United States Patent (19)
`Fu Lu et al.
`
`54 AEROSOL DRUG FORMULATIONS
`CONTAINING POLYGLYCOLYZED
`GLYCERDES
`
`75) Inventors: Mou-Ying Fu Lu, Lake Bluff; Akwete
`L. Adjei, Wadsworth; Pramod K.
`Gupta, Gurnee, all of Ill.
`(73) Assignee: Abbott Laboratories, Abbott Park, Ill.
`
`
`
`21 Appl. No.: 296,778
`22 Filed:
`Aug. 26, 1994
`(51) int. Cl. ......................
`.............. A61K 9/12
`52 U.S. Cl. ................
`o 424/45; 424/46
`58) Field of Search .....................
`www. 424/43, 45, 46
`56)
`References Cited
`U.S. PATENT DOCUMENTS
`7/1989 Adjei et al. ............................... 424/45
`4,851.211
`l/1990 Adjei et al. ............................... 424/43
`4,897.256
`FOREIGN PATENT DOCUMENTS
`0510731 10/1992 European Pat. Off. ................. 424/45
`
`US005635159A
`Patent Number:
`Date of Patent:
`
`11
`45
`
`5,635,159
`Jun. 3, 1997
`
`518600 12/1992
`518601 12/1992
`561166 9/1993
`93/18746 9/1993
`
`European Pat. Off. .
`European Pat. Off. .
`European Pat. Off. .
`WIPO.
`
`Primary Examiner-Raj Bawa
`Attorney, Agent, or Firm-Mona Anand
`57
`ABSTRACT
`Pharmaceutical compositions for aerosol delivery compris
`ing (a) a medicament, (b) a non-chlorofluorocarbon
`propellant, and (c) a polyglycolized glyceride having a
`hydrophilic lipophilic balance of between and including 6
`and 14, wherein the medicament is present in a concentra
`tion of between about 0.05% and about 5% by weight and
`the polyglycolized glyceride is present in a concentration of
`between about 0.001% and about 10% by weight, the
`nonchlorofluorocarbon propellant is selected from the group
`consisting of HCFC 123, HCFC 124, HCFC 141b, HCFC
`225, HCFC 125, FC-C 51-12, DYMELA, DYMEL 152a,
`HFC 134a and HFC 227ea in which unwanted aggregation
`of the medicament is prevented without the use of
`surfactants, protective colloids or cosolvents.
`
`12 Claims, 3 Drawing Sheets
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`5 10 20 30 40 50 60 7O 8O 90 95
`PROBABILITY (%under)
`
`99
`
`99.9 99.99
`
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`
`

`

`U.S. Patent
`
`Jun. 3, 1997
`
`Sheet 1 of 3
`
`5,635,159
`
`
`
`Upper Limit
`
`O
`
`10
`
`6O
`5O
`4O
`3O
`20
`NUMBER OF SPRAYS
`F. G. 1
`
`7O
`
`8O
`
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`
`

`

`U.S. Patent
`
`Jun. 3, 1997
`
`Sheet 2 of 3
`
`5,635,159
`
`17.5
`
`
`
`15.O
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`12.5 - . . . . . . . .
`
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`Upper Limit
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`
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`
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`
`2.5 -O-Lot # 49157-105A
`-A-Lot # 49157-105B
`-- Lot if 49157-105C
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`2
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`
`12
`
`4.
`
`4.
`6
`8
`TIME (Days)
`F. G. 2
`
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`

`

`US. Patent
`
`Jun. 3, 1997
`
`Sheet 3 of 3
`
`5,635,159
`
`33.
`
`8 a
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`s.
