Europadisches Patentamt
`
`9 European PatentOffice
`
`Office européen des brevets
`
`@) Publication number:
`
`0 386 951
`
`A2
`
`®
`
`EUROPEAN PATENT APPLICATION
`
`@) Application number: 90302236.6
`
`@) Dateof filing: 62.03.90
`
`@)
`
`tnt. cL8: A61K 37/02, A61K 9/08,
`A6I1K 47/04
`
`
`@) Priority: 06.03.89 US 319248
`@) Applicant: ELI LILLY AND COMPANY
`Lilly Corporate Center
`Indianapolis Indiana 46285(US)
`
`Date of publication of application:
`12.09.90 Bulletin 90/37
`
`Designated Contracting States:
`AT BE CH DE DK ES FR GB GRIT LI LU NL SE
`
`
`
`
`@)
`
`Inventor: Inman, Eugene Lee
`8061 Castle Cove Road
`Indianapolis, Indiana 46256(US)
`Inventor: Kirsch, Lee Edwin
`7630 CamelbackDrive
`
`Indianapolis, Indiana 46250(US)
`
`Representative: Hudson, Christopher Mark et
`al
`Erl Wood Manor
`Windlesham Surrey GU20 6PH(GB)
`
`® An improved diluent formulation for daptomycin.
`
`the lipopeptide antibiotic, daptomycin, are provided. Also provided are an
`Improved formulations for
`@)
`improved kit for parenteral administration of daptomycin and a buffered pharmaceutical composition comprising
`daptomycin and a parenterally-acceptable buffer.
`
`EP0386951A2
`
`Xerox Copy Centre
`
`AMNEALEX. 1008
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`

`

`EP 0 386 951 A2
`
`AN IMPROVED DILUENT FORMULATION FOR DAPTOMYCIN
`
`In the field of antibiotics, particularly in the field of lipopeptide antibiotics, searches are constantly
`ongoing for new and improved formulations for delivery of the active ingredients into the subject under
`antimicrobial treatment.
`In this regard,
`it is of paramount importance that the formulation of the active
`ingredient be one that allows the drug to be bioavailable, while at the same time inhibiting, or at feast not
`contributing to, premature degradation of the active ingredient. Further,
`it
`is of equal,
`if not greater,
`importance that the formulation itself be one that does not unacceptably enhance toxicity or any other
`untoward effect to the subject.
`_ The present invention provides a solution to the problem of the premature "in solution” degradation of
`the known lipopeptide antibiotic daptomycin. Daptomycin is represented by the following structural Formula
`(!)
`
`CH,
`
`HO2c
`
`: a2x
`aN veN
`
`CH3
`
`Oo
`
`H
`
`CONH,
`
`
`
`(T)
`
`20
`
`HO
`
`noe
`
`10
`
`15
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`HO.C
`
`and is described in U.S. Patent No. 4,537,717. Stabilized daptomycin formulations are provided herein
`which allow the antibiotic to be prepared for parenteral administration in commonly used diluents such as
`5% dextrose solution, with minimal degradation. Following the realization that daptomycin, when dissolved
`in a 5% dextrose solution, undergoes 15-20% degradation in 24 h at 25°C or in 7 days at 5 C,it was
`discovered that formulations with sufficient buffer capacity in the pH range 6-8 reduce the degradation to
`approximately 1%.
`The present invention provides stabilized formulations of daptomycin (I) which possess sufficient buffer
`capacity to allow for storage of daptomycin solutions in 5% dextrose without significant degradation.
`It has recently been discovered that daptomycin, when dissolved in 5% dextrose solution, undergoes
`15-20% degradation into two unidentified products in 24 h at 25°C or 7 days at 5 C. The degradation,
`which also was found to be unique to reducing sugars and especially aldoses (6.g., glucose, mannose,
`galactose, arabinose, etc.), appears to be pH related and is accompanied by a significant loss of antibiotic
`potency. Asanillustration of this phenomenon, the following study was conducted:
`First, 8 vials of daptomycin (100 mg each) were reconstituted to a concentration of 1 mg/ml with normal
`saline and 5% dextrose (4 each). Next,
`the solutions were stored at room temperature (approximately
`25°C) and refrigerated temperatures and assayed at the 6 h and 24 h timepoints.
`
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`

