Appl. No.: 09/333,245
`
`Filed:
`
`Jun. 15, 1999
`
`Related US. Application Data
`
`
`
`21
`
`22
`
` 56
`
`62
`
`Division of application No. 08/827,510, Mar. 28, 1997, Pat.
`No. 5,952,300.
`Provisional application No. 60/015,638, Apr. 19, 1996.
`60
`Int. Cl.7 ....................... A61K 38/00
`51
`52 US. Cl.
`. 514/11; 924/499
`
`
`Field of Search ............
`58
`514/11; 424/465,
`424/499; 530/317
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,037.644
`5,120,859
`5,336,756
`5,378,804
`5,466,781
`5,514.650
`5,552,521
`5,665,760
`
`.
`
`8/1991 Shaked et al.
`6/1992 Webb .
`8/1994 Schwartz et al. .
`1/1995 Balkovcc ct al.
`11/1995 Dorin et al.
`,
`5/1996 Balkovec et al. .
`9/1996 Belyk et al.
`.
`.
`9/1997 Brown et al.
`OTHER PUBLICATIONS
`
`....................... 530/317
`
`“The Merck Manual,” 16th edition. Berkovv, editor. (1992)
`(Merck & Co, lnc.: Rahway NJ), p. 159—171.
`The Merck Manual, 16” Edition, pp. 159—171 (1992).
`Remington’s Pharma. Sciences, pp.
`146371469
`1478—1484 (1980).
`Remington’s Pharma. Sciences. p. 238 (1980).
`The Determination of Ionization Constants, 3"1 Edition,
`Chapman & Hall, p. 74 (1984), by Albert, et a1.
`Remington’s Pharma. Sciences, 18“ Edition, Chapter 17,
`pp. 241—243 (1990).
`
`and
`
`[19]
`United States Patent
`6,136,783
`[11] Patent Number:
`
`Neururkar et al. Oct. 24, 2000 [45] Date of Patent:
`
`
`
`U8006136783A
`
`[54] ANTIFUNGAI. COMPOSITIONS
`
`[75]
`
`Inventors: Maneesh J. Neururkar, Lansdale;
`Michael J. Kaufman, New Hope;
`William A. Hunke, Harleysville, all of
`Pa.
`
`73
`
`Assignee: Merck & C0., Inc., Rahway, NJ.
`
`Primary Examiner—Irene Marx
`Attorney, Agent, or Firm—Elliott Korsen; Mark R. Daniel
`
`[57]
`
`ABSTRACT
`
`The invention is a pharmaceutical composition for intrave—
`nous administration to a patient comprising
`
`a pharmaceutically effective amount of a compound
`a)
`having the formula
`
`(I)
`
`
`
`and the pharmaceutically acceptable salts thereof;
`
`b) a pharmaceutically acceptable amount of an excipient
`such as a bulking agent effective to form a lyophilized cake;
`and
`
`c) a pharmaceutically acceptable amount of acetate buffer
`elIective to provide a pH of between about 4 and 7.
`
`6 Claims, N0 Drawings
`
`AMNEAL EX. 1005
`
`AMNEAL EX. 1005
`
`

