(cid:38)(cid:68)(cid:83)(cid:86)(cid:88)(cid:74)(cid:72)(cid:79)(cid:3)(cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87)(cid:3)(cid:20)(cid:19)(cid:21)(cid:20)
`
`Page 1 of 20
`
`

`

`US 6,232,333 B]
`
`1
`PHARMACEUTICAL COMPOSITION
`
`This application claims the benefit of US. Provisional
`Application for Patent No. 60}031,463, filed Nov. 21, 1996
`now abandoned.
`
`TECHNICAL FIELD
`
`A liquid pharmaceutical composition providing improved
`oral bioavailability is disclosed for compounds which are
`inhibitors of HIV protease. In particular, the composition is
`a solution which comprises (a) the HIV protease inhibitor,
`(b) a phannaceutically acceptable organic solvent and,
`optionally, (c) a surfactant. The composition can optionally
`be encapsulated in either hard gelatin capsules or soft elastic
`capsules (SEC).
`
`10
`
`15
`
`BACKGROUND OF THE INVENTION
`
`2t]
`
`One measure of the potential usefulness of an oral dosage
`form of a new pharmaceutical agent
`is the bioavailability
`observed after oral administration of the dosage form. Vari—
`ous factors can affect the bioavailability of a drug when
`administered orally. These factors include aqueous
`solubility, drug absorption throughout the gastrointestinal
`tract, dosage strength and first: pass elfect. Aqueous solu—
`bility is one of the most important of these factors. When a _
`drug has poor aqueous solubility, attempts are often made to
`identify salts or other derivatives of the drug which have
`improved aqueous solubility. When a salt or other derivative
`of the drug is identified which has good aqueous solubility,
`it is generally accepted that an aqueous solution formulation
`of this salt or derivative will provide the optimum oral
`bioavailability. The bioavailability of the oral solution for—
`mu lation of a drug is then generally used as the standard or
`idea] bioavailability against which other oral dosage forms
`are measured.
`
`2
`Mar. 23, 1993, which is incorporated herein by reference;
`5(S)—Boc—amino—4(S)—hydroxy—6—phenyl—2(
`R)—pheny[methylhexanoyl—(L)—Val—(L)—Phe—morpholin—4—
`ylamide and related compounds, disclosed in European
`Patent Application No. EP532466, published Mar. 17, 1993,
`which is incorporated herein by reference;
`
`1—Naphthoxyacetyl—beta—methylthio—Ala—(ZS,38)—3—
`alTIino-2-hydroxy-4-butanoyl-1,3-thiazolidine-4-t-
`butylal'rlide (i.e., 1-Naphthoxyacetyl-Mta-(ZS,3S)-
`AHPBA—Thz—NH—tBu), 5—isoquinolinoxyacetyl—beta—
`methylthio—Ala—(2S,3S)—3—amino—2—hydroxy—4—
`butanoyl—t,3—thiazolidine—4—t—butylamide {i.e.,
`iQoa—
`Mta-Apns-Thz-Nlltliu) and related compounds,
`disclosed in European Patent Application No.
`EP490667, published Jun. 17, 1992 and Chem. Pharm.
`Bull. 40 (8) 2251 (1992), which are both incorporated
`herein by reference;
`[ts-[l R*(R*),2S*]}—NJ[3—[[[( 1,1 —dimethylethyl)amino]
`carbonyl](2—methylpropyl)amino]—2—hydroxy—1—
`(phenylmelhyl)propyl]-2-[(2-quinolinylcarbonyl)
`amino]—butanediamide (i.e., SC-52151) and related
`compounds, disclosed in PC’I‘ Patent Application No.
`W092f08701, published May 29, 1992 and PCT Patent
`Application No. W093f2336, published Nov. 25, 1993,
`both of which are incorporated herein by reference;
`
`91]
`
`NH:
`
`: 0
`
`Pt
`h.
`
`=
`
`O
`
`{4"
`
`0
`
`.1:-
`
`/-
`
`N‘f‘s
`M
`O
`0
`
`For a variety of reasons, such as patient compliance and
`taste masking, a solid dosage form, such as capsules, is
`usually preferred over a liquid dosage form. However, oral
`solid dosage forms of a drug generally provide a
`lower
`bioavailability than oral solutions of the drug. One goal of
`the development of a suitable capsule dosage form is to
`obtain a bioavailability of the drug that is as close as possible
`to the ideal bioavailability demonstrated by the oral solution
`formulation of the drug.
