SI9400222A - Non-chlorofluorocarbon aerosol formulations - Google Patents

Abstract

Opisane so formulacije aerosolov popolnoma brez klorofluoroogljikov za oralno in/ali nazalno dajanje. Formulacije vsebujejo 1,1,1,2, tetrafluoroetana, zdravilo, poljubno ekscipient in poljubno surfaktant. Prav tako so opisane metode zdravljenja, kjer se formulacije uporabljajo.Aerosol formulations are described in full free of chlorofluorocarbons for oral and / or nasal administration. The formulations contain 1,1,1,2, tetrafluoroethane, drug, any excipient and any surfactant. Treatment methods are also described where formulations used.

Description

Predstavitev izumaPresentation of the invention

Predstavljeni izum je usmerjen k formulacijam aerosolov, ki so popolnoma brez klorofluoroogljikov (CFC). Bolj specifično, predstavljeni izum je usmerjen k formulacijam, ki so brez CFC in imajo posebno uporabnost v medicinskih sredstvih, posebej v inhalatorjih z odmerjeno dozo pod pritiskom (MDI).The present invention is directed to formulations which are completely chlorofluorocarbons (CFC) aerosols. More specifically, the present invention is directed to formulations that are CFC-free and have particular utility in medical devices, especially in metered dose inhalers (MDI).

Dokazano je, da so inhalatorji z odmerjeno dozo pod pritiskom učinkovita metoda za dajanje zdravil oralno in nazalno. Široko jih uporabljajo pri dajanju bronhodilatantnih in steroidnih spojin astmatikom in so lahko prav tako uporabni za dajanje drugih spojin, kot so pentamidin in antiinflamatorna zdravila, ki niso bronhodilatatorji. Rapidno zvišanje aktivnosti spojin, ki jih dajemo na ta način, in odsotnost kakršnihkoli stranskih učinkov sta dala veliko število spojin, ki so formulirane za dajanje po tej poti. Tipično dajemo zdravilo pacientom s sistemom s pogonskim sredstvom (propellant), ki na splošno vsebuje enega ali več pogonskih sredstev, ki imajo ustrezni parni tlak in so primerna za oralno in nazalno dajanje. Najbolj zaželjeni sistemi pogonskih sredstev vsebujejo pogonsko sredstvo 11, pogonsko sredstvo 12, pogonsko sredstvo 114 ali pa njihovo mešanico. Pogosto reguliramo parni tlak sistema s pogonskim sredstvom z mešanjem tekočega ekscipienta s pogonskim sredstvom.Dosing pressure inhalers have been shown to be an effective method of administering drugs orally and nasally. They are widely used in the administration of bronchodilator and steroid compounds to asthmatics and may also be useful for the administration of other compounds such as pentamidine and anti-inflammatory drugs other than bronchodilators. The rapid increase in the activity of the compounds administered in this manner and the absence of any side effects produced a large number of compounds formulated for administration by this route. Typically, the drug is administered to patients with a propellant system, which generally contains one or more propellants that have adequate vapor pressure and are suitable for oral and nasal administration. Most preferred propellant systems include propellant 11, propellant 12, propellant 114, or a mixture thereof. We often regulate the vapor pressure of the system with the propellant by mixing the liquid excipient with the propellant.

Vendar pa pogonska sredstva 11, 12 in 114 spadajo v razred spojin, ki so znane kot klorofluoroogljiki, ki so povezani z odvajanjem ozona iz atmosfere. Ugotovljeno je bilo, da ozon zadrži določene škodljive UV žarke in, da bo upadanje vsebnosti ozona v atmosferi povzročilo povečano pogostnost kožnega raka. Leta 1970 so naredili določene korake, da bi zmanjšali emisijo CFC iz aerosolov. Uporabljali so druga pogonska sredstva, kot so ogljikovodiki, ali pa so proizvod dajali na drugačen način. Ker je uporaba CFC v medicinskih sredstvih relativno nizka, t.j. manj kot 1% celotne emisije, in zaradi koristnosti zdravju, ki je povezana z inhalatorji z odmerjeno dozo pod pritiskom, v tistem času niso omejili uporabe CFC pogonskih sredstev v inhalatorjih z odmerjeno dozo.However, propellants 11, 12 and 114 belong to the class of compounds known as chlorofluorocarbons, which are associated with the release of ozone from the atmosphere. Ozone has been found to retain certain harmful UV rays and that a decrease in the ozone content of the atmosphere will lead to an increased incidence of skin cancer. In 1970, certain steps were taken to reduce CFC emissions from aerosols. They used other propellants, such as hydrocarbons, or otherwise marketed the product. Because the use of CFC in medical devices is relatively low, i.e. less than 1% of total emissions, and because of the health benefits associated with metered dose inhalers, did not limit the use of CFC propellants in metered dose inhalers at that time.

Vendar so nadaljnje in bolj izpopolnjene meritve ozona nakazale, da so bile prejšnje omejitve uporabe CFC nezadostne in, da je potrebno še dodatno znatno zmanjšati emisijo CFC. Nedavno je bilo priporočeno, da bi do konca stoletja dejansko zaustavili proizvodnjo CFC. Zato ne bo mogoče nadaljevati uporabe CFC pogonskih sredstev vmes in dolgoročno. Čeprav je bilo vloženega precej truda v uporabo inhalatorjev z odmerjeno dozo brez pritiska, mnoga izmed teh sredstev niso bila popolnoma uspešna. Mnoga ne dostavijo določenih doz in so mehansko kompleksna, ne omogočajo 100-200 doz na enoto sedanjih rezervoarjev aerosolov, so posameznikom težavna za uporabo ter so obsežna in/ali nerodna za uporabo, posebej še, ko imajo pacienti akutno potrebo po zdravilu.However, further and more sophisticated measurements of ozone indicated that previous restrictions on CFC use were insufficient and that significant further reductions in CFC emissions were required. It was recently recommended that by the end of the century, the production of CFCs should actually be stopped. Therefore, it will not be possible to continue using CFC propellants in the long term. Although considerable effort has been made to use non-pressure metered dose inhalers, many of these agents have not been completely successful. Many do not deliver fixed doses and are mechanically complex, do not allow 100-200 doses per unit of current aerosol reservoirs, are difficult for individuals to use and are bulky and / or awkward to use, especially when patients have an acute need for medication.

