of which comprises dispersing at least one phospholipid of general formula I, optionally but preferably, mixed with a fatty oil, in a solid or liquid diluent together with a pharmaceutically active agent , or in solution or powder, the diluent of which may optionally include auxiliary pH buffering, protection and osmotic pressure control agents.

Poželjna podgrupa jedinjenja formule I su jedinjenja u kojem su i R’ i R” -alkilkarbonil. Osim ove, poželjna podgrupa jedinjenja formule I su jedinjenja u kojima R ' predstavlja 2-(trimetilamonio)etil, takva jedinjenja koja su poznata kao lecitini. Jos poželjnija su jedinjenja formule I, u kojima i R’ i R” predstavljaju alkilkarbonil sa od oko 4 atoma karbona, poželjno ne više od 12 atoma karbona. Najpoželjnija podgrupa jedinjenja formule I su jedinjenja u kojima i R’ i R predstavljaju nonilkarbonil.Preferred subgroups of compounds of formula I are compounds wherein both R 'and R' are alkylcarbonyl. In addition, preferred subgroups of compounds of formula I are compounds wherein R 'represents 2- (trimethylammonio) ethyl, such compounds known as lecithins. More preferred are the compounds of formula I, in which both R 'and R' represent alkylcarbonyl of about 4 carbon atoms, preferably not more than 12 carbon atoms. The most preferred subgroups of compounds of formula I are compounds wherein both R 1 and R 4 represent nonylcarbonyl.

Poželjan preparat ovog pronalaska je onaj koji sadrži smešu dva fosfolipida formule I. Jedan od. ova dva fosfolipida može biti jedinjenje u kojem su i R* i R“ oktanoil,A preferred formulation of the present invention is one containing a mixture of two phospholipids of formula I. One of. these two phospholipids may be a compound in which both R * and R are octanoyl,

7. .7..

dekanoil ili lauroil. Drugi od ova dva fosfolipida može biti jedinjenje u kojem je jedan od dvč oznake R’ i R vodonik i druga od dve oznake R’ i R” je oktanoil,dekanoil ili dodekanoil (lauroil).decanoyl or lauroyl. The other of these two phospholipids may be a compound in which one of the two labels is R 'and R is hydrogen and the other of the two labels R' and R 'is octanoyl, decanoyl or dodecanoyl (lauroyl).

Primeri poželjnih jedinjenja formule I su:Examples of preferred compounds of formula I are:

diooktanoil L-^-fosf atidilholin, diokt il-O-L-<^-f o sf atidilholin, didekanoil L-</-fosfatidilholin, didekil-0-L-c/-fosf atidilholin, dekil-0-L-</-lizof atidilholin, dilauroil L-<X-fosfatidilholin, lauroil L-oi-lizofosfatidilholin.dioctanoyl L - ^ - phosphid atidylcholine, dioct il-OL - <^ - fo sf atidylcholine, didecanoyl L - </ - phosphatidylcholine, didekyl-O-Lc / -phosphididylcholine, decyl-0-L - </ - lysophididylcholine, dilauroyl L- <X-phosphatidylcholine, lauroyl L-o-lysophosphatidylcholine.

Jedinjenja formule I, od kojih su neka poznata, mogu biti pripremljena pomocu poznatog postupka per se.The compounds of formula I, some of which are known, can be prepared by a known method per se.

Masno ul j e p neobavezno pripojeno u sistem koji poboljšava apsorbciju ovog pronalaska, je poželjno kao biljno ulje, ili još poželjnije kao sojino ulje, ulje kikirikija, kokosovo ulje, kukuruzno ulje, maslinovo ulje, suncokretovo ulje ili njihove smeše.The fatty oil is optionally attached to a system that enhances the absorption of the present invention, preferably as vegetable oil, or more preferably as soybean oil, peanut oil, coconut oil, corn oil, olive oil, sunflower oil or mixtures thereof.

