CA2183557A1 - Aerosol drug formulations containing vitamin e - Google Patents
Aerosol drug formulations containing vitamin eInfo
- Publication number
- CA2183557A1 CA2183557A1 CA002183557A CA2183557A CA2183557A1 CA 2183557 A1 CA2183557 A1 CA 2183557A1 CA 002183557 A CA002183557 A CA 002183557A CA 2183557 A CA2183557 A CA 2183557A CA 2183557 A1 CA2183557 A1 CA 2183557A1
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- CA
- Canada
- Prior art keywords
- tocopherol
- pharmaceutical composition
- propellant
- composition according
- alpha tocopherol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Dispersion Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Otolaryngology (AREA)
- Pulmonology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Pharmaceutical compositions for aerosol delivery comprising (a) a medicament, (b) a non-chlorofluorocarbon propellant, and (c) tocopherol or a pharmaceutically acceptable derivative thereof, as well as a method for preparing such compositions in which unwanted aggregation of the medicament is prevented without the use of surfactants or cosolvents.
Description
~ wo 9sl24892 2 1 8 3 5 5 7 r~-~u~ N ~76l AEROSOL DRuG FORMULATIONS CONTAINING VITAMIN E
The present invention relates to drug fnnnlllstinns for aerosol delivery which are compatible with non-chlorofluorocarbon propellants~ and especially to excipients which are 5 useful therein. In particular, the invention relates to inhalab~e fntrn~ innc comprising tocopherol (vitamin E) or tocopherol analogs or derivatives, which r ~ c possess a variety of advantageous properties.
BACICGROUND OF THE INVENTION ~
Numerous ~ " ,~ ~ ~; ,,l compounds are preferentially delivered by means of metered dose inhalation (MDI) devices, in which a physiological~y inert propellant of high vapor pressure is used to discharge a precise amount of medication with each operation. These MDI
devices, a~so known as aeroso~s or inhalers, have found widespread use among patients suffering, for example, from episodic or chronic asthma. The propellants of choice have historically been chlorofluoro-carbons, such Propellant 11 (trich~ulunuu~u~ .al,~), Propellant ~2 (dichloro linuvlul--villal-e) and Propellant 114 (dichlu,u~ dnuuluvLl In recent years, however, there have been growing concems that ul~lvluAuuluvauvu~
(CFC) propellants have detrimental environmental effects, and in particular that they interfere with the protective upper-atmosphere ozone layer. Under an int~srinnsl accord (the Montreal Protoco~), the use of CFC propellants will be prohibited by the start of the year 2000, and possibly sooner. Altemative propellant vehicles are being deve~oped which exhibit little or no ozone dep~etion potential (ODP). Such altemative propellants include two -- HFC-134a (1,1,1,2-tetrafluoroethane) and HFC-227ea (1,~,1,2,3,3,3 h.v~Ldr~uulul~lu~àl.e) -- which have negligib~e ODP and are currently undergoing safety and v.l~uu.u~ Lal testing.
U.lru,i ~/, surfactants which are generally used in known MDl r.~ have been found to be imiscible in and therefore , ~ with these new, non-CFC propellants.
Such surfactants are necessary to prevent PV~Ptinn (in the form of caking or crystallization, for example) of the medicinally active compound in the reservoir of the inhaler, to faci~itate unifomm dosing upon aerosol ~ rl;nn and to provide an aerosol spray discharge having a favorable respirable fraction (that is, a partic~e size distribution such that a ~arge portion of the discharge reaches the alveo~i where absorption takes p~ace, and thus producing high lung deposition efficiencies). To overcome this illvulll~alivili~y, it has previously been taught to include cosolvents (such as ethanol) with the non-CFC propellants so as to b~end the surfactants into the ru,lllu~aLiù,,. Another suggested approach has been to emulsify the MDl r~ ll in the presence of a surfactant with low-vapor pressure additives, such as polyl.~vlu, y alcoho~s as for examp~e propylene glyco~.
~'0 9S124~92 2 1 8 3 5 5 7 PCTII~S9S10276-1 Such cosolvents or additives may of course be phy~io~ogically active, and in some instances may not be tolerated by the user of an MDI mP~iir~inn There is therefore a need for MDI formulations compatible with non-CFC, norl-ozone depleting propellants, which prevent aggregation of drug particles without the use of cosolvents or simi~ar carrier additives, and 5 which provide uniformity of dosing and a favorable respirable fraction.
SUMMARY OF THE INVENTION
It has now been found that tocopherol, or vitamin E, and its derivatives are capable of stabilizing MDI fnrm~ irnc utilizing the propellants HFC-134a and HFC-227ea so as to (i) 10 prevent aggregation, (ii) provide dosing uniformity. and (iii) afford high lung deposition efficiency without the need for either surfactants or cosolvents. Additionally, the tocopherol has the unexpected benefit of providing adequate lubrication for the valve used in an MDI
product without the need for additional lubricants, thus aiding satisfactory functioning of the aerosol device throughout the life of the product.
The tocopherols utilized herein are known to be ~iocul,,ualil,le (or even beneficial), and present no known toxicologic orpathologic ~ at the rnnrPnlr~rirnc proposed for their use. Non-CFC r.. , ~ which include IUUUIJtl~ lS do not require the addition of cosolvents or even of cu,. ~..Liu..dl surfactants such as sorbitan trioleate (SPAN ~5), sorbitan ~uI~O~' and oleic acid, yet provide high lung deposition effficiencies and respirable fractions 20 comparable to those obtained with tcnown cFc-propellant r(J~ It is thus expected that non-CFC rl -. " " ,~ comprising Lucu,ul~,luls wili be useful for the delivery of both peptide and non-peptide I~ for which MDI delivery is deemed favorable.
Accordingly, in one aspect of the present invention are disclosed ~
25 u~ c for ærosol delivery, as for example by inhalation and pulmonary absorption, comprising a 11 ~. . ,1l .. . 1 l ;. ,~lly effective amount of a mPA -- t, a non-I " unuul uual bull propellant, and tocopherol. The propellant in such c~ ~ I; . - are preferably lluuluualbulls and, more preferably, the non-ozone depleting fluu.u.,dll,c,..~ HFC-134a or HFC-227ea. The . ". .1;. - I I. I in the c . ,~ I i, ; of the invention are preferably LHRH analogs, S-lil.lUl~ ldsG
30 inhibitors, ,, or bI~ ' "I . especially preferred .,. ii~ include leuproiide acetdte, the LHRH antdgonist Ac-D-2-Nal-D i ClPhe-D-3-Pal-Ser-N-MeTyr-D-Lys(Mc)-Leu-Lys(N-Isp)-Pro-D-Ala-NH2 (hereinafter "D-2-Nal"), the 5~1i~w~y~ a ,e inhibitor N-[3-[5-(4-fluorophenylmethyl)-2-thienyl]-1-methyl-2-propynyl]-N-lIydlu~.yul.,d, the ~ Sa~ .lO:>lJU~ ,, and the adrenergic IJIII 1 ---1;~ '`1- i:>u~)lululcllol~ (As 35 used herein, "S-lil~u~ dse inhibitor", or "5-LO inhibitor", refers to any physiologically active compound capable of affecting leukotriene biusy.~ ;s.) WO 9512J892 . PCT/US95J027G~
The tocopherol used in the pl~ rnmrn~iitinni of the present invention ma~l be vitamin E or any of its ~ y acceptable derivatives which are well tolerated upon inhalation. Suitable forms of tocopherol may include. but ate not limited to. d- or dl-alpha tocopherol (C2gHsoo2)~ d- or dl-alpha tocopheryl acetate (C3lHs2O3), and d- or dl-alpha S tocopheryl acid succinate (C33H~4Os), as well as mixtures thereof.