Kot rezultat obstaja potreba po formulacijah aerosolov, ki so popolnoma brez CFC. Pogonska sredstva brez CFC morajo zadostiti več kriterijem za inhalatorje z odmerjeno dozo pod pritiskom. Morajo biti nestrupeni, stabilni in nereaktivni z zdravilom in drugimi važnejšimi komponentami v ventilu/sprožilu. Pogonsko sredstvo, ki se je izkazalo za primerno, je CF3-CH2F, znan tudi kot Freon 134a, HFA 134a, HFC 134a ali 1,1,1,2 tetrafluoroetan. Kakorkoli že, fizikalne lastnosti HFC 134a, t.j. parni tlak, polarnost, gostota, viskoznost in topnost, se razlikujejo od lastnosti CFC pogonskih sredstev, ki jih uporabljamo običajno. Pogonsko sredstvo HFC 134a ima parni tlak 5.84x10⁵ N/m² absolutno (84.7 psia), kar je preveč za uporabo v inhalatorjih z odmerjeno dozo. Še dodatno, surfaktanti, ki jih običajno uporabljamo so v HFC 134a lahko netopni. Še več, kjer moramo zdravilo dajati v raztopini, je zdravilo lahko slabše topno v tem pogonskem sredstvu. Razlika v polarnosti in gostoti med HFC 134a in prej uporabljanimi CFC pogonskimi sredstvi lahko povzroči drugačno dostavo zdravila, če CFC zamenjamo s HFC 134a pogonskim sredstvom. V pogonskem sredstvu brez CFC se zdravilo lahko razsloji, posede ali aglomerira, tudi, če se to ni pojavljalo v CFC pogonskem sredstvu.As a result, there is a need for formulations that are completely CFC free. Non-CFC propellants must satisfy several criteria for metered dose inhalers. They must be non-toxic, stable and non-reactive with the drug and other major components in the valve / trigger. The propellant that has proven to be suitable is CF3-CH2F, also known as Freon 134a, HFA 134a, HFC 134a or 1,1,1,2 tetrafluoroethane. However, the physical properties of HFC 134a, ie vapor pressure, polarity, density, viscosity and solubility, are different from the properties of CFC propellants commonly used. The HFC 134a propellant has a vapor pressure of 5.84x10 ⁵ N / m ² absolute (84.7 psia), which is too much to use in metered dose inhalers. In addition, the surfactants commonly used may be insoluble in HFC 134a. Moreover, where the drug is to be administered in solution, the drug may be less soluble in this propellant. The difference in polarity and density between HFC 134a and previously used CFC propellants may result in a different drug delivery if CFCs are replaced by HFC 134a propellants. In a non-CFC propellant, the drug may be stratified, possessed or agglomerated even if it did not appear in the CFC propellant.

Uporaba HFA 134a je bila predhodno razkrita za uporabo pri medicinskih inhalatorjih. European Patent Publication No. 0 372 777 je usmerjena k medicinski formulaciji aerosola, ki vključuje Freon 134a in adjuvans, ki ima višjo polarnost kot pogonsko sredstvo. Ta publikacija našteva več možnih adjuvansov in surfaktantov za uporabo v kombinaciji s pogonskim sredstvom in zdravilom.The use of HFA 134a has been previously disclosed for use in medical inhalers. European Patent Publication 0 372 777 is directed to a medical aerosol formulation comprising Freon 134a and an adjuvant having a higher polarity than the propellant. This publication lists several possible adjuvants and surfactants for use in combination with a propellant and a drug.

International Patent Application No. WO 91/04011 razkriva kombinacijo 1,1,1,2 tetrafluoroetana in zdravila v prahu, ki je pred dispergiranjem v pogonsko sredstvo prej-prekrito z neperfluoriranim surfaktantom. Strani publikacije 6-7 naštevata primerne surfaktante za uporabo s pogonskim sredstvom. Poljubno lahko dodamo perfluoriniran adjuvans. Vendar pa je lahko predhodno prekrivanje zdravila neprednostno, ker v proizvodni proces dodaja dodatno kompleksno stopnjo.International Patent Application No. WO 91/04011 discloses a combination of 1,1,1,2 tetrafluoroethane and a powdered drug which is pre-coated with a non-perfluorinated surfactant prior to dispersion into the propellant. Pages 6-7 list suitable surfactants for use with a propellant. Perfluorinated adjuvant may be added optionally. However, prior overlapping of the drug may be advantageous because it adds an additional complex rate to the production process.

Research Disclosure No. 30161, maj, 1989 razkriva, da pogonska sredstva brez CFC, kot so tluorohidroogljiki, lahko uporabljamo pri zdravilih pod pritiskom, ki jih dovajamo direktno v pljuča, t.j. bronhodilatatorjih.Research Disclosure No. 30161, May 1989 discloses that non-CFC propellants, such as fluorohydrocarbons, can be used in pressurized drugs that are fed directly into the lungs, i.e. bronchodilators.

U.S.Patent No. 4 174 295 razkriva kombinacijo HFC 134a z različnimi klorofluoroogljiki in poljubno z nasičenimi ogljikovodiki.U.S. Pat. 4 174 295 discloses the combination of HFC 134a with various chlorofluorocarbons and optionally with saturated hydrocarbons.

U.S.Patent No. 2 885 427 razkriva uporabo HFC 134a za pogonsko sredstvo za aerosole.U.S. Pat. 2 885 427 discloses the use of HFC 134a for propellant for aerosols.

U.S.Patent No. 3 261 748 razkriva uporabo HFC 134a za anastezijo.U.S. Pat. 3 261 748 discloses the use of HFC 134a for anesthesia.

U.S.Patent No. 4 129 603, 4 311 863, 4 851 595 in European Publication No. 379 793 tudi razkrivajo uporabo HFC 134a kot pogonsko sredstvo za aerosole.U.S. Pat. 4 129 603, 4 311 863, 4 851 595 in European Publication No. 3 379 793 also disclose the use of HFC 134a as a propellant for aerosols.

Vendar specifične kombinacije, ki so omenjene zgoraj, lahko ne zagotovijo zaželjene topnosti, stabilnosti, nizke strupenosti, natančnega odmerjanja (doziranja), pravilne velikosti delcev (v primeru suspenzije) in /ali kompatibilnosti z načini montaže ventilov, ki jih navadno uporabljamo pri inhalatorjih z odmerjeno dozo.However, the specific combinations mentioned above may not provide the desired solubility, stability, low toxicity, precise dosing, correct particle size (in the case of suspension) and / or compatibility with the valve assembly methods commonly used in inhaler inhalers metered dose.

POVZETEK IZUMASUMMARY OF THE INVENTION

Predstavljeni izum je usmerjen k nestrupenim formulacijam popolnoma brez CFC, ki imajo izboljšano stabilnost in kompatibilnost z zdravilom in komponentami ventilov ter jo je relativno lahko proizvesti.The present invention is directed to non-toxic, CFC-free formulations that have improved stability and compatibility with the drug and valve components and are relatively easy to manufacture.

