(12) Granted patent specificaon (19) NZ (11) 773548 (13) B2(47) Publicaon date: 2021.12.24(54) STABLE INTRANASAL FORMULATIONS OF CARBETOCIN(51) Internaonal Patent Classificaon(s):A61K 9/08 A61K 38/095(22) Filing date: (73) Owner(s):2019.09.20 LEVO THERAPEUTICS, INC.(23) Complete specificaon filing date: (74) Contact:2019.09.20 RnB IP Pty Ltd(30) Internaonal ty Data: (72) or(s):US ,152 2018.09.20 BRYANT, ChristopherUS 62/876,857 2019.07.22 MANNING, Mark C.
HOLCOMB, Ryan E.(86) aonal Applicaon No.: KATAYAMA, Derrick S.(87) Internaonal Publicaon :WO/2020/061414(57) Abstract:The applicaon describes stable aqueous composions comprising relavely high concentraonsof carbetocin and a solubilizer and/or surface acve agent. The disclosed carbetocin composionsare effecve in the treatment of a neurodevelopmental disorder, such as Willi syndrome.
Addionally, the disclosed carbetocin composions show improved stability at room temperatureand/or under accelerated condions of stress.773548 B2 PCT/USZOl9/052090STABLE INTRANASAL FORMULATIONS OF CARBETOCINReferences to Related App_lications This application claims ty from US. Provisional Patent Application No.62/734,152, filed September 20, 2018, and US. Provisional Patent Application No. 62/876,857, filed July22, 2019, both of which are hereby incorporated by reference in their entirety.
Field of the Disclosure The present disclosure relates to stable intranasal pharmaceutical preparations ofocin, including those that demonstrate improved stability under various long-term storageconditions and/or under accelerated conditions of stress. The t disclosure also relates to methods ofpreparing such pharmaceutical ations. The present disclosure r relates to kits and the use ofthe intranasal pharmaceutical preparations for the treatment of evelopmental disorders, such as-Willi me, and related symptoms.
Background of the Disclosure Although both peptides and proteins are composed of amino acids, peptides aretypically distinguished from ns as having a r amino acid sequence, such as, for example, lessthan 50 amino acids. Because of this difference in size, peptides and proteins often possess differentthree-dimensional structures, properties, and functions. Peptides are used to treat various diseases andconditions. Owing to their low oral bioavailability, most peptides are administered parenterally. (FrokjaerS. et al. (2005) Nat Rev Drug Discov. 42298-306.) Parental drug delivery includes enous,subcutaneous (s.c.), and intramuscular routes of administration. An alternative to parenteral injections isnasal drug administration. (Pathak K. (2011) Int J Pharm Investig. 1(2): 62—63.) Nasal drug delivery hasseveral advantages, including ic delivery that avoids first-pass lism, easy administration,rapid onset of effect, and the possibility to circumvent the blood-brain barrier. In addition, intranasaladministration offers several practical advantages either from the viewpoint of ts (e.g.,noninvasiveness, essentially painless, ease of drug delivery, and favorable tolerability profile) orpharmaceutical ry (e.g., sterilization of nasal preparations is often unnecessary).
Depending on potency, it may be necessary to formulate a peptide at a highconcentration, but doing so may increase the likelihood of peptide aggregation. (Shire S.J. et al. (2004) JPharm Sci. 0-1402; Payne R. W. et al. (2006) Biopolymers 84:527-533.) One way to mitigatepeptide aggregation is to formulate the peptide at a pH far from its isoelectric point to generate a high netcharge. But for peptides t ionizable groups, pH optimization may not be possible. Consequently,maintaining a sufficient stability at high peptide concentrations may be challenging, ally sincepeptides generally do not possess higher-order structure, and their physical ity thus primarilydepends on the nature of their peptide-peptide interactions. Peptides in solution may also degrade via,in some cases necessary.e.g., deamidation, oligomerization, and oxidation, making refrigeration Carbetocin [(l-desamino—l-monocarba—2(O-methyl)-tyrosine) oxytocin] is anexample of an uncharged peptide. Carbetocin is a long-acting tic oxytocin analog. The structure ofcarbetocin is shown below.