The tocopherol of the present invention nnay be present in a cn~r~ ntr~tinn of between about 0.00001% and about 10% by weight, and preferably in a cr~n~ PntrAtinn of between about 0.001% and about 5% by weight.
In a further aspect of the present invention is disclosed a method of preparing a stable Suspension of particles of a " . 1;~ ~ ". " f in a liquid phase non-chlu.unuu.u~d bu~ aerosol propellant, which method comprises the addition to the suspension of tocopherol in an amount sufficient to prevent A~rC~tinn of the particles. Preferably, the tocopherol may be added in an amount of between about 0.00001% and about 10% by weight; more preferably, the tocopherol may be added in an amount of between about 0.û01% and about 5'~c by weight.
The propellants, I)lr~l;l A~llrll;~ and ~u~u,ullci~uls suitable for use in the method of the present invention are those described above in connection with the l~ Al cnmrniitinns of this invention.
DETAILED DESCRIPTION OF T~TF ~VENTION
It is expected that numerous non-ozone depleting aerosol propellants may be used with the ~" ., . ,l.o ~ and methods of the present invention. These include not only HFC- 1 34a and HFC-27ea, described above, but also hAln~ ' alkanes in general, such as HCFC-123(1,1,1-trifluoro-2,2-dichloroethane), HCFG124 (1,1,1,2-L~LIAllublu~llloroethane)~
HCFC-141b, HCFC-225, HFC-125, FC-C51-12 (u~,lnuuludi~ illyl~yclobutane)~ DYMEL A(dimethyl ether) and DYMEL 152a (I,l-dilluulu~,iha~
It is further expected that the r l'~ ~ 'I"J`; I; .~r C and methods of the invention will be suitable fortheA,l"- ~ ;nnofawidevarietyofpeptideandnon-peptidedrugs. Examplesof peptides which may be delivered in this fashion are interferons and other llld~luulla~ activation factors, such as Iy, . .l ,l .~L; . ..; muramyl dipeptide (MDP), ~-interferon, and interferons a and b, 30 and related antiviral and tumoricidal agents; opioid peptides and ll.,~u~ idu~, such as Pnk~rh-Uinc endorphins and dynorphins, and related analgesics; renin inhibitors including new g~-.u~ld~iull anti-hypertensive agents; ~ blc.,y~ul~iluills (CCK analogs) such as CCK, ceruletide and eledoisin, and related cardiovascular- and CNS-targeting agents; 1. . .~ . .l . :. .~., and prrJ~og' ' l~ such as oxytocin, and relâted '' y, oxytocic and àbul ~iràc;~,..t 35 uu~ uu~ yi u~,u;~ii.. and analogs thereof, as well as related i ~ LHRH analogs, such as leuprolide, buserelin and nafarelin, and related down-regulators of pituitary receptors;
Udl dl]lylUid hormone and other growth hormone analogs; enzymes, such as DNase, catalase wo 9sl2~q92 2 ~ 8 3 5 5 7 PCTIUS95/0276 1 and alpha- l antitrypsin; i ~ d.l~ such as cyclosporin; G~-CS~ and other j""""""",~,.l"l~rnrc and insulin. Such pephdes orpeptide ana~ots are frequendy not well-absorbed when given orally.
Examples of non-peptides which may readily be delivered using the UU~ Jo~i~iUl~s and S methods of the present invention are beta-agonists. such as isuulut~lcllul~ albuterol, isoetherine and ~ .ululu.~,lullol, and related anti-asdlmatics; steroids, such as flunisolide, and similar anti-asdhmatics; cholinergic agents, such as cromolyn, and related anti-asdhmatics; and S-l;~JU~y~.,.ldjc inhibitors, such as zileuton and the hydroxyurea compound described above, and related leukotriene inhibitors. Such non-peptides may lend themselves to oral 10 il. l" ~ n ;",~ ~ but when given by inhalation are found to produce rapid reversal of bl~ inn in cases of allergic airway disease and asthma. Also, these compounds may be ddl~ lcd more frequently as MDI formulations than when given orally.
It is also expected that analogs and derivatives of the above ~Ur~u~ull~l uls will be 15 identified which are suitable for use in the ~ and methods of the present invention.
To the extent dlat these analogs and derivatives are similar in structure to or are readily obtained by chemical l l ln~ l: r~ of the tocopherol molecule~ while ~ub~LrlllLidlly retaining the physica properties and hiocnmrqtihilily of vitamin E, such analogs and derivatives are intended to be included among the ~ and methods of the present invention.
The " ..~ useful in the ~ .r.~ of the present invention include not only those specifically named above, but also where appropriate the ~ lly accaptable salts, esters, amides and prodrugs thereof. By "1~ Ally acceptable salts, esters, amides and prodrugs" is meant those carboxylate salts, amino acid addition salts, esters, 25 amides and prodrugs of a compound which are, within the scope of sound medical judgement, suitable for use in contact with with the tissues of humans and lower animals with undue toxicity, irritation, allergic response and the like, r .. , ~ ~ ~ Ir widh a reasonable benefit/risk ratio and effective for their intended use.
The tam "salts" refers to the relatively non-toxic, inorganic and organic acid addition 30 salts of a medicinal compound. These salts can be prepared in situ during the final isolation and purif~cation of the compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
Representative salts include the l~ydlublulllide~ hydrochloride, sulfate, bisulfate, phosphate, ,.
nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, 35 phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, ~lu~llLl~y' . mesylate, ~ , , Iqrtj-L and ~ salts and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lidlium, potassium, Wo 9s/2~i8s2 2 1 8 3 5 5 7 PCT/U595/0276 1 calcium, mAAn~ cil~m and the like, as well as nontoxic Amm~nillm quatemary ammonium and amine cations inclu&g, but not limited to, Ammonillm tetramethylammonium, tetraethyl~nm(millm methylamine. di~ ylA~ , trimethylamine, triethylamine, ethylamine andthelike. (See~forexampleS M Berge~etal~'Fl~ ,,s ~ Salts~'LPharm Sci~
5 66:1-19 (1977).) Examples of ~ y acceptable, non-toxic esters of a compound include (Cl-to-C6 a'ikyl) esters wherein the aikyl group is a straight or branched chain. Acceptable esters also include (Cs-to-C7 cycloalkyl) esters as well as arylalkyl esters such as, but not limited to, benzyl; (Cl-to-C4 aLkyl) esters are preferred..
Examples of ~ c l l ~ ly acceptable~ non-toxic amides of medicinal compounds include amides derived from ammonia, primary (Cl-to-C6 alkyl) amines and secondary (Cl-to-C6 dialkyl) amines wherein the allcyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, (Cl-to-C3 allcyl) primary 15 amides and (Cl-to-C2 dialkyl) secondary amides are preferred. Amides of the cvmpounds of the invention may be prepared according to conventional methods.
The term "prodrug" refers to compounds that are rapidly l ~ r ~ i in vivo to yield the parent medicinal compound, as for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol 14 of the 20 A.C.S . Symposium Series, and in Biu, ~ . ~, ..Z,l~ Carriers ir~ Drug Design, ed. Edward B.
Roche, American pl - ", ~ Association and Pergamon Press (1987).