Predstavljeni izum je tudi usmerjen k formulacijam, ki bi jih lahko uporabljali v obstoječi opremi za polnjenje aerosolov z le relativno majhnimi modifikacijami in brez poprejšnjega prekrivanja zdravila.The present invention is also directed to formulations that could be used in existing aerosol dispensing equipment with only relatively minor modifications and no overlapping of the drug.

Izum vključuje formulacijo aerosola, ki vsebuje:The invention includes an aerosol formulation comprising:

A. Učinkovito količino zdravila; inA. The effective amount of drug; and

B. 1,1,1,2 tetrafluoroetanB. 1,1,1,2 Tetrafluoroethane

Formulacija lahko nadalje poljubno vsebuje ekscipient, ki ga najraje izberemo iz skupine, ki vsebuje:The formulation may further optionally contain an excipient, preferably selected from the group consisting of:

propiien glikolol diestre maščobnih kislin s srednjimi verigami; triglicerid estre maščobnih kislin s srednjimi verigami; perfluorodimetilciklobutan;propylene glycol medium-chain fatty acid diesters; medium chain fatty acid ester triglyceride; perfluorodimethylcyclobutane;

pertluorociklobutan; polietilen glikol; mentol; luroglikol;pertluorocyclobutane; polyethylene glycol; menthol; luroglycol;

dietilen glikol monoetileter;diethylene glycol monoethyl ether;

poliglikolirane gliceride maščobnih kislin s srednjimi verigami;medium chain polyglycolated fatty acid glycerides;

alkohole;alcohols;

eukaliptusovo olje;eucalyptus oil;

maščobne kisline s kratkimi verigami;short-chain fatty acids;

ter njihove kombinacije.and combinations thereof.

Formulacija lahko poljubno vsebuje še surfaktant. Surfaktant najraje izberemo iz skupine, ki sestoji iz:The formulation may optionally contain a surfactant. The surfactant is preferably selected from the group consisting of:

oleinske kisline; sorbitan trioleata; cetil piridin klorida; sojinega lecitina;oleic acids; sorbitan trioleate; cetyl pyridine chloride; soya lecithin;

polioksietilen (20) sorbitan monolaurata; polioksietilen (10) stearil etra; polioksietilen (2) oleil etra; polioksipropilen-polioksietilen-etilen diamin blok kopolimerov;polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (10) stearyl ether; polyoxyethylene (2) oleyl ether; polyoxypropylene-polyoxyethylene-ethylene diamine block copolymers;

polioksietilen (20) sorbitan monostearatov; polioksietilen (20) sorbitan monooleatov; polioksipropilen-polioksietilen blok kopolimerov; etoksilata ricinovega olja; in njihovih kombinacij.polyoxyethylene (20) sorbitan monostearates; polyoxyethylene (20) sorbitan monooleates; polyoxypropylene-polyoxyethylene block copolymers; castor oil ethoxylate; and combinations thereof.

Zaželjeni tekoči ekscipienti so: dietilen glikol monoetileter, propilenglikol diestri maščobnih kislin s srednjimi verigami, perfluorodimetilciklobutan in polietilen glikol.Desirable liquid excipients are: diethylene glycol monoethyl ether, propylene glycol mid-chain fatty acid diesters, perfluorodimethylcyclobutane and polyethylene glycol.

Zaželjeni surfaktanti so: oleinska kislina, sorbitan trioleat cetilpiridin klorid, polioksietilen (20) sorbitan monolaurat, polioksipropilen-polioksietilen blok kopolimeri, sojin lecitin in polioksipropilen-polioksietilen-etilendiamin blok kopolimeri, oleinska kislina je posebej zaželjena.Desirable surfactants are: oleic acid, sorbitan trioleate cetylpyridine chloride, polyoxyethylene (20) sorbitan monolaurate, polyoxypropylene-polyoxyethylene block copolymers, soya lecithin and polyoxypropylene-ethyleneimine ethylene ether ethylene ether

Izum je posebej uporaben tam, kjer je zdravilo albuterol, monometazon furoat ali beklometazon dipropionat in njihove soli in klatrati.The invention is particularly useful where the medicament is albuterol, monomethasone furoate or beclomethasone dipropionate and their salts and clathrates.

Okvir formulacije obsega:The formulation framework comprises:

A. 1,1,1,2 tetrafluoroetanA. 1,1,1,2 Tetrafluoroethane

B. zdraviloB. medicine

C. ekscipientC. excipient

E.surfaktant (če je prisoten) wt% označuje masne odstotke.E.surfactant (if present) wt% indicates mass percentages.

25-99.9 wt% 0.01-1.0 wt% 0-75 wt%25-99.9 wt% 0.01-1.0 wt% 0-75 wt%

0-3 wt%0-3 wt%

Predstavljeni izum je tudi usmerjen k metodi zdravljenja astme pri sesalcih, ki obsega dajanje sesalcu, ki tako zdravljenje potrebuje, učinkovite količine formulacije aerosola, ki vsebuje:The present invention is also directed to a method of treating asthma in a mammal comprising administering to the mammal in need of such treatment an effective amount of an aerosol formulation comprising:

A. zdravilo, izbrano iz skupine, ki vsebuje albuterol, monometazon furoat, beklometazon dipropionat in njihove soli in klatrate;A. a medicine selected from the group consisting of albuterol, monomethasone furoate, beclomethasone dipropionate and their salts and clathrates;

B. 1,1,1,2 tetrafluoroetan; inB. 1,1,1,2 tetrafluoroethane; and

C. poljubno ekscipient, najraje izbran iz skupine, ki vsebuje:C. any excipient, preferably selected from the group consisting of:

propilen glikolol diestre maščobnih kislin s srednjimi verigami;propylene glycolol medium chain fatty acid diesters;

triglicerid estre maščobnih kislin s srednjimi verigami;medium chain fatty acid ester triglyceride;

perfluorodimetilciklobutan;perfluorodimethylcyclobutane;

perfluorociklobutan;perfluorocyclobutane;

polietilen glikol;polyethylene glycol;

mentol;menthol;

luroglikol;luroglycol;

dietilen glikol monoetileter;diethylene glycol monoethyl ether;

poliglikolirane gliceride maščobnih kislin s srednjimi verigami;medium chain polyglycolated fatty acid glycerides;

alkohole;alcohols;

eukaliptusovo olje;eucalyptus oil;

maščobne kisline s kratkimi verigami;short-chain fatty acids;

ter njihove kombinacije.and combinations thereof.