NIH2H21»: 0>“‘% ‘i 0o HNo ‘ao 0 NH HN‘1 ‘2 3 a s 6 7 a 9CHz—CO-Tyr(M‘e)«I|e—Gln—Asn~HN~ICH-rCO-ProoLeu-GIy—NH,CHZW CH2 S CH2 Carbetocin is an unusual peptide: it is small (8 amino acids); possesses no charge,is cyclic, and is highly lipophilic. It is also known that carbetocin lacks a stable and well-defined tertiarystructure. Carbetocin is currently used outside the U.S. to treat or t postpartum hemorrhage duringor following caesarean section. As such, carbetocin is administered by slow intravenous (IV) singleion at a dose of 100 ug. This formulation (Duratocin®, Ferring) requires refrigeration and contains0.1 mg/mL of carbetocin, 9 mg sodium chloride, acetic acid — glacial to pH 3.8 and water for injection to1 mL. (Widmer M. et a1. (2016) Trials. 17:143.) Carbetocin (IV form) is currently registered in more than1O 70 countries under the trade names PABAL/DURATOCIN/ LONACTENE/DURATOBAL. r inj ectable carbetocin drug product currently in clinical trials,CARBETOCIN RTS, can be stored at 30 °C for at least 3 years. (Widmer M. et a1. (2016) Trials. 17: 143.)Other prior attempts to develop a heat—stable oxytocin formulation for injection have been essful.
(Hawe A. et al. (2009) Pharm Res. l679—1688; Avanti C. et al. (2012) M01 Pharm. 9(3):554—562;Avanti C. et al. (2011) AAPSJ. 284—290; Gard J.W. et al. (2002) Am J Obstet Gynecol. 186(3):496-498.) This room temperature stable (RTS) variant of carbetocin has ly been developed and is nowapproved in the European Union; this variant differs from the current carbetocin formulation in itsents. CARBETOCIN RTS contains 0.1 mg/mL of carbetocin, 1.19 succinic acid, 47.0 mg/mLmannitol, 1 mg/mL L—methionine, sodium ide 2N to pH 5.45, and water for injection to 1 mL.
(Widmer M. et a1. (2016) Trials. 17: 143.) Other attempts have been made to make stable high carbetocin ations usingtypical peptide excipients (e.g., surfactants); however, none of the studied excipients ted carbetocinaggregation. (Hggstedt U. B. et al. (2018). J Pharm Sci. 107(3):838—847.) Only in the absence ofheadspace was 15 mM sodium dodecyl e (SDS) capable of preventing shaking induced carbetocinaggregation.
In addition, when aqueous carbetocin solutions are manufactured, packaged,transported, stored, and d prior to administration to a patient, they are subject to mechanical andchemical stresses. These types of stresses can be detrimental to various ations of carbetocin insolution.
Given the propensity of carbetocin to aggregate in solution, a stable carbetocinpharmaceutical formulation that optimizes and s carbetocin’s in-use period, as well as deliversrelatively high content uniformity is ble. For example, an asal formulation that can be thawedby a patient and used for several days without aggregation or a change in the ocin content from onedose to another would enhance patient compliance and safety.
Thus, given carbetocin’s strong propensity to aggregate in solution, there remains aneed for stable carbetocin pharmaceutical preparations, including those that are stable to stress, that showrelatively high content uniformity of carbetocin over long periods of time before and after one or morefreeze/thaw cycles, are suitable for intranasal administration, e enhanced convenience and tcompliance, and/or are highly concentrated.
Summary of the Disclosure
[0012] It has been surprisingly found that improved carbetocin pharmaceuticalpreparations can be ed with n solubilizers and/or surface active agents, such as a viscoelasticr, for example, hydroxypropyl cellulose (HPMC), including those that contain highconcentrations of carbetocin and that are stable under conditions of stress.