~ Vhen used in the above ~ v- ~ ; c, a ~ y effective amount of a 111~ .1 i~ A. I l. . I l of the present invention may be employed in pure form or, where such forms 25 exist, in 1)~ 'Aily acceptable salt, ester or prodrug form. By a "l l ,. . AI.. : i. Ally effective amount" of a '' is meant a sufficient amount of the compound to obtain the intended therapeutic benefit, at a reasonable benefit/risk ratio applicable to any medical treatment. It wil'i be . ' - J, however, that the total daily usage of the ..l. .li ~ and ~l~mrr.ci~i~mc of the present invenrion will be decided by the attending physician within the scope of sound medical 30 judgement. The specific ll . Al.. . ;~ A1ly effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific ~ employed; the age, body weight, general health. sex and diet of the patienti the time of A~ AIi"~, route of A~ and rate of excretion of the specific compound employed; the duration of the 35 treatment; drugs used in c ".l ;, -~; or ~ dl nt~l with the specific compound employed;
and like factors well known in the medical arts. For example, it is well within the skill of the wo gsn~892 2 t 8 ~ 5 5 7 PCT/US95111276~ ~
art to start doses at levels lower than }equired for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effec~ is achieved.
The total daily doses of the ~ l i A, . ,r"l ~ u~ )ldt~d for use with this invention, and 5 ~ Ty the ~ by weight of the l l ~ in the respective composition may vary widely. In the case of an LHRH analog, such as leuprolide acetate, the intended daily dose may range from about 0.01 to about 5 mg/day; accordmgly, where an aerosol inhaler is to be used several times a day with a discharge volume of between about 5 and about 250 lal, the " " " . .1~ of 1 l l. .1;, 1 ,. . Il will be between about 0.2 and about 20 mg/ml.
10 Similarly, in the case of a S~ y~ a~ inhibitor expected to be administered in a daily dose ranging from about 0.01 to about 10 mg/kg/day, the concentration will be between about 0.001 and about lOO mg/ml. Of course, 1., 1;~ cnnr~ n~tion~ outside of the5e range5 may also be suitable, where different potencies, dosing ~ u~ s and discharge volumes are used.
The ~.UIlllJo~;~iul~ of the invention may be prepared by combining tocopherol with a I ". .1;~ 1. .1 l which has been milled or otherwise reduced to a desired particle size, and placing the mixture in a suitable aerosol container or vial. After sealing the container, an aerosol propellant is introduced and the system is agitated to fully blend the ingredients. Altematively, the tocopherol and " ,. .1;, , .. ~ may be milled together, either before or after addition of 20 propellant. In some instances. it may be necessary to wet-mill the .. ,. ,li -., ....1 in a closed system, as for example under ~~ t~C and pressure conditions which permit the " .. .1;~ ~. ". . to be milled while mixed with a liquid-phase aerosol propellant. It is expected that, for any particular . "- "l -;, ~ of " .~ . .- .I propellant and tocopherol, the ideal order of addition of ingredients and the conditions under which they are to be combined may readily 25 be d~t.~nnin~d The .. "~ and methods of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Both below and throughout the ~,.,ir~ tiUII, it is 30 i i~Dd d~hatciiidon6i ihe~y~ Weliiir~twe~ea~ essly.".u.~,~,...~ibyleierenc~
~ wo ssl2~ss2 2 1 8 3 5 5 7 PCT/US9~:i/0276~
Example I
PhYsical StabilitY of MDI Formulation.s Containing Tocopherol A ~ ", i ,~l i"" of the effect of tocopherol on the physical stability of seYeral MDI
5 f""""~ prepared with HFA-I34a was conducted as follows: d-Alpha tocopheryl acetate USP (Aldrich Chemical Co. Inc., Milwaukee, Wisconsin) and each of the drugs being formulated were combined in the amounts shown in appropriate transparent aerosol containers (vials). (Leuprolide acetate and its preparation are described in United States Patent No.
4,005,063, issued January 25, I g77; the LHRH antagonist D-2-Nal and its preparation are described in United States Patent No. 5,110,904, issued May 5, 1992; and the 5-LO inhibitor N-[3-[5-(4-lluuluul~ yll~ yl)-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyureaandits preparation are described in United States Patent No. 5,288,751, issued February 22, 1994;
each of which disclosures are ...cul,uu..lL~d herein by reference.) Additionally, to some of the vials was added a di~,u~ abilizer, sodium d~ ull~ ("DSA", Aldrich Chemical Company, Inc.), in an amount to produce a final ~ ll l of o. l % by weight The vials were crimped and charged with a,u~lu~dlll~ly 10 mL of HFC-134a and agitated to blend the jn nre~ .nl C The dispersion quality in each preparation was evaluated visually after 24 and 48 hours.
Results of these tests are shown below in Table 1. The data obtained show that tocopherol produces good dispersion quality, even in the absence of DSA. By cnmr~ricnn control fnrm~ tinnc of each of the test ~ r - ' (which were prepared without tocopherol or DSA) were seen to have poor dispersion quality after less than 30 seconds.
Table I
Dis~ersion OualitY of Selected Dru~c in HFA-134a Acrive Tocopheryl Ac DSA Dispersion uali In,eredient C~ C.J~ .n~iul. 24 Hours O~ ty Leuprolide Acetate 0.1% 0 Good Good " 0.2% 0 Good Good " 0.3% 0 Good Good " 0.1% 0.1% Good Good 0.2% 0.1% Good Good WO 95/2~892 2 1 8 3 5 5 7 PCT/US9510276~
.
LHRH Anta~onist 0.1% 0 Good Good "0.2% 0 Good Good 0.3% 0 Good Good "0.1% 0.1% Good Good 5-LO Inhibitor 0.1% 0 Good Good "0.2% 0 Good Good 0.3% 0 Good Good "0.1% 0.1% Good Good "0.2% 0.1% Good Good "0.3% 0.1% Good Good Exam~le 2 Preparation of MDI F~rm~ ~ioni for Performance Testin~
For each test formulation, between 7 and 12 g of glass beads were placed into a suitable glass aerosol container (vial), along with 100 mg to 250 mg drug and tocopheryl acetate in the amounts needed to produce the desired final fnn~n~ nc The vials were crimped shut with valYes having delivery values (volumes per spray) of either 50 1ll or 100 lal, and then charged with 10 ml of HFA-134a propellant. The filled vials were then shaken for 24 hours to mill and disperse the drug, after which testing was carried out in vitro or in vivo as described below.
~Lmplç 3 Uniformity of MD~ Deliverv of (~fmrfl~ n~ Containin~ Tocopherol Delivery uniformity and physical stability of the ,u~ uo~;Liulls of the invention containing the 5-LO inhibitor were tested as follows: Each vial was shaken and its valve primed by a~Iu~uli~illg 5 times in succession, after which the vial was weighed. The vial was then actuated a fixed number of times (5 times per cycle), followed by another weighing. This process was repeated until shot weights began to drop off ~,u~ ,;ably ("tail-of~').
The amounts delivered were calculated as total weight per cycle (5 sprays) and compared to a target value, in each case, of 305 mg. Also calculated were the number of cycle weight 111~ which fell within upper and lower range limits of 110% and 90% of the target weight, respectively.
~ wo ssl248s2 ' 2 1 8 3 5 5 7 PCTlUSg5/0276~
The results of these studies, shown below in Table 2, ~if 111~ r the uniforrnity with which the compositions of the present invention are delivered by a MDI device. In each instance, the success rate is the number of 5-shot cycles falling between the upper and lower range limits, relative to the total number of cycles measured, prior to tail-off.