Surfaktant je prisoten poljubno. Zaželjeno je da surfaktant izberemo iz skupine, ki sestoji iz:The surfactant is present arbitrarily. It is desirable that the surfactant is selected from the group consisting of:

oleinske kisline; sorbitan trioleata; cetil piridin klorida: sojinega lecitina;oleic acids; sorbitan trioleate; cetyl pyridine chloride: soya lecithin;

polioksietilen (20) sorbitan monolaurata; polioksietilen (10) stearil etra; polioksietilen (2) oleil etra; polioksipropilen-polioksietilen-etilen diamin blok kopolimerov;polyoxyethylene (20) sorbitan monolaurate; polyoxyethylene (10) stearyl ether; polyoxyethylene (2) oleyl ether; polyoxypropylene-polyoxyethylene-ethylene diamine block copolymers;

polioksietilen (20) sorbitan monostearatov; polioksipropilen-polioksietilen blok kopolimerov: etoksilata ricinovega olja; in njihovih kombinacij.polyoxyethylene (20) sorbitan monostearates; polyoxypropylene-polyoxyethylene block copolymers: castor oil ethoxylate; and combinations thereof.

PODROBEN OPIS IZUMADETAILED DESCRIPTION OF THE INVENTION

V vseh formulacijah iz predstavljenega izuma uporabljamo pogonsko sredstvo 134a v kombinaciji z zdravilom, poljubno s tekočim ekscipientom in poljubno s surfaktantom. Ekscipient omogoča kompatibilnost zdravila s pogonskim sredstvom in tudi znižuje sprožitveni pritisk na sprejemljivo raven t.j. okrog 2.76-5.52x105 N/_m2 absolutno (40 do 80 psia), zaželjeno 3.45-4.83x105 N/m² absolutno (50 do 70 psia). Izbrani ekscipient mora biti nereaktiven z zdravilom, relativno nestrupen in naj ima parni tlak pod okrog 4.35x10⁵ N/m² absolutno (50 psia). Kakor je uporabljan tukaj, se izraz 'maščobne kisline s srednijimi verigami' nanaša na verige alkilnih skupin, ki se končajo s -COOH skupino in imajo 6-12 ogljikovih atomov, najraje 8-10 ogljikovih atomov. Izraz 'maščobne kisline s kratkimi verigami' se nanaša na verige alkilnih skupin, ki se končajo s -COOH skupino in imajo 4-8 ogljikovih atomov. Izraz alkohol vsebuje C-1-O3 alkohole, kot so metanol, etanol in izopropanol. Med zaželjenimi ekscipienti so:In all the formulations of the present invention, propellant 134a is used in combination with a drug, optionally with a liquid excipient, and optionally with a surfactant. The excipient allows the drug to be compatible with the propellant and also lowers the trigger pressure to an acceptable level ie around 2.76-5.52x105 N / _m 2 absolute (40 to 80 psia), preferably 3.45-4.83x105 N / m ² absolute (50 to 70 psia). The selected excipient should be non-reactive with the drug, relatively non-toxic and should have a vapor pressure below about 4.35x10 ⁵ N / m ² absolute (50 psia). As used herein, the term 'medium chain fatty acids' refers to alkyl groups ending with a -COOH group having 6-12 carbon atoms, preferably 8-10 carbon atoms. The term 'short chain fatty acids' refers to chains of alkyl groups ending with a -COOH group having 4-8 carbon atoms. The term alcohol contains C-1-O3 alcohols such as methanol, ethanol and isopropanol. Desirable excipients include:

propilen glikol diestri maščobnih kislin s srednjimi verigami, ki so na voljo pod komercialnim imenom Miglyol 840 (od Hills America, Inc. Piscataway, N.J.);propylene glycol mid-chain fatty acid diesters, commercially available under the trade name Miglyol 840 (from Hills America, Inc. Piscataway, N.J.);

triglicerid estri maščobnih kislin s srednjimi verigami, ki so na voljo pod komercialnim imenom Miglyol 812 (od Hills);medium chain fatty acid triglyceride esters, available under the trade name Miglyol 812 (from Hills);

perfluorodimetilcikiobutan, ki je na voljo po komercialnim imenom Vertrel 245 (od E.l DuPont de Nemours and Co. Inc. Wilmington, Delaware);perfluorodimethylcyclobutane, commercially available under the trade name Vertrel 245 (from E.l DuPont de Nemours and Co. Inc. Wilmington, Delaware);

perfluorociklobutan, ki je na voljo po komercialnim imenom oktafluorociklobutan (od POR Gainsville, Florida);commercially available octafluorocyclobutane (from POR Gainsville, Florida);

polietilen glikol, ki je na voljo po komercialnim imenom PEG 400 (od BASF Parsippany, N.J.);polyethylene glycol, commercially available under the trade name PEG 400 (from BASF Parsippany, N.J.);

mentol (od Pluess-Stauffer International Stanford, Connecticut); propilen glikol monolaurat, ki je na voljo po komercialnim imenom lauroglykol (od Gattefosse Elmsford, N.J.);menthol (from Pluess-Stauffer International Stanford, Connecticut); propylene glycol monolaurate, commercially available under the trade name lauroglycol (from Gattefosse Elmsford, N.J.);

dietilen glikol monoetileter, ki je na voljo po komercialnim imenomdiethylene glycol monoethyl ether available by commercial name

Transcutol (od Gattefosse);Transcutol (from Gattefosse);

poliglikolirani gliceridi maščobnih kislin s srednjimi verigami, ki so na voljo pod komercialnim imenom Labrafac Hydro WL 1219 (od Gattefosse);medium-chain polyglycolated fatty acid glycerides, available under the trade name Labrafac Hydro WL 1219 (from Gattefosse);

alkoholi, kot etanol, metanol in izopropanol; eukaliptusovo olje (od Pluess-Stauffer International); in njihove mešanice.alcohols such as ethanol, methanol and isopropanol; eucalyptus oil (from Pluess-Stauffer International); and mixtures thereof.

Poljubno lahko dodamo surfaktant za zmanjšanje površinskih in notranjih napetosti med zdravilom in pogonskim sredstvom. Kjer morajo zdravilo ekscipient in pogonsko sredstvo tvoriti suspenzijo, lahko uporabimo surfaktant ali pa tudi ne. Kjer morajo zdravilo ekscipient in pogonsko sredstvo tvoriti raztopino, je surfaktant lahko nujen ali pa tudi ne, odvisno od topnosti določenega zdravila in ekscipienta. Surfaktant je lahko katerikoli primeren, nestrupena spojina, ki je nereaktivna z zdravilom in stvarno znižuje površinske napetosti med zdravilom, ekscipientom in pogonskim sredstvom in/ali deluje kot mazivo za ventil. Med zaželjenimi surfaktanti so;Surfactant can be optionally added to reduce the surface and internal stresses between the drug and the propellant. Where the excipient and the vehicle must form a suspension, surfactant may or may not be used. Where the excipient and the propellant must form a solution, the surfactant may or may not be necessary depending on the solubility of the particular drug and excipient. The surfactant may be any suitable, non-toxic compound that is non-reactive with the drug and substantially reduces surface tension between the drug, excipient and propellant and / or acts as a valve lubricant. Desirable surfactants are;

oleinska kislina, ki je na voljo pod komercialnim imenom oleic acid NF6321 (od Henkel Corp. Emery Group, Cincinnati, Ohio);oleic acid, commercially available under the trade name oleic acid NF6321 (from Henkel Corp. Emery Group, Cincinnati, Ohio);

cetilpiridin klorid (od Arrow Chemical, Inc. Westwood, N.J.); sojin lecitin, ki je na voljo pod komercialnim imenom Epikuroncetylpyridine chloride (from Arrow Chemical, Inc. Westwood, N.J.); soybean lecithin available commercially under the name Epikuron