For example, the pharmaceutical ations of the present disclosure remainunexpectedly stable even at relatively high trations of carbetocin (e.g., greater than aboutmg/mL to about 70 mg/mL) and under accelerated stress conditions. In some embodiments of theleast 10present disclosure, carbetocin is present in a pharmaceutical preparation in a concentration of atmg/mL, which is 100 times greater than that of the DURATOCIN® and CARBETOCIN RTS productsreferenced above. The carbetocin pharmaceutical preparations disclosed herein also t improvedstability even under conditions of mechanical stress and for extended periods of time. In addition, thepharmaceutical ations of the present sure are suitable for intranasal administration.
In certain embodiments, the stable intranasal pharmaceutical preparation comprisesIn at least onean aqueous solution of carbetocin and a solubilizer and/or surface active agent.embodiment, the ceutical ation does not include a surfactant (e. g., n-dodecyl-B-D-maltoside(DDM), poloxamer 188, polysorbate 20 or polysorbate 80, sodium dodecyl sulfate). In at least oneembodiment, the pharmaceutical preparation does not have reduced headspace, i.e., the container is notcompletely full.
In at least one embodiment, the present disclosure is directed to a stable intranasalpharmaceutical ation comprising an aqueous solution of carbetocin and a solubilizer and/or surfaceactive agent, wherein the solution has no visible solids after being subjected to agitation stress conditions.
Such a preparation may be sufficiently stable even under conditions of stress (e.g., shaking and stirring,pumping, freeze-thaw processes) for extended periods of time with little to no visible solids. In at leastvisual assessment,some embodiments, the pharmaceutical preparation has little to no aggregates byincluding photographs.
In at least one embodiment, the present disclosure is directed to a stable intranasalpharmaceutical preparation comprising an aqueous solution of carbetocin and a solubilizer and/or surfaceactive agent, such as HPMC, wherein the resulting preparation exhibits a vely high contentuniformity of carbetocin for long periods of time at room temperature, and also after one or morefreeze/thaw .
For example, the disclosed preparations show content uniformity of carbetocinafter thawing for up to 7 days (longer shelf life and/or in-use ). In at least some ments, thedisclosed carbetocin preparation is stable and does not aggregate for a period of time after one or more1O freeze/thaw cycles. In some ments, the pharmaceutical ation has little to no aggregates byvisual assessment, which may include photographs. In some embodiments, the carbetocin in the disclosedpreparation is evenly distributed throughout the preparation to ensure that ifthe preparation is, forexample, split in one or more preparations, each resulting preparation has an equal dose of carbetocin. Inwhich isone embodiment, the disclosed carbetocin preparations have a consistent dose of carbetocin,maintained between various preparation batches so that the patient receives the correct dose consistentlyover various strations. In at least one embodiment, the disclosed carbetocin ations eenhanced convenience and t compliance.
In at least one embodiment, the concentration of carbetocinIn at least one embodiment, the concentration ofranges from about 10 mg/mL to about 70 mg/mL.carbetocin ranges from about 10 mg/mL to about 40 mg/mL. In at least one embodiment, theconcentration of carbetocin ranges from about 11 mg/mL to about 36 mg/mL. In at least oneembodiment, the concentration of carbetocin is about 34.3 mg/mL. In at least one embodiment, theconcentration of carbetocin is about 11.4 mg/mL. In some embodiments, the high trationcarbetocin pharmaceutical preparation has no visible solids when stored at room temperature (e.g., 25 0C)for a sustained period of time. For example, the carbetocin pharmaceutical preparation has no visiblesolids for up to 3 years. In some embodiments, the carbetocin pharmaceutical preparation has novisible solids for 2 years. In some embodiments, the carbetocin pharmaceutical preparation has novisible solids for 1 year. In some embodiments, the carbetocin pharmaceutical preparation has novisible solids for up to 3 years when the headspace is near zero. In one embodiment, the carbetocin3O pharmaceutical preparation has no e solids for up to 3 years when the ace is substantiallyzero.