U drugom poželjnom otelotvorenju ovog pronalaska, faraaceutski aktivno sredstvo je polipeptid. Jedna grupa poželjnih polipeptida je insulin i derivati insulina, n. pr.In another preferred embodiment of the present invention, the pharmaceutically active agent is a polypeptide. One group of preferred polypeptides is insulin and insulin derivatives, n. BC

insulin modifikovan hemijskim ili cnziraatskim postupkom ili pomocu tehnologije rokombinanta DNA, ili smeše takvihinsulin modified by a chemical or csiraat method or by using DNA rocombinant technology, or mixtures thereof

ό.ό.

insulina, proin3ul.in i glulcagon. Drugi poželjni polipeptidi su paratiroidni hormon, antagonist paratiroidnog hormona, kalcitonin, vazopresin, renin, prolaktin, hormon rasta, hormon koji stimuliše tiroidu, kortikotropin, faktor koji oslobadja kortikotropin, folikulo stimulirajuci hormon, luteinizirajuči hormon, horion, gonadotropin, atrial peptidi, interferon, aktivator tkivnog plazminogena, gamaglobulini, faktor VII, faktor VIII, hormon koji oslobadja hormon rasta, hormon koji oslobadja luteinizirajuči hormon, somatostatin i holekistokinini.insulin, proin3ul.in and glulcagon. Other preferred polypeptides are parathyroid hormone, parathyroid hormone antagonist, calcitonin, vasopressin, renin, prolactin, growth hormone, thyroid stimulating hormone, corticotropin, corticotropin releasing factor, follicle stimulating hormone, luteinizing hormone, chorion, chorion, chorion tissue plasminogen activator, gamaglobulins, factor VII, factor VIII, growth hormone releasing hormone, luteinizing hormone releasing hormone, somatostatin and cholecystokinins.

Preparat iz ovog pronalaska može biti tečnost, n. pre podešena za davanje kao spre j, ili u čvrstom stanju, n. pr. prašak koji je podešen za ušmrkavanje. Tečni preparati, kao što su ovi na bazi vodnih formulacija če uobičajeno ukljuČivati pomočna sredstva, na primer, sistem pH-puferovanja, poželjnijc pufer kao što je fosfat, citrat ili acetat pu— feri, zaštitu i sredstvo koje kontroliše osmotski pritisak, n. pr. glicerol ili natrijum hlorid. Prahasti preparati mogu sadržavati farmaceutski aktivno sredstvo i sistem koji poboljšava apsorbciju u smeši sa nazalno prihvatljivim rastvarač ima praška ili njihovih smeša, n. pr. celuloza ili njeni derivati, na primer eteri celuloze ili natrijum karboksimetilceluloza, škrob ili delimično degradiran škrob,kao što su dekstrini, masna kiselina dugog lanca, ili njena so, n. pr. aluminijum 3tcarat, organski polimer,The composition of the present invention may be a liquid, n. previously adjusted for administration as spray j, or in solid state, n. BC powder set to sniff. Liquid preparations such as those based on aqueous formulations will typically include adjuvants, for example, a pH buffering system, more preferably a buffer such as phosphate, citrate or acetate buffers, protection and an osmotic pressure control agent, e.g. BC glycerol or sodium chloride. Powder preparations may contain a pharmaceutically active agent and a system that enhances the absorption in a mixture with a nasally acceptable solvent of the powder or mixtures thereof, n. BC cellulose or derivatives thereof, for example cellulose ethers or sodium carboxymethylcellulose, starch or partially degraded starch, such as dextrins, long chain fatty acids, or a salt thereof, n. BC aluminum 3tcarat, organic polymer,

9< : . - . .9 <:. -. .

n. pr. iz derivata akrilik kiseline ili neorganskog prenosnika, kao što je talk, ili dijatomejska zemlja. l)odavanje polimera koji apsorbuju vodu, na primer, polietilen glikola ili polivinil pirolidona može biti poželjno da bi se obezbedila adhezija preparata u obliku praška za nazalnu sluzokožu.n. BC from an acrylic acid derivative or inorganic carrier such as talc or diatomaceous earth. l) dispensing water-absorbing polymers, for example, polyethylene glycol or polyvinyl pyrrolidone, may be desirable to provide adhesion of the preparations in the form of nasal mucosa powder.