200 (od Lucas Meyer Decatur, Illinois);200 (from Lucas Meyer Decatur, Illinois);

polioksietiien (20) sorbitan monolaurat, ki je na voljo pod komercialnim imenom Tween 20 (od ICI Specialty Chemicals. Wilmington, Delaware);polyoxyethylene (20) sorbitan monolaurate, commercially available under the trade name Tween 20 (from ICI Specialty Chemicals. Wilmington, Delaware);

polioksietiien (20) sorbitan monostearat, ki je na voljo pod komercialnim imenom Tween 60 (od ICI);polyoxyethylene (20) sorbitan monostearate, commercially available under the trade name Tween 60 (from ICI);

polioksietiien (20) sorbitan monooleat, ki je na voljo pod komercialnim imenom Tween 80 (od ICI);polyoxyethylene (20) sorbitan monooleate, commercially available under the trade name Tween 80 (from ICI);

polioksietiien (10) stearil eter, ki je na voljo pod komercialnim imenom Brij 76 (od ICI);polyoxyethylene (10) stearyl ether, available under the commercial name Brij 76 (from ICI);

polioksietiien (2) oleil eter, ki je na voljo pod komercialnim imenom Brij 92 (od ICI);polyoxyethien (2) oleyl ether, available under the commercial name Brij 92 (from ICI);

polioksietilen-polioksipropilen-etilendiamin blok kopolimer, ki je na voljo pod komercialnim imenom Tetronic 150 R1 (od BASF);polyoxyethylene-polyoxypropylene-ethylenediamine block copolymer, commercially available under the trade name Tetronic 150 R1 (from BASF);

polioksietilen-polioksipropilen blok kopolimeri, ki so na voljo pod komercialnimi imeni Pluronic L-92 Pluronic L-121 in Pluronic F 68 (od BASF);polyoxyethylene-polyoxypropylene block copolymers available under the trade names Pluronic L-92 Pluronic L-121 and Pluronic F 68 (from BASF);

etoksilat ricinovega olja, ki je na voljo pod komercialnim imenom Alkasurf CO-40 (od Rhone-Poulenc Mississauga Ontario, Canada);castor oil ethoxylate, commercially available under the trade name Alkasurf CO-40 (from Rhone-Poulenc Mississauga Ontario, Canada);

in njihove mešanice.and mixtures thereof.

Zdravila iz predstavljenega izuma lahko vključujejo katerekoli farmacevtsko aktivne spojine, ki naj bi jih dali z oralno inhalacijo ali nazalno. Tipični razredi spojin vključujejo bronhodilatatorje, antiinflamatorne spojine, antihistaminike, antialergene, analgetike, zdravila proti kašlju, zdravila proti angini, steroide, kortikosteroide, vazokonstriktorje in antibiotike. Specifične spojine v teh razredih spojin so albuterol, mometazon furoat, belkometazon dipropionat, izoproterenol, heparin, terbutalin, rimiterol, perbuterol, dinatrijev kromoglikat, izoprenalin, adrenalin, pentamidin in ipratopij bromid. Te spojine lahko uporabimo kot proste baze ali kot soli ali pa kot klatrate, odvisno od stabilnosti in topnosti aktivne spojine v specifični formulaciji. Ko uporabljamo klatrate, so posebej zaželjeni P-11 in heksanovi klatrati.The medicaments of the present invention may include any pharmaceutically active compounds to be administered by oral inhalation or nasal. Typical classes of compounds include bronchodilators, anti-inflammatory compounds, antihistamines, anti-allergens, analgesics, cough drugs, anti-angina drugs, steroids, corticosteroids, vasoconstrictors and antibiotics. The specific compounds in these classes of compounds are albuterol, mometasone furoate, belkometazone dipropionate, isoproterenol, heparin, terbutaline, rimiterol, perbuterol, disodium chromoglycate, isoprenaline, adrenaline, pentamidine and ipratopium bromide. These compounds can be used as free bases or as salts or as clathrates, depending on the stability and solubility of the active compound in a specific formulation. When using clathrates, P-11 and hexane clathrates are especially desirable.

Kjer aktivna spojina tvori suspenzijo, mora biti velikost delcev relativno izenačena, zaželjeno s popolnoma vsemi delci v okviru med 0.1-25 pm, raje 0.5-10 pm, najraje 1-5 pm. Dleci večji od 25 pm se lahko zadržijo v žrelni votlini, medtem ko delcev manjših od okrog 0.5 pm raje ne uporabljamo, ker je večja verjetnost da jih izdihnemo in tako ne dosežejo pljuč pacienta.Where the active compound forms a suspension, the particle size should be relatively uniform, preferably with all particles within the range of 0.1-25 pm, preferably 0.5-10 pm, preferably 1-5 pm. Lumps greater than 25 pm may be retained in the pharynx, while particles smaller than about 0.5 pm may not be used because they are more likely to be exhaled and thus not reach the lungs of the patient.

Formulacije predstavljenega izuma lahko polnimo v rezervoarje za aerosol z uporabo konvencionalne polnilne opreme. Ker je pogonsko sredstvo 134a lahko nekompatibilno z vsemi elastomernimi spojinami, ki jih tekoče uporabljamo pri obstoječi montaži ventilov, jih je lahko nujno nadomeščati z drugimi materiali, kot je bel sintetični kavčuk, ali pa uporabljati ekscipiente in neobvezno surfaktante, ki blažijo ali nasprotujejo učinkom pogonskega sredstva 134a na komponente ventila. Poljubno lahko uporabimo napravo z vmesnikom, ki zmanjša moč spreja iz MDI.The formulations of the present invention can be filled into aerosol tanks using conventional filling equipment. As propellant 134a may be incompatible with all the elastomeric compounds currently used in existing valve assembly, it may be necessary to replace it with other materials, such as white synthetic rubber, or to use excipients and optional surfactants that mitigate or counteract the effects of propellant means 134a to valve components. We can optionally use a device with an interface that reduces the power of spray from MDI.

