as) United States
`a2) Patent Application Publication 10) Pub. No.: US 2019/0060240 Al
`
` Sundaram (43) Pub. Date: Feb. 28, 2019
`
`
`US 20190060240A1
`
`(54) STORAGE STABLE SINCALIDE
`FORMULATIONS
`
`(71) Applicant: MAIA Pharmaceuticals, Inc.,
`Princeton, NJ (US)
`
`(72)
`
`Inventor: Srikanth Sundaram, Somerset, NJ
`(US)
`
`(21) Appl. No.: 15/958,854
`(22)
`Filed:
`Apr. 20, 2018
`
`Related U.S. Application Data
`(60) Provisional application No.62/550,484,filed onAug.
`25, 2017.
`
`sas
`:
`:
`Publication Classification
`
`(51)
`
`Int. Cl.
`AGOIK YVI19
`A6IK YI16
`A6IK VYO8
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`A61K 38/08
`A6IP 1/16
`AOIP 1/18
`(52) US. CL
`CPC ween A61K 9/19 (2013.01); A6LK 9/1682
`(2013.01); A6LK 9/1617 (2013.01); A6LP 1/18
`(2018.01); AGOIK 908 (2013.01), AG6IK 38/08
`(2013.01); A6IP 1/16 (2018.01); A6LK 9/1611
`(2013.01)
`
`ABSTRACT
`
`57
`67)
`Disclosed herein are solid compositions that comprise sin-
`calide and are storage stable and which lack a buffer, and
`optionally, also lack a surfactant/solubilizer, wherein such
`compositions are storage stable. Also disclosed herein are
`.
`i
`toe
`.
`liquid compositions that comprise sincalide, wherein such
`compositions are storage stable, and may lack buffer and/or
`surfactant/solubilizer. Also provided are methods of making
`and administering the solid or liquid storage stable compo-
`sitions to a patient
`in need of, e.g., for the treatment,
`prevention, and/or diagnosis of gall bladder- and/or pancre-
`atic disorders; or other diagnostic imaging.
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`

`Patent Application Publication
`
`Feb. 28, 2019
`
`US 2019/0060240 Al
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`US 2019/0060240 Al
`
`Feb. 28, 2019
`
`STORAGE STABLE SINCALIDE
`FORMULATIONS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application claims benefit under 35 U.S.C. §
`119(e) of U.S. Provisional Patent Application No. 60/550,
`484,
`filed Aug. 25, 2017, and entitled “Storage Stable
`Sincalide Formulations” which application is hereby incor-
`porated by reference.
`
`TECHNICAL FIELD
`
`[0002] Disclosed herein are storage stable solid composi-
`tions of sincalide that are substantially free of buffers (and
`optionally surfactants/solubilizers), methods of making and
`using the compositions, and kits comprising the composi-
`tions. Also disclosed herein are storage stable liquid com-
`positions of sincalide, methods of making and using the
`compositions, and kits comprising the liquid compositions.
`Such liquid compositions may also be substantially free of
`buffers (and optionally surfactants/solubilizers).
`
`BACKGROUND OF THE INVENTION
`
`Sincalide is a cholecystopancreatic-gastrointestinal
`[0003]
`hormone peptide for parenteral administration. The active
`pharmaceutical
`ingredient, 1-De(5-oxo-L-glutamine-5-L-
`proline)-2-de-L-methioninecaerulein or “sincalide” (CAS
`#25126-32-3), is a synthetically prepared C-terminal octa-
`peptide of cholecystokinin (CCK-8), with the following
`amino acid sequence: Asp-Tyr(SO,H)-Met-Gly-Trp-Met-
`Asp-Phe-NH,.
`[0004]
`Sincalide (KINEVAC® Sincalide for Injection)
`wasfirst approved by Food and Drug Administration (FDA)
`in 1976, and was supplied as a sterile, nonpyrogenic,
`lyophilized white powder in containing nominally 5 ug
`sincalide, 45 mg sodium chloride as a bulking/tonicity agent,
`and sodium hydroxide or hydrochloric acid to adjust the pH
`to pH 5.5-6.5. The 5-mL Type I glass vial was sealed under
`a nitrogen headspace with a relative humidity (RH)ofless
`than 30% in the headspace of the vial (Huber RC (1978) J.