`

`6,136,783
`
`1
`ANTIFUNGAL COMPOSITIONS
`
`This application is a division of Ser. No. 08/827,510 filed
`Mar. 28, 1997 now U.S. Pat. No. 5,952,300, and a provi-
`sional application Ser. No. 60/015,638 filed Apr. 19, 1996.
`BACKGROUND OF THE INVENTION
`
`
`
`This invention relates to compositions for treating and/or
`preventing ilngal infections.
`
`There is an increasing need for novel antifungal agents
`
`which are e ‘ective against opportunistic mycotic infections
`by such agents as Candida, Aspergillus, Cryptococcus and
`Pneunmcystzls carinii. The present treatments, i.e., amphot-
`ericin B and fluconazole, are inadequate due to their toxicity
`and resistance selection. The compositions of the present
`invention are considered to be both safe and fungicidal.
`The compositions of the present
`invention contain a
`compound which is useful as an antibiotic, especially as an
`antifungal agent or as an antiprotozoal agent. As an anti-
`fungal agent, it is useful for the control of both filamentous
`fungi and yeast. It is especially adaptable to be employed for
`the treatment of mycotic infections in mammals, especially “
`those caused by Candida species such as C. albicans, C.
`tropicalis, C. krusei, C. g/abram and C. pseudofmpicalis,
`and Aspergillus species such as A. fumnigalus, A. flavus and
`A. niger. In particular, the compositions contain a compound
`which has been found effective against putatively Ampho-
`tericin B and Fluconazole-resistant Candida isolates. The
`compositions are also useful for the treatment and/or pre-
`vention of Pneumocystis carinii pneumonia to which
`immune compromised patients, such as those suffering from
`AIDS, are especially susceptible.
`The compositions of the present invention are safe, stable,
`lyophilized dosage forms for reconstitution which are par-
`ticularly usefill for delivering antifungal agents to patients in
`need of such agents.
`SUMMARY OF THE INVENTION
`
`15
`
`30
`
`35
`
`2
`c) a pharmaceutically acceptable amount of an excipient
`such as a sucrose/mannitol mixture to form a lyophilized
`cake.
`In a specific embodiment of this invention, the formula-
`tion is prepared as a solution of 42 mg/ml of compound I, 30
`mg/ml of sucrose, 20 mg/ml of mannitol, 1.5 mg/ml (25
`mM) of acetic acid, which is adjusted to about pH 6 with
`sodium hydroxide. The solution is subsequently filled in a
`Vial at a volume of 1.25 ml and lyophilized, The lyophilized
`cake thus produced contains 52.5 mg of compound I, 62.5
`mg of the sugars and 31.25 micromoles of acetate buffer per
`via]. The lyophilized cake is then reconstituted for use by
`dilution with 21 m1 of a diluent. 20 m1 of the diluent is
`withdrawn and reconstituted into a 200 ml infiision bag. The
`patient is then infused with this solution comprising about
`0.25 lug/ml of compound I, about 0.03 millimoles or 0.15
`millimolar acetate buffer, about 0.3 mg/ml of bulking agents,
`with the resultant composition having a pH of about 5 to 7.
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The formulations of the invention provide enhanced
`chemical stability to the pharmaceutical compositions. One
`advantage of such stability is extended pharmaceutical prod—
`uct shelf life. Prior formulations employing a tartrate buffer
`contained pharmaceutically significant amounts of
`unwanted degradation products. The use of an acetate buff-
`ered formulation results in the generation of fewer degra-
`dates and a more stable formulation. Extended pharmaceu—
`tical shelf life offers significant economic advantages.
`It has been found that the compound of the formula
`
`(I)
`
`
`
`The invention relates to a pharmaceutical composition
`comprising:
`a) a pharmaceutically effective amount of a compound
`(also referred to herein as the “active ingredient”) having the
`formula
`
`40
`
`(I)
`
`
`
`and the pharmaceutically acceptable salts thereof,
`b) a pharmaceutically acceptable amount of an acetate
`buffer effective to provide a pH of between about 4 and 7;
`and
`
`55
`
`60
`
`65
`
`and the pharmaceutically acceptable salts thereof are sig-
`nificantly more stable on storage when formulated in the
`presence of an acetate buffer.
`Compound I is claimed and described in US. Pat. No.
`5,378,804. Methods for its preparation are disclosed in that
`patent as well as in US. Pat. No. 5,552,521 which issued on
`Sep. 3, 1996,
`The compound by itself is highly unstable and degrades
`by various pathways including, but not
`limited to,
`hydrolysis, dimerization and oxidation. However, this insta-
`
`
`bility was previously combated by lyophilizing the com-
`
`
`pound in a tartrate bu ered formulation, This formulation,
`however, while relatively stable, resulted in the generation
`of degradates at a relatively high rate.
`By switching to an acetate buffer, the lyophilized product
`is more stable, contains less of unwanted degradates while
`
`AMNEAL EX. 1005
`
`AMNEAL EX. 1005
`
`