Za zagotovitev enakomerne disperzije aktivne sestavine bodo formulacije tipično vsebovale komponente, ki sledijo:In order to ensure uniform dispersion of the active ingredient, the formulations will typically contain components as follows:

Okvir wt% Box wt% Zaželjeni okvir wt% Desired box wt% Najbolj zaželjeni okvir wt% The most desirable framework wt% Zdravilo Medication 0.01-1 0.01-1 0.03-0.7 0.03-0.7 0.05-0.5 0.05-0.5 Pogonsko sredstvo Propellant 25-99.99 25-99.99 50-99.97 50-99.97 50-99.95 50-99.95 Ekscipient(i) Excipient (s) 0-75 0-75 0-50 0-50 0-50 0-50 Surfaktant(i) Surfactant (s) 0-3 The scoreboard is now 0-3 0-2 The scoreboard is now 0-2 0-1 The scoreboard is now 0-1

V odvisnosti od določene uporabe je lahko rezervoar napolnjen s prej določeno količino formulacije za enkratno ali večkratno odmerjanje. Tipično je rezervoar načrtovan za večkratno odmerjanje, zatorej je zelo pomembno, da je formulacija, ki jo dajemo, popolnoma enaka pri vsakem odmerjanju. Na primer, kjer je formulacija za bronhodilatacijo, je rezervoar tipično napolnjen z zadostno količino formulacije za 200 dajanj.Depending on the particular application, the tank may be filled with a predetermined amount of single or multiple dosage formulation. Typically, the reservoir is designed for multiple dosing, so it is very important that the formulation administered is exactly the same at each dosage. For example, where the formulation is for bronchodilation, the reservoir is typically filled with sufficient formulation for 200 administrations.

Primerne suspenzije lahko podvržemo selekciji z opazovanjem nekaterih fizikalnih lastnosti formulacije, t.j. stopnje aglomeracije delcev, velikosti aglomeratov in stopnje razslojevanja/posedanja in primerjavi le teh s sprejetimi standardi. Primerne raztopine lahko podvržemo selekciji z opazovanjem topnosti zdravila Čez celotni priporočeni okvir skladiščenja in temperature.Suitable suspensions can be selected by observing some of the physical properties of the formulation, i.e. the particle agglomeration rates, the size of the agglomerates, and the stratification / settling rate, and comparing them with accepted standards. Suitable solutions can be selected by observing the solubility of the drug Over the entire recommended storage and temperature framework.

Suspenzije iz predstavljenega izuma najraje pripravimo z obojim, polnjenjem pod pritiskom ali s postopki hladnega polnjenjenja, ki so strokovnjakom dobro znani.The suspensions of the present invention are preferably prepared by both pressurized, pressurized, or cold-fill processes well known to those skilled in the art.

Za inhalatorje z odmerjeno dozo so najbolj zaželjene suspenzije zaradi precejšnje učinkovitosti in stabilnosti.For metered dose inhalers, suspensions are most preferred because of their high efficiency and stability.

Strokovnjaki lahko kot dodatek izberejo eno ali več sredstev za konzerviranje, pufer, antioksidant, sladilo in/ali arome ali druge agenske, ki zakrijejo (maskirajo) okus, odvisno od značilnosti formulacije.Experts may opt for one or more preservatives, buffer, antioxidant, sweetener and / or flavors or other agents that mask (mask) the taste depending on the characteristics of the formulation.

Primeri 1 do 32 spodaj nadalje opisujejo reprezentančne formulacije predstavljenega izuma, nekateri primeri prikazujejo alternativne formulacije, ki so označene kot A in B.Examples 1 to 32 below further describe representative formulations of the present invention, some examples show alternative formulations designated A and B.

PRIMER 1EXAMPLE 1

Komponenta Component wt% wt% Albuterol Albuterol 0.1 0.1 Vertrel 245 Vertrel 245 9.9 9.9 HFC-134a HFC-134a 90.0 90.0 PRIMER 2 EXAMPLE 2 Komponenta Component wt% wt% Albuterol Albuterol 0.5 0.5 Vertrel 245 Vertrel 245 49.9 49.9 HFC-134a HFC-134a 49.6 49.6 PRIMER 3 EXAMPLE 3 Komponenta Component wt% wt% Albuterol Albuterol 0.1 0.1 Oleinska kislina Oleic acid 0.01 0.01 Miglyol 840 Miglyol 840 9.0 9.0 HFC-134a HFC-134a 90.89 90.89

PRIMER 4EXAMPLE 4

Komponenta Component wt% wt% Albuterol Albuterol 0.1 0.1 Tetronic 150 R1 Tetronic 150 R1 0.1 0.1 Miglyol 840 Miglyol 840 9.8 9.8 HFC-134a HFC-134a 90.0 90.0 PRIMER 5 EXAMPLE 5 Komponenta Component wt% wt% Albuterol Albuterol 0.1 0.1 Pluronic L-121 Pluronic L-121 0.1 0.1 Miglyol 840 Miglyol 840 9.8 9.8 HFC-134a HFC-134a 90.0 90.0 PRIMER 6 EXAMPLE 6 Komponenta Component wt% wt% Albuterol Albuterol 0.1 0.1 Oleinska kislina Oleic acid 0.2 0.2 Transcutol Transcutol 18.0 18.0 HFC-134a HFC-134a 81.7 81.7

PRIMER 7 wt%EXAMPLE 7 wt%

Komponenta Component A A B B Albuterol Albuterol 0.10 0.10 0.10 0.10 Oleinska kislina Oleic acid 0.01 0.01 0.01 0.01 Etanol Ethanol 30.0 30.0 15.0 15.0 HFC-227 HFC-227 69.89 69.89 84.89 84.89

PRIMER 8 wt%EXAMPLE 8 wt%

Komponenta Component A A B B Albuterol sulfat Albuterol sulfate 0.10 0.10 0.10 0.10 Oleinska kislina Oleic acid 0.01 0.01 0.01 0.01 Etanol Ethanol 30.0 30.0 15.0 15.0 HFC-227 HFC-227 69.89 69.89 84.89 84.89

PRIMER 9EXAMPLE 9

Komponenta Component wt% wt% Albuterol Albuterol 0.1 0.1 Vertrel 245 Vertrel 245 17.0 17.0 Miglyol 840 Miglyol 840 9.0 9.0 HFC-134a HFC-134a 73.9 73.9 PRIMER 10 EXAMPLE 10 Komponenta Component wt% wt% Albuterol Albuterol 0.10 0.10 Oleinska kislina Oleic acid 0.01 0.01 Etanol Ethanol 10.0 10.0 Vertrel 245 Vertrel 245 9.90 9.90 HFC-134a HFC-134a 79.99 79.99