`EP 0 386 951 A2
`
`
`
`(hrs.)|Temp. Visual|(mg/mL)(NTU) Total Appearance of
`
`
`Degradation Products
`
`
`
`0.9% NaCl:
`
`icin|Time| Clarity [|Potency||Poteney|
`
` Initial
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`“Inspection for appearance, color, package and clarity.
`“1 indicates no change from initial.
`
`In sum, solutions of daptomycin and dextrose held at refrigerated temperature demonstrated a potency
`loss of about 5% at the 24 h timepoint, while solutions held at room temperature showed a 17%loss over
`the sametime period.
`Further, a series of degradation kinetic studies demonstrate that the rate of appearance of degradation
`products is pH-dependent. For example, the appearance half-life for the degradation products at 25°C and
`pH 4.5 was 6 h, while at 25°C and pH 7.0, the half-life was 63 h.
`The nature of the degradation products has as yet not been determined; although, as indicated by the
`loss in potency of unstabilized solutions of daptomycin, these products exhibit far less antibiotic activity
`than the present antibiotic.
`The stabilized formulations provided herein are suitable for administration by the parenteral routes and
`comprise an antibiotically effective amount of daptomycin, a pharmaceutically acceptable buffer and a
`pharmaceutically acceptable diluent. in addition, the formulations can contain excipients.
`Pharmaceutically acceptable buffers which can be used include sodium or potassium salts of phos-
`phoric acid, boric acid, citric acid, carbonic acid, hydroxide, and thelike: tris(hydroxymethyl)aminomethane
`(TRIS® buffer), amino acids, and like buffers.
`Diluents which can be used include water for injection, 5% dextrose, 0.9% saline, Ringer's solution and
`like commonly used diluents for the parenterally administered antibiotics.
`Excipients which can be usedinclude, for example, mannitol, tonicity modifiers (e.g., sodium chloride or
`glycerol), preservatives and solubilizing agents. Further examplesof acceptable diluents and excipients can
`be found in Remington's Pharmaceutical Sciences, 17th Ed., A. R. Gennaro, Ed., Mack Publishing Co.,
`Easton, PA, 1985, incorporated herein by reference: particularly relevant are pages 1518-1552.
`Preferred buffers of this invention are dibasic sodium phosphate and TRIS® (tris(hydroxymethy})-
`aminomethanebuffer.
`Thus, in broadest terms, the present invention provides an improved formulation comprising daptomycin
`and a parenterally-acceptable buffer possessing sufficient buffer capacity to maintain the pH of
`the
`reconstituted daptomycin between a pH of between about 6.0 to about 8.0.
`Specific examples of preferred parenterally acceptable buffer systems are provided in the following
`Table 1:
`
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`

`EP 0 386 951 A2
`
`Table 1
`
`Formulation A|Isotonic Sodium Phosphate Dibasic Solution (8.73 mg/mL)
`Formulation B|tsotonic Sodium Phosphate Dibasic Solution (15.76 mg/mL)
`Formulation C|TRIS® (Tris(hydroxymethyljaminomethane) Solution (3.30 mg/mL)
`Formulation D|TRIS® (Tris(hydroxymethyl)aminomethane) Solution (3.74 mg/mL)
`
`Formulation E|TRIS® (Tris(hydroxymethyl)aminomethane) Solution (4.96 mg/mL)
`
`Formulations comprising the buffers in Table 1 were tested by reconstituting freeze-dried daptomycin
`(150 mg) and 50 mg mannitol (50 mg) in 10 mL of each buffer, then diluting the resultant solution in 100 mL
`of 5% dextrose solutions. The effectiveness of the buffered diluents in suppressing the appearance of
`degradation products is shown below in Tabie 2:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`Table 2:
`
`Summary Stability Results . Percent Increase in Daptomycin
`Degradation Products at 1 day storage (25°C) and 7 days
`storage (5 C).
`
`5% dextrose (control)
`
`% Increase in Dextrose Related
`
`——— Products
`
`Further examples of buffer systems meant by the term “pharmaceutically-acceptable buffer" include
`sodium or potassium salts of phosphoric acid, boric acid. citric acid, carbonic acid, hydroxide, and thelike:
`tris(hydroxymethyl}aminomethane (TRIS® buffer) and all amino acids and like buffers.
`in the case where sodium phosphate dibasic is used as buffer,
`it is preferred that the concentration be
`in the range of about 0.02 mMolar to about 0.13 mMolar, most preferably about 0.05 mMolar to about 0.10
`mMolar. One skilled in the art will appreciate that the amount of buffer necessary to maintain the pH in the
`desired range is directly related to the amount of daptomycin present in solution. Thus, the above ranges
`are preferred when daptomycin is present in a concentration of about 6 x 107* mMolar.
`The following is a nonexhaustive list of examples of unit dose formulations for daptomycin:
`
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`