`

`6,136,783
`
`
`
`15
`
`30
`
`3
`extending the shelf life of the composition. This makes it
`attractive as a commercial product.
`The present invention also relates to a method for treating
`fungal infections caused by Candida, As wergillus and Pneu-
`mucystis carim'i which comprises administering the compo-
`
`sition containing the compound of formula I to a patient in
`
`need of such treatment in an amount e ‘ective to treat the
`fungal
`infection. The invention additionally relates to a
`method for preventing Pneunmcystzls carinii infections in a
`patient which comprises administration of a preventative
`amount of the compound of formula I.
`The acetate buffered formulation of the invention includes
`an amount of acetate effective to provide a pharmaceutically
`acceptable pH, e.g. to provide a pH environment in the range
`of 5 to 8, preferably about 6 to about 7. In order to provide
`a pharmaceutically acceptable amount of acetate butfer
`effective to achieve the desired pH, suitable amounts of
`
`sodium acetate and acetic acid or suitable amounts of acetic
`
`
`
`acid and sodium hydroxide can be used. The bu er is
`typically present in the range of about 12.5 mM to about 200
`mM with a preferred range of about 25 mM to about 50 mM.
`Excipients such as bulking agents, i.e., excipient sugars, “
`are used to provide an aesthetically suitable lyophilized
`cake, solid dilution of the active ingredient, and sorption of
`available moisture. Sugars useful in the invention include
`sucrose, lactose, mannitol or combinations thereof. It has
`been found that sucrose and mannitol provide a more stable
`formulation and form a pharmaceutically elegant cake for
`the composition. The excipients are generally present in
`amounts of about 10—200 mg/ml with a preferred amount of
`about 40760 mg/ml.
`The compositions are not limited to the active ingredient,
`acetate buffer and bulking agent and may also include other
`pharmaceutically acceptable diluents, excipients or carriers.
`The formulations are suitable for long-term storage in glass
`containers commonly used in the pharmaceutical industry,
`e.g., in concentrated form in standard USP Type I borosili-
`cate glass containers.
`The compositions of the invention are generally prepared
`as follows:
`1) a bulking agent or combination of agents is dissolved
`in water;
`2) acetic acid is added and the pH is adjusted to about 3.7,
`if required;
`is added and dissolved with the pH
`3) compound I
`subsequently adjusted to about 5 to about 6 with base;
`4) the solution is filtered and filled into a lyophilization
`vial and frozen at —50° C.;
`5) the frozen formulation is freeze dried at —20° C., with
`a secondary drying at 15° C. (the complete cycle takes over
`two days); and
`6) lyophilized vials are stoppered and stored at about 5°
`C.
`
`35
`
`40
`
`The lyophilized formulations of the compositions can be
`diluted at the time of administration with a suitable diluent
`to obtain a finished concentration, for example, of about 5.0
`mg/ml, which is suitable for transfer to an infusion bag for
`use by the patient in need of the desired active ingredient.
`The term “pharmaceutically acceptable salts” means non-
`toxic salts of the active ingredient, including the mono—, di—
`and tri-acid forms, which are generally prepared by reacting
`the free base with a suitable organic or inorganic acid.
`Pharmaceutically acceptable salts suitable as acid addition
`salts as well as salts providing the anion of the quaternary
`salt are those from acids such as hydrochloric, hydrobromic,
`phosphoric, sulfuric, maleic, citric, acetic, tartaric, succinic,
`oxalic, malic, glutamic, pamoic and the like, and include
`other acids related to the pharmaceutically acceptable salts
`listed in Journal of Pharmaceutical Science, 66, 2 (1977).
`The term “pharmaceutically effective amount” shall mean
`that amount of active ingredient that will elicit the biological
`
`55
`
`60
`
`65
`
`4
`or medical response of a tissue, system or animal that is
`being sought by a researcher or clinician.
`
`Compositions of the invention may be administered to
`patients Where treatment and/or prevention of fungal infec—
`tions is desired. They are useful in the treatment of Candida
`species such as C. albicans, C.
`tropicalis, C. krusei, C.
`glabrata and C. pseudotropicalis, and Aspergillus species
`such asA. fumigatus, A. flavus and A. niger. They are also
`useful for the treatment and/or prevention of Pneumocystis
`carinii pneumonia to which immune compromised patients,
`such as those suffering from AIDS, are especially suscep—
`tible.
`
`The dosage regimen utilizing the compositions of the
`present invention is selected in accordance with a variety of
`factors including type, species, age, weight, sex and medical
`condition of the patient; the severity of the condition to be
`treated;
`the route of administration; the renal and hepatic
`function of the patient; and the particular active ingredient or
`salt thereof employed. An ordinarily skilled physician can
`readily determine and prescribe the effective amount of the
`drug required to prevent, counter, or arrest the progress of
`the condition.
`
`Intravenously, the most preferred doses of active ingre-
`dient will range from about 1.67 to about 33 Mg/kg/minute
`with an infusion rate of about 200 ml/hour. In order to
`administer this amount of active ingredient, a composition
`of the invention should have 0.025 to 0.50 mg/ml of active
`ingredient based on a 50 kg patient.
`
`Compound I, the active ingredient, is generally prepared
`as follows:
`
`Starting compound II of the formula:
`
`(II)
`
`
`
`(SEQ ID No. 1)
`
`AMNEAL EX. 1005
`
`AMNEAL EX. 1005
`
`