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`
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`
`Purdue2033
`
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`
`

`

`5,635,159
`
`1
`AEROSOLDRUG FORMULATONS
`CONTAINING POLYGLYCOLYZED
`GLYCERDES
`
`2
`2609BS, Labraface) CM 8, Labrafac03 CM 10, Labrafil&M
`10, Labrafile NA 10, Labrafac(E) CM 12, Labrasol®
`(Labrafacts CM 14) and the like are capable of stabilizing
`MDI formulations utilizing non-ozone depleting propellants
`such as HFC-134a and HFC-227ea so as to (i) prevent
`aggregation, (ii) provide dosing uniformity, and (iii) afford
`high lung deposition efficiency without the need for either
`surfactants or cosolvents. Additionally, the polyglycolyzed
`glycerides have the unexpected benefit of providing
`adequate lubrication for the valve used in an MDI product
`without the need for additional lubricants, thus aiding reli
`able functioning of the aerosol device throughout the life of
`the product.
`Significant characteristics of such polyglycolyzed glycer
`ides used are that: (i) they are non-ionic surface active agents
`which do not chemically interact with drug; (ii) they have
`been used previously in oral drug delivery liquid dosage
`form, thereby establishing their physiological acceptability;
`(iii) their hydrophilic lipophilic balance (HLB) values are
`much higher than sorbitan trioleate (SPAN 85), ranging in
`the case of Labrafaces from 6 to 14 and in the case of
`Labrafils) products of interest from 6 to 10 (compared to 4
`for SPAN 85); and (iv) they are highly soluble in HFC 134a.
`Non-CFC formulations which include polyglycolyzed glyc
`erides do not require the addition of (i) cosolvents like
`ethanol to blend the surfactant into the formulation, (ii)
`conventional surfactants such as sorbitan trioleate (SPAN
`85), sorbitan monooleate and oleic acid, or (iii) protective
`colloids like sodium lauryl sulfate, cholesterol and palmitic
`acid, yet provide high lung deposition efficiencies and
`respirable fractions comparable to those obtained with
`known CFC-propellant formulations. It is thus expected that
`non-CFC formulations comprising polyglycolyzed glycer
`ides will be useful for the delivery of both peptide and
`non-peptide pharmaceutical medicaments for which MDI
`delivery is deemed preferable.
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 illustrates the drug content uniformity of formu
`lations of the present invention containing cyclosporin A (25
`mg/mL) and Labraface in the propel/ant HFC-134a.
`FIG. 2 illustrates dosimetry reproducibility of formula
`tions of the present invention containing cyclosporin A (25
`mg/mL) and Labrafacts (3 mg/mL) in the propellant HFC
`134a.
`FIG. 3 illustrates particle size distribution obtained using
`a formulation of the present invention containing leuprolide
`(10 mg/mL) and 0.2% Labrafacts CM 10 and 0.05% aspar
`tane.
`
`SUMMARY OF THE INVENTION
`According to one aspect of the present invention, phar
`maceutical compositions are disclosed which are useful for
`aerosol delivery, as for example by inhalation and pulmo
`nary absorption, comprising a therapeutically effective
`amount of a medicament, a non-chlorofluorocarbon
`propellant, and a polyglycolyzed glyceride such as
`LabrafacG) CM 6, Labrafil WL 2609 BS, Labraface CM
`8. Labrafac{E} CM 10, Labrafile M 10, Labrafilos NA10,
`Labrafacg) CM 12 or Labrasolo) (Labrafac?& CM 14). The
`compositions may optionally comprise a Sweetener such as
`Nutrasweet(s) (aspartame) an/or a taste-masking agent such
`as menthol. The propellants in such compositions are pref
`erably fluorocarbons and, more preferably, non-ozone
`depleting fluorocarbons such as HFC-134a or HFC-227ea.
`The medicaments to be delivered are preferably LHRH
`
`55
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`65
`
`5
`
`O
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`15
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`20
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`25
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`30
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`35
`
`45
`
`The present invention relates to drug formulations for
`aerosol delivery which are compatible with non
`chlorofluorocarbon propellants, and especially to excipients
`which are useful therein. In particular, the invention relates
`to inhalable formulations comprising polyglycolyzed
`glycerides, which formulations possess a variety of advan
`tageous properties.
`BACKGROUND OF THE INVENTION
`Numerous pharmaceutical compounds are preferentially
`delivered by means of metered dose inhalation (MDI)
`devices, in which a physiologically inert propellant of high
`vapor pressure is used to discharge a precise amount of
`medication with each operation. These MDI devices, also
`known as aerosols 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
`(trichlorofluorome thane),
`Propellant
`12
`(dichlorodifluoromethane) and Propellant 114
`(dichlorotetrafluoroethane).