Poželjni tečni preparati su oni u kojima je rastvarač voda. Takvi preparati mogu biti pripremljeni disperzijora sistema koji poboljšava apsorbciju u vodnoj sredini koja sadrži farmaceutski aktivno sredstvo i pomočna sredstva, disperzija biva sprovedena pomocu bilo kog postupka uobičajeno primenjenog za suspenzi ju ili emulgovanje, n. pr. ultrazvučnim postupkom. Podešavanje vodne faze na neutralnu (tj. na pHu opsegu od oko 6,5 do oko 8) može biti izvršeno u bilo kom delu pripremanja. Poželjno, mikroe,nulzije su pripremljenc tako da je veličina disperzovanih delova ili kapljica reda od 10 nm, zbog čega sc olakšava njihov prolaz kroz nazalnu sluzokožu. Ovakve mikrocmulzije mogu biti sterilizovane filtracijom. Sadržaj fosfoli♦ pida formule I i masnog ulja u po željnim preparat ima iz ovog pronalaska je u opsegu od 0,01 do 105« (vz/v), odnosno 0,01 - 50$ (w/v) preparata. Zahvaljujuci einjenici da su proteaze i peptidaze povezane sa nazalnom sluzokožom (vidi R.E. Stratford i V.H.L. Lee: Int.Joura.Pharmaceutics 30 (1936), 73-82) poželjno bi bilo da se spoje biokompatibi10Preferred liquid formulations are those wherein the solvent is water. Such preparations may be prepared by a dispersant of a system that enhances absorption in an aqueous medium containing a pharmaceutically active agent and adjuvants, the dispersion being carried out by any of the methods commonly used for suspension or emulsification, n. BC by ultrasound. Adjustment of the aqueous phase to neutral (i.e. at a pH range of about 6.5 to about 8) can be accomplished in any part of the preparation. Preferably, the microe, nulsions are prepared such that the size of the dispersed parts or droplets is of the order of 10 nm, which facilitates their passage through the nasal mucosa. Such microculsions can be sterilized by filtration. The content of the phospholipid of formula I and the fatty oil in the preferred formulation of the present invention is in the range of 0.01 to 105 "(v / v) and 0.01 to 50 $ (w / v) of the formulation. Owing to the fact that proteases and peptidases are associated with nasal mucosa (see R.E. Stratford and V.H.L. Lee: Int.Joura.Pharmaceutics 30 (1936), 73-82) it would be desirable to fuse biocompatibilities10

Ini proteaz i peptidaz inhibitori u preparat ima koji sadrže polipcptide.Other protease and peptidase inhibitors in the preparation have polypeptide containing.

Koncentracija farmaceutski aktivnog sredstva u preparatoma iz ovog pronalaska če se kretati u zavisno sti od izbora sredstva, njegove efikasnosti, uporedbe njegove bioupotrebijivosti u nazalnoj upotrebi sa drugim naeinima upotrebe, na primer, parenteralnim ubrizgavanjem, i od željene učestanosti primene, kombinovano sa željenim pojcdinaenim dozama preparata. Ovakav farmakološki podatak može biti redovno dobijen od iskusnog stručnjaka iz ekspcrimenata. sa šivotinjama, na primer, u odnosu na vrednosti indeksa, kao što su ove procene insulinskih preparata u primerima koji se dole mogu nači.The concentration of the pharmaceutically active agent in the compositions of the present invention will vary depending on the choice of the agent, its efficacy, comparison of its bioavailability in nasal use with other uses, for example, parenteral injection, and on the desired frequency of administration, combined with desired single doses preparations. Such pharmacological information can be obtained regularly from an experienced expert in the field of excretions. with animals, for example, relative to index values, such as these estimates of insulin preparations in the examples below.

Uzmimo insulin kao primer, njegova koncentracija u preparatu iz ovog pronalaska može biti u opsegu od oko 5 do 1000 internacionalnih jedinica (I.U.) prema ml, ili još bolje od 50 do 500 I.U. prema ml.Take insulin as an example, its concentration in the composition of the present invention may be in the range of about 5 to 1000 International Units (I.U.) per ml, or more preferably 50 to 500 I.U. according to ml.

Insulinski preparati iz ovog pronalaska poželjno sadrže govedji, svinjski ili ljudski insulin.The insulin compositions of the present invention preferably contain bovine, porcine or human insulin.