`Pharm. Sci. 67(9): 1239-1243). This two-ingredient formu-
`lation was approved with an 18-month shelf life when stored
`at -20° C. or below (U.S. Pat. No. 3,937,819; FDA Sum-
`mary Basis of Approval for NDA 017697). The recom-
`mended storage temperature is reported to be -4° C. else-
`where (Sargent NE (1976) Am. J. Roentgenol. 127: 267-
`271). This
`two-ingredient
`formulation (Sincalide
`for
`Injection) was incorporated into the U.S. Pharmacopeia,
`USP 24, NF 19, Jan.1, 2000, but the monograph remained
`unenforceable and was withdrawn in 2011.
`
`[0005] Various drawbacksin the manufacturing and analy-
`sis of the two-ingredient formulation of sincalide have been
`reported (U.S. Pat. No. 6,803,046). For example,
`the
`potency of the two-ingredient formulation was analyzed
`using a guinea pig gallbladder contraction bioassay, with a
`wide acceptance range of 80-125%. This bioassay was
`reportedly unable to distinguish between the bioactivity of
`sincalide and the bioactivity of sincalide degradants.
`Accordingly, a 20% overage of sincalide was required in
`previous sincalide formulations to compensate for the limi-
`tations of the bioassay (U.S. Pat. No. 6,803,046, supra). The
`U.S. Pharmacopeia has since removed the Sincalide for
`Injection monograph from the USP since it deemed the
`
`complex functional bioassay not suitable for use as a public
`standard and its attempts to replace the functional bioassay
`with a quantitative chemical assay were not successful.
`Another lyophilized formulation of Sincalide (KINEVAC®)
`was approved in 2002, and contained the following ingre-
`dients: 170 mg mannitol as a bulking agent/tonicity adjuster;
`30 mg oflysine, 15 mg of arginine, and 4 mg of methionine
`as stabilizers; 2 mg of pentetic acid as a chelator; 0.04 mg
`of sodium metabisulfite as a stabilizer/antioxidant; 0.005 mg
`of polysorbate (Tween) 20 as a surfactant/solubilizer; 9 mg
`potassium phosphate dibasic as a buffer; and hydrochloric
`acid and/or sodium hydroxide to adjust the pH to 6.0 to 8.0
`(Daily Med “Label: Kinevac—sincalide injection, powder,
`lyophilized, for solution” NIH: U.S. National Library of
`Medicine, last updated Jul. 13, 2015; U.S. Pat. No. 6,803,
`046, supra). The purity of this formulation was assessed by
`a sincalide-specific assay such as high-performance liquid
`chromatography (HPLC).
`[0006] The current formulation of KINEVAC® has been
`in recurrent shortages: it was first listed in the FDA Drug
`Shortages database from June 2013 to December 2015, and
`is currently on the FDA shortage list again since Mar. 1,
`2017. Additionally, the current formulation of KINEVAC®
`appears to have issues with stability, as in January 2015,
`FDA approved a request to have KINEVAC’s® shelf-life
`reduced from 24 months to 15 months when stored at 25° C.
`
`[0007] There is thus need for additional solid formulations
`of sincalide with pharmaceutically acceptable stability pro-
`files.
`
`ready-to-use (e.g., ready-to-dilute)
`[0008] Additionally,
`formulations for sincalide are currently not available.
`Lyophilized products must be reconstituted in the appropri-
`ate diluent with the appropriate volumeof the diluent prior
`to administration to the patient. In some cases, the recon-
`stituted solution may further need to be dilutedpriorto use.
`Additional drug preparation steps such as reconstitution and
`dilution can result in errors in the drug preparation process
`(wrong drug-preparation error as defined by ASHP Guide-
`lines on Preventing Medication Errors in Hospitals). Medi-
`cation errors compromise patients’ health and safety, their
`confidence in the health care system, and increase health-
`care costs. This ASHP guideline thus recommendsthe use of
`medications in ready-to-administer forms whenever pos-
`sible.
`
`including
`[0009] There is thus need for ready-to-use,
`ready-to-dilute,
`liquid formulations of sincalide that are
`storage stable and eliminate or reduce the potential for drug
`preparation errors.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0010]
`
`FIG. 1 is the chemical structure of sincalide.
`
`SUMMARY OF THE INVENTION
`
`[0011] Described herein are solid (lyophilized) or liquid
`(aqueous ready-to-use (e.g., ready-to-dilute) formulations,
`reconstituted formulations, etc.) of sincalide that are sur-
`prisingly stable in storage. See, e.g., Tables 3, 5-8. Such
`stability is unexpected in light of the stability profile of
`previous sincalide formulations that demonstrated a shelf-
`life of less than 18 months in long term storage (25° C.)
`conditions in lyophilized forms. Such unexpected findings
`are seen despite solid compositions herein lacking a buffer,
`or lacking a buffer and surfactant/solubilizer.
`
`3
`
`

`

`US 2019/0060240 Al
`
`Feb. 28, 2019
`
`[0012] More surprising is the demonstration herein that an
`humidity, e.g., wherein after 9 months of storage at 25° C.
`
`aqueoussolution of sincalide may haveashelf-life ofat least and 60% relative humidity, and as measured by HPLC,the
`3 months, 6 months, or 12 months in long term storage
`composition comprises
`(2°-8° C.) conditions. Such aqueous sincalide compositions
`[0031]
`(a) less 2.5% total impurities,
`may also lack a buffer or also lack both a buffer and
`[0032]
`(b) retains at least 95% of active sincalide
`surfactant/solubilizer.
`[0033]
`(c) less than 1.5% of any individual impurity,
`and
`
`[0013] Compositions comprising the storage stable formu-
`lations, methods of making the compositions, kits compris-
`ing the compositions(e.g., in appropriate vials, and option-
`ally a
`fluid portion (e.g., Water
`for
`Injection)
`for
`reconstituting the
`lyophilized compositions described
`herein), and use of the compositions, e.g., in therapeutic,
`diagnostic, and/or imaging methods, are provided.
`[0014] Described herein are compositions comprising sin-
`calide, wherein the compositions have an unexpected shelf-
`life. The sincalide compositions described herein may be in
`the form of a lyophilized powder, e.g., may be solid, for
`example, one which is packaged under a vacuum orpartial
`vacuum.
`
`(d) any combination of(a)-(c),
`[0034]
`and wherein the solid (lyophilized) composition does not
`comprise dibasic potassium phosphate.
`[0035]
`In some embodiments, the solid (lyophilized) com-
`position does not comprise a phosphate buffer. In some
`embodiments, the solid (lyophilized) composition does not
`comprise any buffers. In some further embodiments, the
`solid (lyophilized) compositions do not comprise buffer and
`also do not comprise surfactant/solubilizer.
`[0036] The solid compositions described herein include,
`for example, pharmaceutical sincalide compositions includ-
`ing: a therapeutically effective amount of sincalide; 1 to 4
`mg pentetic acid; 15 to 45 mg arginine hydrochloride; 2 to
`8 mg methionine; 7.5 to 30 mg lysine hydrochloride; 0.02 to
`1 mg sodium metabisulfite; 85 to 340 mg mannitol; and have
`a pH from 6.5 to 7.5, wherein the composition does not
`contain a buffer having a pKa within one unitof the pH, and
`wherein the composition is storage stable. Such composi-
`tions can be a lyophilized powder, and can be packaged
`under a vacuum.
`
`In some embodiments, described herein is a solid
`[0015]
`(lyophilized) composition comprising sincalide, wherein the
`shelf-life of the solid (lyophilized) composition is at least 18
`months, or, for example, at least 24 months when stored at
`25° C. and 60% relative humidity, e.g., wherein after 18
`months (or 24 months) of storage at 25° C. and 60% relative
`humidity, and as measured by HPLC,
`the composition
`comprises
`(a) less than 5% total impurities,
`[0016]
`[0037] Compositions described herein may beliquid,e.g.,
`(b) retains at least 90% of active sincalide
`[0017]
`in the form of a ready-to-use aqueous sincalide solution
`(c) less than 2% of any individual impurity, and
`[0018]
`which exhibits storage stability. For example, the aqueous
`(d) any combination of (a)-(c),
`[0019]
`sincalide solutions described herein, after being stored for 6
`and wherein the solid (lyophilized) composition does not
`months at 2°-8° C. contain less than 5% total impurities,
`comprise dibasic potassium phosphate.
`more than 90% of active sincalide, and less than 2% of any
`[0020]
`In some embodiments, described herein is a solid
`individual impurity.
`(lyophilized) composition comprising sincalide, wherein the
`[0038] Also described herein is a liquid (e.g., an aqueous
`shelf-life of the solid (lyophilized) composition is at least 15
`ready-to-use composition, a reconstituted lyophilized com-
`months when stored at 25° C. and 60% relative humidity,
`position, etc.) comprising sincalide, wherein the shelf-life of
`e.g., wherein after 15 months of storage at 25° C. and 60%
`the aqueous composition is at least 18 months when stored
`relative humidity, and as measured by HPLC, the composi-
`at 2°-8° C., e.g., wherein after 18 months of storage at 2°-8°
`tion comprises
`C., and as measured by HPLC, the composition comprises
`[0021]
`a) less than 5% total impurities,
`[0039]
`(a) less than 5% total impurities,
`[0022]
`b) retains at least 90% of active sincalide
`[0040]
`(b) at least 90% of active sincalide
`[0023]
`c) less than 2% of any individual impurity, and
`[0041]
`(c) less than 2% of any individual impurity, and
`[0024]
`d) any combination of(a)-(c),
`[0042]
`(d) any combination of(a)-(c).
`and wherein the solid (lyophilized) composition does not
`[0043] Also described herein is a liquid (e.g., an aqueous
`comprise dibasic potassium phosphate.
`ready-to-use composition, a reconstituted lyophilized com-
`[0025]
`Insome further embodiments, described herein is a
`position, etc.) comprising sincalide, wherein the shelf-life of
`
`solid (lyophilized) composition comprising—sincalide,
`the aqueous composition is at least 18 months when stored
`wherein the shelf-life of the solid (lyophilized) composition
`at 2°-8° C., e.g., wherein after 15 months of storage at 2°-8°
`is at least 12 months when stored at 25° C. and 60% relative
`C., and as measured by HPLC, the composition comprises
`[0044]
`(a) less than 5% total impurities,
`[0045]
`(b) at least 90% of active sincalide
`[0046]
`(c) less than 2% of any individual impurity, and
`[0047]
`(d) any combination of(a)-(c).
`[0048] Also described herein a liquid (e.g., an aqueous
`ready-to-use composition, a reconstituted lyophilized com-
`position, etc.) composition comprising sincalide, wherein
`the shelf-life of the aqueous composition is at
`least 12
`months when stored at 2°-8° C., e.g., wherein after 12
`months of storage at 2°-8° C., and as measured by HPLC,
`the composition comprises
`[0049]
`(a) less than 5% total impurities,
`[0050]
`(b) at least 90% of active sincalide
`
`humidity, e.g., wherein after 12 months of storage at 25° C.
`and 60% relative humidity, and as measured by HPLC,the
`composition comprises
`[0026]
`(a) less than 4% total impurities,
`[0027]
`(b) retains at least 90% of active sincalide
`[0028]
`(c) less than 1.5% of any individual impurity,
`and
`
`(d) any combination of (a)-(c),
`[0029]
`and wherein the solid (lyophilized) composition does not
`comprise dibasic potassium phosphate.
`[0030]
`In some other further embodiments, described
`herein is a solid (lyophilized) composition comprising sin-
`calide, wherein the shelf-life of the lyophilized composition
`is at least 9 months when stored at 25° C. and 60% relative
`
`4
`
`

`

`US 2019/0060240 Al
`
`Feb. 28, 2019
`
`(c) less than 2% of any individual impurity, and
`[0051]
`(d) any combination of (a)-(c).
`[0052]
`[0053] Also described herein is a liquid (e.g., an aqueous
`ready-to-use composition, a reconstituted lyophilized com-
`position, etc.) composition comprising sincalide, wherein
`the shelf-life of the aqueous composition is at least 6 months
`when stored at 25° C./65% relative humidity, e.g., wherein
`after 6 months of storage at 2°-8° C., and as measured by
`HPLC, the composition comprises
`[0054]
`(a) less than 5% total impurities,
`[0055]
`(b) at least 90% ofactive sincalide
`[0056]
`(c) less than 2% of any individual impurity, and
`[0057]
`(d) any combination of (a)-(c).
`[0058] Also described herein is a liquid (e.g., an aqueous
`ready-to-use composition, a reconstituted lyophilized com-
`position, etc.) composition comprising sincalide, wherein
`the shelf-life of the aqueous composition is at least 3 months
`when stored at 25° C./65% relative humidity, e.g., wherein
`after 3 months of storage at 2°-8° C., and as measured by
`HPLC, the composition comprises
`[0059]
`(a) less than 5% total impurities,
`[0060]
`(b) at least 90% ofactive sincalide
`[0061]
`(c) less than 2% of any individual impurity, and
`[0062]
`(d) any combination of (a)-(c).
`[0063]
`In some embodiments, the liquid composition does
`not comprise dibasic potassium phosphate. In some embodi-
`ments, the liquid composition does not comprise a phos-
`phate buffer. In some embodiments, the liquid composition
`does not comprise any buffers. In some embodiments, the
`liquid compositions do not comprise any buffers and do not
`comprise any surfactant/solubilizer.
`[0064] Other embodiments of such compositions can be
`ready-to-use aqueous solutions, for example, comprising: a
`therapeutically effective amount of sincalide; 0.4 to 5
`mg/mL pentetic acid; 6 to 30 mg/mL arginine hydrochloride;
`0.8 to 5 mg/mL methionine; 3 to 15 mg/mL lysine hydro-
`chloride; 0.008 to 1 mg/mL sodium metabisulfite; and 34 to
`170 mg/mL mannitol, exhibiting storage stability, such that
`the compositions, for example, stored at 2°-8° C. for 6
`months contain less than 5% total impurities, more than 90%
`active sincalide, and less than 2% of any individual impurity.
`Such aqueous compositions may lack a buffer, or optionally
`may additionally lack a surfactant/solubilizer
`compositions
`[0065] The
`solid or
`liquid
`sincalide
`described herein may comprise a stabilizer and/or a bulking
`agent/tonicity adjuster. In some embodiments, the stabilizer
`is selected from the group consisting of pentetic acid,
`arginine hydrochloride, L-methionine, L-lysine hydrochlo-
`ride, sodium metabisulfite, and a combination thereof. In
`some embodiments, the bulking agent/tonicity adjuster com-
`prises mannitol.
`[0066]
`In particular embodiments, compositions described
`herein may comprise sincalide, wherein the composition
`does not contain a buffer (e.g., does not contain a phosphate
`buffer, such as dibasic potassium phosphate), and wherein
`the composition is stable in storage. Sincalide compositions
`described herein may further comprise a stabilizer (e.g.,
`pentetic acid, arginine hydrochloride, L-methionine, L-ly-
`sine hydrochloride, sodium metabisulfite, or combinations
`thereof) and/or a bulking agent/tonicity adjuster (e.g., man-
`nitol). The sincalide compositions described herein may also
`not contain a surfactant/solubilizer (e.g., polysorbate 20 or
`
`polysorbate 80). Some particular sincalide compositions
`described herein contain neither dibasic potassium phos-
`phate, nor polysorbate 20.
`[0067] The sincalide compositions described herein may
`contain chelators (e.g. pentetic acid), stabilizers (e.g., com-
`binations of L-arginine hydrochloride, L-methionine, L-ly-
`sine hydrochloride, and sodium metabisulfite), and bulking
`agents/tonicity adjusters (e.g., mannitol), buffers(e.g., diba-
`sic potassium phosphate), and surfactants/solubilizers (e.g.,
`polysorbate 20).
`[0068] The description also includes methods of making
`storage stable sincalide compositions by mixing: a thera-
`peutically effective amount of sincalide; and an excipient,
`wherein the excipient consists essentially of: at least one
`stabilizer; at least one bulking agent/tonicity adjuster; at
`least one chelator, or any combination of these (e.g., L-ar-
`ginine hydrochloride, L-methionine, L-lysine hydrochlo-
`ride, sodium metabisulfite, mannitol, and pentetic acid.), and
`water, wherein the composition has a pH from 6.5 to 7.5, and
`the storage stable solid sincalide composition does not
`contain a buffer having a pKa within one unit of the pH, or
`neither contains a buffer nor a surfactant/solubilizer. Such
`
`methods of making storage stable solid sincalide composi-
`tions can also include lyophilizing the mixture ofsincalide,
`excipients and water, e.g., under a vacuum.
`[0069] Aqueous sincalide compositions can also be made
`by mixing: a therapeutically effective amount of sincalide;
`and excipients, wherein the excipients comprise: at least one
`stabilizer; at least one bulking agent/tonicity adjuster; at
`least one chelator, or any combination of these (e.g., L-ar-
`ginine hydrochloride, L-methionine, L-lysine hydrochlo-
`ride, sodium metabisulfite, mannitol, and pentetic acid.), and
`water, wherein the composition has a pH from 6.5 to 7.5.
`These storage stable aqueous sincalide compositions also
`maylack a buffer having a pKa within one unit of the pH,
`or lack both a buffer and a surfactant/solubilizer.
`
`[0070] The description also includes methodsforthe treat-
`ment, prevention, and/or diagnosis of gall bladder- and/or
`pancreatic disorders; or other diagnostic imaging a patient in
`need thereof by administering to the patient pharmaceutical
`sincalide compositions described herein (containing excipi-
`ents, for example, L-arginine hydrochloride, L-methionine,
`L-lysine hydrochloride, sodium metabisulfite, mannitol, and
`pentetic acid).
`[0071] Also described herein are kits comprising the
`described compositions optionally also including a fluid
`component.
`
`DETAILED DESCRIPTION
`
`[0072] Described herein are solid formulations of sin-
`calide that are surprisingly as stable and/or morestable than
`KINEVAC® even though the compositions lack a buffer
`(e.g., lack dibasic potassium phosphate, lack any phosphate
`buffer, and/or lack any buffer), and optionally, lack both a
`buffer and a surfactant/solubilizer. In addition, described
`here are liquid formulations of sincalide which display
`storage stability, and optionally lack a buffer or lack both a
`buffer and surfactant/solubilizer. Since sincalide may be
`administered as an intravenous bolus or by intravenous
`infusion or by intramuscular administration, there is a need
`for aqueous liquid formulationsof sincalide that are storage
`stable either under USP controlled room temperature or
`refrigerated conditions.
`
`5
`
`

`

`US 2019/0060240 Al
`
`Feb. 28, 2019
`
`to the marketed lyophilized KINE-
`In contrast
`[0073]
`VAC® sincalide formulation (for which the ingredients are
`dissolved in water, sterilized by filtration, filled into vials,
`and subjected to a lyophilization process in order to remove
`the water, and thus require KINEVAC® reconstitution in 5
`mLofSterile Water for Injection and/or dilution in 30 or 100
`mL of 0.9% Sodium Chloride Injectionprior to use), the use
`of aqueous ready-to-dilute or ready-to-use formulations and
`storage stable compositions described herein reduces the
`number of errors introduced in preparation of the drug
`product.
`the synthetically-prepared
`“Sincalide” includes
`[0074]
`C-terminal octapeptide of cholecystokinin (CCK-8), with
`the amino acid sequence: Asp-Tyr(SO,H)-Met-Gly-Trp-
`Met-Asp-Phe-NH,, as well as derivatives thereof which
`have been optimized or modified (to improve stability,
`potency, pharmacokinetics, etc.), but retain the biological
`activity ofthe original octapeptide. For example, monomeric
`or multimeric forms of the octapeptide, portions of the
`octapeptide, and/or or octapeptides in which the methionine
`and/or aspartic acid residues are included within the term
`“sincalide” so long as the forms, portions and/or derivatives
`thereof retain the biological activity of CCK8.
`[0075]
`“Ready-to-dilute” and/or “ready-to-use”refers to a
`sterile aqueous (liquid) injectable composition that has not
`been reconstituted from a lyophilized composition. In some
`embodiments (e.g., ready-to-dilute), the “ready-to-use” for-
`mulation can be further diluted in an appropriate diluent,
`e.g., a pharmaceutically acceptable carrier, such as but not
`limited to Sterile Water for Injection, 0.9% Sodium Chloride
`Injection, or 5% Dextrose in Water, to a lower sincalide
`concentration for administration.
`
`Solid Compositions
`
`[0076] Described herein are solid compositions compris-
`ing sincalide, wherein the compositions lack a buffer, or lack
`both a buffer and a surfactant/solubilizer, and wherein the
`compositions are storage stable. Although the solid compo-
`sitions described herein comprise sincalide, are storage
`stable, and lack a buffer, and optionally lack a surfactant/
`solubilizer, the compositions may otherwise include a vari-
`ety of excipients that are not a buffer (and optionally not a
`surfactant/solubilizer)
`including,
`antioxidants,
`bulking
`agents/tonicity adjusters, chelating agents,
`complexing
`agents, crosslinking agents, co-solvents, osmolality adjus-
`tors,
`stabilizers, pH adjustors,
`lyoprotectants/cryopro-
`tectants, air/liquid and/or ice-liquid interface protectants
`(protectants against surface induced denaturation), freeze-
`thaw protectants, protectants against protein/peptide dena-
`turation, protectants for rehydration, and wetting agents. In
`some embodiments, the solid compositions described herein
`comprise sincalide, are storage stable, lack a buffer and also
`optionally lack a surfactant/solubilizer, and further comprise
`excipients that perform the functions of at
`least:
`(4) a
`stabilizer, (11) a bulking agent/tonicity adjuster, and/or(iii) a
`chelator. Typically, each of these functions is performed by
`a different excipient. However, in some embodiments of the
`invention a single excipient may perform more than one
`function. For example, a single excipient may be multi-
`functional, e.g. amino acids may function as bulking agents
`and/or stabilizers and other excipients may function, for
`example, as both a stabilizer and a chelator or as both a
`bulking agent and a tonicity adjuster. Alternatively, multiple
`excipients serving the same function may be used. For
`
`example, the formulation may contain one or more excipi-
`ents that function as, for example, a stabilizer. “Excipient”
`as used herein does not include any ingredient having a pKa
`within one unit of the pH of a solid composition disclosed
`herein prior to lyophilization, which is generally between
`6.5 to 7.5.
`
`Liquid Compositions
`
`[0077] Described herein are storage stable liquid compo-
`sitions comprising sincalide. The liquid compositions may
`optionally lack a buffer, and may further optionally lack both
`a buffer and a surfactant/solubilizer. The compositions may
`include a variety of excipients including, antioxidants, bulk-
`ing agents/tonicity adjusters, chelating agents, complexing
`agents, crosslinking agents, co-solvents, osmolality adjus-
`tors,
`stabilizers, pH adjustors,
`lyoprotectants/cryopro-
`tectants, air/liquid and/or ice-liquid interface protectants
`(protectants against surface induced denaturation), freeze-
`thaw protectants, protectants against protein/peptide dena-
`turation, protectants for rehydration, and wetting agents. In
`some embodiments,
`the liquid compositions described
`herein comprise sincalide, are storage stable, and comprise
`excipients that perform the functions of at
`least:
`(4) a
`stabilizer, (11) a bulking agent/tonicity adjuster, and/or(iii) a
`chelator (such liquid sincalide compositions may lack a
`buffer and optionally may also lack both a buffer and a
`surfactant/solubilizer). Typically, each of these functions is
`performed by a different excipient. However,
`in some
`embodiments of the invention a single excipient may per-
`form more than one function. For example, a single excipi-
`ent may be multi-functional, e.g. amino acids may function
`as bulking agents and/orstabilizers and other excipients may
`function, for example, as both a stabilizer and a chelator or
`as both a bulking agent and a tonicity adjuster. Alternatively,
`multiple excipients serving the same function may be used.
`For example,
`the formulation may contain one or more
`excipients that function as, for example, a stabilizer. In
`embodiments described herein, wherein the liquid sincalide
`formulations lack a buffer, an excipient as used herein does
`not include any ingredient having a pKa within one unit of
`the pH of a liquid composition disclosed herein, which is
`generally between 6.5 to 7.5.
`
`Buffers
`
`[0078] The solid sincalide formulations as described
`herein lack, and the liquid sincalide formulations as
`described herein optionally lack, buffers. Buffers are gener-
`ally employed to stabilize the pH of a given formulation. In
`particular embodiments, a buffer has a pKa within one unit
`of a desired formulation pH.
`In some embodiments, a
`composition as described herein comprises sincalide,
`is
`storage stable, and lacks a buffer having a pKa within one
`unit of the pH of the composition. A buffer may be phos-
`phoric acid, phosphate (e.g., monobasic or dibasic sodium
`phosphate, monobasic or dibasic potassium phosphate, etc.),
`citric acid, citrate (e.g., sodium citrate, etc.), sulfosalicylate,
`acetic acid, acetate (e.g., potassium acetate, sodium acetate,
`etc.), methyl boronic acid, boronate, disodium succinate
`hexahydrate, lactic acid, lactate (e.g., sodium lactate,etc.),
`maleic acid, maleate, potassium chloride, benzoic acid,
`sodium benzoate, carbonic acid, carbonate (e.g., sodium
`carbonate, etc.), bicarbonate (e.g., sodium bicarbonate,etc.),
`boric acid, sodium borate, sodium chloride, succinic acid,
`
`6
`
`

`

`US 2019/0060240 Al
`
`Feb. 28, 2019
`
`embodiments, a composition as described herein comprises
`succinate (e.g., sodium succinate), tartaric acid, tartrate (e.g.,
`sincalide,
`is storage stable,
`lacks a buffer (e.g., dibasic
`sodium tartrate, etc.),
`tris-(hydroxymethyl)aminomethane,
`biological buffers (such as N-2-hydroxyethylpiperazine,N'-
`potassium phosphate) and comprises or lacks a surfactant/
`
`
`
`2-ethanesulfonic (HEPES), CHAPS and_otheracid solubilizer, wherein the surfactant/solubilizer is a polysor-
`“Good’s” buffers), or any combination thereof. In some
`bate.
`In some embodiments,
`a
`solid composition as
`embodiments, a composition as described herein comprises
`described herein comprises sincalide,is storage stable, lacks
`sincalide, is storage stable, and lacks a buffer, wherein the
`a buffer (e.g., dibasic potasstum phosphate), and lacks or
`buffer is a phosphate buffer. In some embodiments, a com-
`comprises a surfactant/solubilizer, wherein the surfactant/
`position as described herein comprises sincalide, is storage
`solubilizer is a polysorbate 20.
`stable, and lacks a buffer, wherein the buffer is dibasic
`potassium phosphate. Despite lacking a buffer, a sincalide
`composition described herein preferably has a pH from 6.0
`to 8.0, e.g., as a ready-to-use or ready-to-dilute aqueous
`formulation or, for the lyophilized forms described herein, as
`an aqueous composition just prior to lyophilization and/or
`just after reconstitution of a lyophilized formulation. In
`some embodiments, despite lacking a buffer, compositions
`described herein preferably have a pH from 6.5 to 7.5, e.g.,
`as a solid formulation prior to lyophilization or after recon-
`stitution from the solid phase, or as ready-to-use or ready-
`to-dilute aqueous formulations.
`
`Stabilizers/Chelators
`
`In some embodiments, a composition as described
`[0080]
`herein comprises sincalide and a stabilizer, wherein the
`composition does not contain (1.e.,
`lacks) a buffer (e.g.,
`dibasic potasstum phosphate) and optionally also does not
`contain a surfactant/solubilizer (e.g., polysorbate 20), and
`wherein the composition is storage stable. A wide variety of
`antioxidants or reducing agents can be usedasstabilizers,
`including but not limited to, acetylcysteine, cysteine, ascor-
`bic acid, benzyl alcohol, citric acid, pentetic acid or dieth-
`ylenetriamine pentaacetic acid (DTPA), propyl gallate,
`methylparaben, sulfoxylate, propylparaben, edetic acid or
`ethylenediaminetetraacetic acid (EDTA), disodium EDTA
`dihydrate, dithiothreitol, glutathione, monothioglycerol,
`potassium metabisulfite, sodium formaldehyde sulfoxylate,
`sodium sulfite, sodium succinate, sodium metabisulfite,
`stannous chloride, thioacetic acid, thiodiglycerol, thioetha-
`nolamine, thioglycolic acid, 2-aminoethanethiol (cysteam-
`ine), butylated hydroxyanisole (BHT), and sodium sulfate
`and derivatives thereof, including salts and sulfurous acid
`salts. Sodium metabisulfite is a preferred antioxidant stabi-
`lizer. In some embodiments, a composition as described
`herein comprises sincalide and a stabilizer (e.g., sodium
`metabisulfite), wherein the composition does not contain
`(1.e., lacks) a buffer (e.g., dibasic potassium phosphate) and
`optionally also does not contain a surfactant/solubilizer
`(e.g., polysorbate 20), and wherein the composition is stor-
`age stable.
`[0081]
`Pentetic acid (DTPA)an antioxidantstabilizer, may
`also act as a chelator. Another non-limiting example of a
`chelator includes edetic acid (EDTA). In some embodi-
`ments, a solid composition as described herein comprises
`sincalide and chelator (e.g., pentetic acid), wherein the
`composition does not contain (1.e.,
`lacks) a buffer