Deliverv of S-LO Inhibitor cullll)u~l~;ol)s Cnnr~inin~ Tocopherol Drugcu~ Liull Tocor~hervl AcConc. SuccessRate 1.0% 0.1% 32/33 (97%) 1.0% 0.1% 34/34 (100%) 1.0% 0.2% 33/33 (loo%) 2.0% 0.1% 33/34 (97%) 2.5% 0.2% 35/36 (97%) 2.5% 0.3% 32/32 (100%) Fxarrlole 4 Uniformity of MD1 Deliverv of Compositions Containing Tocopherol ~he ~ lL~ of ~xample 3 were repeated using cyclosporin (cyclosporine A) and 15 i~u~. ut~ ol base (Sigma Chemical Co., St. Louis, Missouri). In the case of ~,y~,lu~ a f( l., . l ~ of the invention contâining 2.5% drug and O. 1% tocopheryl acetate in HFC-134a propellant was prepared as before, prirned, and aerosolized into a beaker for six cycles of three sprays each. In the case of isu~,lut~,.u..ol, each of two fnrrmll~tii-n~ containing 2.5% drug and 0.1% tûcopherol in HFC-134a propellant was prepared as before, prirned, and aerosolized into a beaker for a single cycle of five sprays. In both cases, shot weights were recorded by measuring the weight of the aerosol vials before and after the cycle; additionally, unit spray contents (actual weights of drug sprayed per cycle) were determined by high ~ rUIllla~l~,r liquid ~ y analysis of appropriate solvents (such as ethanol) placed in each of the beakers before testing.
For both drugs and for all testing cycles, shot weights and unit spray contents were well within the upper and lower range limits of 110% and 90% of the target values, g the ~ dlJiliLy of the ~ l ll l llll)- ~ ;....~ of the present invention to a variety of il Al agentS.
g WO 95/2 ~892 PCT/US9510276 Example 5 Biodvaiiabilitv of MDI Compoiitioni Contdinin~ Tocophelol Using a test preparation of the 5-LO inhibitor containing 1.275% (by weight) drug and 0.05% (by weight) tocopheryl acetdte in HFC- I 34a propellant, bioavailability of aerosol-delivered drug was compared to that of an aqueous control ~u~ ulaLiv~l delivered illLlav~llvu~ly (IV). Eight L~ I beagle dogs (two-year-old females, Marshall Labs) were used foreach group. To the dogs in the lV group, 0.5 mg/kg drug was given intravenously over a I
minute period as a I mg/ml solution in 60% PEG 400 (polyethylene glycol, Union Carbide Co., Institute, W. Virginia) in water. To the dogs in the aerosol group, the same amount of drug was aduul~ ul by sprays of the test forrnulation delivered into the trachea. Blood samples were collected at specified time intervals and analyzed for drug cnn~rntrqti~n using high l,~,lru.,.,d,..,~ liquid .,hl~ ,, , ' y.
The results of these studies, shown below in Table 3, ' that drugs are effectively a.l--u~ ,J using the MDI r",, " 1 1l ;""C of the present invention. In particular, biudvailal)ili~y of the aerosolized drug over a 24-hour period was 42% that of the same amount delivered illLlav~llv~ ly~ based on area-under-curve (AUC) ~ i""~ Net bioavailability was even better: When corrected for non-absorptive loss of drug (as for example due to loss in the dosing device, inertial impaction of the sprây in the trachea, and expulsion with exhaled air), bioaYailability exceeded 80% ûf that obtained using illLI.,~,~l~)..~ ,..i.ll;ll:~ll.,li....
Table 3 tp~lmp~ rm of Intravenous and MDI Deliverv of 5-LO Inhibitor ~ a~,.lv~ Aerosol Cma,~ (~Lg/ml) 0.73 i: 0.07 0.19 i 0.08 Tma~ (hours) ~ 10.67 ~ 7.06 AUC~ g-hour/ml) 5.89 ~ 0.73 2.53 :t 1.03 Similar studies were carried out using MDI ~"" " l ~ ;. .. ~ of the invention containing leuprolide acetate in place of the 5-LO inhibitor. The results obtained were virtually identical to those 30 above, in that bioavailability was found to be a~J~Jlu~ l..~ly 42% and more than 80% (with and without correction for non-absorptive loss, respectively) of that achieved using intravenous ~,. ... ..
~ wo gs/24892 2 1 8 3 5 5 7 PCT/US9~ 0276 1f It is understood that the foregoing detailed descrfption and d~Ulll~J~lyillg examples are 5 merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and thefr equivalents. Various changes and Af i~ to the disclosed rl I ~h~ 1; " ~ will be apparent to those skiLed in the art. Such changes and mn f ifir~tir~n c, including without ~imitation those relatdng to the ~
means of preparation and/or methods of use of the invention, may be made without departing 10 from the spirit and scope thereof.
The present invention relates to drug fnnnlllstinns for aerosol delivery which are compatible with non-chlorofluorocarbon propellants~ and especially to excipients which are 5 useful therein. In particular, the invention relates to inhalab~e fntrn~ innc comprising tocopherol (vitamin E) or tocopherol analogs or derivatives, which r ~ c possess a variety of advantageous properties.
BACICGROUND OF THE INVENTION ~
Numerous ~ " ,~ ~ ~; ,,l compounds are preferentially delivered by means of metered dose inhalation (MDI) devices, in which a physiological~y inert propellant of high vapor pressure is used to discharge a precise amount of medication with each operation. These MDI
devices, a~so known as aeroso~s or inhalers, have found widespread use among patients suffering, for example, from episodic or chronic asthma. The propellants of choice have historically been chlorofluoro-carbons, such Propellant 11 (trich~ulunuu~u~ .al,~), Propellant ~2 (dichloro linuvlul--villal-e) and Propellant 114 (dichlu,u~ dnuuluvLl In recent years, however, there have been growing concems that ul~lvluAuuluvauvu~
(CFC) propellants have detrimental environmental effects, and in particular that they interfere with the protective upper-atmosphere ozone layer. Under an int~srinnsl accord (the Montreal Protoco~), the use of CFC propellants will be prohibited by the start of the year 2000, and possibly sooner. Altemative propellant vehicles are being deve~oped which exhibit little or no ozone dep~etion potential (ODP). Such altemative propellants include two -- HFC-134a (1,1,1,2-tetrafluoroethane) and HFC-227ea (1,~,1,2,3,3,3 h.v~Ldr~uulul~lu~àl.e) -- which have negligib~e ODP and are currently undergoing safety and v.l~uu.u~ Lal testing.
U.lru,i ~/, surfactants which are generally used in known MDl r.~ have been found to be imiscible in and therefore , ~ with these new, non-CFC propellants.
Such surfactants are necessary to prevent PV~Ptinn (in the form of caking or crystallization, for example) of the medicinally active compound in the reservoir of the inhaler, to faci~itate unifomm dosing upon aerosol ~ rl;nn and to provide an aerosol spray discharge having a favorable respirable fraction (that is, a partic~e size distribution such that a ~arge portion of the discharge reaches the alveo~i where absorption takes p~ace, and thus producing high lung deposition efficiencies). To overcome this illvulll~alivili~y, it has previously been taught to include cosolvents (such as ethanol) with the non-CFC propellants so as to b~end the surfactants into the ru,lllu~aLiù,,. Another suggested approach has been to emulsify the MDl r~ ll in the presence of a surfactant with low-vapor pressure additives, such as polyl.~vlu, y alcoho~s as for examp~e propylene glyco~.
~'0 9S124~92 2 1 8 3 5 5 7 PCTII~S9S10276-1 Such cosolvents or additives may of course be phy~io~ogically active, and in some instances may not be tolerated by the user of an MDI mP~iir~inn There is therefore a need for MDI formulations compatible with non-CFC, norl-ozone depleting propellants, which prevent aggregation of drug particles without the use of cosolvents or simi~ar carrier additives, and 5 which provide uniformity of dosing and a favorable respirable fraction.