In at least some embodiments, the pharmaceutical preparation of carbetocincomprises a hydrotrope and/or HPMC, and the concentration of carbetocin in the ation ranges fromabout 1 mg/mL to about 15 mg/mL. In at least one embodiment, the concentration of carbetocin rangesfrom about 1 mg/mL to about 10 mg/mL. In at least one embodiment, the concentration of carbetocinranges from about 1 mg/mL to about 5 mg/mL. In at least one embodiment, the concentration ofcarbetocin is about 1 mg/mL. In at least one ment, the concentration of carbetocin is about 11.4mg/mL. In some embodiments, the ocin pharmaceutical preparation has no visible solids whenstored at room temperature (e.g., 25 °C) for a ned period of time. For example, the carbetocinpharmaceutical preparation has no visible solids for up to 3 years. In some embodiments, thecarbetocin pharmaceutical ation has no e solids for up to 3 years when the headspace isnear zero. In one embodiment, the carbetocin pharmaceutical preparation has no visible solids for upto 3 years when the headspace is ntially zero.
In some embodiments, the concentration of carbetocin in the ceuticalpreparation does not change over time (e. g., storage at 40 °C for 1 week, 40 °C for 2 weeks, 40 °C for 3weeks, 40 °C for 4 weeks, 40 0C for 5 weeks). In at least one embodiment, carbetocin is not subject tochemical degradation as measured by HPLC. For example, the tographic purity of carbetocin is1O thanr than 98%. In at least one embodiment, the chromatographic purity of carbetocin is greater99%. In at least one embodiment, the chromatographic purity of carbetocin is greater than 99.4%. In atleast one embodiment, the chromatographic purity of carbetocin is greater than 99.5%.
In at least one embodiment, the ocin pharmaceutical preparation is stable toshaking stress. In some embodiments, the preparation is subjected to shaking stress for at least 14 dayswhen the headspace is limited, and the aqueous carbetocin solution remains clear with little to no visibleparticles. In some embodiments, the preparation is subjected to intermittent shaking stress for at least 14days, and the aqueous carbetocin solution remains clear with little to no visible particles. In at least onement, carbetocin does not chemically degrade before or after shaking stress. For example, thechromatographic purity of ocin is greater than 98%. In at least one embodiment, thetographic purity of carbetocin is greater than 99%. In at least one embodiment, thechromatographic purity of carbetocin is 2 99.4. In at least one embodiment, the chromatographic purityof ocin is 2 99.5. Such chromatographic purity occurs with and without exposure to shaking stress.
The pharmaceutical preparations of carbetocin disclosed comprise a lizerand/or HPMC. The solubilizer is chosen from an amino acid, an interfacial stabilizer, or a hydrotrope. Inat least one embodiment, the amino acid may be chosen from a natural or unnatural amino acid. In oneembodiment, the natural amino acid is arginine. In at least some ments, the unnatural amino acidsand pyruvic acid derivatives, 3-substitutedmay be chosen from B-amino acids, homo-amino acids, prolinealanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linearis ancore amino acids, or N-methyl amino acids. In some embodiments, the unnatural amino acid3O arginine derivative chosen from L-2—aminoguanidinopropionic acid hydrochloride and 4-guanidinobutyric acid. In at least one ment, the acial stabilizer is a cyclodextrin derivative.
In at least one ment, the cyclodextrin may be chosen from methyl-B-cyclodextrin, randomlymethylated-B—cyclodextrin (RM-B—CD), sulfobutylether-B—cyclodextrin (SBE-B-CD), epichlorohydrin-,8;cyclodextrin, and carboxy methyl epichlorohydrin beta cyclodextrin. In at least one embodiment, thecyclodextrin is methyl-B-cyclodextrin. In at least one embodiment, the hydrotrope is an aromatic anioniccompound. In at least one embodiment, the rope is selected from the group consisting ofnicotinamide, sodium benzoate, and salicylate salts (e.g., sodium salicylate, potassium salicylate, lithiumsalicylate, ammonium salicylate, calcium salicylate, and magnesium salicylate).
In at least one embodiment, the ceutical ation comprisesnicotinamide. In another embodiment, the pharmaceutical preparation comprises sodium salicylate. Insome embodiments, the pharmaceutical ation comprises nicotinamide, sodium benzoate, salicylatesalt (e.g., sodium salicylate), methyl—B—cyclodextrin, or arginine and HPMC. The pharmaceuticalation of the present disclosure may also include additional excipients, such sorbitol, mannitol,e, lactose, trehalose, ethylenediaminetetraacetic acid (EDTA), potassium sorbate, acetate, andmethyl-B-cyclodextrin among others. In at least one embodiment, the additional excipient is sorbitol.
If present in the pharmaceutical preparation, the solubilizer may be chosen from acyclodextrin derivative. In at least some embodiments, the extrin derivative is chosen from methyl—B-cyclodextrin, randomly methylated-fl-cyclodextrin (RM-,B-CD), sulfobutylether—,B—cyclodextrin (SEE—,8-CD), epichlorohydrin-fl-cyclodextrin, and carboxy methyl epichlorohydrin beta cyclodextrin. In someembodiments, the extrin derivative is methyl-B-cyclodextrin.
If present in the pharmaceutical preparation, the surface active agent may bechosen from a viscoelastic r, for example, hydroxypropyl methylcellulose (HPMC). In at leastsome embodiments, the surface active agent is a cellulose derivative. In at least one embodiment, thecellulose derivative may be chosen from hydroxypropyl ose (HPC), hydroxypropyl methylcellulose, and carboxy methyl ethyl cellulose (CMEC). In some embodiments, the cellulose derivative isHPMC. If present in the pharmaceutical preparation, HPMC is present in an amount g from 0.005%to 0.05% w/v. In at least one embodiment, HPMC is present in an amount ranging from 0.0075% to0.0125% w/v. And, in some embodiments, HPMC is present in an amount ranging from 0.0075% to0.01% w/v. In at least one embodiment, HPMC is high viscosity grade. In at least one embodiment, thehigh ity HPMC is 4000 CF.
If present in the pharmaceutical preparation, namide is present in aconcentration ranging from 50 mM to 500 mM. In at least one embodiment, the concentration ofnicotinamide is about 400 mM. In at least one embodiment, the concentration of nicotinamide is about300 mM. In another embodiment, the concentration of nicotinamide is about 200 mM.
If present in the pharmaceutical preparation, sodium salicylate is present in aconcentration ranging from 50 mM to 500 mM. In at least one embodiment, the concentration of sodiumsalicylate is about 400 mM. In at least one embodiment, the concentration of sodium salicylate is about300 mM. In another embodiment, the concentration of sodium late is about 200 mM.
In some embodiments, the pharmaceutical preparation further comprises a tonicityenhancer to adjust the osmolality from about 220 mOsm/Kg to about 370 mOsm/Kg. In at least oneembodiment, the osmolality is about 225 mOsm/Kg. In at least one embodiment, the lity is about290 mOsm/Kg. In at least one ment, the osmolality is about 352 mOsm/Kg. In at least oneembodiment, the osmolality is about 370 mOsm/Kg. In at least one ment, the tonicity enhancer issorbitol. In some embodiments, sorbitol is present in a concentration ranging from 100 mM to 287 mM.
In at least one embodiment, the tration of sorbitol is about 110 mM. In at least one embodiment,the concentration of sorbitol is about 130 mM.
In at least one embodiment, the pH of the ocin pharmaceutical ationfrom 5.15 to 5.65, from 5.25 to 5.55, or 5.35 toranges from 3.0 to 5.8, for example, from 3.5 to 5.75,.45. In at least one embodiment, the pH is 5.4 i 0.5. In another embodiment, the pH is 5.4 i 0.3. In oneembodiment, the pH is about 5.4 i 0.1.