Uzorni način pripremanja insulinskih preparata iz ovog pronalaska u kojem je rastvarač voda, obuhvata rastvorljiv insulin, na primer, kristalni cink insulin, na primer, visoki stepen očišcenog insulina iz Britanskog patenta Ko.1,235,023, u vodi u prisustvu jedne kiseline, na primer, hidrolorične kiseline. Vodni rastvor zaštitnika, na primer, fenol, clkilAn exemplary method of preparing insulin compositions of the present invention in which the solvent is water, comprises soluble insulin, for example, crystalline zinc insulin, for example, a high degree of purified insulin from British Patent Ko.1,235,023, in water in the presence of an acid, for example, hydrolytic acid. An aqueous solution of the protector, for example, phenol, clkil

11. ·· .-. --.11. ·· .-. -.

fenol, leno sto je krezol ili metil p-hidroksibcnzoat, je odvojeno pripremijen, neobavezno sadržava sredstvo koje izvodi izotoničen rastvor, kao što je natrijum hlorid ili glicerol. Osim toga, rastvor zaštitnika može sadržavati sredstvo za puferovanje, kao što je natrijum fosfat, natrijum citrat, natrijum acetat ili TRIS (tri(liidroksimetil)aminometan) i proteaz inhibitor. Dobljeni rastvor zaštitnika je tada izmešan sa kiselim insulinskim rastvorom pracen dodavanjem baze, na primer, rastvor natrijum hidroksida, da bi se podesila pH vrednost na neutralnu. Posfolipid formule I neobavezno iznesen sa masnim uljem, može biti dodat u insulinski rastvor kao rastvor ili emulzija koji je pripremijen rastvaranjem ili suspendovanjem fosfolipida formule I u vodi i ako je potrebno, podvrgavanjem bilo koje suspenzije ultrazvučnom postupku pre mešanja sa insulinskim rastvorom. Alternativno, rastvor fosfolipida ili emulzije može, ako je potrebno, da sadržava sredstvo puferovanja i zaštitnik. Ilakon mešanja, pH vrednost insulinskog preparata može biti prepodešena do neutralne. Na kraju, dobljeni insulinski rastvor je napravljen do prpračunate zapremine dodavanjem vode.phenol, such as cresol or methyl p-hydroxybenzoate, is separately prepared, optionally containing an agent that performs an isotonic solution, such as sodium chloride or glycerol. In addition, the protector solution may contain a buffering agent, such as sodium phosphate, sodium citrate, sodium acetate or TRIS (tri (liidroxymethyl) aminomethane) and a protease inhibitor. The resulting protector solution is then mixed with an acidic insulin solution followed by the addition of a base, for example, sodium hydroxide solution, to adjust the pH to neutral. Posfolipid of Formula I optionally taken with fatty oil may be added to the insulin solution as a solution or emulsion prepared by dissolving or suspending the phospholipid of Formula I in water and, if necessary, subjecting it to an ultrasonic procedure before mixing with the insulin solution. Alternatively, the phospholipid or emulsion solution may, if necessary, contain a buffering agent and a protector. When mixed, the pH of the insulin preparation may be adjusted to neutral. Finally, the resulting insulin solution was made to a calculated volume by the addition of water.

Preparati iz ovog pronalaska mogu biti upotrcbljeni u bilo kojem uredjaju za odredjivanje doze podešenom za intranazalnu upotrebu. Uredjaj može biti konstruisan sa obzirom na ustanovijavanje optimuma. ispravnosti merenja i kompatibilnosti njegovih konstruktivnih elemenata, kao što je sud, ventilThe compositions of the present invention can be used in any dose-setting device adapted for intranasal use. The device can be constructed with respect to the optimum setting. correct measurement and compatibility of its structural elements, such as a vessel, a valve

12.12.

i pokretač sa nazalnom formulacij o m i mogao bi biti na bazi sistema mehaničke pumpe, n. pr. dozimctar ncbulizcr, ili acro sol sistem pod pritiskom. Aerosol sistem zahteva da propelant bude inertan prema formulaciji. Odgovarajuči propclanti mogu biti odabrani med ju gasovima kao što su fluorokarboni, hidrokarboni, azot i azotoksid ili njihove smeše.and a mover with a nasal formulation o m and could be based on a mechanical pump system, n. BC dosimeter ncbulizcr, or acro salt pressure system. The aerosol system requires the propellant to be inert to the formulation. Suitable propellants may be selected from among gases such as fluorocarbons, hydrocarbons, nitrogen and nitrous oxide or mixtures thereof.