SUMMARY OF THE INVENTION
It has now been found that tocopherol, or vitamin E, and its derivatives are capable of stabilizing MDI fnrm~ irnc utilizing the propellants HFC-134a and HFC-227ea so as to (i) 10 prevent aggregation, (ii) provide dosing uniformity. and (iii) afford high lung deposition efficiency without the need for either surfactants or cosolvents. Additionally, the tocopherol has the unexpected benefit of providing adequate lubrication for the valve used in an MDI
product without the need for additional lubricants, thus aiding satisfactory functioning of the aerosol device throughout the life of the product.
The tocopherols utilized herein are known to be ~iocul,,ualil,le (or even beneficial), and present no known toxicologic orpathologic ~ at the rnnrPnlr~rirnc proposed for their use. Non-CFC r.. , ~ which include IUUUIJtl~ lS do not require the addition of cosolvents or even of cu,. ~..Liu..dl surfactants such as sorbitan trioleate (SPAN ~5), sorbitan ~uI~O~' and oleic acid, yet provide high lung deposition effficiencies and respirable fractions 20 comparable to those obtained with tcnown cFc-propellant r(J~ It is thus expected that non-CFC rl -. " " ,~ comprising Lucu,ul~,luls wili be useful for the delivery of both peptide and non-peptide I~ for which MDI delivery is deemed favorable.
Accordingly, in one aspect of the present invention are disclosed ~
25 u~ c for ærosol delivery, as for example by inhalation and pulmonary absorption, comprising a 11 ~. . ,1l .. . 1 l ;. ,~lly effective amount of a mPA -- t, a non-I " unuul uual bull propellant, and tocopherol. The propellant in such c~ ~ I; . - are preferably lluuluualbulls and, more preferably, the non-ozone depleting fluu.u.,dll,c,..~ HFC-134a or HFC-227ea. The . ". .1;. - I I. I in the c . ,~ I i, ; of the invention are preferably LHRH analogs, S-lil.lUl~ ldsG
30 inhibitors, ,, or bI~ ' "I . especially preferred .,. ii~ include leuproiide acetdte, the LHRH antdgonist Ac-D-2-Nal-D i ClPhe-D-3-Pal-Ser-N-MeTyr-D-Lys(Mc)-Leu-Lys(N-Isp)-Pro-D-Ala-NH2 (hereinafter "D-2-Nal"), the 5~1i~w~y~ a ,e inhibitor N-[3-[5-(4-fluorophenylmethyl)-2-thienyl]-1-methyl-2-propynyl]-N-lIydlu~.yul.,d, the ~ Sa~ .lO:>lJU~ ,, and the adrenergic IJIII 1 ---1;~ '`1- i:>u~)lululcllol~ (As 35 used herein, "S-lil~u~ dse inhibitor", or "5-LO inhibitor", refers to any physiologically active compound capable of affecting leukotriene biusy.~ ;s.) WO 9512J892 . PCT/US95J027G~
The tocopherol used in the pl~ rnmrn~iitinni of the present invention ma~l be vitamin E or any of its ~ y acceptable derivatives which are well tolerated upon inhalation. Suitable forms of tocopherol may include. but ate not limited to. d- or dl-alpha tocopherol (C2gHsoo2)~ d- or dl-alpha tocopheryl acetate (C3lHs2O3), and d- or dl-alpha S tocopheryl acid succinate (C33H~4Os), as well as mixtures thereof.
The tocopherol of the present invention nnay be present in a cn~r~ ntr~tinn of between about 0.00001% and about 10% by weight, and preferably in a cr~n~ PntrAtinn of between about 0.001% and about 5% by weight.
In a further aspect of the present invention is disclosed a method of preparing a stable Suspension of particles of a " . 1;~ ~ ". " f in a liquid phase non-chlu.unuu.u~d bu~ aerosol propellant, which method comprises the addition to the suspension of tocopherol in an amount sufficient to prevent A~rC~tinn of the particles. Preferably, the tocopherol may be added in an amount of between about 0.00001% and about 10% by weight; more preferably, the tocopherol may be added in an amount of between about 0.û01% and about 5'~c by weight.
The propellants, I)lr~l;l A~llrll;~ and ~u~u,ullci~uls suitable for use in the method of the present invention are those described above in connection with the l~ Al cnmrniitinns of this invention.
DETAILED DESCRIPTION OF T~TF ~VENTION
It is expected that numerous non-ozone depleting aerosol propellants may be used with the ~" ., . ,l.o ~ and methods of the present invention. These include not only HFC- 1 34a and HFC-27ea, described above, but also hAln~ ' alkanes in general, such as HCFC-123(1,1,1-trifluoro-2,2-dichloroethane), HCFG124 (1,1,1,2-L~LIAllublu~llloroethane)~
HCFC-141b, HCFC-225, HFC-125, FC-C51-12 (u~,lnuuludi~ illyl~yclobutane)~ DYMEL A(dimethyl ether) and DYMEL 152a (I,l-dilluulu~,iha~
It is further expected that the r l'~ ~ 'I"J`; I; .~r C and methods of the invention will be suitable fortheA,l"- ~ ;nnofawidevarietyofpeptideandnon-peptidedrugs. Examplesof peptides which may be delivered in this fashion are interferons and other llld~luulla~ activation factors, such as Iy, . .l ,l .~L; . ..; muramyl dipeptide (MDP), ~-interferon, and interferons a and b, 30 and related antiviral and tumoricidal agents; opioid peptides and ll.,~u~ idu~, such as Pnk~rh-Uinc endorphins and dynorphins, and related analgesics; renin inhibitors including new g~-.u~ld~iull anti-hypertensive agents; ~ blc.,y~ul~iluills (CCK analogs) such as CCK, ceruletide and eledoisin, and related cardiovascular- and CNS-targeting agents; 1. . .~ . .l . :. .~., and prrJ~og' ' l~ such as oxytocin, and relâted '' y, oxytocic and àbul ~iràc;~,..t 35 uu~ uu~ yi u~,u;~ii.. and analogs thereof, as well as related i ~ LHRH analogs, such as leuprolide, buserelin and nafarelin, and related down-regulators of pituitary receptors;
Udl dl]lylUid hormone and other growth hormone analogs; enzymes, such as DNase, catalase wo 9sl2~q92 2 ~ 8 3 5 5 7 PCTIUS95/0276 1 and alpha- l antitrypsin; i ~ d.l~ such as cyclosporin; G~-CS~ and other j""""""",~,.l"l~rnrc and insulin. Such pephdes orpeptide ana~ots are frequendy not well-absorbed when given orally.
Examples of non-peptides which may readily be delivered using the UU~ Jo~i~iUl~s and S methods of the present invention are beta-agonists. such as isuulut~lcllul~ albuterol, isoetherine and ~ .ululu.~,lullol, and related anti-asdlmatics; steroids, such as flunisolide, and similar anti-asdhmatics; cholinergic agents, such as cromolyn, and related anti-asdhmatics; and S-l;~JU~y~.,.ldjc inhibitors, such as zileuton and the hydroxyurea compound described above, and related leukotriene inhibitors. Such non-peptides may lend themselves to oral 10 il. l" ~ n ;",~ ~ but when given by inhalation are found to produce rapid reversal of bl~ inn in cases of allergic airway disease and asthma. Also, these compounds may be ddl~ lcd more frequently as MDI formulations than when given orally.
It is also expected that analogs and derivatives of the above ~Ur~u~ull~l uls will be 15 identified which are suitable for use in the ~ and methods of the present invention.
To the extent dlat these analogs and derivatives are similar in structure to or are readily obtained by chemical l l ln~ l: r~ of the tocopherol molecule~ while ~ub~LrlllLidlly retaining the physica properties and hiocnmrqtihilily of vitamin E, such analogs and derivatives are intended to be included among the ~ and methods of the present invention.
