ao United States
`a2) Patent Application Publication co) Pub. No.: US 2010/0137197 Al
`
` Mittaletal. (43) Pub. Date: Jun. 3, 2010
`
`
`US 20100137197A1
`
`(54) LYOPHILIZED ANTI-FUNGAL
`COMPOSITION
`
`(76)
`
`Inventors:
`
`Sachin Mittal, Telford, PA U8);
`Hossain Jahansouz, Foster City,
`CA (US), Suttilug Sotthivirat,
`Lansdale, PA (US)
`
`Correspondence Address:
`MERCK
`PO BOX 2000
`RAHWAY,NJ 07065-0907 (US)
`
`(21) Appl. No.:
`
`12/666,426
`
`4a.
`PCTFiled:
`(22)
`(86) PCI No.:
`
`Jun. 23, 2008
`PC'T/US08/07810
`
`§ 371 (c)(1),
`(2), (4) Date:
`
`Dec. 23, 2009
`
`Related U.S. Application Data
`(60) Provisional application No. 60/937,360, filed on Jun.
`26, 2007.
`
`Publication Classification
`
`(51)
`
`Int. Cl
`wl.
`ne,
`(2006.01)
`AGIK 38/12
`(52) US. CD. oe cceeee cece eeneee ee creneeeeeceeeneeeee senses 514/9
`(7)
`ABSTRACT
`A lyophilized anti-fungal composition comprises (A) caspo-
`fungin, or a pharmaceutically acceptable salt thereof, in an
`effective amount; (B) one or more non-reducing sugars hav-
`ing, a glass transition temperature ‘I’,(s) of at least about 90°
`C.; and (C) an acetate buffer in an amounteffective to provide
`a pH ina range offrom about5 to about 7; wherein 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; the composi-
`tion has a moisture content ofabout 0.8 wt. % or less; and the
`composition has a glass transition temperature T_(c) of at
`least about 55° C. The lyophilized composition ‘has good
`storage stability at temperatures up to and including room
`temperature. The composition can be reconstituted for use in
`preventing ortreating fungal infections.
`
`AMNEALEX. 1007
`
`AMNEAL EX. 1007
`
`

`

`US 2010/0137197 Al
`
`Jun. 3, 2010
`
`LYOPHILIZED ANTI-FUNGAL
`COMPOSITION
`FIELD OF THE INVENTION
`
`[0001] The inventionis directed to caspofungin-containing
`pharmaccutical compositions uscful for treating and/or pre-
`venting fungal infections.
`BACKGROUND OF THE INVENTION
`
`[0002] Caspofungin is a macrocyclic lipopeptide echi-
`nocandin whosestructural formula is disclosed in column 2,
`lines 32-52 of U.S. Pat. No. 5,952,300. Caspofungin is also
`described in U.S. Pat. No. 5,378,804, and methods for its
`preparation are described in U.S. Pat. No. 5,378,804, U.S.
`Pat. No. 5,552,521, U.S. Pat. No. 5,952,300 and U:S. Pat. No.
`6,136,783. Caspofungin is an inhibitor of the synthesis of
`B-(1,3)-D-glucan, whichis an integral part of the fungal cell
`wall. Caspofungin is useful as an antibiotic, especially as an
`antifungal agentor as an antiprotozoal agent. As an antifungal
`agent, itis 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 suchas C. albicans, C.tropicalis,
`C. krusei, C. glabrata and C. pseudotropicalis, and Aspergil-
`lus species such as A. fumigatus, A. flavus and A. niger. In
`particular, the compound has been found effective against
`putatively Amphotericin B- and Fluconazole-resistant Can-
`dida isolates. The compoundis also useful for the treatment
`and/or prevention of Pneumocystis carinii pneumonia to
`whichimmune compromisedpatients, such as thosesuffering
`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 acelalte-