Dodatni detalji izvodjenja ovog pronalaska su dobijeni putem sledečih primera koji, ipak, ne mogu biti shvačcni kao da odredjuju bilo koju vrstu ograničenja delokruga ovog pronalaska.Further details of the embodiment of the present invention have been obtained by the following examples, which, however, cannot be understood to determine any type of scope of the invention.

Početni insulinski materijal upotrebljen u Primerima 1-12 je sadržavao oko 20 do cinka prema mg azota.The starting insulin material used in Examples 1-12 contained about 20 to zinc per mg of nitrogen.

Sojino ulje i ulje kikirikija su takvog stepena čistoče da odgovaraju njihovim U.S.P. XXI, odnosno IIP. XVI.Soybean oil and peanut oil are of such purity as to correspond to their U.S.P. XXI and IIP respectively. XVI.

Primer 1Example 1

772 mg čovečijcg insulina je rastvoreno u 40 ml 0,02 M hidrohlorične kiseline i dodato je 1,6 g nevodnog glicerola. Osim ovog, dodato je do 80 ml destilovane vode. Vrednost pH je podešena do 7,4 sa 0,2 M rastvora natrijum hidroksida.772 mg of human insulin was dissolved in 40 ml of 0.02 M hydrochloric acid and 1.6 g of non-aqueous glycerol was added. In addition, up to 80 ml of distilled water was added. The pH was adjusted to 7.4 with 0.2 M sodium hydroxide solution.

1,0 g didekanoil L-«/-fosfatidilholina je rastvorcno u 2 ml etanola (96%) i sve je putem hipodermičkog sprica ubrizgano u 10 ml destilovane vode. Rezultirajuci mutan rastvor je podvrgnut ultrazvuČnom postupku sa visoko energetskom ultrazvučnom sondom za 10 minuta i rezultujuci koloidni rastvor1.0 g of didecanoyl L - N - phosphatidylcholine was dissolved in 2 ml of ethanol (96%) and injected into the 10 ml of distilled water via a hypodermic syringe. The resulting turbid solution was sonicated with a high-energy ultrasound probe for 10 minutes and the resulting colloidal solution

13je dodat insulinskom rastvoru sa mešanjem i dodata je do 100 ml destilovana voda. Ovaj preparat koji sadrži 200 I.U./ml insulina je davan u spre ju podesnom za nazalnu upotrebu i 100 mikrolitara je dato kroz nazalnu šupljinu mužjaka KZT/ zceeva. Slišan: preparat, ali bez didekanoil L-pi-fosf atidilholina, je takodje isproban na Zečevima.13 was added with stirring insulin solution and up to 100 ml of distilled water was added. This preparation containing 200 IU / ml insulin was administered in a spray suitable for nasal use and 100 microliters was administered through the nasal cavity of male KZT / rabbits. Hearing: The preparation, but without didecanoyl L-py-phosphid atidylcholine, was also tested on Rabbits.

U odredjenim vremenskim razmacima uzeti su uzorci krvi iz marginalne usne vene i izmerena je koncentracija glukoze pomoču heksokinazne metode.At certain intervals, blood samples from the marginal oral vein were taken and glucose concentration was measured using the hexokinase method.

Dobljeni rezultati su:The results obtained are:

Minuti nakon Minutes after £5-1. U.-U.U XI tu ΙΛ £ 5-1. U.-U.U XI tu ΙΛ postupka procedure 0 0 30 30 60 60 90 90 120 120 Insulin bez Insulin without dodataka supplements 100 100 100 100 103 103 99 99 100 100 Insulin sa Insulin with didekano il didekano il L-rZ-fosfatidil- L-rZ-phosphatidyl- ho lin ho lin 100 100 56 56 65 65 70 70 81 81

Primer 2Example 2

100 mg didekanoil Ii-o<-fosf atidilholina jc rastvorcno ti100 mg of didecanoyl II-o <? - phosphid atidylcholine is soluble

100 mg sojino g ulja i rastvor je dodat u 5 ml 0,01 1.1 natrijum fosfat pufera, pH 7,4.100 mg of soybean g oil and solution were added to 5 ml of 0.01 1.1 sodium phosphate buffer, pH 7.4.