The " ..~ useful in the ~ .r.~ of the present invention include not only those specifically named above, but also where appropriate the ~ lly accaptable salts, esters, amides and prodrugs thereof. By "1~ Ally acceptable salts, esters, amides and prodrugs" is meant those carboxylate salts, amino acid addition salts, esters, 25 amides and prodrugs of a compound which are, within the scope of sound medical judgement, suitable for use in contact with with the tissues of humans and lower animals with undue toxicity, irritation, allergic response and the like, r .. , ~ ~ ~ Ir widh a reasonable benefit/risk ratio and effective for their intended use.
The tam "salts" refers to the relatively non-toxic, inorganic and organic acid addition 30 salts of a medicinal compound. These salts can be prepared in situ during the final isolation and purif~cation of the compound or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
Representative salts include the l~ydlublulllide~ hydrochloride, sulfate, bisulfate, phosphate, ,.
nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, 35 phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, ~lu~llLl~y' . mesylate, ~ , , Iqrtj-L and ~ salts and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lidlium, potassium, Wo 9s/2~i8s2 2 1 8 3 5 5 7 PCT/U595/0276 1 calcium, mAAn~ cil~m and the like, as well as nontoxic Amm~nillm quatemary ammonium and amine cations inclu&g, but not limited to, Ammonillm tetramethylammonium, tetraethyl~nm(millm methylamine. di~ ylA~ , trimethylamine, triethylamine, ethylamine andthelike. (See~forexampleS M Berge~etal~'Fl~ ,,s ~ Salts~'LPharm Sci~
5 66:1-19 (1977).) Examples of ~ y acceptable, non-toxic esters of a compound include (Cl-to-C6 a'ikyl) esters wherein the aikyl group is a straight or branched chain. Acceptable esters also include (Cs-to-C7 cycloalkyl) esters as well as arylalkyl esters such as, but not limited to, benzyl; (Cl-to-C4 aLkyl) esters are preferred..
Examples of ~ c l l ~ ly acceptable~ non-toxic amides of medicinal compounds include amides derived from ammonia, primary (Cl-to-C6 alkyl) amines and secondary (Cl-to-C6 dialkyl) amines wherein the allcyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, (Cl-to-C3 allcyl) primary 15 amides and (Cl-to-C2 dialkyl) secondary amides are preferred. Amides of the cvmpounds of the invention may be prepared according to conventional methods.
The term "prodrug" refers to compounds that are rapidly l ~ r ~ i in vivo to yield the parent medicinal compound, as for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol 14 of the 20 A.C.S . Symposium Series, and in Biu, ~ . ~, ..Z,l~ Carriers ir~ Drug Design, ed. Edward B.
Roche, American pl - ", ~ Association and Pergamon Press (1987).
~ Vhen used in the above ~ v- ~ ; c, a ~ y effective amount of a 111~ .1 i~ A. I l. . I l of the present invention may be employed in pure form or, where such forms 25 exist, in 1)~ 'Aily acceptable salt, ester or prodrug form. By a "l l ,. . AI.. : i. Ally effective amount" of a '' is meant a sufficient amount of the compound to obtain the intended therapeutic benefit, at a reasonable benefit/risk ratio applicable to any medical treatment. It wil'i be . ' - J, however, that the total daily usage of the ..l. .li ~ and ~l~mrr.ci~i~mc of the present invenrion will be decided by the attending physician within the scope of sound medical 30 judgement. The specific ll . Al.. . ;~ A1ly effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific ~ employed; the age, body weight, general health. sex and diet of the patienti the time of A~ AIi"~, route of A~ and rate of excretion of the specific compound employed; the duration of the 35 treatment; drugs used in c ".l ;, -~; or ~ dl nt~l with the specific compound employed;
and like factors well known in the medical arts. For example, it is well within the skill of the wo gsn~892 2 t 8 ~ 5 5 7 PCT/US95111276~ ~
art to start doses at levels lower than }equired for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effec~ is achieved.
The total daily doses of the ~ l i A, . ,r"l ~ u~ )ldt~d for use with this invention, and 5 ~ Ty the ~ by weight of the l l ~ in the respective composition may vary widely. In the case of an LHRH analog, such as leuprolide acetate, the intended daily dose may range from about 0.01 to about 5 mg/day; accordmgly, where an aerosol inhaler is to be used several times a day with a discharge volume of between about 5 and about 250 lal, the " " " . .1~ of 1 l l. .1;, 1 ,. . Il will be between about 0.2 and about 20 mg/ml.
10 Similarly, in the case of a S~ y~ a~ inhibitor expected to be administered in a daily dose ranging from about 0.01 to about 10 mg/kg/day, the concentration will be between about 0.001 and about lOO mg/ml. Of course, 1., 1;~ cnnr~ n~tion~ outside of the5e range5 may also be suitable, where different potencies, dosing ~ u~ s and discharge volumes are used.
The ~.UIlllJo~;~iul~ of the invention may be prepared by combining tocopherol with a I ". .1;~ 1. .1 l which has been milled or otherwise reduced to a desired particle size, and placing the mixture in a suitable aerosol container or vial. After sealing the container, an aerosol propellant is introduced and the system is agitated to fully blend the ingredients. Altematively, the tocopherol and " ,. .1;, , .. ~ may be milled together, either before or after addition of 20 propellant. In some instances. it may be necessary to wet-mill the .. ,. ,li -., ....1 in a closed system, as for example under ~~ t~C and pressure conditions which permit the " .. .1;~ ~. ". . to be milled while mixed with a liquid-phase aerosol propellant. It is expected that, for any particular . "- "l -;, ~ of " .~ . .- .I propellant and tocopherol, the ideal order of addition of ingredients and the conditions under which they are to be combined may readily 25 be d~t.~nnin~d The .. "~ and methods of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Both below and throughout the ~,.,ir~ tiUII, it is 30 i i~Dd d~hatciiidon6i ihe~y~ Weliiir~twe~ea~ essly.".u.~,~,...~ibyleierenc~
~ wo ssl2~ss2 2 1 8 3 5 5 7 PCT/US9~:i/0276~
Example I
PhYsical StabilitY of MDI Formulation.s Containing Tocopherol A ~ ", i ,~l i"" of the effect of tocopherol on the physical stability of seYeral MDI
5 f""""~ prepared with HFA-I34a was conducted as follows: d-Alpha tocopheryl acetate USP (Aldrich Chemical Co. Inc., Milwaukee, Wisconsin) and each of the drugs being formulated were combined in the amounts shown in appropriate transparent aerosol containers (vials). (Leuprolide acetate and its preparation are described in United States Patent No.
4,005,063, issued January 25, I g77; the LHRH antagonist D-2-Nal and its preparation are described in United States Patent No. 5,110,904, issued May 5, 1992; and the 5-LO inhibitor N-[3-[5-(4-lluuluul~ yll~ yl)-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyureaandits preparation are described in United States Patent No. 5,288,751, issued February 22, 1994;
each of which disclosures are ...cul,uu..lL~d herein by reference.) Additionally, to some of the vials was added a di~,u~ abilizer, sodium d~ ull~ ("DSA", Aldrich Chemical Company, Inc.), in an amount to produce a final ~ ll l of o. l % by weight The vials were crimped and charged with a,u~lu~dlll~ly 10 mL of HFC-134a and agitated to blend the jn nre~ .nl C The dispersion quality in each preparation was evaluated visually after 24 and 48 hours.
Results of these tests are shown below in Table 1. The data obtained show that tocopherol produces good dispersion quality, even in the absence of DSA. By cnmr~ricnn control fnrm~ tinnc of each of the test ~ r - ' (which were prepared without tocopherol or DSA) were seen to have poor dispersion quality after less than 30 seconds.