`buffered products such as those described in U.S. 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. Sucha product is available from Merck &
`Co., Inc. underthe trade name CANCIDASin 35 mg, 50 mg,
`and 70 mg doses. CANCIDASis indicated for empirical
`therapy for fungal infection in patients with fever and neutro-
`penia,the treatment ofCandidemia andcertain other Candida
`infections, the treatment of esophageal Candidiasis, and the
`treatment of invasive Aspergillosis in patients whoare resis-
`tant to or cannot tolerate other therapies.
`[0004] Lyophilized, acetate-buffered, caspofungin prod-
`ucts such as CANCIDASare characterized by good storage
`stability at low temperature (e.g., 2° C. to 8° C.) under ambi-
`ent storage conditions. More particularly, the compositions
`can be 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/orsatisfactory 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
`climinate the need for refrigeration and the special handling
`and extra costs associated therewith.
`SUMMARYOFTHE 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) onc or more non-reducing sugars having a glass
`[0007]
`transition temperature T,(s) of at least about 90° C.; and
`[0008]
`(C) an acetate buffer in an amounteffective 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
`T,(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., al 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 T,(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 embodimentofthe present invention (alter-
`natively referred to herein as “Embodiment E1”) is a lyo-
`philized composition as originally described (i.e,
`as
`described. in the Summary of the Invention) wherein 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 of the sug-
`ars. In an aspect of this embodiment, the one or more non-
`reducing sugarsis trehalose ora mixture oftrehalose with any
`one ofsucrose, raffinose and sorbitol. In a feature ofthis
`aspect, the non-reducing sugaris trehalose or a major amount
`of trehalose (i.c., trehalose is more than 50 wt. % of the
`mixture) with any oneof sucrose, raffinose and sorbitol. In
`another feature ofthis aspect, the non-reducing sugar is tre-
`halose or is a combination ofat least about 80 wt. %trehalose
`with any oneof sucrose,raffinose and sorbitol.
`[0016] Asecond embodimentofthe present invention (Em-
`bodiment E2) is a lyophilized composition as originally
`described whercin trehalose is the one or more non-reducing
`sugars; ie., 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 embodimentofthe present invention (Em-
`bodiment E3) is a lyophilized composition as originally
`described or as sct forth in cither Embodiment El or E2
`wherein the moisture content of the composition is about 0.5
`wi. % or less.
`
`[0018] A fourth embodimentofthe present invention (Em-
`bodiment E4) is a lyophilized composition as originally
`described or as set forth in either Embodiment E] or E2
`wherein the moisture content of the composition is about 0.3
`wt. % orless.
`
`[0019] A fifth embodimentof the present invention (Em-
`bodiment E5) is a lyophilized composition as originally
`
`AMNEALEX. 1007
`
`AMNEAL EX. 1007
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`

`

`US 2010/0137197 Al
`
`Jun. 3, 2010
`
`described or as set forth in any one of the foregoing embodi-
`ments wherein the glass transition temperature T,,(c) of the
`compositionis al least about 90° C.
`[0020] A sixth embodimentofthe present invention (Em-
`
`bodiment E6) is a lyophilized composition as originally
`described or as set forth in any one of the foregoing embodi-
`ments whercin the glass transition temperature T,(c) of the
`composition is in a range of from about 90° C. to about 125°
`C.
`
`invention
`[0021] A seventh embodiment of the present
`
`(Embodiment E7) 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-caspofungin
`weightratio ofthe composition is in a range of from about 2:1
`to about 8:1.
`
`invention
`[0022] An eighth embodiment of the present
`
`(Embodiment E8) is a lyophilized composition as originally
`described oras set forth in any one ofthe foregoing embodi-
`ments wherein the non-reducing sugar-to-caspofungin
`weightratio ofthe composition is in a range of from about 2:1
`to about 6:1.
`[0023] A ninth embodimentofthe present invention (Em-
`
`bodiment E9) is a lyophilized composition as originally
`described wherein trehalose is the non-reducing sugar, the
`moisture content ofthe composition is about 0.5 wt. % orless,
`the glass transition temperature T,,(c) of the compositionis at
`least about 90° C., and the trehalose-to-caspofungin weight
`ratio is in arrange of from about 2:1 to about 8:1. In an aspect
`of this embodiment, the glass transition temperature ‘I’,(c) is
`in a range of from about 90° C. to about 125° C.
`[0024] A tenth embodimentofthe 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 T,(c) is at least about 90° C., andthe trehalose-
`to-caspofungin weight ratio is in a range of from about 2:1 to
`about 6:1. In an aspect of this embodiment, the glass transi-
`tion temperature T,(c) is in a range of from about 90° C.to
`about 125°C.
`
`[0025] An eleventh embodimentof the present invention
`(Embodiment F.11) is a lyophilized compositionas originally
`described whichis prepared by lyophilizing an aqueous solu-
`tion comprising the caspofunginorits salt, the acetate buffer,
`and the one or more non-reducing sugars, wherein in the
`solution:
`
`(A) the caspofunginorits 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 amg/mL basis withrespect to caspofungin
`in a range of from about 2:1 to about 10:1; and
`[0028]
`(C) the acetate buffer has a concentrationin a range
`of from about 12.5 mMto about 200 mM.
`
`[0029] Aspects of Embodiment El] include the lyo-
`philized composition as just described in Embodiment Fl],
`wherein:
`
`(A1) the one or more non-reducing sugars1s a sugar
`[0030]
`selected from the group consisting oftrchalose, sucrose, raffi-
`nose, sorbitol and combinationsthereof.
`[0031]
`(A2) trehalose is the non-reducing sugar.
`[0032]
`(A3) the moisture content of the composition is
`about 0.5 wt. % orless.
`
`(A4) the moisture content of the composition is
`[0033]
`about 0.3 wt. % orless.
`
`
`
`(A5) the glass transition temperature T,(c) of the
`[0034]
`composition is at least about 90° C.
`[0035]
`(A6) the glass transition temperature T,(c) of the
`composition is in a range of from about 90° C. to about 125°
`Cc.
`the non-reducing sugar(s)-to-caspofungin
`(A7)
`[0036]
`weightratio ofthe composition is in a range of from about 2:1
`to about 8:1.
`the non-reducing sugar(s)-to-caspofungin
`[0037]
`(A8)
`weightratio 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 compositionis about 0.5 wt. % or less, and
`the glass transition temperature T,(c) is at least about 90° C.
`[0039]
`(A 10) the composition is the sameasset forth in A9,
`except that the moisture content is about 0.3 wt. %orless.
`[0040]
`(A111) trehaloseis the non-reducing sugar, the mois-
`ture content is of about 0.5 wt. % orless, the glass transition
`temperature T,(c) is at cast about 90° C., and the trchalosc-
`to-caspofungin weight ratio is in a range of from about 2:1 to
`about 8:1.
`[0041]
`(A12) trehaloseis the non-reducing sugar, the mois-
`ture content is about 0.3 wt. % or less, the glass transition
`temperature T,(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 6:1.
`[0042]
`(A13)thecompositionis the sameasset forthinAl1
`exceptthatthe glass transition temperature T,(c) is ina range
`of from about 90° C. to about 125° C.
`[0043]
`(A14)thecompositionis the sameasset forth inA12
`exceptthatthe glass transition temperature T,(c) is ina range
`of from about 90° C. to about 125° C.
`[0044] A twelfth embodimentofthe present invention (Em-
`bodiment E12) is a lyophilized composition as set forth mn
`
`Embodiment Ell, wherein in the aqueous solution from
`whichthe lyophilized composition is prepared:
`[0045]
`(A) the concentration of caspofungin orits 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 caspofungin is in a range of from about 4:1 to about
`8:1; 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 embodimentof the present invention
`
`(Embodiment E13) is a lyophilized compositionas set forth
`
`in Embodiment E12, whereintrehalose is the non-reducing
`sugar, the moisture content ofthe composition is about 0.5 wt.
`%orless (e.g., about 0.3 wt. % or less), and the glass transi-
`tion temperature T,,(c) ofthe compositionis 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, whercin in the aqueous solution from
`whichthe lyophilized composition is prepared:
`[0050]
`(A) the concentration of caspofungin orits 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 mg/mL to about 300 mg/mL(1.e., a trehalose
`to caspofungin concentration ratio of about 6:1); and
`[0052]
`(C) the acctate buffer has a concentration in a range
`of from about 20 mM to about 60 mM.
`[0053] A fifteenth embodiment of the present invention
`
`(Embodiment E15) is a lyophilized composition asoriginally
`describedoras set forth in any ofthe foregoing embodiments
`
`AMNEALEX. 1007
`
`AMNEAL EX. 1007
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`

`

`US 2010/0137197 Al
`
`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 thestability 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 meansthat
`no reducing sugar is included as a component in the prepara-
`tion of the lyophilized composition and/orthat essentially no
`reducing sugaris present in the lyophilized composition.
`[0054] An “effective amount” 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 infectionor the like.
`[0055] The term“pharmaceutically acceptable salt” refers
`to a salt which is not biologically or otherwise undesirable
`(c.g., is neither toxic nor otherwise deleteriousto the recipient
`thereof). The caspofungin salt can suitably be amono-, di-, or
`tri-acid salt. The salls are suitably prepared by treating the
`free base with a suitable organic or morganic 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 lo 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 bythe Fehling’s test, which monitors the reduc-
`tion ofCu ++ to Cu+, with concomitant oxidationofthe sugar.
`Non-reducing sugars do not react in the Fehling’s test (i.c.,
`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, raffinose, and sorbitol.
`[0057] A “reducing sugar” refers to a carbohydrate 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 compoundscontaining primary amines.
`[0058]
`Theglass transition temperaturesreferred to herein
`(e.g., T,(s) and T,(c)) are the transition temperatures deter-
`mined using differential scanning calorimetry (DSC). DSC
`measures the change in heat capacity betweenthe glassy and
`rubberystates and is typically indicated by a change in base-
`line in a DSC thermogram.
`[0059] The glass transition temperature T,(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 andstill have a suitable T,(c), the presence ofa 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 ingredientby, for example, hydroly-
`sis. Accordingly, the lyophilized composition of the present
`invention is characterized by having a low moisture content.
`Moreparticularly. for the purposes ofthis invention,if (i) the
`amount of moisture in the composition is about 0.8 wt. % or
`less and(11) the T,(c) ofthe lyophilized compositionisat 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) mustbe satisfied for the composition to
`be a composition of the present invention. Thus, if a lyo-
`
`
`
`philized composition has a moisture content of less than
`about 0.8 wt. % but its T,(c) is below about 55° C., the
`composition is not a composition of the present invention.
`Furthermore, if a lyophilized composition has a T,(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 amois-
`ture content ofless than about 0.5 wt. % and a T,(c) above
`about 55° C., and preferably has a moisture content ofless
`than about 0.5 wt. % and a T,(c) above about 90° C.
`[0060] T,(s), the glass transition temperature ofthe one or
`more non-reducing sugars employed in the lyophilized anti-
`fungal composition of the invention is the glass transition
`temperature of the sugar(s) after lyophilization of the non-
`reducing sugar(s) in the same mannerasthe anti-fungal com-
`position is lyophilized, wherein the lyophilization generates
`an amorphous form of the non-reducing sugar(s). ‘The ‘l’,(s)
`value of the one or more non-reducing sugars used in the
`present invention is at least about 90° C. andis 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 T,(s) value of the sugars together in a
`mixture (after lyophilization) that must be at least about 90°
`C. A non-reducing sugar whose glass transition temperature
`is below90° C.can be included in the composition, provided
`that the T,(s) ofall of the non-reducing sugars together (after
`lyophilization) is about 90° C. or higher. Typically, however,
`each of the non-reducing sugars employedin the lyophilized
`composition has anindividual glasstransition 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 someother suitable extraction agent. The
`water present in the methanolor other reagentis then titrated
`with a Karl Fischersolution that reacts with the water to form
`colorless hydrogen iodide. Whenall 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 HI formed
`during thetitration.
`[0063] The term “about”, when modifying the quantity ofa
`substance or composition,or the value ofa physical property
`(e.g., moisture content, T,(c), T,(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 usc solutions in the real
`world; through inadvertenterror in these procedures; through
`differences in the manufacture, source, or purily 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” meansthe reported numerical value +10% thereof. In
`an aspect of this embodiment, the term “about” means the
`reported numerical value +5% thereof.
`[0064] An “cffective amount” of an acctate 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
`NaO8), a pH inthe indicated range in the aqueous solution
`
`AMNEALEX. 1007
`
`AMNEAL EX. 1007
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`

`US 2010/0137197 Al
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`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 25°C.
`[0066] The lyophilized compositions of the present inven-
`tion are not limited to the active ingredient (i-e., caspofungin)
`orits salt, the acetate buffer and the non-reducing sugar(s).
`The composition can include other components such as (i) a
`minor amountofa bulking agent(e.g., a polyol) in addition to
`the non-reducing sugar(s) or (11) an anti-oxidant such as BHT,
`BHA,alpha-tocopherol, or ascorbic acid. If employed, the
`bulking agent is typically present in an amountof 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 P1”), 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 T,(s) ofat least about 90° C., and an
`acetate buffer, wherein the concentration ratio, on a weight
`per unit volumebasis, ofthe one or more non-reducing sugars
`to caspofungin is in a range offrom about 1.1:1 to about 10:1;
`and
`
`(B) freeze-drying the aqueous solution to provide
`[0069]
`the lyophilized anti-fungal composition.
`[0070] A first embodiment of Process P1 (alternatively
`
`referred to herein as “Embodiment P1-E1”) 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 acctic acid and then adjusting the pH to
`[0072]
`be in a range of from about 4.5 to about 5.5 byaddition of
`base;
`(a3) adding caspofunginorits salt and adjusting the
`[0073]
`pH to a value in a range offrom about5 to about 7 (e.g., about
`6) by addition of more base; and
`[0074]
`(a4) optionallyfiltering 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 Pl, the
`sugars canbe 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 1f necessary to give the solution employed
`in sub-step a2,or alternatively the sugars can be added scpa-
`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-E2) is the processas originally described oras set forth in
`
`Embodiment P1-E1, wherein in the aqueoussolution result-
`ing from Step A the caspofungin orits salt has a concentration
`in a range offrom about 5 mg/mLto about 200 mg/mL, and
`
`
`
`the concentration ratio ofthe non-reducing sugar(s) to caspo-
`fungin is in a range of from about 2:1 to about
`10:1.
`[0077] A third embodiment of Process P1 (Embodiment
`P1-E3) is the processas originally described or as set forth in
`Embodiment P1-E1, wherein in the aqueoussolutionresult-
`ing from Step A the caspofunginorits salt has 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-
`funginis in a range offrom about 4:1 to about 8:1.
`
`[0078] A fourth embodiment of Process Pl (Embodiment
`P1-F4) is the processas originally described oras set forth in
`any one of Embodiments P1-F1 to P1-E3, wherein the one or
`more non-reducing sugars is selected from the group consist-
`ing, of trehalose, sucrose, raffinose, sorbitol and mixtures
`thereof.
`[0079] A fifth embodiment of Process Pl (Embodiment
`P1-E5) is the processas originally described or as sct forth in
`
`any one of Embodiments P1-E1 to P1-E3, wherein trehalose
`is the non-reducing sugar.
`[0080] A sixth embodiment of Process P1 (Embodiment
`P1-E6) is the processas 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 0.5
`wt. % orless.
`[0081] Aseventh embodimentof Process P1 (Embodiment
`P1-E7)is the process as originally described oras set forth in
`any one of the foregoing embodiments of P1, wherein the
`moisture content of the lyophilized composition is about 0.3
`wt. % orless.
`
`[0082] An eighth embodimentof Process P1 (Embodiment
`P1-E8)is the processas originally described or as set forth in
`any one of the foregoing embodiments of P1, wherein the
`lyophilized composition has a glass transition temperature
`T,(c) ofat least about 90° C. (e.g., ina range offrom about 90°
`C. to about 125° C.).
`[0083] The present invention also includes a lyophilized
`anti-fungal composition prepared by the process P1 as origi-
`nally described or as set forth in any one ofthe foregoing
`embodiments of P1.
`
`
`
`‘The freeze-drying (i.e, lyophilizing) of the aqueous
`[0084]
`solution resulting from Step A of Process P1 involvesfirst
`cooling the solution to a temperatureat 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 solutionis crystalline). The frozen
`solution is then typically subjectedto 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 removethe 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 guidelinesfor designing suitable freeze drying processes.
`Further descriptionof freeze drying is found in Remington—
`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 al temperatures up to and including room tempera-
`ture. Caspofungin has two main degradation products. The
`
`AMNEALEX. 1007
`
`AMNEAL EX. 1007
`
`

`

`US 2010/0137197 Al
`
`Jun. 3, 2010
`
`
`
`first is formed via hydrolysis in the pre-lyophilization solu-
`tion, and the secondis formedin 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
`sameor 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 Summaryof the Invention or as set forth in any one of
`Embodiments E1 to E15 or in anyaspectsor features thereof
`
`or (it) the lyophilized anti-fungal composition resulting from
`Process P1 as originally described or as set forth in any one
`Embodiments P1-[1 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
`M1 asoriginally described, wherein the parenterally accept-
`able solvent comprises water.
`[0088] Asecond embodiment of Method M1 (Embodiment
`M1-E2) is the Method M1 asoriginally described, wherein
`the parenterally acceptable solvent is selected from the group
`consisting of 0.9% 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
`M1-[3) is the Method M1 as originally described or as set
`
`forth in cither Embodiment M1-E1 or M1-E2, wherein 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
`M1-E4) is the Method M1 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 dosage formulation for parenteral administration
`prepared by the Method M1 asoriginally described or as set
`forth in any one of the foregoing embodiments of M1.
`[0092] The present inventionstill further includes a method
`for the treatment or prophylaxis of a fungal infection which
`comprises parenterally administering to a subject in need
`thereof an anti-fungal liquid formulation prepared by the
`Method M1 asoriginally described or as described in any one
`of the foregoing embodiments of Method M1.
`[0093] The present invention also includes an anti-fungal
`liquid dosage formulation prepared by the Method M1 as
`originally desc