`In recent years, however, there have been growing con
`cerns that chlorofluorocarbon (CFC) propellants have det
`rimental environmental effects, and in particular that they
`interfere with the protective upper-atmosphere ozone layer.
`Under an international accord (the Montreal Protocol), the
`use of CFC propellants will be prohibited by the start of the
`year 2000, and possibly sooner. Alternative propellant
`vehicles are being developed which exhibit little or no ozone
`depletion potential (ODP). Such alternative propellants
`include two-HFC-134a (1.1.1.2-tetrafluoroethane) and
`HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane)--which
`have negligible ODP and are currently undergoing safety
`and environmental testing.
`Unfortunately, many surfactants which are generally used
`in known MDI formulations have been found to be
`iniscible, and therefore incompatible, with these new, non
`CFC propellants. Such surfactants are necessary to prevent
`aggregation (in the form of "caking" or crystallization, for
`example) of the medicinally active compound in the reser
`voir of the inhaler, to facilitate uniform dosing upon aerosol
`administration, and to provide an aerosol spray discharge
`having a favorable respirable fraction (that is, a particle size
`distribution such that a large portion of the discharge reaches
`the alveoli where absorption takes place, and thus produces
`high lung deposition efficiencies). To overcome this
`incompatibility, it has previously been taught to include
`cosolvents (such as ethanol) with the non-CFC propellants
`so as to blend the surfactants into the formulation. Another
`suggested approach has been to emulsify the MDI formu
`lation in the presence of a surfactant with low-vapor pres
`sure additives, such as polyhydroxy alcohols as for example
`propylene glycol.
`Such cosolvents or additives may of course be physiologi
`cally active, and in some instances may not be tolerated by
`the user of an MIDI medication. There is therefore a need for
`MDI formulations compatible with non-CFC, non-ozone
`depleting propellants, which prevent aggregation of drug
`particles without the use of cosolvents or similar carrier
`additives, and which provide uniformity of dosing and a
`favorable respirable fraction.
`Surprisingly, it has now been found that polyglycolyzed
`glycerides, as for example Labrafac®) CM 6. Labrafiles WL
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`5,635,159
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`
`3
`analogs, 5-lipoxygenase inhibitors, immunosuppressants or
`bronchodilators; especially preferred medicaments include
`leuprolide acetate, the LHRH antagonist Ac-D-2-Nal-D-4-
`Cl-Phe-D-3-Pal-Ser-N-MeTyr-D-Lys(Nic)-leu-Lys(N-Isp)-
`Pro-D-Ala-NH (hereinafter "D-2-Nal"), the 5-lipoxygenase
`inhibitor N-3-5-(4-fluorophenylmethyl)-2-thienyl)-1-
`methyl-2-propynyl)-N-hydroxyurea, the immunosuppres
`sant cyclosporin A, and the adrenergic bronchodilators iso
`proterenol and albuterol. (As used herein, the terms
`"5-lipoxygenase inhibitor" or "5-LO inhibitor" refer to any
`physiologically active compound capable of affecting leu
`kotriene biosynthesis.)
`The polyglycolyzed glycerides used in the present inven
`tion may be present in a concentration of between about
`0.001% and about 10% by weight, preferably in a concen
`tration of between about 0.002% and about 5% by weight
`and more preferably in a concentration of between 0.01%
`and about 1%.
`A sweetener such as aspartame and/or a taste-masking
`agent such as menthol may also be present in concentrations
`of between about 0.0001% and about 10% each by weight.
`Particularly preferred pharmaceutical compositions
`embodying the present invention include those comprising
`leuprolide acetate in a concentration of between 0.05% and
`5% by weight, Labrafac(8 in a concentration of between
`0.01% and 1% by weight, aspartame in a concentration of
`between 0.02% and 0.5% by weight, and menthol in a
`concentration of between 0.01 and 0.25% by weight.
`Especially preferred pharmaceutical compositions
`embodying the present invention are those comprising leu
`prolide acetate in a concentration of between 0.125% and
`0.5% by weight, Labrafacts in a concentration of between
`0.1% and 0.5% by weight, aspartame in a concentration of
`between 0.05% and 0.2% by weight, and menthol in a
`concentration of between 0.025 and 0.1% by weight.
`Alternative, especially preferred pharmaceutical compo
`sitions embodying the present invention are those compris
`ing leuprolide acetate in a concentration of between 0.5%
`and 2% by weight, LabrafacS) in a concentration of between
`0.2% and 1% by weight, aspartame in a concentration of
`about 0.1% by weight, and menthol in a concentration of
`about 0.05% by weight.
`In a further aspect of the present invention is disclosed a
`method of preparing a stable suspension of particles of a
`medicament in a liquid phase non-chlorofluorocarbon aero
`sol propellant, which method comprises (a) combining the
`medicament, the propellant, and a polyglycolyzed glyceride
`in an amount sufficient to prevent aggregation of the par
`ticles to form a mixture and (b) agitating the mixture to
`completely blend the various components. (The order of
`addition may alternatively be varied so that the medicament
`and the polyglycolized glyceride, or the propellant and the
`polyglycolized glyceride, or the medicament and the pro
`pellant are first mixed prior to addition of the third
`component.) Preferably, the polyglycolyzed glyceride may
`55
`be added in an amount of between about 0.001% and about
`5% by weight; more preferably, the polyglycolyzed glycer
`ide may be added in an amount of between about 0.01% and
`about 1% by weight. The propellants, medicaments and
`polyglycolyzed glycerides suitable for use in the method of
`the present invention are those described above in connec
`tion with the pharmaceutical compositions of this invention.
`DETALED DESCRIPTION OF THE
`INVENTION
`It is expected that numerous non-ozone depleting aerosol
`propellants may be used with the compositions and methods
`
`30
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`60
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`65
`
`4
`of the present invention. These include not only HFC-134a
`and HFC-27ea, described above, but also halogenated
`alkanes in general, such as HCFC-123 (1.1.1-trifluoro-22
`dichloroethane),
`HCFC-124
`(1,1,1,2-
`tetrafluorochloroethane), HCFC-141b, HCFC-225. HFC
`125, FC-C51-12 (perfluorodimethylcyclobutane), DYMEL
`A (dimethyl ether) and DYMEL 152a (1,1-difluoroethane).
`The preferred propellants are HFC-134a and HFC-27ea,
`HFC-134a being especially preferred.
`The term "polyglycolyzed glyceride" as used herein refers
`to specific mixtures of mono, di and triglycerides and
`polyethylene glycol mono and diesters, obtained either by
`partial alcoholysis of hydrogenated vegetable oils using
`polyethylene glycol of relative molecular weight ranging
`from about 200 to about 2000, or by esterification of fatty
`acids using polyethylene glycol of relative molecular weight
`ranging from about 200 to about 2000 and glycerol. The
`polyglycolyzed glycerides of the present invention have
`Hydrophilic Lipophilic Balance (HLB) values of between
`and including 6 and 14. The free glycerol content is less than
`3%. Examples of suitable polyglycolyzed glycerides include
`Labrafac) (CM 6, Labrafil WL 2609 BS, Labrafact CM
`8, Labrafact) CM 10, Labrafile M 10, Labrafil NA10.
`Labraface CM 12, Labrasolo) (Labraface CM 14) and the
`like.
`Examples of polyglycolyzed glycerides include
`Labraface) CM 6, Labrafil WL 2609 BS, Labrafacg CM
`8, Labrafac) CM 10, Labrafilo M 10, Labrafil NA10.
`Labraface CM 12, and Labrasole (Labraface CM 14).
`Preferred polyglycolyzed glycerides having HLB values of
`between 6 and 14, inclusive, and containing medium chain
`(C-C) triglycerides, are Labrafaces CM 6, Labrafacts
`CM 8, Labrafac6 CM 10, LabrafacCE CM 12, and Labra
`solo) (Labrafac® CM 14). Of these, especially preferred and
`regarded as the best mode of carrying out the present
`invention is the polyglycolyzed glyceride Labraface CM
`10.