PRIMERUEXAMPLE

Komponenta Component wt% wt% Albuterol Albuterol 0.10 0.10 Pluronic L-121 Pluronic L-121 0.4 0.4 Vertrel 245 Vertrel 245 9.90 9.90 Miglyol 840 Miglyol 840 9 9 HFC-134a HFC-134a 73.9 73.9

PRIMER 12EXAMPLE 12

Komponenta Component wt% wt% Albuterol Albuterol 0.10 0.10 Pluronic L-121 Pluronic L-121 0.90 0.90 Oleinska kislina Oleic acid 0.01 0.01 Miglyol 840 Miglyol 840 9.00 9.00 HFC-134a HFC-134a 89.99 89.99 PRIMER 13 EXAMPLE 13 Komponenta Component wt% wt% Albuterol Albuterol 0.10 0.10 Tetronic 150 R1 Tetronic 150 R1 0.10 0.10 Oleinska kislina Oleic acid 0.01 0.01 Miglyol 840 Miglyol 840 9.80 9.80 HFC-134a HFC-134a 89.99 89.99

PRIMERU wt%EXAMPLE wt%

Komponenta Component A A B B Mometazon turoat Mometasone turoate 0.10 0.10 0.10 0.10 Oleinska kislina Oleic acid 0.01 0.01 0.01 0.01 Etanol Ethanol 30.0 30.0 15.0 15.0 HFC-227 HFC-227 69.89 69.89 84.89 84.89

PRIMER 15EXAMPLE 15

Komponenta Component wt% wt% Mometazon furoat Mometasone furoate 0.10 0.10 Oleinska kislina Oleic acid 0.2 0.2 Transcutol Transcutol 18.0 18.0 HFC-134a HFC-134a 81.7 81.7

PRIMER 16EXAMPLE 16

Komponenta Component wt% wt% Mometazon furoat Mometasone furoate 0.10 0.10 Tween 20 Tween 20 0.1 0.1 Miglyol 840 Miglyol 840 9.8 9.8 HFC-134a HFC-134a 90.0 90.0

PRIMER 17EXAMPLE 17

Komponenta Component wt% wt% Mometazon furoat Mometasone furoate 0.10 0.10 Pluronic L-121 Pluronic L-121 0.4 0.4 Miglyol 840 Miglyol 840 9.0 9.0 HFC-134a HFC-134a 90.5 90.5

PRIMER 18EXAMPLE 18

Komponenta Component wt% wt% Mometazon furoat Mometasone furoate 0.10 0.10 Tetronic 150 R1 Tetronic 150 R1 0.1 0.1 Miglyol 840 Miglyol 840 9.8 9.8 HFC-134a HFC-134a 90.0 90.0

PRIMER 19EXAMPLE 19

Komponenta Component wt% wt% Beklometazon dipropionat Beclomethasone dipropionate 0.10 0.10 Oleinska kislina Oleic acid 0.01 0.01 Etanol Ethanol 5 5 HFC-134a HFC-134a 94.89 94.89

PRIMER 20EXAMPLE 20

Komponenta Component wt% wt% Beklometazon ktatrat P-11 Beclomethasone ktatrat P-11 dipropionat dipropionate 0.10 0.10 Oleinska kislina Oleic acid 0.01 0.01 Miglyol 840 Miglyol 840 1.5 1.5 HFC-134a HFC-134a 98.39 98.39 PRIMER 21 EXAMPLE 21 Komponenta Component wt% wt% Beklometazon Beclomethasone dipropionat dipropionate 0.10 0.10 heksanov klatrat hexane clathrate Pluronic L121 Pluronic L121 0.01 0.01 Miglyol 840 Miglyol 840 1.5 1.5 HFC-134a HFC-134a 98.3 98.3 PRIMER 22 EXAMPLE 22 Komponenta Component wt% wt% Mometazon furoat Mometasone furoate 0.10 0.10 HFC-134a HFC-134a 99.9 99.9 PRIMER 23 EXAMPLE 23 Komponenta Component wt% wt% Beklometazon Beclomethasone dipropionat dipropionate 0.10 0.10 klatrat P-11 clathrate P-11 HFC-134a HFC-134a 99.9 99.9

PRIMER 24EXAMPLE 24

Komponenta Component wt% wt% Mometazon furoat Mometasone furoate 0.10 0.10 Tween 20 Tween 20 0.01 0.01 HFC-134a HFC-134a 99.89 99.89

PRIMER 25EXAMPLE 25

Komponenta Component wt% wt% Beklometazon dipropionat klatrat P-11 Beclomethasone dipropionate clathrate P-11 0.10 0.10 Tween 20 Tween 20 0.01 0.01 HFC-134a HFC-134a 99.89 99.89 PRIMER 26 EXAMPLE 26 Komponenta Component wt% wt% Mometazon turoat Mometasone turoate 0.10 0.10 Tween 20 Tween 20 0.01 0.01 Oleinska kislina Oleic acid 0.0005 0.0005 HFC-134a HFC-134a 99.8895 99.8895 PRIMER 27 EXAMPLE 27 Komponenta Component wt% wt% Mometazon turoat Mometasone turoate 0.10 0.10 Tetronic 150 R1 Tetronic 150 R1 0.01 0.01 Oleinska kislina Oleic acid 0.005 0.005 Miglyol 840 Miglyol 840 9 9 HFC-134a HFC-134a 90.885 90.885 PRIMER 28 EXAMPLE 28 Komponenta Component wt% wt% Beklometazon dipropionat klatrat P-11 Beclomethasone dipropionate clathrate P-11 0.10 0.10 Miglyol 840 Miglyol 840 3 3 Oleinska kislina Oleic acid 0.005 0.005 Pluronic L121 Pluronic L121 0.01 0.01 HFC-134a HFC-134a 96.885 96.885

PRIMER 29EXAMPLE 29

Komponenta Component wt% wt% Beklometazon dipropionat Beclomethasone dipropionate 0.10 0.10 Oleinska kislina Oleic acid 0.2 0.2 Transcutol Transcutol 5 5 HFC-134a HFC-134a 94.7 94.7 PRIMER 30 EXAMPLE 30 Komponenta Component wt% wt% Beklometazon dipropionat klatrat P-11 Beclomethasone dipropionate clathrate P-11 0.10 0.10 Miglyol 840 Miglyol 840 1.5 1.5 Pluronic L121 Pluronic L121 0.1 0.1 HFC-134a HFC-134a 98.7 98.7 PRIMER 31 EXAMPLE 31 Komponenta Component wt% wt% Beklometazon dipropionat Beclomethasone dipropionate 0.10 0.10 PEG 400 PEG 400 5 5 HFC-134a HFC-134a 94.9 94.9 PRIMER 32 EXAMPLE 32 Komponenta Component wt% wt% Beklometazon dipropionat klatrat P-11 Beclomethasone dipropionate clathrate P-11 0.10 0.10 Miglyol 840 Miglyol 840 1.5 1.5 HFC-134a HFC-134a 94.9 94.9

Čeprav so primeri zgoraj usmerjeni k albuterolu, albuterol sulfatu, mometazon furoatu, beklometazon dipropionatu in klatratom beklometazon dipropionata, mislimo, da je mogoče uporabljati tudi druga zdravila, ki jih dajemo oralno ali nazalno. Podobno mislimo, da je mogoče uporabljati razen naštetih še druge ekscipiente in surfaktante.Although the examples above are directed to albuterol, albuterol sulfate, mometasone furoate, beclomethasone dipropionate, and clathrates beclomethasone dipropionate, we believe that other medicines administered orally or nasally may also be used. Similarly, we think that other excipients and surfactants can be used in addition to the above.