Smeša je cmulgovana ultrazvučnim postupkom; 2 ml insulin14. . . .. ..The mixture was ultrasonicly cured; 2 ml insulin14. . . .. ..

skog rastvora od 400 jedinica prema ml su dodati emulziji i pH je podešen do 7,4 i dodato je vode do 10 ml.of 400 units per ml were added to the emulsion and the pH was adjusted to 7.4 and water was added to 10 ml.

Nakon: nazalne primene ovog preparata u Zečevima, koncentracija krvne glukoze je kontrolisana za 120 minuta. Prostoi iznad krive, gde su vrednosti krvne glukoze prikazane u procentima prema poeetnoj vrednosti, je izračunat pomocu metoda trougla. Indeks je tada izračunat u skladu sa ovom formulom:After nasal administration of this preparation in Rabbits, blood glucose concentration was controlled for 120 minutes. Above the curve, where blood glucose values are expressed as a percentage by initial value, was calculated using triangle methods. The index is then calculated according to this formula:

Indeks - 0,053 x a/D u kojoj je A prostor iznad krive test preparata, D je doza test preparata, i faktor 0,053 je empirieki izveden faktor iz potkožne primene insulinskog preparata brzog deloven ja.Index - 0.053 x a / D in which A is above the curve of the test preparation, D is the dose of the test preparation, and the factor 0.053 is an empirically derived factor from the subcutaneous administration of the fast-acting insulin preparation.

Testirana na ovaj način emulzija nazalnog insulina ima indeks od 24%.The nasal insulin emulsion tested in this way has an index of 24%.

Sličan preparat, ali napravljen bez biljnog ulja ima indeks od 12-15%.A similar preparation, but made without vegetable oil, has an index of 12-15%.

Primeri 3-12Examples 3-12

Preparati Primera 3-6, 8 i 12 su pripremljeni na slišan način kao što je opisano u Primeru. 1, dok su preparati Primera 7 i 9-11 pripremljeni postupkom iz Primera 2. Sledeče skračenice su upotrebljene u tabeli:The preparations of Examples 3-6, 8 and 12 were prepared in an audible manner as described in Example. 1, while the preparations of Examples 7 and 9-11 were prepared by the procedure of Example 2. The following abbreviations were used in the table:

Posfatidilholin: PCPosfatidylcholine: PC

Didekanoil fosfatidilholin: DDPCDidecanoyl phosphatidylcholine: DDPC

Lilauril fosfatidilholin:. DLPCLilauryl phosphatidylcholine:. DLPC

Procentualni sadržaji su u težini prema zapremini. Svi preparati sadržavaju 80 I.U./ml insulina.Percentage contents are weighted by volume. All preparations contain 80 IU./ml of insulin.

15.15.

Primer br. Posfolipid Biljno ulje IndeksExample no. Posfolipid Vegetable Oil Index

3 4 5 3 4 5 0,5$ lauroil lizoPC 0,5$ miristoil lizoPC 0,5$ stearoil lizoPC $ 0.5 lauroyl lizoPC $ 0.5 myristoyl lizoPC $ 0.5 stearoyl lizoPC bez without 10,9/S 31 0,8$ 10.9 / S 31 $ 0.8 6 6 0,5$ DDPC 4- 0,2$ lauroil lizoPC $ 0.5 DDPC 4- $ 0.2 lauroyl lizoPC bez without 13,9/. 13.9 /. 7: 7: 0,5$ DDPC 4-0,2$ lauroil lizoPC $ 0.5 DDPC $ 4-0.2 lauroil lizoPC ulje kikirikija 2$ peanut oil $ 2 21,9, 21.9, 8 8 0,5$ didekil-O-PC $ 0.5 didekil-O-PC bez without 21,9$ $ 21.9 9 9 0,5$ didekil-O-PC + 0,5$ DDPC $ 0.5 didekil-O-PC + $ 0.5 DDPC ulje kikirikija 1$ peanut oil $ 1 28,7/ 28,7 / 10 10 0,5$ DDPC 0,5$ DLPC $ 0.5 DDPC $ 0.5 DLPC ulje kikirikija 1$ peanut oil $ 1 13,9$ $ 13.9 11 11 0,5$ DDPC 0,5$ dimiristoil PC $ 0.5 DDPC $ 0.5 dimiristoyl PC ulje kikirikija Ί t/ 1/σ peanut oil Ί t / 1 / σ 14,3$ $ 14.3 12 12 0,5$ DDPC $ 0.5 DDPC bez without 11$ $ 11

Podaci pokazuju izvanredno poboljšanje apsorbcionih efekata od fosfatidilholina sa srednjom dužinom lanca alkil ili alkil grupa.The data show a remarkable improvement in the absorption effects of phosphatidylcholine with medium chain alkyl or alkyl groups.