Table I
Dis~ersion OualitY of Selected Dru~c in HFA-134a Acrive Tocopheryl Ac DSA Dispersion uali In,eredient C~ C.J~ .n~iul. 24 Hours O~ ty Leuprolide Acetate 0.1% 0 Good Good " 0.2% 0 Good Good " 0.3% 0 Good Good " 0.1% 0.1% Good Good 0.2% 0.1% Good Good WO 95/2~892 2 1 8 3 5 5 7 PCT/US9510276~
.
LHRH Anta~onist 0.1% 0 Good Good "0.2% 0 Good Good 0.3% 0 Good Good "0.1% 0.1% Good Good 5-LO Inhibitor 0.1% 0 Good Good "0.2% 0 Good Good 0.3% 0 Good Good "0.1% 0.1% Good Good "0.2% 0.1% Good Good "0.3% 0.1% Good Good Exam~le 2 Preparation of MDI F~rm~ ~ioni for Performance Testin~
For each test formulation, between 7 and 12 g of glass beads were placed into a suitable glass aerosol container (vial), along with 100 mg to 250 mg drug and tocopheryl acetate in the amounts needed to produce the desired final fnn~n~ nc The vials were crimped shut with valYes having delivery values (volumes per spray) of either 50 1ll or 100 lal, and then charged with 10 ml of HFA-134a propellant. The filled vials were then shaken for 24 hours to mill and disperse the drug, after which testing was carried out in vitro or in vivo as described below.
~Lmplç 3 Uniformity of MD~ Deliverv of (~fmrfl~ n~ Containin~ Tocopherol Delivery uniformity and physical stability of the ,u~ uo~;Liulls of the invention containing the 5-LO inhibitor were tested as follows: Each vial was shaken and its valve primed by a~Iu~uli~illg 5 times in succession, after which the vial was weighed. The vial was then actuated a fixed number of times (5 times per cycle), followed by another weighing. This process was repeated until shot weights began to drop off ~,u~ ,;ably ("tail-of~').
The amounts delivered were calculated as total weight per cycle (5 sprays) and compared to a target value, in each case, of 305 mg. Also calculated were the number of cycle weight 111~ which fell within upper and lower range limits of 110% and 90% of the target weight, respectively.
~ wo ssl248s2 ' 2 1 8 3 5 5 7 PCTlUSg5/0276~
The results of these studies, shown below in Table 2, ~if 111~ r the uniforrnity with which the compositions of the present invention are delivered by a MDI device. In each instance, the success rate is the number of 5-shot cycles falling between the upper and lower range limits, relative to the total number of cycles measured, prior to tail-off.
Deliverv of S-LO Inhibitor cullll)u~l~;ol)s Cnnr~inin~ Tocopherol Drugcu~ Liull Tocor~hervl AcConc. SuccessRate 1.0% 0.1% 32/33 (97%) 1.0% 0.1% 34/34 (100%) 1.0% 0.2% 33/33 (loo%) 2.0% 0.1% 33/34 (97%) 2.5% 0.2% 35/36 (97%) 2.5% 0.3% 32/32 (100%) Fxarrlole 4 Uniformity of MD1 Deliverv of Compositions Containing Tocopherol ~he ~ lL~ of ~xample 3 were repeated using cyclosporin (cyclosporine A) and 15 i~u~. ut~ ol base (Sigma Chemical Co., St. Louis, Missouri). In the case of ~,y~,lu~ a f( l., . l ~ of the invention contâining 2.5% drug and O. 1% tocopheryl acetate in HFC-134a propellant was prepared as before, prirned, and aerosolized into a beaker for six cycles of three sprays each. In the case of isu~,lut~,.u..ol, each of two fnrrmll~tii-n~ containing 2.5% drug and 0.1% tûcopherol in HFC-134a propellant was prepared as before, prirned, and aerosolized into a beaker for a single cycle of five sprays. In both cases, shot weights were recorded by measuring the weight of the aerosol vials before and after the cycle; additionally, unit spray contents (actual weights of drug sprayed per cycle) were determined by high ~ rUIllla~l~,r liquid ~ y analysis of appropriate solvents (such as ethanol) placed in each of the beakers before testing.
For both drugs and for all testing cycles, shot weights and unit spray contents were well within the upper and lower range limits of 110% and 90% of the target values, g the ~ dlJiliLy of the ~ l ll l llll)- ~ ;....~ of the present invention to a variety of il Al agentS.
g WO 95/2 ~892 PCT/US9510276 Example 5 Biodvaiiabilitv of MDI Compoiitioni Contdinin~ Tocophelol Using a test preparation of the 5-LO inhibitor containing 1.275% (by weight) drug and 0.05% (by weight) tocopheryl acetdte in HFC- I 34a propellant, bioavailability of aerosol-delivered drug was compared to that of an aqueous control ~u~ ulaLiv~l delivered illLlav~llvu~ly (IV). Eight L~ I beagle dogs (two-year-old females, Marshall Labs) were used foreach group. To the dogs in the lV group, 0.5 mg/kg drug was given intravenously over a I
minute period as a I mg/ml solution in 60% PEG 400 (polyethylene glycol, Union Carbide Co., Institute, W. Virginia) in water. To the dogs in the aerosol group, the same amount of drug was aduul~ ul by sprays of the test forrnulation delivered into the trachea. Blood samples were collected at specified time intervals and analyzed for drug cnn~rntrqti~n using high l,~,lru.,.,d,..,~ liquid .,hl~ ,, , ' y.
The results of these studies, shown below in Table 3, ' that drugs are effectively a.l--u~ ,J using the MDI r",, " 1 1l ;""C of the present invention. In particular, biudvailal)ili~y of the aerosolized drug over a 24-hour period was 42% that of the same amount delivered illLlav~llv~ ly~ based on area-under-curve (AUC) ~ i""~ Net bioavailability was even better: When corrected for non-absorptive loss of drug (as for example due to loss in the dosing device, inertial impaction of the sprây in the trachea, and expulsion with exhaled air), bioaYailability exceeded 80% ûf that obtained using illLI.,~,~l~)..~ ,..i.ll;ll:~ll.,li....
Table 3 tp~lmp~ rm of Intravenous and MDI Deliverv of 5-LO Inhibitor ~ a~,.lv~ Aerosol Cma,~ (~Lg/ml) 0.73 i: 0.07 0.19 i 0.08 Tma~ (hours) ~ 10.67 ~ 7.06 AUC~ g-hour/ml) 5.89 ~ 0.73 2.53 :t 1.03 Similar studies were carried out using MDI ~"" " l ~ ;. .. ~ of the invention containing leuprolide acetate in place of the 5-LO inhibitor. The results obtained were virtually identical to those 30 above, in that bioavailability was found to be a~J~Jlu~ l..~ly 42% and more than 80% (with and without correction for non-absorptive loss, respectively) of that achieved using intravenous ~,. ... ..
~ wo gs/24892 2 1 8 3 5 5 7 PCT/US9~ 0276 1f It is understood that the foregoing detailed descrfption and d~Ulll~J~lyillg examples are 5 merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and thefr equivalents. Various changes and Af i~ to the disclosed rl I ~h~ 1; " ~ will be apparent to those skiLed in the art. Such changes and mn f ifir~tir~n c, including without ~imitation those relatdng to the ~
means of preparation and/or methods of use of the invention, may be made without departing 10 from the spirit and scope thereof.
Claims (14)
1. A pharmaceutical composition for aerosol delivery comprising a medicament, a non-chlorofluorocarbon propellant, and tocopherol.