`It is also expected that analogs and derivatives of the
`above polyglycolyzed glycerides will be identified which are
`suitable for use in the compositions and methods of the
`present invention. To the extent that these analogs and
`derivatives are similar in structure to or are readily obtained
`by chemical modification of the polyglycolyzed glycerides,
`while substantially retaining the physical properties of the
`polyglycolyzed glycerides, such analogs and derivatives are
`intended to be included among the compositions and meth
`ods of the present invention.
`It is expected that the compositions and methods of the
`invention will be suitable for the administration of a wide
`variety of peptide and non-peptide drugs. Examples of
`peptides which may be delivered in this fashion are inter
`ferons and other macrophage activation factors, such as
`lymphokines, muramyl dipeptide (MDP), Y-interferon, and
`interferons a and b, and related antiviral and tumoricidal
`agents; opioid peptides and neuropeptides, such as
`enkaphalins, endorphins and dynorphins, and related anal
`gesics; renin inhibitors including new-generation anti
`hypertensive agents; cholecystokinins (CCK analogs) such
`as CCK, ceruletide and eledoisin, and related
`cardiovascular- and CNS-targeting agents; leukotrienes and
`prostaglandins, such as oxytocin, and related
`antiinflammatory, oxytocic and abortifacient compounds;
`erythropoietin and analogs thereof, as well as related hae
`matinics; LHRH analogs, such as leuprolide, buserelin and
`nafarelin, and related down-regulators of pituitary receptors;
`parathyroid hormone and other growth hormone analogs;
`enzymes, such as DNase, catalase and alpha-1 antitrypsin;
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`5,635,159
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`immunosuppressants such as cyclosporin; GM-CSF and
`other immunomodulators; and insulin. Such peptides or
`peptide analogs are frequently not well-absorbed when
`given orally. A preferred medicament for use in the formu
`lations of the present invention is leuprolide acetate.
`Examples of non-peptides which may readily be delivered
`using the compositions and methods of the present invention
`are beta-agonists, such as isoproterenol. albuterol, isoet
`herine and metoproteronol, and related anti-asthmatics;
`steroids, such as flunisolide, and similar anti-asthmatics;
`cholinergic agents, such as cromolyn, and related anti
`asthmatics; and 5-lipoxygenase inhibitors, such as zileuton
`and the hydroxyurea compound described above, and related
`leukotriene inhibitors. Such non-peptides may lend them
`selves to oral administration, but when given by inhalation
`are found to produce rapid reversal of bronchoconstriction in
`cases of allergic airway disease and asthma. Also, these
`compounds may be administered more frequently as MDI
`formulations than when given orally,
`The medicaments useful in the compositions of the
`present invention include not only those specifically named
`above, but also where appropriate the pharmaceutically
`acceptable salts, esters, amides and prodrugs thereof. By
`"pharmaceutically acceptable salts, esters, amides and pro
`drugs" is meant those carboxylate salts, amino acid addition
`salts, esters, amides and prodrugs of a compound which are,
`within the scope of sound medical judgement, suitable for
`use in contact with the tissues of humans and lower animals
`with undue toxicity, irritation, allergic response and the like,
`commensurate with a reasonable benefit risk ratio and effec
`tive for their intended use. In particular, the term "salts'
`refers to the relatively non-toxic, inorganic and organic acid
`addition salts of a medicinal compound. These salts can be
`prepared in situ during the final isolation and purification of
`the compound or by separately reacting the purified com
`35
`pound in its free base form with a suitable organic or
`inorganic acid and isolating the salt thus formed. Represen
`tative salts include the hydrobromide, hydrochloride,
`sulfate, bisulfate, phosphate, nitrate, acetate, oxalate,
`valerate, oleate, palmitate, stearate, laurate, borate,
`benzoate, lactate, phosphate, tosylate, citrate, maleate,
`fumarate, succinate, tartrate, naphthylate, mesylate.
`glucoheptonate, lactiobionate and laurylsulphonate salts and
`the like. These may include cations based on the alkali and
`alkaline earth metals, such as sodium, lithium, potassium,
`calcium, magnesium and the like, as well as nontoxic
`ammonium, quaternary ammonium and amine cations
`including, but not limited to, ammonium,
`tetramethylammonium, tetraethylammonium, methylamine,
`dimethylamine, trimethylamine, triethylamine, ethylamine
`and the like. (See, for example S. M. Berge, et al., "Phar
`maceutical Salts." J. Pharm. Sci., 66:1-19 (1977). incorpo
`rated herein by reference.)
`Examples of pharmaceutically acceptable. non-toxic
`esters of a compound include (C-to-C alkyl) esters
`wherein the alkyl group is a straight or branched chain.
`Acceptable esters also include (C-to-C, cycloalkyl) esters
`as well as arylalkyl esters such as, but not limited to, benzyl;
`(C-to-C alkyl) esters are preferred.
`Examples of pharmaceutically acceptable, non-toxic
`amides of medicinal compounds include amides derived
`from ammonia, primary (C-to-C alkyl) amines and sec
`ondary (C-to-C dialkyl)amines wherein the alkyl 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, (C-to-C alkyl) primary
`
`65
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`6
`amides and (C-to-C dialkyl) secondary amides are pre
`ferred. Amides of the compounds of the invention may be
`prepared according to conventional methods.
`The term "prodrug” refers to compounds that are rapidly
`transformed in vivo to yield the parent medicinal compound,
`as for example by hydrolysis in blood. A thorough discus
`sion is provided in T. Higuchi and V. Stella, "Pro-drugs as
`Novel Delivery Systems". Vol 14 of the A.C.S. Symposium
`Series, and in Bioreversible Carriers in Drug Design, ed.
`Edward B. Roche, American Pharmaceutical Association
`and Pergamon Press (1987), both of which are incorporated
`herein by reference.
`When used in the above compositions, a therapeutically
`effective amount of a medicament of the present invention
`may be employed in pure form or, where such forms exist,
`in pharmaceutically acceptable salt, ester or prodrug form.
`By a "therapeutically effective amount" of a medicament 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 will be
`understood, however, that the total daily usage of the medi
`caments and compositions of the present invention will be
`decided by the attending physician within the scope of sound
`medical judgement. The specific therapeutically 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 com
`pound employed; the specific composition employed; the
`age, body weight, general health, sex and diet of the patient;
`the time of administration, route of administration, and rate
`of excretion of the specific compound employed; the dura
`tion of the treatment; drugs used in combination or coinci
`dental with the specific compound employed; and like
`factors well known in the medical arts. For example, it is
`well within the skill of the art to start doses at levels lower
`than required to achieve the desired therapeutic effect and to
`gradually increase the dosage until the desired effect is
`achieved.
`The total daily doses of the medicaments contemplated
`for use with this invention, and consequently the concen
`trations by weight of the medicaments in the respective
`compositions, 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; accordingly,
`where an aerosol inhaler is to be used several times a day
`with a discharge volume of between about 5 and about 250
`L, the concentration of medicament will be between about
`0.2 and about 20 mg/mL. Similarly, in the case of a
`5-lipoxygenase 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 100
`mg/mL. Of course, medicament concentrations outside of
`these ranges may also be suitable, where different potencies,
`dosing frequencies and discharge volumes are used.
`The compositions of the invention may be prepared by
`combining the polyglycolyzed glyceride with a medicament
`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. Alternatively, the polyglycolyzed
`glyceride and medicament may be milled together, either
`before or after addition of propellant. In some instances, it
`may be necessary to wet-mill the medicament in a closed
`system, as for example under temperature and pressure
`conditions which permit the medicament to be milled while
`mixed with a liquid-phase aerosol propellant. It is expected
`
`Purdue 2033
`Collegium v. Purdue, PGR2018-00048
`
`

`

`5,635,159
`
`7
`that, for any particular combination of medicament, propel
`lant and polyglycolyzed glycerides, the ideal order of addi
`tion of ingredients and the conditions under which they are
`to be combined may readily be determined.
`The compositions 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 specification, it is intended that citations to
`the available literature are expressly incorporated by refer
`C.
`
`EXAMPLE 1.
`
`Characterization of Labrafact CM 10
`Labraface CM 10 comprises medium chain (Cs co)
`polyglycolyzed glycerides, and has a Hydrophilic Lipophilic
`Balance value of about 10. It is an oily liquid with a hint
`odor and a color on the Gardner Scale of <5. Specific gravity
`at 20° C. is 1.000-1040. Refractive Index at 20° C. is
`1.430-1485. Viscosity at 20° C. (mPas) is 20-90. Solubil
`ity at 20° C.: (95% in HO), very soluble; chloroform, very
`soluble; methylene chloride, very soluble; water, dispers
`ible; mineral oil, insoluble; vegetable oil, very soluble.
`Chemical characteristics: Acid Value (mg KOH/g), <2.00;
`Saponification Value (mg KOHg), 160-200;Iodine Value (g
`I/100 g). <2; Hydroxyl Value (mg KOHAg), 115-155;
`Peroxide Value (meq O/kg), <12.5; Alkaline Impurities
`(ppm MaoH), <80; Water Content (%), <1.00; Free Glyc
`erol Content (%). <3.0; 1 Monoglycerides Content (%),
`<15.0; Sulphated Ashes (%), <0.10; Heavy Metals (ppm Pb),
`g10.
`
`EXAMPLE 2
`physical Stability of MDI Formulations Containing
`Labrafact
`A determination of the effect of Labrafac03 CM 10 on the
`physical stability of several MDI formulations prepared with
`HFA-134a was conducted as follows: LabrafacS CM 10
`(Gatefossé, Westwood, N.J.) and each of the drugs being
`formulated were combined in the amounts shown in appro
`priate transparent aerosol containers (vials). (Leuprolide
`acetate and its preparation are described in United States
`Patent No. 4,005,063, issued Jan. 25, 1977, which is incor
`porated herein by reference.) Additionally, to some of the
`vials was added the sweetener aspartame (NutraSweet Corp.,
`Skokie, Ill.) in an amount to produce a final concentration of
`0.2% by weight. The vials were crimped and charged with
`approximately 10 mL of HFC-134a and agitated to blend the
`ingredients. The dispersion quality in each preparation was
`evaluated visually after 24 hours using the following crite
`1.
`Poor: Phase separation; top phase clear, bottom phase
`containing solids
`Fair: Partial phase separation; cloudiness in the top phase
`Good: Grainy appearance; no phase separation
`Excellent: Milky homogeneous appearance; no phase
`separation
`Results of these tests are shown below in Tables 1 and 2.
`The data obtained show that the formulations of the present
`invention maintain a high degree of dispersion even after 24
`hours. By comparison, control formulations of each of the
`test compounds (which were prepared without polyglyco
`lyzed glyceride) are seen to have unacceptable dispersion
`
`8
`quality (which was evident in each case after less than 30
`seconds).
`
`TABLE 1.
`Dispersion Quality of Leuprolide Acetate in HFA-134a
`Labrafacts
`Dispersion
`CM 10
`Quality
`Concentration
`(24 Hours)
`
`Aspartame
`Concentration
`
`Leuprolide
`Concentration
`
`10
`
`15
`
`25
`
`19.
`19
`1%
`19.
`19
`19.
`19.
`19.
`
`OO5%
`0.10%
`O.30%
`OSO%
`0.20%
`0.20%
`O.20%
`0.20%
`
`0.00%
`OOO
`0.00%
`0.00%
`0.01%
`0.05%
`0.10%
`O.20%
`
`Good
`Good
`Good
`Good
`Good
`Good
`Good
`Good
`
`TABLE 2
`Dispersion Quality of Cyclosporin A in HFA-134a
`
`Cyclosporin. A
`Concentration
`
`Labrafiac {
`CM 10
`Concentration
`
`Dispersion Quality
`(24 Hours)
`
`2.5%
`2.5%
`2.5%
`2.5%
`2.5%
`
`0.00%
`OO52
`0.10%
`0.15%
`0.259,
`
`Poor
`Good
`Good
`Good
`Good
`
`A further comparison of various dispersants was con
`ducted as before. The results, shown in Table 3, demonstrate
`that dispersion quality of the formulation of the present
`invention, after 24 hours, is superior to that obtained using
`other known dispersants.