`

`5
`is reduced to afford Compound III of the formula:
`
`6,136,783
`
`(III)
`
`(Iv—a)
`
`15
`
`(SEQ ID No. 1)
`
`
`
`(SEQ IL) No. 1)
`
`Which is subsequently converted to Compound IV of the 30
`formula :
`
`(IV)
`
`Compound IV—a is subsequently reduced to Compound IV of
`the formula:
`
`(IV)
`
`35
`
`4O
`
`50 55
`
`(SEQ ID No. 1)
`
`which is stereoselectively converted to Compound I by
`displacement of the phenylthio group.
`
`60
`
`In an alternative process, Compound II is reacted with 65
`thiophenol to afford Compound IV—a of the formula:
`
`
`
`(SEQ ID No. 1)
`
`which is stereoselectively converted to Compound I by the
`displacement of the phenylthio group.
`PREPARATION OF COMPOUND I
`a) Synthesis and separation of Compound III
`Compound II (15.9 g, 89 area % pure, 3.4 wt % water,
`0.0128 mol) was added to dry THF (0.64 I.) and the
`suspension was dried to <10 mol % water by refluxing
`through a bed of 3A molecular sieves. Additional dry 'l‘l-IF
`was added to reconstitute the mixture to the original volume
`and the suspension was cooled to <4° C. with an ice/water/
`methanol bath.
`
`AMNEAL EX. 1005
`
`AMNEAL EX. 1005
`
`