`It has recently been determined that IIIV protease inhib-
`iting compounds are useful for inhibiting IIIV protease in
`vitro and in vivo, are useful for inhibiting IIlV (human
`immunodeficiency virus) infections and are useful for treat—
`ing AIDS (acquired immunodeficiency syndrome). HIV
`protease inhibiting compounds typically are characterized
`by having poor oral bioavailability and there is a continuing
`need for the development of improved oral dosage forms for
`HIV protease inhibitors which have suitable oral
`bioavailability, stability and side efi'ects profiles.
`Examples of HIV protease inhibiting compounds include
`N-(2(R)-hydroxy-1(S)—indanyl)—2(R)-phenylmethyl-4(S)-
`hydroxy-S-(l-(4-(3-pyridylmethyl)-2(S)-N'-(t-
`butylcarboxamido)—piperazinyl))—peritaneamide {i.e.,
`indinavir) and related compounds, disclosed in European
`Patent Application No. Lil-’541168, published May 12, 1993,
`and U.S. Pat. No. 5,413,999, issued May 9, 1995 which are
`both incorporated herein by reference; N—tert—butyl—
`decahydro—Z—[2(R)—hydroxy—4—phenyl—3(S)—[[N—(2—
`quinolylcarbonyl)—L—asparaginyl]amino]butyl]—{4aS,8aS)—
`isoquinoline-3(S)-carboxamide (i.e., saquinavir) and related
`compounds, disclosed in U.S. Pat. No. 5,196,438, issued
`
`Page 2 of 20
`
`40
`
`(i.e., VX—478) and related compounds, disclosed in PC'I‘
`Patent Application No. W094f05639, published Mar. 17,
`1994, which is incorporated herein by reference;
`
`{OnirQfi
`
`N
`
`N
`
`01-] or
`
`50
`
`60
`
`65
`
`{i.e., UMP—323,1
`
`out,
`
`['IgN
`
`NI'Ig
`
`(i.e., UMP—450]
`
`and related compounds, disclosed in PCI‘ Patent Application
`No. W()93;’I)7128, published Apr. 15, 1993, which is incor-
`porated herein by reference;
`
`Page 2 of 20
`
`

`

`US 6,232,333 B]
`
`3
`
`[1.
`fi'“
`
`1'
`
`N
`H
`
`‘5)“
`a
`-
`
`o
`
`5
`g
`o
`PhS/
`(i.e., A6343, (nelfinavim
`
`m,”
`
`,
`
`k
`
`a
`
`4
`and related compounds disclosed in PCT Patent Application
`No. W0 9506061, published Mar. 2, 1995, which is incor-
`porated herein by reference and at 2nd National Conference
`_ on Human Retroviruses and Related Infections,
`3
`(Washington, DC, Jan. 29—Feb. 2, 1995), Session 88; and
`
`10
`
`Q”
`Val—NIIWE
`=
`
`/
`N
`
`N
`
`HO
`
`disclosed in PCI' Patent Application No. W095t’09843,
`published Apr. 13, 1995 and U.S. Pat. No. 5,484,926, issued 15
`Jan. 16,1996, which are both incorporated herein by refer—
`ence;
`
`30 (Le, BILA 1096 BS) and related compounds disclosed in
`.
`.
`.
`.
`.
`anpean Patent Application No. LLP560268, publlshed Sep.
`15, 1993, which is incorporated herein by reference; and
`
`Q 25
`
`()H /
`
`
`
`5
`015’ \\O
`(i.e., U—l40690)
`
`/
`
`CFJ
`
`I
`
`and rclalcel
`
`[I
`
`OH
`
`IJIIIO
`1-1
`‘.‘
`3
`.
`IOLNHWN
`P11
`
`‘
`NHBOL
`
`(i.e.,BMS 186,313]
`
`disclosed in European Patent Application No. EP580402,
`published Jan. 26, 1994, which is incorporated herein by
`reference;
`
`3‘3
`
`II
`
`IIIIIIO
`
`EWNTN7<
`
`0
`
`[’11
`(i.e., SC—553S9a}
`
`compounds disclosed in PCT Patent Application No. W0
`
`9530670, published Nov. 16, [995,-which is incorporated
`
`40 herein by reference; or a pharmaceutically acceptable salt 01
`any of the above.
`
`Other examples of HIV protease inhibiting compounds
`include compounds of the formula [:
`
`[13c
`
`Cllx
`'
`
`“H N
`
`(“11‘
`
`WTNHR NII
`
`o
`011 ANH 0
`
`
`
`w"
`
`N
`
`0
`
`H
`
`/N\‘)kN
`
`Page 3 of 20
`
`Page 3 of 20
`
`

`

`5
`
`US 6,232,333 B]
`
`is lower alkyl and R2 and R3 are phenyl and
`wherein R]
`related compounds or a pharmaceutically acceptable salt
`thereof, disclosed in PCT Patent Application No.