2. A pharmaceutical composition according to Claim 1 wherein the propellant is a halogenated alkane.
3. A pharmaceutical composition according to Claim 2 wherein the propellant is selected from the group consisting of HFC- 134a and HFC-227ea.
4. A pharmaceutical composition according to Claim 2 wherein the tocopherol ispresent in a form selected from the group consisting of d-alpha tocopherol, dl-alpha tocopherol, d-alpha tocopherol acetate, dl-alpha tocopherol acetate, d-alpha tocopherol acid succinate and dl-alpha tocopherol acid succinate.
5. A pharmaceutical composition composition according to Claim 1 wherein the tocopherol is present in a concentration of between 0.00001% and 10% by weight.
6. A pharmaceutical composition according to Claim 1 wherein the tocopherol is present in a concentration of between 0.001% and 5% by weight.
7. A pharmaceutical composition according to claim 3 wherein the medicament is selected from the group consisting of LHRH analogs, 5-lipoxygenase inhibitors, immunosuppressants and bronchodilators.
8. A pharmaceutical composition according to Claim 2 wherein the medicament is selected from the group consisting of leuprolide acetate, Ac-D-2-Nal-D-4-ClPhe-D-3-Pal-Ser-N-MeTyr-D-Lys(Nic)-Leu-Lys(N-Isp)-Pro-D-Ala-NH2; N-[3-[5-(fluorophenylmethyl)-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea; cyclosporine; and isoproterenol.
9. A pharmaceutical composition according to Claim 8 wherein the propellant is HFC-134a.
10. A pharmaceutical composition according to claim 9 wherein the tocopherol is present in a concentration of between 0.001% and 5% by weight.
11. A method of preparing a stable suspension of particles of a medicament in aliquid phase non-chloro fluorocarbon aerosol propellant, comprising the addition to the suspension of tocopherol in an amount sufficient to prevent aggregation of the particles.
12. A method according to Claim 11 wherein the propellant is selected from the group consisting of HFC-134a and HFC-227ea.
13. A method according to Claim 11 herein the tocopherol is in a form selected from the group consisting of d-alpha tocopherol, dl-alpha tocopherol, d-alpha tocopherol acetate, dl-alpha tocopherol acetate, d-alpha tocopherol acid succinate and dl-alpha tocopherol acid succinate.
14. A method according to Claims 12 or 13 wherein the medicament is selected from the group consisting of leuprolide acetate, Ac-D-2-Nal-D-4-ClPhe-D-3-Pal-Ser-N-MeTyr-D-Lys(Nic)-Leu-Lys(N-Isp)-Pro-D-Ala-NH2; N-[3-[5-(4-fluorophenylmethyl)-2-thienyl]-1-methyl-2-propynyl]-N-hydroxyurea; cyclosporine; and isoproterenol.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US21247294A | 1994-03-14 | 1994-03-14 | |
| US08/212,472 | 1994-03-14 | ||
| PCT/US1995/002764 WO1995024892A1 (en) | 1994-03-14 | 1995-03-02 | Aerosol drug formulations containing vitamin e |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2183557A1 true CA2183557A1 (en) | 1995-09-21 |
Family
ID=22791169
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002183557A Abandoned CA2183557A1 (en) | 1994-03-14 | 1995-03-02 | Aerosol drug formulations containing vitamin e |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0804157A1 (en) |
| JP (1) | JPH09510445A (en) |
| KR (1) | KR970701535A (en) |
| AU (1) | AU709783B2 (en) |
| CA (1) | CA2183557A1 (en) |
| IL (1) | IL112897A0 (en) |
| WO (1) | WO1995024892A1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9409778D0 (en) | 1994-05-16 | 1994-07-06 | Dumex Ltd As | Compositions |
| WO1998001147A1 (en) * | 1996-07-08 | 1998-01-15 | Rhone-Poulenc Rorer Limited | Medicinal cyclosporin-a aerosol solution formulation |
| US6458373B1 (en) | 1997-01-07 | 2002-10-01 | Sonus Pharmaceuticals, Inc. | Emulsion vehicle for poorly soluble drugs |
| US6193954B1 (en) | 1997-03-21 | 2001-02-27 | Abbott Laboratories | Formulations for pulmonary delivery of dopamine agonists |
| US20060165606A1 (en) | 1997-09-29 | 2006-07-27 | Nektar Therapeutics | Pulmonary delivery particles comprising water insoluble or crystalline active agents |
| US7030155B2 (en) | 1998-06-05 | 2006-04-18 | Sonus Pharmaceuticals, Inc. | Emulsion vehicle for poorly soluble drugs |
| US7871598B1 (en) | 2000-05-10 | 2011-01-18 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
| DK1458360T3 (en) | 2001-12-19 | 2011-08-29 | Novartis Ag | Pulmonary release of aminoglycosides |
| DE102006051512A1 (en) | 2005-12-06 | 2007-06-14 | Pari GmbH Spezialisten für effektive Inhalation | Pharmaceutical drug compositions with cyclosporin |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9024365D0 (en) * | 1990-11-09 | 1991-01-02 | Glaxo Group Ltd | Medicaments |
| EP0504112A3 (en) * | 1991-03-14 | 1993-04-21 | Ciba-Geigy Ag | Pharmaceutical aerosol formulations |
| DE69232818T2 (en) * | 1991-06-10 | 2003-06-18 | Schering Corp., Kenilworth | Chlorofluorocarbon free aerosol formulations |
| ES2084360T3 (en) * | 1991-06-10 | 1996-05-01 | Schering Corp | FORMULATIONS OF CHLOROFLUOROCARBON-FREE AEROSOLS. |
| DE69205177T2 (en) * | 1991-12-12 | 1996-03-21 | Glaxo Group Ltd., Greenford, Middlesex | Pharmaceutical aerosol formulation. |
| EP1086688B1 (en) * | 1991-12-18 | 2004-03-03 | Minnesota Mining And Manufacturing Company | Suspension aerosol formulations |
| DE4203306A1 (en) * | 1992-02-06 | 1993-08-12 | Ig Spruehtechnik Gmbh | ASTHMA OR PULMONAL AEROSOL PREPARATIONS WITH LECITHIN |
| US5301664A (en) * | 1992-03-06 | 1994-04-12 | Sievers Robert E | Methods and apparatus for drug delivery using supercritical solutions |
| DE4230876A1 (en) * | 1992-03-17 | 1993-09-23 | Asta Medica Ag | COMPRESSED GAS PACKS USING POLYOXYETHYLENE GLYCERYL OLEATES |
-
1995
- 1995-03-02 KR KR1019960705052A patent/KR970701535A/en not_active Application Discontinuation
- 1995-03-02 CA CA002183557A patent/CA2183557A1/en not_active Abandoned
- 1995-03-02 WO PCT/US1995/002764 patent/WO1995024892A1/en not_active Application Discontinuation
- 1995-03-02 AU AU19804/95A patent/AU709783B2/en not_active Ceased
- 1995-03-02 EP EP95912746A patent/EP0804157A1/en not_active Withdrawn
- 1995-03-02 JP JP7524061A patent/JPH09510445A/en not_active Withdrawn
- 1995-03-06 IL IL11289795A patent/IL112897A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MX9604004A (en) | 1997-12-31 |
| JPH09510445A (en) | 1997-10-21 |
| AU1980495A (en) | 1995-10-03 |
| EP0804157A1 (en) | 1997-11-05 |
| WO1995024892A1 (en) | 1995-09-21 |
| KR970701535A (en) | 1997-04-12 |
| IL112897A0 (en) | 1995-06-29 |
| AU709783B2 (en) | 1999-09-09 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |