(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2010/0137197 A1
`
` Mittal et a]. (43) Pub. Date: Jun. 3, 2010
`
`
`US 20100137197A1
`
`(54) LYOPHILIZED ANTI-FUNGAL
`
`Related US Application Data
`
`CONIPOM ”ON
`
`(76)
`
`Inventors:
`
`Sachin NIittal, Telford, PA (US);
`Hossain Jahansouz, Foster City,
`CA (US); Suttilug Sotthivirat,
`Lansdale, PA (US)
`
`Correspondence Address:
`NIERCK
`P 0 BOX 2000
`RAHVVAY, NJ 07065—0907 (US)
`
`(21) APPI- NOJ
`
`12/666,426
`
`.
`-
`(22) PCT FIICd'
`
`Jun. 23’ 2008
`
`(86) PCT N 0.:
`
`PCT/US08/07810
`
`§ 371 (c)( 1),
`(2), (4) Date:
`
`Dec. 23, 2009
`
`(60) Provisional application No. 60/937,360, filed on Jun.
`26, 2007.
`
`Publication Classification
`
`(51)
`
`I t Cl
`'
`n '
`(2006.01)
`A61K 38/12
`(52) US. Cl.
`............................................................ 514/9
`
`ABSTRACT
`(57)
`A lyophilized anti-fungal composition comprises (A) easpo-
`fungin, or a pharmaceutically acceptable salt thereof, in an
`effective amount; 03) one or more non—reducing sugars hav—
`ing a glass transition temperature 'l'g(s) of at least about 90"
`C.; and (C) an acetate buffer in an amount effective to provide
`a pH in a range offrom about 5 to about 7; wherein the weight
`ratio of the one or more lion—reducing sugars to easpofungin
`is in a range of from about 1.1:1 to about 10:]; the composi-
`tion has a moisture content of about 0.8 wt. % or less; and the
`composition has a glass transition temperature T (c) of at
`least about 55° C. The lyophilized composition lias good
`storage stability at temperatures up to and including room
`temperature. The composition can be reconstituted for use in
`preventing or treating fungal infections.
`
`AMNEAL EX. 1007
`
`AMNEAL EX. 1007
`
`

`

`US 2010/0137197 A1
`
`Jun. 3,2010
`
`LYOPHILIZED ANTI-FUNGAL
`COMPOSITION
`FIELD OF THE INVENTION
`
`[0001] The invention is directed to cas poftmgin-containing
`pharmaceutical compositions useful for treating and/or pre-
`venting fungal infections.
`BACKGROUND OF THE INVENTION
`
`[0002] Caspofungin is a macrocyclic lipopeptide echi-
`nocandin whose structural formula is disclosed in column 2,
`lines 32-52 of US. Pat. No. 5,952,300. Caspofungin is also
`described in US. Pat. No. 5,378,804, and methods for its
`preparation are described in US. Pat. No. 5,378,804, U.S.
`Pat. No. 5,552,521, US. Pat. No. 5,952,300 and US. Pat. No.
`6,136,783. Caspofungin is an inhibitor of the synthesis of
`[3 -(1,3)-D-glucan, which is an integral part of the fungal cell
`wall. Caspofungin is usefiil as an antibiotic, especially as an
`antifungal agent or as an antiprotozoal agent. As an antifungal
`agent, it is useful for the control ofboth filamentous fungi and
`yeast. It is especially adaptable to be employed for the treat-
`ment of mycotic infections in mammals, especially those
`caused by Candida species such as C. albicans, C. tropicalis,
`C. krusei, C. glabraza and C. pseudmropicalis, and Aspergil—
`lus species such as A. fitmigalus, A. flavus and A. niger. In
`particular, the compound has been found effective against
`putatively Amphotericin E- and Fluconazole-resistant Can-
`dida isolates. The compound is also useful for the treatment
`and/or prevention of Pneumocyszis carinii pneumonia to
`which immune compromised patients, such as those suffering
`from AIDS, are especially susceptible.
`[0003] Caspofungin is typically employed in a lyophilized
`composition that is reconstituted for intravenous infusion.
`Preferred lyophilized caspofungin compositions are acetate-
`buffered products such as those described in US Pat. No.
`5,952,300. Of particular interest is the lyophilized, acetate-
`buffered product containing caspofungin in the form of a
`diacetate salt, sucrose, mannitol, glacial acetic acid, and
`sodium hydroxide. Such a product is available from Merck &
`Co., Inc. under the trade name CANCIDAS in 35 mg, 50 mg,
`and 70 mg doses. CANCIDAS is indicated for empirical
`therapy for fungal infection in patients with fever and neutro—
`penia, the treatment ofCandidemia and certain other Candida
`infections, the treatment of esophageal Candidiasis, and the
`treatment of invasive Aspergillosis in patients who are resis-
`tant to or cannot tolerate other therapies.
`[0004] Lyophilized, acetate-buffered, caspofungin prod-
`ucts such as CANCIDAS are characterized by good storage
`stability at low temperature (e.g., 2° C. to 8° C.) under ambi-
`ent storage conditions. More particularly, the compositions
`canbe stored at low temperature (e.g., 5° C.) for many months
`with minimal formation of degradates. Nonetheless,
`lyo-
`philized caspofungin-containing products with improved
`storage stability at low temperatures and/or satisfactory stor-
`age stability at higher temperatures is desirable. Improved
`storage stability at about 5° C. would provide for a longer
`shelf life thereby reducing the potential for product loss.
`Satisfactory storage stability at room temperature would
`eliminate the need for refrigeration and the special handling
`and extra costs associated therewith.
`SUMMARY OF THE INVENTION
`
`[0005] The present invention includes a lyophilized anti-
`fungal composition which comprises:
`[0006]
`(A) caspofungin, or a pharmaceutically acceptable
`salt thereof, in an effective amount;
`
`(B) one or more non-reducing sugars having a glass
`[0007]
`transition temperature Tg(s) of at least about 90° C.; and
`[0008]
`(C) an acetate buffer in an amount effective to pro—
`vide a pH in a range of from about 5 to about 7;
`[0009] wherein:
`[0010]
`the weight ratio of the one or more non-reducing
`sugars to caspofungin is in a range of from about 1.1:1 to
`about 10:1;
`[0011]
`the composition has a moisture content of about 0.8
`wt. % or less; and
`[0012]
`the composition has a glass transition temperature
`Tg(c) of at least about 55° C.
`[0013] The lyophilized anti-fungal composition of the
`present invention has good chemical and storage stability at
`and below room temperature (i.e., at or below about 30° C.).
`The composition typically has a stability exceeding that of
`known lyophilized caspofungin-containing compositions
`which employ sucrose and mannitol and have a Tg(c) in a
`range of from about 40° C. to about 45° C.
`[0014] Embodiments, aspects and features of the present
`invention are either further described in or will be apparent
`from the ensuing description, examples, and appended
`claims.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`
`
`[0015] A first embodiment of the present invention (alter—
`natively referred to herein as “Embodiment 31”) is a lyo-
`philized composition as originally described (i.e.,
`as
`described in the Summary of the Invention) w ierein the one
`or more non—reducing sugars is selected from the group con—
`sisting of trehalose, sucrose, raffinose, sorbitol and combina—
`tions thereof. Suitable combinations include any two of the
`sugars (e.g., trehalose and sucrose), any three of the sugars
`(e.g., trehalose, sucrose, and sorbitol), or all four ofthe sug-
`ars. In an aspect of this embodiment, the one or more non—
`reducing sugars is trehalose or a mixture oftrehalose with any
`one of sucrose, raflinose and sorbitol. In a feature of this
`aspect, the non-reducing sugar is trehalose or a major amount
`of trehalose (i.e., trehalose is more than 50 wt. % of the
`mixture) with any one of sucrose, raffinose and sorbitol. In
`another feature of this aspect, the non-reducing sugar is tre-
`halose or is a combination of at least about 80 wt. % trehalose
`with any one of sucrose, raffinose and sorbitol.
`[001 6] A second embodiment ofthe present invention (Em-
`bodiment E2) is a lyophilized composition as originally
`described wherein trehalose is the one or more non-reducing
`sugars; i.e., there is one non—reducing sugar present in the
`composition and that sugar is trehalose. This is alternatively
`and more simply expressed herein as “trehalose is the non-
`reducing sugar”.
`[0017] A third embodiment of the present invention (Em-
`bodiment E3) is a lyophilized composition as originally
`described or as set forth in either Embodiment E1 or E2
`wherein the moisture content of the composition is about 0.5
`wt. % or less.
`
`[0018] A fourth embodiment ofthe present invention (Em—
`bodiment E4) is a lyophilized composition as originally
`described or as set forth in either Embodiment E1 or E2
`wherein the moisture content of the composition is about 0.3
`wt. % or less.
`
`[0019] A fifth embodiment of the present invention (Em-
`bodiment E5) is a lyophilized composition as originally
`
`AMNEAL EX. 1007
`
`AMNEAL EX. 1007
`
`

`

`US 2010/0137197 A1
`
`Jun. 3,2010
`
`described or as set forth in any one of the foregoing embodi-
`ments wherein the glass transition temperature Tg(c) of the
`composition is at least about 900 C.
`[0020] A sixth embodiment of the present invention (Em-
`
`bodiment 36) is a lyophilized composition as originally
`described or as set forth in any one of the foregoing embodi-
`ments wherein the glass transition temperature T‘g (c) of the
`composition is in a range offrom about 90° C. to about 125°
`C.
`
`invention
`[0021] A seventh embodiment of the present
`
`(Embodiment 37) is a lyophilized composition as originally
`described or as set forth in any one of the foregoing embodi-
`ments wherein the non-reducing sugar-to-caspofiungin
`weight ratio ofthe composition is in a range of from about 2: 1
`to about 8: 1.
`
`invention
`[0022] An eighth embodiment of the present
`
`(Embodiment 38) is a lyophilized composition as originally
`described or as set forth in any one ofthe foregoing embodi-
`ments wherein the non-reducing sugar-to-caspofiungin
`weight ratio ofthe composition is in a range of from about 2: 1
`to about 6: 1.
`[0023] A ninth embodiment of the present invention (Em—
`
`bodiment 39) is a lyophilized composition as originally
`described wherein trehalose is the non-reducing sugar, the
`moisture content ofthe composition is about 0.5 wt. % or less,
`the glass transition temperature Tg(c) of the composition is at
`least about 90° C., and the trehalose—to—caspofiingin weight
`ratio is in a range offrom about 2:1 to about 8:1. In an aspect
`of this embodiment, the glass transition temperature 'l'g(c) is
`in a range of from about 90° C. to about 1250 C.
`[0024] A tenth embodiment of the present invention (Em-
`bodiment E10) is a lyophilized composition as originally
`described wherein trehalose is the non—reducing sugar, the
`moisture content is about 0.3 wt. % or less, the glass transition
`temperature Tg(c) is at least about 900 C., and the trehalose-
`to-caspofiJngin weight ratio is in a range offrom about 2: l to
`about 6:1. In an aspect of this embodiment, the glass transi—
`tion temperature Tg(c) is in a range of from about 90° C. to
`about 125° C.
`
`[0025] An eleventh embodiment of the present invention
`(Embodiment E11) is a lyophilized composition as originally
`described which is prepared by lyophilizing an aqueous solu-
`tion comprising the caspofungin or its salt, the acetate buffer,
`and the one or more non—reducing sugars, wherein in the
`solution:
`
`(A) the caspofungin or its salt has a concentration in
`[0026]
`a range of from about 5 mg/mL to about 200 mg/mL;
`[0027]
`(B) the one or more non-reducing sugars has a con-
`centration ratio on a rug/mL basis with respect to caspofungin
`in a range of from about 2:1 to about 10:1; and
`[0028]
`(C) the acetate buffer has a concentration in a range
`of from about 12.5 mM to about 200 mM.
`
`[0029] Aspects of Embodiment E11 include the lyo-
`philized composition as just described in Embodiment El 1,
`wherein:
`
`(Al) the one or more non-reducing sugars is a sugar
`[0030]
`selected from the group consisting oftrehalose, sucro sc, raifi-
`nose, sorbitol and combinations thereof
`[0031]
`(A2) trehalose is the non-reducing sugar.
`[0032]
`(A3) the moisture content of the composition is
`about 0.5 wt. % or less.
`
`(A4) the moisture content of the composition is
`[0033]
`about 0.3 wt. % or less.
`
`
`
`A5) the glass transition temperature Tg(c) of the
`[0034]
`composition is at least about 90° C.
`[0035]
`A6) the glass transition temperature Tg(c) of the
`composition is in a range of from about 90° C. to about 125°
`C.
`the non—reducing sugar(s)—to—caspofungin
`A7)
`[0036]
`weight ratio ofthe composition is in a range of from about 2:1
`to about 8:1.
`the non-reducing sugar(s)-to-caspofungin
`[0037]
`A8)
`weight ratio ofthe composition is in a range of from about 2:1
`to about 6:1.
`[0038]
`A9) trehalose is the non-reducing sugar. the mois-
`ture content of the composition is about 0.5 wt. % or less, and
`the glass transition temperature Tg(c) is at least about 900 C.
`[0039]
`A 10) the composition is the same as set forth inA9,
`except that the moisture content is about 0.3 wt. % or less.
`[0040] Al 1) trehalose is the non-reducing sugar, the mois-
`ture content is of about 0.5 wt. % or less, the glass transition
`temperature Tg(c) is at least about 90° C., and the trehalose-
`to—caspofungin weight ratio is in a range of from about 2: 1 to
`about 8:1.
`[0041]
`(A12) trehalose is the non-reducing sugar, the mois-
`ture content is about 0.3 wt. % or less, the glass transition
`temperature Tg(c) is at least about 90° C., and the trehalose—
`to-caspofungin weight ratio is in a range of from about 2: 1 to
`about 6: l.
`[0042]
`(A13) the compositionis the same as set forth inAll
`except that the glass transition temperature Tg(c) is in a range
`offrom about 90° C. to about 125° C.
`[0043]
`(A14) the compositionis the same as set forthinA12
`except that the glass transition temperature Tg(c) is in a range
`offrom about 90° C. to about 125° C.
`[0044] A twelfth embodiment ofthe present invention (Em-
`bodiment E12) is a lyophilized composition as set forth in
`
`Embodiment 311, wherein in the aqueous solution from
`which the lyophilized composition is prepared:
`[0045]
`(A) the concentration of caspofungin or its salt is in
`a range of from about 30 mg/mL to about 50 mg/mL;
`[0046]
`(B) the concentration ratio of the non-reducing sug-
`ar(s) to caspoftmgin is in a range of from about 4:1 to about
`8: l
`; and
`(C) the concentration of the acetate buffer is in a
`[0047]
`range of from about 20 mM to about 60 mM.
`[0048] A thirteenth embodiment of the present invention
`
`(3mbodiment E 3) is a lyophilized composition as set forth
`
`in Embodiment 312, wherein trehalose is the non-reducing
`sugar, the moisture content ofthe composition is about 0.5 wt.
`% or less (e.g., about 0.3 wt. % or less), and the glass transi—
`tion temperature Tg(c) ofthe composition is at least about 90°
`C. (e.g., in a range of from about 90° C. to about 125° C.).
`[0049] A fourteenth embodiment of the present invention
`(Embodiment E14) is a lyophilized composition as set forth
`in Embodiment E13, wherein in the aqueous solution from
`which the lyophilized composition is prepared:
`[0050]
`(A) the concentration of caspofungin or its salt is in
`a range of from about 30 mg/mL to about 50 mg/mL;
`[0051]
`(B) the concentration of trehalose is in a range of
`from about 180 mgdmL to about 300 mg/mL (i.e., a trehalose
`to caspofungin concentration ratio of about 6: l); and
`[0052]
`(C) the acetate buffer has a concentration in a range
`of from about 20 mM to about 60 mM.
`[0053] A fifteenth embodiment of the present invention
`
`(3mbodiment E15) is a lyophilized composition as originally
`described or as set forth in any ofthe foregoing embodiments
`
`AMNEAL EX. 1007
`
`AMNEAL EX. 1007
`
`

`

`US 2010/0137197 A1
`
`Jun. 3,2010
`
`or aspects or features thereof, wherein the composition is
`substantially free of reducing sugars. Reducing sugars can
`have a detrimental effect on the stability of the lyophilized
`compositions of the present invention (see below), and thus
`the compositions preferably contain little or no reducing
`sugar. The term “substantially free” in this context means that
`no reducing sugar is included as a component in the prepara-
`tion of the lyophilized composition and/or that essentially no
`reducing sugar is present in the lyophilized composition.
`[0054] An “effective amoun ” of caspofungin in the lyo-
`philized composition is an amount of caspofungin (on a free
`base basis) that upon reconstitution of the lyophilized com—
`position can be employed (e.g., via parenteral administration)
`in a therapeutically or prophylactically effective amount to
`treat or prevent a fungal infection or the like.
`[0055] The term “pharmaceutically acceptable salt” refers
`to a salt which is not biologically or otherwise undesirable
`(e. g., is neither toxic nor otherwise deleterious to the recipient
`thereof). The caspofungin salt can suitably be a mono—, di—, or
`tr‘i-acid salt. The salts are suitably prepared by treating the
`free base with a suitable organic or inorganic acid. Suitable
`salts include acid addition salts such as the salts formed by
`treating the free base with hydrochloric acid, hydrobromic
`acid. phosphoric acid, sulfuric acid, maleic acid, critic acid, or
`acetic acid.
`[0056] The term “non-reducing sugar” refers to a carbohy-
`drate that does not reduce alkaline solutions of copper. Non-
`reducing sugars do not participate in the Maillard reaction
`with compounds containing primary amines (e.g., amino
`acids). The reducing or non—reducing nature of a sugar can be
`determined by the Fehling’s test, which monitors the reduc-
`tion ofCu ++ to C11+, with concomitant oxidation ofthe sugar,
`Non-reducing sugars do not react in the Fehling’s test (i.e.,
`they do not lead to the formation of cuprous oxide). Exem—
`plary non-reducing sugars suitable for use in the present
`invention include trehalose, sucrose, raflinose, and sorbitol.
`[0057] A “reducing sugar” refers to a carbohydra e that
`does reduce alkaline solutions of copper (e.g., does react in
`the Fehling’s test) and does participate in the Maillard reac-
`tion with compounds containing primary amines.
`[0058] The glass transition temperatures referred to herein
`(e.g., Tg(s) and Tg(c)) are the transition temperatures deter—
`mined using differential scanning calorimetry (DSC). DSC
`measures the change in heat capacity between the glassy and
`rubbery states and is typically indicated by a change in ba se-
`line in a DSC themiogram.
`[0059] The glass transition temperature Tg(c) of the lyo-
`philized composition of the present invention will typically
`decrease as the amount of moisture in the composition
`increases. Furthermore, even in cases where the lyophilized
`composition can tolerate a relatively large amount of mois-
`ture and still have a suitable Tg(c), the presence of a relatively
`large amount of moisture is often deleterious for other rea—
`sons. For example, the moisture can be a source of chemical
`degradation ofthe active ingredient by, for example, hydroly-
`sis. Accordingly, the lyophilized composition of the present
`invention is characterized by having a low moisture content.
`More particularly. for the purposes of this invention, if (i) the
`amount of moisture in the composition is about 0.8 wt. % or
`less and (ii) the Tg(c) ofthe lyophilized composition is at least
`about 55° C., then the composition is deemed to have a low
`moisture content and to be a composition ofthe present inven—
`tion. Both (i) and (ii) must be satisfied for the composition to
`be a composition of the present invention. Thus, if a lyo-
`
`
`
`philizcd composition has a moisture content of less than
`about 0.8 wt. % but its Tg(c) is below about 55° C., the
`composition is not a composition of the present invention.
`Furthermore, if a lyophilized composition has a Tg(c) above
`about 55° C. but its moisture content is more than 0.8 wt. %,
`the composition is not considered as having a low moisture
`content and is not a composition of the present invention. The
`lyophilized composition ofthe invention typically has a mois—
`ture content of less than about 0.5 wt. % and a Tg(c) above
`about 55° C., and preferably has a moisture content of less
`than about 0.5 wt. % and a Tg(c) above about 90° C.
`[0060]
`Tg(s), the glass transition temperature ofthe one or
`more non-reducing sugars employed in the lyophilized anti-
`fiingal composition of the invention is the glass transition
`temperature of the sugar(s) after lyophilization of the non—
`reducing sugar(s) in the same manner as the anti-fungal com-
`position is lyophilized, wherein the lyophilization generates
`an amorphous form of the non-reducing sugar(s). The '1'g(s)
`value of the one or more non-reducing sugars used in the
`present invention is at least about 90° C. and is typically in a
`range of from about 90° C. to about 125° C.
`is
`[0061] When more than one non-reducing sugar
`employed, it is the Tg(s) value of the sugars together in a
`mixture (after lyophilization) that must be at least about 90°
`C. A non-reducing sugar who se glass transition temperature
`is below 90° C. can be included in the composition, provided
`that the Tg(s) of all of the non-reducing sugars together (after
`lyophilization) is about 90° C. or higher. Typically, however,
`each of the non-reducing sugars employed in the lyophilized
`composition has an individual glass transition temperature of
`at least about 90° C.
`
`[0062] The moisture content of the lyophilized composi-
`tion is determined by the Karl Fisher coulometry method,
`wherein the residual water is extracted from the composition
`using methanol or some other suitable extraction agent. The
`water present in the methanol or other reagent is then titrated
`with a Karl Fischer solution that reacts with the water to form
`colorless hydrogen iodide. When all of the water has been
`consumed, free iodine, which has color, appears, thereby
`indicating an end point before which the conductivity of the
`solution will have changed. The moisture content can then be
`determined from a measurement of the amount of H1 formed
`during the titration.
`[0063] The term “about”, when modifying the quantity of a
`substance or composition, or the value of a physical property
`(e.g., moisture content, Tg(c), Tg(s), or the like) ofa substance
`or composition, or the value of a parameter characterizing a
`process, or the like refers to variation in the numerical quan—
`tity that can occur. for example, through typical measuring
`and handling procedures employed in the preparation, char-
`acterization, and use of the lyophilized compositions of the
`invention; for making concentrates or use solutions in the real
`world; through inadvertent error in these procedures; through
`differences in the manufacture, source, or purity of the ingre-
`dients employed to make or use the compositions or carry out
`the procedures; and the like. In one embodiment, the term
`“about” means the reported numerical value 210% thereof. In
`an aspect of this embodiment, the term “about” means the
`reported numerical value 15% thereof.
`[0064] An “effective amount” of an acetate buffer is an
`amount of the buffer that can provide, with suitable adjust—
`ment as needed by addition ofbase (e.g., a hydroxide such as
`NaOH), a pH in the indicated range in the aqueous solution
`
`AMNEAL EX. 1007
`
`AMNEAL EX. 1007
`
`

`

`US 2010/0137197 A1
`
`Jun. 3,2010
`
`from which the lyophilized composition of the invention is
`prepared (i.e, in the pre—lyophilization solution).
`[0065] Unless expressly stated to the contrary, a reference
`to pH herein means the pH at ambient temperature; i.e., at a
`temperature in a range of from about 20° C. to about 250 C.
`[0066] The lyophilized compositions of the present inven-
`tion are not limited to the active ingredient (i.e, caspofungin)
`or its salt, the acetate buffer and the non-reducing sugar(s),
`The composition can include other components such as (i) a
`minor amount of a bulking agent (e.g., a polyol) in addition to
`the non-reducing sugar(s) or (ii) an anti-oxidant such as BHT,
`BHA, alpha-tocopherol, or ascorbic acid lf employed, the
`bulking agent is typically present in an amount of less than
`about 10 wt. %, preferably less than about 5 wt. %, with
`respect to the non-reducing sugar(s).
`[0067] The present invention also includes a process for
`preparing a lyophilized anti-fungal composition with a mois-
`ture content of less than about 0.8 wt. % (alternatively
`referred to herein as “Process Pl”), which comprises
`[0068]
`(A) preparing an aqueous solution with a pH in a
`range of from about 5 to about 7 and comprising an effective
`amount of caspofungin or a pharmaceutically acceptable salt
`thereof one or more non-reducing sugars having a glass
`transition temperature Tg(s) of at least about 900 C., and an
`acetate buffer, wherein the concentration ratio, on a weight
`per unit volume basis, ofthe one or more non-reducing sugars
`to caspofunginis inarange offrom about 1.121 to about 10:1 f.
`and
`
`(B) freeze—drying the aqueous solution to provide
`[0069]
`the lyophilized anti-fungal composition.
`[0070] A first embodiment of Process Pl (altematively
`
`referred to herein as “Embodiment P1—El”) is the process as
`originally described, wherein Step A further comprises:
`[0071]
`(al) dissolving the one or more non—reducing sugars
`in water;
`(a2) adding acetic acid and then adjusting the pH to
`[0072]
`be in a range of from about 4.5 to about 5.5 by addition of
`base;
`(a3) adding caspofungin or its salt and adjusting the
`[0073]
`pH to a value in a range offrom about 5 to about 7 (e.g., about
`6) by addition of more base; and
`[0074]
`(a4) optionally filtering the resulting aqueous solu—
`tion.
`
`is
`[0075] When more than one non-reducing sugar
`employed in sub—step al of Step A in the Process P1, the
`sugars can be dissolved in any convenient way. For example,
`the sugars can be mixed together and the dry mixture dis-
`solved in water to provide the solution employed in sub-step
`a2, or alternatively the sugars can be dissolved individually in
`separate portions of water to provide separate aqueous sub-
`solutions and the separate sub-solutions added together and
`optionally diluted if necessary to give the solution employed
`in sub-step a2, or altematively the sugars can be added sepa-
`rately to the same portion of water and dissolved therein and
`optionally diluted if necessary to provide the solution
`employed in sub-step a2. When added separately, the indi-
`vidual non-reducing sugars can be added concurrently or at
`different times in any order.
`[0076] A second embodiment of Process Pl (Embodiment
`P1 -EZ) is the process as originally described or as set forth in
`
`Emoodiment Pl—El, wherein in the aqueous solution result—
`ing from Step A the caspofungin or its salt has a concentration
`in a range of from about 5 lug/mL to about 200 mg/mL, and
`
`
`
`the concentration ratio ofthe non-reducing sugar(s) to caspo-
`fiingin is in a range of from about 2:1 to about 0:1.
`[0077] A third embodiment of Process P1 (Embodiment
`Pl-E3) is the process as originally described or as set forth in
`Embodiment Pl-El, wherein in the aqueous so ution result-
`ing from Step A the caspofungin or its salthas a concentration
`in a range of from about 30 mg/mL to about 50 mg/mL, and
`the concentration ratio ofthe non-reducing sugar(s) to caspo-
`fungin is in a range of from about 4:1 to about 8:1.
`
`[0078] A fourth embodiment of Process P1 (Embodiment
`P 1 -E4) is the process as originally described or as set forth in
`any one of Embodiments Pl—El to P1—E3, wherein the one or
`more non—reducing sugars is selected from the group consist—
`ing of trehalose, sucrose, rafiinose, sorbitol and mixtures
`thereof.
`[0079] A fifth embodiment of Process Pl (Embodiment
`Pl-E5) is the process as originally described or as set forth in
`
`any one of Embodiments P1—E1 to P1—E3, wherein trehalose
`is the non-reducing sugar.
`[0080] A sixth embodiment of Process Pl (Embodiment
`Pl-E6) is the process as originally described or as set forth in
`any one of the foregoing embodiments of P 1, wherein the
`moisture content of the lyophilized composition is about 0.5
`wt. % or less.
`[0081] A seventh embodiment of Process P1 (Embodiment
`Pl-E7) is the process as originally described or as set forth in
`any one of the foregoing embodiments of P1, wherein the
`moisture content of the lyophilized composition is about 0.3
`wt. % or less.
`
`[0082] An eighth embodiment of Process P1 (Embodiment
`Pl-E8) is the process as originally described or as set forth in
`any one of the foregoing embodiments of P1, wherein the
`lyophilized composition has a glass transition temperature
`Tg(c) ofat least about 90° C. (e.g., in a range offrom about 90°
`C. to about 125° C.).
`[0083] The present invention also includes a lyophilized
`anti-fungal composition prepared by the process Pl as origi-
`nally described or as set forth in any one of the foregoing
`embodiments ofPl .
`
`
`
`[0084] The freeze-drying (i.e, lyophilizing) ofthe aqueous
`solution resulting from Step A of Process Pl involves first
`cooling the solution to a temperature at or below the freezing
`point of the solution (i.e., below its glass transition tempera-
`ture if the solution forms a glass upon cooling and below its
`eutectic point if the frozen solution is crystalline). The frozen
`solution is then typically subjected to a primary drying step in
`which the temperature is gradually raised under vacuum in a
`drying chamber to remove most of the water, and then to a
`secondary drying step typically at a higher temperature than
`employed in the primary drying step to remove the residual
`moisture in the lyophilized composition. The freeze drying
`step typically requires 48 hours or more to complete. The
`lyophilized composition is then appropriately sealed and
`stored (e.g., in stoppered vials) for later use. Tang et al.,
`Pharmaceutical Research 2004, vol. 21, pp.
`191—200
`describes the scientific principles pertaining to freeze drying
`and guidelines for designing suitable freeze drying processes.
`Further description of freeze drying is found in Remingroni
`The Science and Practice of Pharmacy, 2006, 21” edition,
`Lippincott Williams & Wilkins, pp. 828—831.
`[0085] The lyophilized compositions of the present inven-
`tion are characterized by having good chemical and storage
`stability at temperatures up to and including room tempera-
`ture. Caspofungin has two main degradation products. The
`
`AMNEAL EX. 1007
`
`AMNEAL EX. 1007
`
`

`

`US 2010/0137197 A1
`
`Jun. 3,2010
`
`
`
`first is formcd via hydrolysis in thc prc-lyophilization solu-
`tion, and the second is formed in the lyophilized composition
`as a result of intramolecular rearrangement. It has been found
`that the lyophilized compositions of the present invention
`exhibit reduced growth of the second degradate during stor-
`age compared to analogous known compositions with the
`same or similar moisture content.
`[0086] The lyophilized compositions of the present inven-
`tion are reconstituted for use in preventing or treating fungal
`infections. The present
`invention accordingly includes a
`method of preparing an anti—fungal liquid formulation for
`parenteral administration (alternatively referred to herein as
`“Method M1”), which comprises reconstituting (i) the lyo-
`philized anti-fungal composition as originally described in
`
`
`the Summary of the Invention or as set forth in any one of
`Embodiments A 1 to - 15 or in any aspects or features thereof
`
`or (ii) the lyophilizec anti-fungal composition resulting from
`Process P1 as originally described or as set forth in any one
`Embodiments 3l-El to P1-E8 with a parenterally acceptable
`solvent to form an anti-fungal solution concentrate and then
`mixing the concentrate with a diluent comprising water to
`provide the formulation.
`[0087] A first embodiment of Method M1 (alternatively
`referred to herein as “Embodiment M1 -E1”) is the Method
`Ml as originally described, wherein the parenterally accept-
`able solvent comprises water.
`[0088] A second embodiment of Method M1 (Embodiment
`Ml -E2) is the Method M1 as originally described, wherein
`the parenterally acceptable solvent is selected from the group
`consisting of0.9% Sodium Chloride Injection, Sterile Water
`for Injection, Bacteriostatic Water for Injection with meth—
`ylparaben and propylparaben, and Bacteriostatic Water for
`Injection with 0.9% benzyl alcohol.
`[0089] A third embodiment of Method M1 (Embodiment
`Ml -E3) is the Method M] as originally described or as set
`
`forth in either Embodiment Ml-El or M1-E2, whcrcin the
`diluent is 0.9%, 0.45% or 0.225% Sodium Chloride Injection
`or Lactated Ringer’s Injection.
`[0090] A fourth embodiment of Method M1 (Embodiment
`Ml -E4) is the Method M] as originally described or as set
`forth in any ofthe foregoing embodiments of M1 , wherein the
`concentrate contains from about 5 mg/mL to about 8 mg/mL
`of caspofungin, and the liquid formulation resulting from
`dilution ofthe concentrate contains from about 0.2 mg/mL to
`about 0.5 mg/mL of caspofungin.
`[0091] The present invention further includes an anti-fun-
`gal liquid dosagc formulation for parcntcral administration
`prepared by the Method M1 as originally described or as set
`forth in any one of the foregoing embodiments of M].
`[0092] The present invention still further includes a method
`for the treatment or prophylaxis of a fungal infection which
`comprises parenterally administering to a subject in need
`thcrcof an anti-fungal l