`W094114436, published Jul. 7, 1994 and US. Pat. No.
`5,541,206, issued Jul. 30, 1996. both of which are incorpo-
`rated herein by reference. The compounds of formula I are
`useful to inhibit HIV infections and, thus, are useful for the
`treatment of AIDS.
`In particular, the compound of formula I I, has been found
`to be especially elfective as an inhibitor of HIV protease.
`
`A most preferred compound of the formula I V is (25,38,
`SS)-2-(2,6-I)imethylphenoxyacetyl)amino-3-hydroxy-5-
`
`I[
`
`
`
`is
`The most preferred compound of formula II
`(28,38,:SS)—5—(N—(N—((N—Methyl—N—((2—isopropy1—4—
`thiazolyl)methyl)-amino)carbonyl)valinyl)amino)-2-(N-((5-
`lhiazoly])methoxycarbonyl)amino)-1,6-diphenyl-3-
`hydroxyhexane (ritonavir; compound III) or a pharmaceu-
`tically acceptable salt thereof.
`
`Other examples of HIV protease inhibiting compounds
`also include compounds of the formula IV:
`
`H3(T
`
`0
`
`R]
`
`R3
`
`H
`
`N
`H
`
`CH 3
`
`OH
`
`R;
`
`0
`
`[V
`
`R
`
`5
`
`wherein R1 is benzyl, R2 is benzyl or loweralkyl, R3 is
`loweralkyl and R5 is
`
`O!
`
`and related compounds or a pharmaceutically acceptable salt
`thereof, disclosed in U.S. patent application Ser. No. 08572,
`226, filed IJec. 13, 1996 and U.S. patent application Ser. No.
`08;“753301, filed Nov. 21, 1996 and International Patent
`Application No. W097t'21685, published Jun. 19, 1997, all
`of which are incorporated herein by reference.
`
`A preferred compound is the compound of formula IV
`wherein R1 and R2 are benzy], R3 is isopropy] and R5 is
`
`Page 4 of 20
`
`[ZS—(1—tetrahydro—pyrimid—2—onyl)—3—rnethyl butanoyl]
`amino—1,6—diphenylhexane (compound V) or
`a
`pharmaceutically acceptable salt thereof. The preparation of
`compound V is disclosed in U.S. patent application Ser. No.
`08.-’572,226, filed Dec. 13,1996 and US. patent application
`Ser. No. 08;“7'53201, filed Nov. 21, 1996 and International
`Patent Application No. W()97;’21685, published Jun. 19,
`19.07.
`Compound III has an aqueous solubility of approximately
`6 micrograms per milliliter at plI>2. This is considered to be
`extremely poor aqueous solubility and, therefore, compou nd
`[11 in the free base form would be expected to provide very
`low oral bioavailability.
`In fact,
`the free base form of
`compound [11, administered as an unformulated solid in a
`capsule dosage form, is characteriZed by a bioavailability of
`less than 2% following a 5 mgfkg oral dose in dogs.
`Acid addition salts of compound III {for example, bis—
`hydrochloride, bis—tosylate, bis—methane sulfonate and the
`like) have aqueous solubilities of <0.l milligramstmilliliter.
`This is only a slight improvement over the solubility of the
`free base. This low aqueous solubility would not make
`practical the administration of therapeutic amounts of an
`acid addition salt of compound III as an aqueous solution.
`l-Turthen'nore, in view of this low aqueous solubility, it is not
`surprising that the bis-tosylate of compound III, adminis-
`tered as an unformulated solid in a capsule dosage form, is
`characterized by a bioavaiIability of less than 2% following
`a 5 mgflcg oral dose in dogs.
`In order to have a suitable oral dosage fom1 of com pound
`III,
`the oral bioavailability of compound III should be at
`least 20%. Preferably, the oral bioavailability of compound
`III from the dosage form should be greater than about 40%
`and, more preferably, greater than about 50%.
`While some drugs would be expected to have good
`solubility in organic solvents,
`it would not necessarily
`follow that oral administration ofsuch a solution would give
`good bioavailability for the drug. It has been found that
`compound III has good solubility in phannaceutically
`acceptable organic solvents and that the solubility in such
`solvents is enhanced in the presence of a pharmaceutically
`acceptable long chain fatty acid. Administration of the
`
`40
`
`50
`
`60
`
`Page 4 of 20
`
`

`

`US 6,232,333 B]
`
`7
`
`solution as an encapsulated dosage fonn (soft elastic cap-
`sules or hard gelatin capsules) provides an oral bioavailabil—
`ity of as high as about 60% or more.