`EP 0 386 951 A2
`
`Ingredient
`
`1)
`
`Daptomycin
`Mannitol
`
`Isotonic Sodium Phosphate
`
`Dibasic Solution (8.73
`
`mg/ml )
`
`Dextrose (5%)
`
`2)
`
`Daptomycin
`
`Mannitol
`
`Isotonic Sodium Phosphate
`
`Dibasic Solution (8.73
`
`mg/ml )
`
`Dextrose (5%)
`
`3)
`
`Daptomycin
`Mannitol
`
`Isotonic Sodium Phosphate
`
`Dibasic Solution (8.73
`
`mg/ml)
`
`Dextrose (5%)
`
`4)
`
`Daptomycin
`
`Mannitol
`
`Isotonic Sodium Phosphate
`
`Dibasic Solution (8.73
`
`mg/ml )
`
`Dextrose (5%)
`
`Amount
`
`150
`
`50
`
`mg
`
`mg
`
`10
`
`ml
`
`90
`
`ml
`
`200
`
`66
`
`mg
`
`mg
`
`13
`
`ml
`
`87
`
`m1
`
`250
`
`82
`
`mg
`
`mg
`
`16
`
`ml
`
`84
`
`ml
`
`300
`
`100
`
`mg
`
`mg
`
`20
`
`ml
`
`80
`
`ml
`
`20
`
`26
`
`30
`
`35
`
`40
`
`45
`
`50
`
`56
`
`AMNEALEX. 1008
`
`AMNEAL EX. 1008
`
`

`

`EP 0 386 951 A2
`
`3)
`
`Daptomycin
`
`Mannitol
`
`Isotonic Sodium Phosphate
`Dibasic Solution (15.76 mg/ml)
`Dextrose (5%)
`
`6)
`
`Daptomycin
`
`Mannitol
`
`Isotonic Sodium Phosphate
`Dibasic Solution (15.76 mg/ml)
`
`Dextrose (5%)
`
`7)
`
`Daptomycin
`Mannitol
`
`Isotonic Sodium Phosphate
`Dibasic Solution (15.76 mg/ml)
`
`Dextrose (5%)
`
`8}
`
`Daptomycin
`
`Mannitol
`
`Isotonic Sodium Phosphate
`Dibasic Solution (15.76 mg/ml)
`Dextrose (5%)
`
`9)
`
`Daptomycin
`
`Mannitol
`
`Tris (hydroxymethyl )amminomethane
`Solution (3.30 mg/ml)
`
`Dextrose (5%)
`
`150
`
`50
`
`10
`
`mg
`
`mg
`
`ml
`
`90
`
`ml
`
`200
`
`60
`
`13
`
`mg
`
`mg
`
`ml
`
`87
`
`ml
`
`250
`
`82
`
`mg
`
`mg
`
`16
`
`ml
`
`84
`
`mi
`
`300
`
`100
`
`mg
`
`mg
`
`20
`
`ml
`
`80
`
`ml
`
`150
`
`50
`
`mg
`
`mg
`
`10
`
`mi
`
`90
`
`ml
`
`10
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`35°
`
`AMNEALEX. 1008
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`