`

`6,136,783
`
`7
`Neat BH3.SMe2 (10.91 g, 0.144 mol) was added over ten
`minutes and the reaction mixture was maintained at 0—4° C.
`The reaction progress was monitored by HPLC until the
`ratio of starting material to product was 1:1 indicating the
`end of the reaction age (3.5 h). At 4 hours, the mixture was
`cooled to —12° C. and slowly quenched with 2N HCl (0.036
`L). This solution was diluted to 1.14 Lwith water. The assay
`yield of Compound III was 6.60 g (47%).
`The quenched solution was diluted to 4 L and loaded onto
`a medium-pressure column of LiChroprep RP-C18 adsor-
`bent (158 g). After loading, the column was washed with 1.2
`L water and the amine was eluted with 1.9 L of 1:4 v/v
`acetonitrile/water, and then 0.38 L of 1:3 v/v acetonitrile/
`water.
`
`
`
`8
`aged an additional 1 h. The crystalline solid was collected on
`a sintered—glass funnel and washed with a solution of
`ethanol/ethyl acetate/water (6 mL/9 mL/0.5 mL,
`respectively). The wet cake was dried with a nitrogen flow
`to give 1.91 g (1.75 assay g, 88% recovery) of the diacetate
`salt of compound I—1.
`
`EXAMPLE 1
`
`Preparation Of Formulation 1
`
`Ingredient
`
`Compound I
`sucrose
`mannitol
`acetic acid
`sodium hydroxide
`
`Amount
`
`42 mg/ml
`30 mg/ml
`20 mg/ml
`1.5 mg/ml
`q.s. to pH 5 to 6.2
`
`fill volume—0.875 ml to 1.8 ml
`
`Typically, to a 25 mL volumetric flask was added 0.75 g
`of sucrose and 0.5 g of mannitol, about 17.5 mL of water, 0.5
`mL of a 75 mg/mL acetic acid solution, and 42 mg/ml
`equivalent of Compound I. The solution was mixed and the
`pH was adjusted to 6 using 1M NaOH. The volume was
`adjusted with water and the pH was confirmed. The solution
`was filtered through a Millex-GV syringe filter and filled
`into 10 mL tubing glass vials at 1.75 mL each. The vials
`were partially stoppered with lyophilization stoppers and
`lyophilized to yield a solid lyophilized cake at the bottom of
`the vial.
`
`The lyophilized formulation is diluted with 10.5 ml, and
`10 ml is withdrawn and diluted into 200 ml resulting in a
`finished concentration of 0.25 mg/ml prior to administration
`to the patient.
`formulations were prepared as described
`Additional
`above containing the following ingredients (each of the
`formulations was prepared at a solution concentration of
`40—42 mg/ml of active ingredient):
`
`TABLE 1
`
`Ex
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`
`
`Buffer
`Tartrate 50 mM
`(7.5 mg/ml)
`Tartrate 50 mM
`(7.5 mg/ml)
`Tartrate 50 mM
`(7 5 mg/ml)
`Acetate 25 mM
`(1.5 mg/ml)
`Tartrate 50 mM
`(7.5 mg/ml)
`Acetate 25 mM
`(1.5 mg/ml)
`Acetate 50 mM
`(3.0 mg/ml)
`
`Sugar(s)
`None
`
`Lactose (30 mg/mL)
`Mannitol (20 mg/mL)
`Mannitol (50 mg/mL)
`
`Lactose (30 mg,’mL)
`Mannitol (20 rug/mL)
`Sucrose (50 rug/mL)
`
`Sucrose (50 rug/mL)
`
`Lactose (30 lug/ml.)
`Mannitol (20 rug/mL)
`
`The formulations were stored in the lyophilized state at 5°
`C. and tested at about 4 week intervals for stability. Stability
`and formation of degradates was determined by gradient
`HPLC using standard methods known to one skilled in the
`art.
`
`It was surprisingly found that Formulations 1, 5, 7 and 8
`were significantly more stable and showed significantly less
`of the unwanted degradates than the other formulations.
`
`AMNEAL EX. 1005
`
`The rich cuts (>80 area %) were combined and diluted
`with water to a 1:7.3 v/v acetonitrile/water solution (1.70 L
`total). This mixture was loaded to the same column
`described above, and the column was washed with 0.57 L
`water. The desired compound was eluted with 0.57 L metha-
`nol. The rich cut fractions (>85 area %) were combined and
`concentrated by rotary evaporation and static high vacuum
`0 give 6.81 g (87 wt % pure, 6.8 wt % water) containing ~
`5.92 g of compound III (where R1 is dimethyltridecyl)
`1ydrochloride salt for an isolated yield of 43%.
`3) Preparation of the phenylsulfide (Compound IV)
`Compound III (5.80 g assay, 0.00533 mol) was charged to
`0.23 Lof dry acetonitrile and cooled to —5° C. at which point
`hiophenol (3.10 g, 0.028 mol) was added. TFA (36 g, 24.5
`mL, 0.318 mol) was added over 20 minutes in order to keep
`he temperature of the reaction mixture below 0° C. The
`reaction was aged at —10° to 0° C. until HPLC analysis
`showed <3 area % starting material (3.75 h). At this time,
`chilled water (0.56 L) was added slowly (1 h) while cooling
`he reaction mixture to maintain the temperature below 5° C.
`The assay yield of the (x— and B—phenylsulfide adduct as the
`rifluoroacetate salt was 4.82 g (71%).
`This solution was loaded on the same column described in
`step a and the column was washed with water (0.57 L), then
`he adsorbed organic compounds were eluted with methanol
`(0.50 L). The rich cuts were concentrated by rotary evapo—
`ration and static high vacuum. This yielded 7.20 g (57 wt %
`aure, 5.1 wt % water) of crude phenylsulfide trifluroacetate
`salt as an amorphous foamy solid. The corrected isolated
`step yield for the phenylsulfide was 4.10 g (61 %) as a 93:7
`mixture of the ot— and B—aminal diastereomers.
`c) Conversion of Compound IV to Compound l-1
`The crude phenylsulfide trifiuoromethanesulfonate salt
`(8.4 g crude, 57 wt % pure, 0.00377 mole) was added to
`ethylenediamine (24 mL) while stirring at ambient tempera-
`ture. The resulting solution was stirred 1.5 h to complete the
`displacement, then methanol (40 mL) was added followed
`by acetic acid (45 mL), keeping the temperature below 25°
`C. with ice-bath cooling. A thick slurry resulted. Water (160 _
`mL) was added to dissolve the slurry, and the aqueous layer
`was extracted by gentle shaking with hexanes (75 mL). The
`hexanes layer was back-extracted with water (40 mL) and
`the combined aq.
`layer was filtered through a medium-
`porosity sintered glass funnel, then purified by prep HPLC
`rising a 50 mm diameter
`(318 column,
`rising 22%
`acetonitrile/78% 0.15% aq. acetic acid as eluent. The rich
`cut was lyophilized to provide 4.2 g of 85 wt % pure
`Compound I—l as the diacetate salt in 78% isolated step
`yield.
`d) Crystallization of Compound I-l
`The solid (2.3 g) was dissolved in ethanol (25 mL) and
`water (2.7 mL) was then added. The solution was passed
`through a sintered glass funnel to remove extraneous matter.
`To this filtrate was added acetic acid (0.14 mL) followed by
`the slow addition (1.75 h) of ethyl acetate (14 mL). The
`solution was seeded and the seed bed was aged for 1 h. The
`remaining ethyl acetate (32 mL) was added over 5 h and
`
`15
`
`35
`
`40
`
`55
`
`60
`
`65
`
`AMNEAL EX. 1005
`
`