`
`DISCLOSURE ()1? THE INVENTION
`
`8
`combinations of IIIV protease inhibitors are the compound
`of formula [II and the compound of formula V, the com—
`pound of formula III and saquinavir,
`the compound of
`formula III and indinavir, the compound of formula III and
`nelfinavir, the compound of formula III and VX-478, nelfl-
`navir and the compound of formula V, nelfinavir and
`saquinavir, nellinavir and indinavir, nelfinavir and VX—478.
`The solution composition of the invention can also com-
`prise an antioxidant (for example, ascorbic acid, BIIA
`(butylated hydroxyanisole), BHT (butylated
`hydroxytoluene), vitamin E, vitamin E PEG 1000 succinate
`and the like} for chemical stability.
`The compositions of this invention (solution or encapsu-
`lated solution) provide improved oral bioavailability for
`HIV protease inhibitors. In particular, the compositions of
`this invention (solution or encapsulated solution) provide
`improved oral bioavailability for compound II] when corn-
`pared to non—formulated compound III (base) or non—
`formulated compound III {acid addition salt).
`The term “pharmaceutically acceptable long chain fatty
`acid" as USed herein refers to saturated, mono-unsaturated or
`di—unsaturated C12 to C1,, carboxylic acids which are liquids
`at room temperature. Preferred long chain fatty acids are
`mono-unsaturated (Tm—C3O carboxylic acids which are liq-
`uids at room temperature. A most preferred long chain fatty
`acid is oleic acid.
`
`The term "pharmaceutically acceptable alcohol” as used
`herein refers to alcohols which are liquids at about room
`temperature, approximately 20° (1, for example, ethanol,
`propylene glycol, 2{Z-ethoxyethoxykthanol ('I‘ranscutol®,
`Gattcfosse, Westwood, NJ. 07675), benzyl alcohol,
`glycerol, polyethylene glycol 200, polyethylene glycol 300,
`polyethylene glycol 400 and the like. A preferred pharma-
`ceutically acceptable alcohol is ethanol or propylene glycol
`or a mixture thereof.
`The term “pharmaceutically acceptable surfactant" as
`used herein refers to a pharmaceutically acceptable non—
`ionic surfactant for example, polyoxyethylene castor oil
`derivatives (for example, polyoxyethyleneglyceroltriri-
`cinoleate or polyoxyl 35 castor oil (Cremophor®EL, BASF
`Corp.) or polyoxyethyleneglycerol oxystearate
`(Cremophor®RH 40 (polyethyleneglycol 40 hydrogenated
`castor oil)) or (Iremophor®RIl fill (polyethyleneglycol 6i)
`hydrogenated castor oil), BASI: Corp. and the like) or block
`copolymcrs of ethylene oxide and propylene oxide, also
`known as polyoxyethylene polyoxypropylene block copoly—
`mers or polyoxyethylenepolypropylene glycol, such as
`Poloxamer®124, Poloxamer®188, Poloxamer®23?,
`Poloxamer®388, Poloxamer®407 and the like, (BASI:
`Wyandotlc Corp.) or a mono fatty acid ester of polyoxyeth—
`ylene (20) sorbitan (for example, polyoxyethylene (20)
`sorbitan monooleate ('I"ween® 80), polyoxyethylene (20)
`sorbitan monostearate (Tween® 60), polyoxyethylene (20)
`sorbitan monopalmilate (Tween® 40), polyoxyethylene (20)
`sorbitan monolaurate (Tween® 20) and the like) and the
`like) or a sorbitan fatty acid ester (including sorbitan lau rate,
`sorbitan oleate, sorbitan palmitate, sorbitan stearate and the
`like). A preferred pharmaceutically acceptable surfactant is
`polyoxyl 35 castor oil
`(Cremophor®EI_, BASE Corp),
`polyoxyethylene (20) sorbitan monolaurate (Tween® 20),
`polyoxyethylene (20) sorbitan monooleate (Tween® 80) or
`a sorbitan fatty acid ester, for example sorbitan oleate. A
`most preferred pharmaceutically acceptable surfactant
`is
`polyoxyl 35 castor oil (Cremophor®EL, BASE Corp)
`A preferred composition of the invention is a solution
`comprising
`(a) an IIIV protease inhibiting compound or a combina-
`tion of I IIV protease inhibiting compounds (preferably,
`
`10
`
`15
`
`2t]
`
`there is a
`invention,
`In accordance with the present
`pharmaceutical composition which is a solution comprising
`(a) an HIV protease inhibiting compound or a combina—
`tion of HIV protease inhibiting compounds (preferably,
`a compound of the fonnula II or IV or saquinavir or
`nelfinavir or indinavir or VX-478, more preferably, a
`compound of the formula III or V or saquinavir or
`nelfinavir or indinavir or VX478, or a combination of
`a compound of the formula II or nelfinavir and another
`IIIV protease inhibitor (preferably, the compound of
`the formula IV or saquinavir or indinavir or nelfinavir
`or VX—478), or, more preferably, a combination of a
`compound of the formula III or nelfinavir and another
`HIV protease inhibitor (preferably, the compound of
`the formula V or saquinavir or indinavir or nelfirlavir or
`VX-478)),
`(b) a pharmaceutically acceptable organic solvent which
`comprises a pharmaceutically acceptable long chain
`fatty acid or a mixture of a pharmaceutically acceptable
`long chain fatty acid and a pharmaceutically acceptable ‘
`alcohol, and, optionally,
`(c) a pharmaceutically acceptable surfactant.
`In the above solution composition, preferred HIV pro—
`tease inhibitors as individual compounds are the compound
`of the formula III or V or saquinavir or nelflnavir or
`indinavir or VX-478. In the above composition, preferred
`combinations of IIIV protease inhibitors are the compound
`of formula III and the compound of formula V, the com—
`pound of formula III and saquinavir,
`the compound of
`formula III and indinavir, the compound of formula III and
`nelfinavir, the compound of formula III and XIX-478, nelfl-
`navir and the compound of formula V, neltinavir and
`saquinavir, nelfinavir and indinavir, nelfinavir and VX—478.
`Also in accordance with the present invention, there is a
`pharmaceutical composition which is a solution comprising
`(a) an HIV protease inhibiting compound or a combina-
`tion of IIIV protease inhibiting compounds (preferably,
`a compound of the formula II or IV or saquinavir or
`nelfinavir or indinavir or VX—478, more preferably, a
`compound of the formula III or V or saquinavir or
`nellinavir or indinavir or VX-478, or a combination of
`a compound of the formula II or nelfinavir and another
`HIV protease inhibitor (preferably, the compound of
`the formula IV or saquinavir or indinavir or nelfinavir
`or VX-478), or, more preferably, a combination of a
`compound of the formula III or nelfinavir and another
`HIV protease inhibitor (preferably, the compound of
`the formula V or saquinavir or indinavir or nelfinavir or
`VX-478)),
`(b) a pharmaceutically acceptable organic solvent which
`comprises a pharmaceutical ly acceptable long chain
`fatty acid or a mixture of a pharmaceutically acceptable
`long chain fatty acid and a pharmaceutically acceptable
`alcohol, and, optionally,
`(c) a pl'larn'iaceutically acceptable surfactant, wherein the
`solution is encapsulated in a soft elastic gelatin capsule
`(SEC) or a hard gelatin capsule.
`In the above enacpsulated solution composition, preferred
`HIV protease inhibitors as individual compounds are the
`compound of the formula III or V or saquinavir or nelfinavir
`or indinavir or VX478. In the above composition, preferred
`
`40
`
`50
`
`60
`
`Page 5 of 20
`
`Page 5 of 20
`
`

`

`US 6,232,333 B]
`
`9
`a compound of the formula [I or IV or saquinavir or
`nclfinavir or indinavir or, more preferably, a compound
`of the formula III or V or saquinavir or nelfinavir or
`indinavir, or, most preferably, a compound of the
`formula III or V); or a combination of a compound of
`the formula II or nelfinavir and another HIV protease
`inhibitor (preferably, the compound of the formula IV
`or saquinavir or
`indinavir or nelfinavir, or, more
`preferably, a combination of a compound of the for-
`mula III or nelfinavir and another HIV protease inhibi—
`tor (preferably,
`the compound of the formula V or
`saquinavir or
`indinavir or nelllnavir), or, most
`preferably, a combination of a compound of formula III
`and a compound of formula V) in the amount of from
`about 1% to about 50% (preferably, from about 1% to
`about 40%; more preferably, from about 10% to about
`40%; most preferably, from about 15% to about 40%)
`by weight of the total solution,
`(b) a pharmaceutically acceptable organic solvent which
`comprises (i) a pharmaceutically acceptable long chain
`fatty acid in the amount of from about 20% to about
`99% (preferably, from about 30% to about 70%; more
`preferably, from about 40% to about 60%) by weight of
`the total solution or (ii) a mixture of (1) a pharmaceu-
`tically acceptable long Chain fatty acid in the amount of
`from about 20% to about 99% (preferably, from about
`30% to about 70%; more preferably, from about 40% to
`about 60%) by weight of the total solution and (2) a
`pharmaceutically acceptable alcohol in the amount of
`from about 0% to about 15% (preferably, from about
`6% to about 12%) by weight of the total solution and
`(c) a pharmaceutically acceptable surfactant in the amount
`of from about 0% to about 40% (preferably, from about
`2% to about 20% and most preferably, from about 5%
`to about 15%) by weight of the total solution.
`In a
`preferred embodiment of the invention, the solution is
`encapsulated in a soft elastic gelatin capsule (SEC) or
`a hard gelatin capsule.
`Preferably, the pharmaceutically acceptable organic sol—
`vent com prises from about 50% to about 99% by weight of
`the total solution. More preferably, the pham‘taCeutically
`acceptable organic solvent or mixture of pharmaceutically
`acceptable organic solvents comprises from about 50% to
`about 75% by Weight of the total solution.
`Preferred pharmaceutically acceptable solvents comprise
`(I) a pharmaceutically acceptable long chain fatty acid in the
`amount of from about 40% to about 70% by weight of the
`total solution and (2) ethanol or propylene glycol in the
`amount of from about 1% to about 15% by weight of the
`total solution or a mixture of ethanol and propylene glycol
`in the amount of from about 1% to about 15% by weight of
`the total solution. More preferred pharmaceutically accept—
`able solvents comprise (1) a pharmaceutically acceptable
`long chain fatty acid in the amount of from about 40% to
`about 70% by weight of the total solution and (2) ethanol in
`the amount of from about 10% to about 12% by weight of
`the total solution or propylene glycol in the amount of from
`about 5% to about 10% by weight of the total solution or a
`mixture of ethanol and propylene glycol in the amount of
`from about 5% to about 15% by Weight of the total solution.
`Even more preferred pharmaceutically acceptable solvents
`comprise (1) oleic acid in the amount of from about 40% to
`about 70% by weight of the total solution and (2) ethanol in
`the amount of from about 10% to about 12% by weight of
`the total solution or propylene glycol in the amount of from
`about 5% to about 10% by weight of the total solution or a
`mixture of ethanol and propylene glycol in the amount of
`from about 10% to about 15% by weight of the total
`solution.
`
`UI
`
`10
`
`15
`
`20
`
`_
`
`40
`
`50
`
`60
`
`10
`
`In one embodiment of the invention, a more prefelTed
`composition of the invention is a solution comprising
`(a) ritonavir in the amount of from about 1% to about 30%
`(preferably, from about 5% to about 25%) by weight of
`the total solution,
`(b) a pharmaceutically acceptable organic solvent which
`comprises (i) a phanTtaceuticallyr acceptable long Chain
`fatty acid in the amount of from about 40% to about
`99% (preferably, from about 30% to about 70%; more
`preferably, from about 40% to about 60%) by weight of
`the total solution or (ii) a mixture of (1) a pharmaceu-
`tically acceptable long chain fatty acid in the amount of
`from about 40% to about 99% (preferably, from about
`030% to about 70%; more preferably, from about 40%
`to about 60%) by weight of the total solution and (2) a
`pharmaceutically acceptable alcohol in the amount of
`from about 0% to about 15% (preferably, from about
`6% to about 12%) by weight of the total solution and
`(c) a pharmaceutica11y acceptable surfactant in the amount
`of from about 0% to about 20% (preferably, from about
`5% to about 10%) by weight of the total Solution. In a
`more preferred embodiment of the invention, the solu-
`tion is encapsulated in a soft elastic gelatin capsule
`(SEC) or a hard gelatin capsule.
`An even more preferred composition of the invention is a
`solution comprising
`(a) ritonavir in the amount of from about 1% to about 30%
`(preferably, from about 5% to about 25%) by weight of
`the total solution,
`(b) a pharmaceutically acceptable organic solvent which
`oomprises (i) oleic acid in the amount of from about
`]5% to about 99% (preferably, from about 30% to
`about 70%; more preferably, from about 40% to about
`60%) by weight of the total solution or (ii) a mixture of
`(1) oleic acid in the amount of from about 15% to about
`99% (preferably, from about 30% to about 70%; more
`preferably, from about 40% to about 60%) by weight of
`the total solution and (2) ethanol in the amount of from
`about 0% to about 12% (preferably, from about 10% to
`about 12%) by weight of the total solution or propylene
`glycol in the amount of from about 0% to about 10%
`(preferably, from about 5% to about 10%) by weight of
`the total solution or a mixture thereof in the amount of
`from about 0% to about 15% (preferably, from about
`]0% to about 15%) by weight of the total solution and
`(c) polyoxyl 35 castor oil in the amount of from about 0%
`to about 20% (preferably, from about 5% to about 10%)
`by weight of the total solution.
`In an even more
`preferred embodiment of the invention, the solution is
`encapsulated in a soft elastic gelatin capsule (SEC) or
`a hard gelatin capsule.
`A most preferred composition of the invention is a solu—
`tion comprising
`(a) ritonavir in the amount of about 20% by weight of the
`total solution,
`(b) a pharmaceutically acceptable organic solvent which
`comprises a mixture of ( 1) oleic acid in the amount of
`from about 62% to about 64% by weight of the total
`solution and (2) ethanol in the amount of from about
`]0% to about 12%, preferably, about 12%, by weight of
`the total solution and
`
`(c) polyoxyl 35 castor oil in the amount of about 6% by
`weight of the total solution.
`In a most preferred
`embodiment of the invention, the solution is encapsu—
`lated in a soft elastic gelatin capsule (SEC) or a hard
`gelatin capsule and the solution also comprises an
`
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`

`US 6,232,333 BI
`
`11
`(preferably, BIIT {butylated
`antioxidant
`hydroxytoluene)) in the amount of about 0.05% by
`weight of the total solution.
`Another most preferred composition of the invention is a
`solution comprising
`(a) ritonavir in the amount of about 20% by weight of the
`total solution,
`(b) a pharmaceutically acceptable organic solvent which
`comprises a mixture of (1) oleic acid in the amount of
`about 65% by weight of the total solution and (2)
`ethanol in the amount of about 10% by weight of the
`total solution and
`
`(c) polyoxyl 35 castor oil in the amount of about 5% by
`weight of the total solution.
`In a most preferred
`embodiment of the invention, the solution is encapsu—
`lated in a soft elastic gelatin capsule (SEC) or a hard
`gelatin capsule and the solution also comprises an
`antioxidant
`(preferably, BII'I' {butylated
`hydroxytoluene)) in the amount of from about 0.01% to
`about 0.08% by weight of the total solution (preferably,
`from about 0.01% to about 0.05% by weight of the total
`solution).
`Another most prefelTed composition of the invention is a
`solution comprising
`(a) ritonavir in the amount of about 20% by weight of the
`total solution,
`(b) a pharmaceutically acceptable organic solvent which
`comprises a mixture of (1) oleic acid in the amount of
`about 60% by weight of the total solution and (2)
`ethanol in the amount of about 10% by weight of the
`lotal solution and
`
`(c) polyoxyl 35 castor oil in the amount of about 10% by
`weight of the total solution.
`In a most preferred
`embodiment of the invention, the solution is encapsu—
`lated in a soft elastic gelatin capsule (SEC) or a hard
`gelatin capsule and the solution also comprises an
`antioxidant
`(preferably, BII'I' {butylated
`bydroxytoluene» in the amount of from about 0.01% to
`about 0.08% by weight of the total solution (preferably,
`from about 0.01% to about 0.05% by weight of the total
`solution).
`Another most prefelTed composition of the invention is a
`solution comprising
`(a) ritonavir in the amount of about 20% by weight of the
`total solution,
`(b) a pharmaceutically acceptable organic solvent which
`comprises a mixture of (1) oleic acid in the amount of
`about 70% by weight of the total solution and (2) a
`mixture ofethanol in the amount ofabout 5% by weight
`ofthe total solution and propylene glycol in the amount
`of about 5% by weight of the total solution. In a most
`preferred embodiment of the invention, the solution is
`encapsulated in a soft elastic gelatin capsule (SEC) or
`a hard gelatin capsule and the solution also comprises
`an antioxidant
`(preferably, BHT {butylated
`bydroxytoluene)) in the amount of from about 0.01% to
`about 0.08% by weight of the total solution (preferably,
`from about 0.01% to about 0.05% by weight of the total
`solution).
`In another embodiment of the invention, a more preferred
`composition of the invention is a solution comprising
`(a)
`(ZS,3S,58)—2-(2,6-dimethylphenoxyacetyl)amino-3-
`hydroxy—S—[2S—(1—tetrahydro—pyrimid—2—onyl)—3—
`methyl butanoyl]amino—1,6—diphenylhexane in the
`amount of from about 1% to about 50% (preferably,
`from about 5% to about 35%) by weight of the total
`solutiOn,
`
`10
`
`15
`
`20
`
`30
`
`40
`
`50
`
`60
`
`12
`
`(b) a pharmaceutically acceptable organic solvent which
`comprises (i) a pharmaceutically acceptable long chain
`fatty acid in the amount of from about 20% to about
`99% (preferably, from about 30% to about 70%; more
`preferably, from about 40% to about 65%) by weight of
`the total solution or (ii) a mixture of (1) a pharmaceu-
`tically acceptable long chain fatty acid in the amount of
`from about 20% to about 99% (preferably, from about
`30% to about 70%; more preferably, from about 40% to
`about 65%) by Weight of the total solution and (2) a
`pharmaceutically acceptable alcohol in the amount of
`from about 0% to about 15% (preferably, from about
`6% to about 12%) by weight of the total solution and
`(c) a pharmaceutically acceptable surfactant in the amount
`of from about 0% to about 40% (preferably, from about
`2% to about 20% and preferably, from about 5% to
`about 15%) by weight of the total solution. In a more
`preferred embodiment of the invention, the solution is
`encapsulated in a soft elastic gelatin capsule (SEC) or
`a hard gelatin capsule.
`A more preferred composition of the invention is a
`solution comprising
`(a) (2S,3S,5S)—2—(2,6—dimethylphenoxyacetyl)amino—3—
`hydroxy—5—[ZS—(1—tetrahydro—pyrimid—Z—onyl)—3—
`methyl butanoyl]amino-1,6-diphenylhexane in the
`amount of from about 1% to about 50% (preferably,
`from about 5% to about 35%) by weight of the total
`solution,
`(b) a pharmaceutically acceptable organic solvent which
`comprises (i) oleic acid in the amount of from about
`20% to about 99% (preferably, from about 30% to
`about 70%; more preferably, from about 40% to about
`65%) by weight of the total solution or (ii) a mixture of
`(1) oleic acid in the amount of from about 20% to about
`99% (preferably, from about 30% to about 70%; more
`preferably, from about 40% to about 65%) by weight of
`the total solution and (2) ethanol in the amount of from
`about 0% to about 12% (preferably, from about 10% to
`about 12%) by weight of the total solution or propylene
`glycol in the amount of from about 0% to about 10%
`(preferably, from about 5% to about 10%) by weight of
`the total solution or a mixture thereof in the amount of
`from about 0% to about 15% (preferably from about
`5% to about 15%, most preferably, about 10%) by
`weight of the total solution and
`(c) polyoxyl 35 castor oil in the amount of from about 0%
`to about 20% (preferably, from about 5% to about 10%)
`by weight of the total solution.
`In an even more
`preferred embodiment of the invention, the solution is
`encapsulated in a soft elastic gelatin capsule (SEC) or
`a hard gelatin capsule.
`A most preferred composition of the invention is a solu—
`tion comprising
`(a) (2S,3S,5S)-2-(2,6-dimetbylphenoxyacetyl)amino-3-
`hydroxy-S-[2S-(l -tetrahydro-pyrimid-2-onyl)-3-
`methyl butanoyl]amino-1,6-diphenylhexane in the
`amount of about 30% by weight of the total solution.
`(b) a pharmaceutically acceptable organic solvent which
`comprises a mixture of (1) oleic acid in the amount of
`about 50% by Weight of the total solution and (2)
`ethanol in the amount of about 10% by weight of the
`total solution and
`
`(c) polyoxyl 35 castor oil in the amount of about 10% by
`weight of the total solution.
`In a most preferred
`embodiment of the invention, the solution is encapsu-
`lated in a soft elastic gelatin capsule (SEC) or a hard
`
`Page 7 of 20
`
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`

`

`US 6,232,333 BI
`
`13
`gelatin capsule and the solution also comprises an
`antioxidant
`(preferably, BHT (butylated
`hydroxytoluene)) in the amount of from about 0.01% to
`about 0.08% by weight of the total solution (preferably,
`from about 0.01% to about 0.05% by weight of the total
`solution).
`In yet another embodiment of the invention, a more
`preferred composition of the invention is a solution com—
`prising
`(a) a mixture of ritonavir in the amount of from about 1%
`to about 30% (preferably, from about 5% to about 25%)
`by weight of the total solution and another HIV pro—
`tease inhibitor in the amount of from about 1% to about
`
`10
`
`15
`
`2t]
`
`50% (preferably, from about 5% to about 40%) by
`weight of the total solution,
`(b) a pharmaceutically acceptable organic solvent which
`comprises (i) a pharmaceutically acceptable long chain
`fatty acid in the amount of from about 10% to about
`98% (preferably, from about 30% to about 70%; more
`preferably, from about 40% to about 65%) by weight of
`the total solution or (ii) a mixture of (1) a pharmaceu-
`tically acceptable long chain fatty acid in the amount of
`from about 20% to about 98% (preferably, from about
`30% to about 70%; more preferably, from about 40% to
`about 65%) by weight