Opisi prej omenjenih izvedb izuma so predstavljeni za ilustracijo in oris. Z njimi ne želimo izčrpati ali omejiti izuma na natančne oblike, ki so razkrite, očitno je ob zgornjem znanju možnih veliko modifikacij in variacij. Izvedbe smo izbrali in opisali z namenom najbolje razložiti principe izuma in njihovo praktično uporabo s tem usposobljenim drugim strokovnjakom, da bi najbolje uporabljali izum v različnih izvedbah in z različnimi modifikacijami, ki ustrezajo nameravani določeni uporabi. Želimo, da območje izuma definirajo zahtevki, ki so tukaj dodani.Descriptions of the aforementioned embodiments of the invention are presented for illustration and outline. They are not intended to be exhausted or to limit the invention to the precise forms disclosed, it is evident that, with the above knowledge, many modifications and variations are possible. Embodiments have been selected and described in order to best explain the principles of the invention and their practical application with this skilled other person skilled in the art in order to best use the invention in different embodiments and with various modifications corresponding to the intended particular use. We want the scope of the invention to be defined by the claims appended thereto.

Claims (8)

PATENTNI ZAHTEVKIPATENT APPLICATIONS 1. Formulacija aerosola, ki je označena s tem, da nujno sestoji iz:1. Aerosol formulation, characterized in that it necessarily consists of: A. učinkovite količine zdravila:A. effective quantities of the medicinal product: B. 1,1,1,2, tetrafluoroetana; inB. 1,1,1,2, tetrafluoroethane; and C. poljubno ekscipienta, ki je izbran iz skupine, ki vsebuje propilen glikol diester maščobne kisline s srednjo verigo in triglicerid ester maščobne kisline s srednjo verigo; surfaktanta, ki je poljubno prisoten skupaj z ekscipientom;C. an optional excipient selected from the group consisting of propylene glycol diester of medium chain fatty acid and medium chain triglyceride ester of fatty acid; a surfactant arbitrarily present together with the excipient; D. poljubno ene ali več komponent, ki so izbrane iz ene ali več sledečih: sredstva za konzerviranje; pufri; antioksidanti; sladila; in agensi za zakrivanje/maskiranje okusa.D. any one or more components selected from one or more of the following: preservatives; buffers; antioxidants; sweeteners; and taste masking / masking agents. 2. Formulacija po 1. zahtevku, ki je označena s tem, da je zdravilo izbrano iz skupine, ki vsebuje: albuterol, mometazon furoat, beklometazon dipropionat, izoproterenol, heparin, terbutalin, rimiterol, perbuterol, dinatrijev kromoglikat, izoprenalin, adrenalin, pentamidin, ipratropium bromid in njihove soli in klatrate.A formulation according to claim 1, characterized in that the drug is selected from the group consisting of: albuterol, mometasone furoate, beclomethasone dipropionate, isoproterenol, heparin, terbutaline, rimiterol, perbuterol, disodium cromoglycate, isoprenaline, adrenaline, adrenaline , ipratropium bromide and their salts and clathrates. 3. Formulacija po 1. zahtevku, ki je označena s tem, da je je zdravilo izbrano iz skupine, ki vsebuje: albuterol, albuterol sulfat, beklometazon dipropionat, klatrate beklometazon dipropionata in mometazon furoat.The formulation of claim 1, wherein the medicament is selected from the group consisting of: albuterol, albuterol sulfate, beclomethasone dipropionate, clathrates beclomethasone dipropionate and mometasone furoate. 4. Formulacija po 1. zahtevku, ki je označena s tem, da vsebuje 0.01 do 1 utežnega odstotka zdravila.The formulation according to claim 1, characterized in that it contains 0.01 to 1 weight percent of the drug. 5. Formulacija po 1. zahtevku, ki je označena s tem, da vsebuje 0.03 do 0.7 utežnega odstotka zdravila.The formulation according to claim 1, characterized in that it contains from 0.03 to 0.7% by weight of the drug. 6. Formulacija po 1. zahtevku, ki je označena s tem, da vsebuje 0.05 do 0.5 utežnega odstotka zdravila.6. A formulation according to claim 1, comprising 0.05 to 0.5% by weight of the drug. 7. Formulacija po 1. zahtevku, ki je označena s tem, da je zdravilo prah, ki ima srednjo velikost delcev okrog 1do 5 gm.The formulation of claim 1, wherein the medicament is a powder having a mean particle size of about 1 to 5 gm. 8. Formulacija aerosola, ki je označena s tem, da nujno vsebuje:8. Aerosol formulation, characterized in that it necessarily contains: A. zdravilo, ki je izbrano iz skupine, ki vsebuje albuterol, mometazon furoat, beklometazon dipropionat in njihove soli in kiatrate;A. a medicament selected from the group consisting of albuterol, mometasone furoate, beclomethasone dipropionate and their salts and kiatrates; B. 1,1,1,2, tetrafluoroetana;B. 1,1,1,2, tetrafluoroethane; C. poljubno ekscipient, ki je izbran iz skupine, ki vsebuje propilen glikol diester maščobne kisline s srednjo verigo in triglicerid ester maščobne kisline s srednjo verigo; surfaktant, ki je poljubno prisoten skupaj z ekscipientom;C. an optional excipient selected from the group consisting of propylene glycol diester of medium chain fatty acid and medium chain triglyceride ester of fatty acid; a surfactant arbitrarily present together with the excipient; D. poljubno eno ali več komponent, ki so izbrane iz ene ali več sledečih: sredstva za konzerviranje; pufri; antioksidanti; sladila; in agensi za zakrivanje/maskiranje okusa.D. any one or more components selected from one or more of the following: preservatives; buffers; antioxidants; sweeteners; and taste masking / masking agents. SCHERING CORPORATION, NewSCHERING CORPORATION, New