`EP 0 386 951 A2
`
`10)
`
`Daptomycin
`
`Mannitol
`
`Tris (hydroxymethyl ) amminomethane
`Solution (3.30 mg/ml)
`
`Dextrose (5%)
`
`11)
`
`Daptomycin
`Mannitol
`
`Tris (hydroxymethyl ) amminomethane
`Solution (3.30 mg/ml)
`
`Dextrose (5%)
`
`12)
`
`Daptomycin
`Mannitol
`
`Tris (hydroxymethyl )amminomethane
`Solution (3.30 mg/ml)
`
`Dextrose (5%)
`
`13)
`
`Daptomycin
`
`Mannitol
`
`Tris (hydroxymethyl )amminomethane
`
`Solution (3.74 mg/ml)
`
`Dextrose (5%)
`
`14)
`
`Daptomycin
`
`Mannitol
`
`Tris (hydroxymethyl ) amminomethane
`Solution (3.74 mg/ml)
`
`Dextrose (5%)
`
`200
`
`66
`
`mg
`
`mg
`
`13
`
`ml
`
`87
`
`ml
`
`250
`
`82
`
`mg
`
`mg
`
`16
`
`ml
`
`84
`
`ml
`
`300
`
`100
`
`mg
`
`mg
`
`20
`
`ml
`
`80
`
`mi
`
`150
`
`50
`
`10
`
`mg
`
`mg
`
`ml
`
`90
`
`ml
`
`200
`
`66
`
`13
`
`mg
`
`mg
`
`ml
`
`87
`
`ml
`
`20
`
`25
`
`30
`
`36
`
`40
`
`45
`
`50
`
`$5
`
`AMNEALEX. 1008
`
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`

`EP 0 386 951 A2
`
`15) Daptomycin
`Mannitol
`Tris (hydroxymethyl ) amminomethane
`Solution (3.74 mg/ml)
`
`Dextrose (5%)
`
`16) Daptomycin
`Mannitol
`Tris (hydroxymethyl ) amminomethane
`Solution (3.74 mg/ml)
`
`Dextrose (5%)
`
`17) Daptomycin
`Mannitol
`Tris (hydroxymethy1l) amminomethane
`Solution (4.96 mg/ml)
`
`Dextrose (5%)
`
`18) Daptomycin
`Mannitol
`Tris ( hydroxymethyl]) amminomethane
`Solution (4.96 mg/ml)
`
`Dextrose (5%)
`
`19) Daptomycin
`Mannitol
`Tris (hydroxymethy1 )amminomethane
`Solution (4.96 mg/ml)
`
`Dextrose (5%)
`
`20) Daptomycin
`Mannitol
`Tris (hydroxymethy1 ) amminomethane
`Solution (4.96 mg/ml)
`
`Dextrose (5%)
`
`250 mg
`82 mg
`16 ml
`
`84 ml
`
`300 mg
`100 mg
`20 ml
`
`80 ml
`
`150 mg
`50 mg
`10 ml
`
`90 ml
`
`200 mg
`66 mg
`13 ml
`
`87 ml
`
`250 mg
`82 mg
`16 ml
`
`84 ml
`
`300 mg
`100 mg
`20 ml
`
`80 ml
`
`20
`
`25
`
`30
`
`35
`
`‘40.
`
`45
`
`50
`
`55
`
`the daptomycin may be
`This aspectof the present invention may be practiced in two ways. First,
`purchasedin a lyophilized form and reconstituted prior to use with a buffered diluent as discussed above.
`
`8
`
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`

`EP 0 386 951 A2
`
`Alternatively, daptomycin may be packaged with a suitable amountof buffer so that upon reconstitution with
`a {non-buffered} diluent, the resulting reconstituted formulation will also have a pH in the range of about 6 to
`about8.
`As another aspect of the presentinvention, there is provided a pharmaceutical composition comprising
`an antibiotically-effective amount of the antibiotic daptomycin, combined with a parenterally-acceptable
`buffer in sufficient quantity so as to afford a solution pH of about 6.0 to about 8.0 when diluted with one or
`more pharmaceutically-acceptable diluents and excipients.
`As a further aspect of the present invention, there is provided a parenteral formulation of daptomycin,
`which comprises admixing daptomycin with one or more pharmaceutically-acceptable diluents and ex-
`cipients characterized in that a sufficient quantity of a parenterally-acceptable buffer is added to maintain
`the formulation at a pH of between about 6.0 and about 8.0.
`
`Claims
`
`1. A parenteral formulation which comprises as an active ingredient daptomycin associated with a
`sufficient amount of a parenterally-acceptable buffer to maintain the pH between about 6.0 and about 8.0,
`and one or more pharmaceutically-acceptable diluents or excipients.
`2. A formulation as claimed in claim 1, wherein the buffer is sodium phosphate dibasic.
`3. A formulation as claimed in claim 1, wherein the buffer is tris(hydroxymethyl)aminomethane.
`4, A formulation as claimed in claim 2, wherein the buffer sodium phosphate dibasic is present in the
`concentration of about 0.02 to about 0.13 mMolar.
`5, A formulation as claimed in claim 3, wherein the buffer tris(hydroxymethyljaminomethaneis present
`in a concentration of about 0.015 to 0.03 mMolar.
`6. A formulation as claimed in claim 4, which comprises
`
`(a) Daptomycin
`
`Mannitol
`
`Isotonic Sodium Phosphate
`
`Dibasic Solution (8.73 mg/ml)
`
`Dextrose (5%)
`
`150 mg
`
`50 mg
`
`10 ml
`
`90 ml;
`
`10
`
`20
`
`26
`
`30
`
`35
`
`40
`
`45
`
`50
`
`$5
`
`9
`
`AMNEALEX. 1008
`
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`
`