`
`35
`
`TABLE 3
`Dispersion Quality of 25 mg/mL Cyclosporin A in HFA-134a
`Dispersant
`Dispersion Quality
`2.5 mg/mL.
`(24 Hours)
`
`Sample No.
`
`2
`3
`4.
`5
`6
`7
`8
`9
`10
`
`Span 85
`Oleic Acid
`Lecithin
`Span 20
`Decanesulfonic Acid
`Sodium Lauryl Sulfate
`Cholesterol
`Witamin E
`Labrafac
`Ascorbic Acid
`
`Poor
`Poor
`Fair
`Poor
`Good
`Good
`Good
`Good
`Excellent
`Good
`
`EXAMPLE 3
`
`Preparation of MDI Formulations for Performance
`Testing
`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, Labraface CM
`10 and Aspartame in the amounts needed to produce the
`desired final concentrations. The vials were crimped shut
`with valves having delivery values (volumes per spray) of
`either 50 L or 100 L, 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.
`
`45
`
`50
`
`55
`
`65
`
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`
`

`

`5,635,159
`
`9
`EXAMPLE 4
`Uniformity of MDI Delivery of Compositions
`Containing Leuprolide
`Delivery uniformity and physical stability of the compo
`sitions of the invention containing the Leuprolide were
`tested as follows: Each vial was shaken and its valve primed
`by aerosolizing 5 times in succession, after which the vial
`was weighed. The valve of each vial was then actuated ten
`times, followed by another weighing. This process was
`repeated until shot weights had been determined for 100
`sprays.
`The shot weight data, shown below in Table 4, demon
`strate the uniformity with which the compositions of the
`present invention are delivered by a MDI device.
`
`TABLE 4
`Shot Weight Data for Leuprolide Aerosol (10 mg/mL)
`Containing 0.2% Labrafac & CM 10 and 0.05% Aspartame
`
`Sprays
`
`1-0
`11-20
`21-30
`31-40
`41-50
`51-60
`61-70
`71-80
`81-90
`91-100
`
`Total
`Can 1 (grams)
`
`Total
`Can 2 (grams)
`
`0.61
`0.60
`0.61
`0.60
`0.64
`0.62
`0.63
`0.61
`0.60
`0.60
`
`0.61
`0.62
`O.6
`0.62
`0.63
`0.59
`0.61
`0.61
`0.61
`0.62
`
`5
`
`O
`
`15
`
`20
`
`25
`
`10
`shaken and its valve (delivering 0.1 ml per spray) was
`primed by aerosolizing 5 times in succession. Then, on Day
`0, the valve of each vial was submerged in a beaker of
`methanol and actuated five times, after which the amount of
`drug delivered was assayed using quantitative HPLC. This
`process was repeated on Days 3, 7, 10 and 12 for each vial.
`The results, shown in FIG. 2, shows the amount of drug
`delivered on each of the sampling dates for each of three test
`formulations. These results demonstrate a right correlation
`with the target dose, and demonstrate excellent dose repro
`ducibility achieved by the present invention.
`EXAMPLE 7
`Bioavailability of MDI Compositions Containing
`Labraface)
`Using a test preparation of leuprolide containing 10
`mg/mL drug, 0.2% (by weight) Labrafacts CM 10 and
`0.05% (by weight) aspartame in HFC 134a propellant,
`bioavailability of aerosol-delivered drug was compared to
`that of an aqueous control formulation delivered intrave
`nously (IV) and a CFC formula containing 0.5% sorbitan
`trioleate (SPAN 85, NDA commercial grade). Three or four
`tracheostomized beagle dogs (two-year-old females, Mar
`shall Labs) were used for each group. To the dogs in the IV
`group,