Primer 13Example 13

100 mg didekanoil I»-v(-fosfatidilholina je rastvoreno u100 mg of didecanoyl I »-v (-phosphatidylcholine was dissolved in

100 mg sojinog ulja i rastvor je dodat u 5 ml 0,01 LI natrijum fosfat pufera, pH 7,4, sadržavajuci 160 mg glicerola, liakon emulgovanja smeše ultrazvučnim postupkom, 100 mg glukagona je dodato u emulziju, pH je podešen do 7,4 i dodato jc vode do 10 ml.100 mg of soybean oil and solution was added to 5 ml of 0.01 LI sodium phosphate buffer, pH 7.4, containing 160 mg of glycerol, the lacon emulsifying the mixture by ultrasonic procedure, 100 mg of glucagon was added to the emulsion, the pH was adjusted to 7.4 and water was added to 10 ml.

16.16.

Prateči nazalnu upotrebu ovog preparata u zečcvima, konce ntracija glukoze u uzorcima krvi uzetim iz marginalne učne vene je kontrolisana heksokinaz motodom.Following the nasal use of this preparation in rabbits, glucose concentration in blood samples taken from the marginal learning vein was controlled by the hexokinase motode.

Sledeče koncentracije krvne glukoze su dobijene za vreme:The following blood glucose concentrations were obtained during:

Minuti nakon postupkaMinutes after the procedure

15 3015 30

12o12o

Glukagon bez sistema poboljšanja 100 107* 113Glucagon without enhancement system 100 107 * 113

111111

107107

Glukagon sa sistemom poboljšanja 100 144 178Glucagon with enhancement system 100 144 178

188188

163 i; :L:163 i; : L:

Claims (15)