`

`EP 0 386 951 A2
`
`(b)
`
`Daptomycin
`
`Mannitol
`
`Isotonic Sodium Phosphate
`Dibasic Solution (8.73 mg/ml)
`
`Dextrose (5%)
`
`(c)
`
`Daptomycin
`
`Mannitol
`
`Isotonic Sodium Phosphate
`Dibasic Solution (8.73 mg/ml)
`
`Dextrose (5%}
`
`(a)
`
`Daptomycin
`
`Mannitol
`
`Isotonic Sodium Phosphate
`Dibasic Solution (8.73 mg/ml)
`
`Dextrose (5%)
`
`(e)
`
`Daptomycin
`
`Mannitol
`
`Isotonic Sodium Phosphate
`Dibasic Solution (15.76 mg/ml)
`
`Dextrose (5%)
`
`200
`
`66
`
`mg
`
`mg
`
`13
`
`ml
`
`87
`
`ml;
`
`250
`
`82
`
`mg
`
`mg
`
`16
`
`ml
`
`84
`
`ml;
`
`300
`
`100
`
`mg
`
`mg
`
`20
`
`mi
`
`80
`
`ml;
`
`150
`
`50
`
`mg
`
`mg
`
`10
`
`ml
`
`90
`
`ml;
`
`10
`
`20
`
`25
`
`3a
`
`35
`
`46
`
`50
`
`55
`
`AMNEALEX. 1008
`
`AMNEAL EX. 1008
`
`

`

`EP 0 386 951 A2
`
`(f)
`
`Daptomycin
`
`Mannitol
`
`Isotonic Sodium Phosphate
`Dibasic Solution (15.76 mg/ml)
`
`Dextrose (5%)
`
`(g)
`
`Daptomycin
`Mannitol
`
`Isotonic Sodium Phosphate
`
`Dibasic Solution (15.76 mg/ml)
`
`Dextrose (5%)
`
`(h)
`
`Daptomycin
`Mannitol
`
`Isotonic Sodium Phosphate
`Dibasic Solution (15.76 mg/ml)
`
`Dextrose (5%)
`
`(i)
`
`Daptomycin
`Mannitol
`
`Tris (hydroxymethyl )aminomethane
`Solution (3.30 mg/ml)
`
`Dextrose (5%)
`
`200
`
`60
`
`mg
`
`mg
`
`13
`
`ml
`
`87
`
`ml;
`
`250
`
`82
`
`mg
`
`mg
`
`16
`
`ml
`
`84
`
`ml;
`
`300
`
`100
`
`mg
`
`mg
`
`20
`
`ml
`
`80
`
`ml;
`
`150
`
`mg
`
`50
`
`mg
`
`10
`
`ml
`
`90
`
`m1;
`
`20
`
`26
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`AMNEALEX. 1008
`
`AMNEAL EX. 1008
`
`

`

`EP 0 386 951 A2
`
`(j)
`
`Daptomycin
`
`Mannitol
`
`Tris (hydroxymethyl )aminomethane
`Solution (3.30 mg/ml)
`
`Dextrose (5%)
`
`(Kk)
`
`Daptomycin
`
`Mannitol
`
`Tris (hydroxymethyl1) aminomethane
`Solution (3.30 mg/ml)
`
`Dextrose (5%)
`
`(1)
`
`Daptomycin
`Mannitol
`
`Tris (hydroxymethyl ) aminomethane
`Solution (3.30 mg/ml)
`
`Dextrose (5%)
`
`{m)
`
`Daptomycin
`
`Mannitol
`
`Tris (hydroxymethy1 ) aminomethane
`Solution (3.74 mg/ml)
`
`Dextrose (5%)
`
`200
`
`66
`
`13
`
`mg
`
`mg
`
`ml
`
`87
`
`ml;
`
`250
`
`mg
`
`82
`
`16
`
`mg
`mi
`
`84
`
`ml;
`
`300
`
`100
`
`20
`
`mg
`
`mg
`
`mi
`
`80
`
`ml;
`
`150
`
`50
`
`mg
`
`mg
`
`10
`
`ml
`
`90
`
`ml;
`
`20
`
`28.
`
`30
`
`35
`
`50
`
`55
`
`AMNEALEX. 1008
`
`AMNEAL EX. 1008
`
`

`

`EP 0 386 951 A2
`
`(n)
`
`Daptomycin
`
`Mannitol
`
`Tris (hydroxymethy1 ) aminomethane
`Solution (3.74 mg/ml)
`
`Dextrose (5%)
`
`(0)
`
`Daptomycin
`Mannitol
`
`Tris (hydroxymethyl ) aminomethane
`Solution (3.74 mg/ml)
`
`Dextrose (5%)
`
`(Pp)
`
`Daptomycin
`Mannitol
`
`Tris (hydroxymethyl ) aminomethane
`Solution (3.74 mg/ml)
`
`Dextrose (5%)
`
`(q)
`
`Daptomycin
`
`Mannitol
`
`Tris (hydroxymethyl )aminomethane
`Solution (4.96 mg/ml)
`
`Dextrose (5%)
`
`200
`
`66
`
`mg
`
`mg
`
`13
`
`ml
`
`87
`
`mi;
`
`250
`
`82
`
`mg
`
`mg
`
`16
`
`m1
`
`84
`
`ml;
`
`300
`
`100
`
`mg
`
`mg
`
`20
`
`ml
`
`80
`
`ml;
`
`150
`
`50
`
`10
`
`mg
`
`mg
`
`ml
`
`90
`
`ml;
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`AMNEALEX. 1008
`
`AMNEAL EX. 1008
`
`

`

`EP 0 386 951 A2
`
`(cr) Daptomycin
`Mannitol
`Tris (hydroxymethy]l) aminomethane
`Solution (4.96 mg/ml)
`Dextrose (5%)
`
`(s) Daptomycin
`Mannitol
`Tris (hydroxymethyl ) aminomethane
`Solution (4.96 mg/ml)
`Dextrose (5%)
`
`(t) Daptomycin
`Mannitol
`Tris (hydroxymethyl ) aminomethane
`Solution (4.96 mg/ml)
`
`Dextrose (5%)
`
`200 mg
`66 mg
`13 ml
`
`87 ml;
`
`250 mg
`82 mg
`16 ml
`
`84 ml; or
`
`300 mg
`100 mg
`20 ml
`
`80 ml.
`
`7. A therapeutic kit for the preparation of a parenteral formulation of the antibiotic daptomycin, said kit
`comprising at least two containers, one of which contains daptomycin; and a second of which contains a
`buffer capable of maintaining the pH of a solution of daptomycin in the first container between a pH of
`about 6.0 and about 8.0 when mixed, each of said first and second containers comprising one or more
`pharmaceutically acceptable carriers or excipients as appropriate.
`8. A pharmaceutical composition comprising an antibiotically-effective amount of the antibiotic dap-
`tomycin, combined with a parenterally-acceptable buffer in sufficient quantity so as to afford a solution pH
`of about 6.0 to about 8.0 when diluted with one or more pharmaceutically-acceptable diluents and
`excipients.
`9. A process for preparing a parenteral formulation of daptomycin, which comprises admixing dap-
`tomycin with one or more pharmaceutically-acceptable diluents or excipients, characterized in that a
`sufficient quantity of a parenterally-acceptable buffer is added to maintain the formulation at a pH of
`beiween about 6.0 and about 8.0.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`46
`
`50
`
`55
`
`14
`
`AMNEALEX. 1008
`
`AMNEAL EX. 1008
`
`