`

`6,136,783
`
`10
`
`SEQUENCE LISTING
`
`( 1) GENERAL INFORMATION:
`
`(iii) NUMBER OF SEQUENCES:
`
`l
`
`(2)
`
`INFORMATION FOR SEQ ID NO:1:
`
`(i) SEQUENCE CHARACTERISTICS:
`(A) LENGTH:
`6 amino acids
`(B) TYPE: amino acid
`(C) STRANDEDNESS: unknown
`(D) TOPOLOGY: circular
`
`(ii) MOLECULE TYPE: peptide
`
`(iii) HYPOTHETICAL: no
`
`(iv) ANTI—SENSE: NO
`
`(xi) SEQUENCE DESCRIPTION: SEQ ID N021:
`Xaa Thr Xaa Xaa Xaa Xaa
`l
`5
`
`What is claimed is:
`
`1. A method for treating an infection caused by Candida
`Sp, in a patient which comprises administering intravenously
`to said patient an effective amount of a composition com-
`prising 42 mg/ml of a compound having the formula
`
`30
`
`(I)
`
`35
`
`(I)
`
`
`
`110
`
`or a pharmaceutically acceptable salt thereof, 25 mM of an
`acetate buffer, 30 mg/ml of sucrose, 20 mg/ml of mannitol,
`and water.
`
`2. A method for treating an infection caused by Candida
`Sp. in a patient which comprises administering intravenously
`to said patient an effective amount of a composition corri-
`prising 42 mg/ml of a compound having the formula
`
`4O
`
`55
`
`60
`
`65
`
`
`
`or a pharmaceutically acceptable salt thereof, 50 mM of an
`acetate buffer, 30 mg/ml of sucrose, 20 m g/ml of mannitol,
`and water.
`
`3. A method for treating an infection caused by Aspergil-
`lus sp. in a patient which comprises administering intrave-
`nously to said patient an effective amount of a composition
`comprising 42 mg/ml of a compound having the formula
`
`AMNEAL EX. 1005
`
`AMNEAL EX. 1005
`
`

`

`6,136,783
`
`(I)
`
`12
`
`(l)
`
`
`
`
`
`or a pharmaceutically acceptable salt thereof, 25 mM of an
`
`acetate bu er, 30 mg/ml of sucrose, 20 mg/ml of mannitol,
`and water.
`4. A metiod for treating an infection caused by Aspergil—
`lus sp. in a patient which comprises administering intrave-
`nously to said patient an effective amount of a composition
`comprising 42 mg/ml of a compound having the formula
`
`
`
`(I)
`
`
`
`
`
`or a pharmaceutically acceptable salt thereof, 50 mM of an
`
`
`acetate bu ‘er, 30 mg/ml of sucrose, 20 mg/ml of mannitol,
`and water.
`5. A method for treating or preventing an infection or
`condition caused by Pneumocystis carinii in a patient in
`need of such treatment or prevention which comprises
`administering intravenously to said patient a preventative or
`therapeutic amount of a composition comprising 42 mg/ml
`of a compound having the formula
`
`15
`
`30
`
`4O
`
`55
`
`
`
`or a pharmaceutically acceptable salt thereof, 25 mM of an
`acetate buffer, 30 mg/ml of sucrose, 20 mg/ml of mannitol,
`and water.
`
`6. A method for treating or preventing an infection or
`condition caused by Pneumocystis carinii in a patient in
`need of such treatment or prevention Which comprises
`administering intravenously to said patient a preventative or
`therapeutic amount of a composition comprising 42 mg/ml
`of a compound having the formula
`
`(I)
`
`
`
`or a pharmaceutically acceptable salt thereof, 50 111M of an
`acetate buifer, 30 mg/ml of sucrose, 20 mg/ml of mannitol,
`and water.
`
`AMNEAL EX. 1005
`
`AMNEAL EX. 1005
`
`