PATENTNI ZAHTEVKIPATENT APPLICATIONS 1. Pripravek za nazalno uporabo, označen s tem, da vsebuje farmacevtsko aktivno sredstvo in sistem, ki izboljšuje absorpcijo, ki vsebuje vsaj en fosfolipid s splošno formulo IA preparation for nasal use, characterized in that it contains a pharmaceutically active agent and an absorption enhancing system containing at least one phospholipid of general formula I H-CH-OR’H-CH-OR ' II CH-ORCH-OR H-CH-0-P(0)(0H)-0R'” (I) v kateri sta R’ in R enaka ali različna in vsak predstavlja vodik, alkil, alkenil, alkilkarbonil, alkenilkarbonil, alkadienilkarbonil, alkatrienilkarbonil ali alkatetraenilkarbonil, ki ne vsebuje več kot 14 ogljikovih atomov pod pogojem, da niti R’ niti R nista vodik in R’ predstavlja hidrofilno skupino, dobljeno iz skupine, ki obsega 2-(trimetilamonio)etil, 2-aminoetil, 2-karboksi-2-aminoetil, 2,3dihidroksipropil ali 2,3,4,5,6-pentahidroksicikloheksil.H-CH-O-P (O) (OH) -O R '' (I) in which R 'and R are the same or different and each represents hydrogen, alkyl, alkenyl, alkylcarbonyl, alkenylcarbonyl, alkadienylcarbonyl, alkatrienylcarbonyl or alkatetraenylcarbonyl, which contains no more than 14 carbon atoms, provided that neither R 'nor R is hydrogen and R' represents a hydrophilic group derived from the group consisting of 2- (trimethylammonio) ethyl, 2-aminoethyl, 2-carboxy-2-aminoethyl, 2,3dihydroxypropyl or 2,3,4,5,6-pentahydroxycyclohexyl. 2. Pripravek po zahtevku 1, označen s tem, da R’ predstavlja 2-(trimetilamonio)etil.A preparation according to claim 1, characterized in that R 'represents 2- (trimethylammonio) ethyl. 3. Pripravek po zahtevku 2, označen s tem, da je tako R’ kot R alkil ali alkilkarbonil, ki vsebujeta od 4 do 12 ogljikovih atomov, ali prednostno alkilkarbonil.A preparation according to claim 2, wherein both R 'and R are alkyl or alkylcarbonyl containing from 4 to 12 carbon atoms, or preferably alkylcarbonyl. 4. Pripravek po zahtevku 3, označen s tem, da predstavljata tako R’ kot R nonilkarbonil.A preparation according to claim 3, characterized in that they represent both R 'and R nonylcarbonyl. 5. Pripravek po zahtevku 2, označen s tem, daje ali R’ ali R vodik.A preparation according to claim 2, characterized in that either R 'or R is hydrogen. 6. Pripravek po zahtevku 1, označen s tem, da sistem za izboljšanje absorpcije vsebuje maščobno olje.Preparation according to claim 1, characterized in that the absorption enhancement system contains fat oil. 7. Pripravek po zahtevku 6, označen s tem, da je maščobno olje rastlinsko olje, prednostno dobljeno iz skupine, ki sestoji iz sojinega olja, kikirikijevega olja, kokosovega olja, koruznega olja, olivnega olja in sončičnega olja.A preparation according to claim 6, characterized in that the fatty oil is a vegetable oil, preferably obtained from the group consisting of soybean oil, peanut oil, coconut oil, corn oil, olive oil and sunflower oil. 8. Pripravek po zahtevkih 1-5, označen s tem, da je vsebnost fosfohpida s formulo I v obsegu od 0,01 do 10 % (rahf), ah prednostno 0,5-5 % (m/v) preparata.A preparation according to claims 1-5, characterized in that the content of the phosphohydride of the formula I is in the range of 0.01 to 10% (rahf), but preferably 0.5-5% (w / v) of the preparation. 9. Pripravek po zahtevkih 6-7, označen s tem, da je vsebnost maščobnega olja v obsegu od 0,01 do 50 % (m/v), prednostno 0,1-10 % (m/v) pripravka.A preparation according to claims 6-7, characterized in that the fat oil content is in the range of 0.01 to 50% (w / v), preferably 0.1-10% (w / v) of the preparation. 10. Pripravek po zahtevkih 1-9, označen s tem, da je farmacevtsko aktivno sredstvo polipeptid.A preparation according to claims 1-9, characterized in that the pharmaceutically active agent is a polypeptide. 11. Pripravek po zahtevku 10, označen s tem, da je polipeptid inzulin ah inzulinski derivat, ali njuna zmes.A preparation according to claim 10, characterized in that the polypeptide is an insulin ah insulin derivative, or a mixture thereof. 12. Pripravek po zahtevku 11, označen s tem, da je vsebnost inzulina v obsegu od 5 do 1000, ali prednostno od 50 do 500 internacionalnih enot na ml pripravka.A preparation according to claim 11, characterized in that the insulin content is in the range from 5 to 1000, or preferably from 50 to 500 international units per ml of the preparation. 13. Pripravek po zahtevku 10, označen s tem, daje polipeptid glukagon.The preparation of claim 10, wherein the polypeptide is glucagon. 14. Postopek za pripravo pripravka po zahtevku 6, označen s tem, da metoda obsega disperzijo vsaj ene mešanice fosfolipida z maščobnim oljem v tekočem ah trdnem razredčilu, skupaj s farmacevtsko aktivnim sredstvom v raztopljenem ah prahastem stanju, katerega razredčilo v danem primeru obsega pomožna sredstva za pHpufranje, konzerviranje in kontrolo osmotskega tlaka.14. A process for preparing a composition according to claim 6, characterized in that the method comprises dispersing at least one mixture of phospholipid with fat oil in a liquid solid solvent, together with a pharmaceutically active agent in a dissolved powder state, whose diluent optionally comprises auxiliary agents. for pH buffering, preservation and control of osmotic pressure. 15. Uporaba pripravka po zahtevku 6, označena s tem, da je naprava za določevanje doze prilagojena intranazalnemu zdravljenju.Use of a composition according to claim 6, characterized in that the dosage device is adapted for intranasal treatment.