The stable pharmaceutical preparation of the present disclosure may be formulatedin a container. The container is chosen from an ampoule, vial, or pre-filled intranasal delivery device.
The present disclosure is also directed to a stable pharmaceutical preparationcomprising an aqueous solution of carbetocin and a solubilizer and/or HPMC in a container, wherein theconcentration of carbetocin ranges from about 1 mg/mL to about 70 mg/mL, and wherein the headspace1O in the container is near zero (i.e., limited headspace). In one embodiment, the headspace in the containeris substantially zero.
In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) an aqueous solution of carbetocin, wherein the tration of carbetocin ranges fromabout 10 mg/mL to about 70 mg/mL; and(b) a solubilizer and/or HPMC, wherein the solution has no visible solids.
In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) an aqueous solution of ocin, wherein the carbetocin is present in a concentration ofabout 10 mg/mL to about 70 mg/mL;(b) an amino acid, hydrotrope and/or HPMC; and(c) optionally an additional excipient, wherein the preparation has a pH ranging from about 3to about 5.8.
In at least one embodiment, a stable intranasal pharmaceutical preparationses:(a) an s solution of carbetocin, wherein the carbetocin is present in a concentration ofabout 1 mg/mL to about 70 mg/mL;(b) a hydrotrope selected from the group consisting of nicotinamide, sodium benzoate, andsodium salicylate; and(c) optionally an onal excipient. In another embodiment, the preparation has a pHranging from about 3 to about 5.8.[003 5] In at least one ment, a stable intranasal pharmaceutical preparationcomprises:(a) an aqueous solution of ocin, wherein the carbetocin is present in a concentration ofabout 1 mg/mL to about 70 mg/mL;(b) hydroxypropyl methylcellulose (HPMC), wherein the HPMC is present in an amountg from 0.005% to 0.05% w/v; and(c) optionally an onal excipient, wherein the solution has a pH ranging from about 3 toabout 5.8.[003 6] In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) an aqueous solution of carbetocin, wherein the carbetocin ispresent in a concentration of about 1 mg/mL to about 70 mg/mL;(b) nicotinamide;(c) HPMC; and(d) sorbitol, wherein the solution has a pH ranging from about 3 to about 5.8.[003 7] In at least one embodiment, a stable intranasal ceutical preparation1O comprises:(a) an s solution of carbetocin, wherein the ocin ispresent in a concentration of about 1 mg/mL to about 70 mg/mL;(b) methyl—B-cyclodextrin;(c) HPMC; and(d) sorbitol, wherein the solution has a pH ranging from about 3 to about 5.8.[003 8] In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) carbetocin, wherein the carbetocin is present in a concentration of about 25 mg/mL toabout 35 mg/mL;(b) namide, wherein the nicotinamide is present in a concentration ranging from about200 mM to about 400 mM;(c) HPMC, wherein the HPMC is present in an amount ranging from 0.0075% to 0.05% w/v;(d) ol, wherein the ol is present in a concentration ranging from about 110 mM toabout 250 mM.[003 9] In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) carbetocin, wherein the carbetocin is present in a concentration of about 34.3 mg/mL;(b) nicotinamide, wherein the nicotinamide is present in a concentration g from about 50mM to about 500 mM;(c) HPMC, wherein the HPMC is present in an amount of about 0.01% w/V; and(d) sorbitol, and optionally an additional excipient chosen from EDTA, potassium sorbate, andcombinations thereof.
In at least one embodiment, a stable intranasal ceutical preparationcomprises:(a) carbetocin, wherein the carbetocin is present in a tration of about 11.4 mg/mL;(b) nicotinamide, wherein the nicotinamide is present in a concentration ranging fromabout 50 mM to about 500 mM;(c) HPMC, wherein the HPMC is present in an amount of about 0.01% w/v; and(d) sorbitol, and optionally an additional ent chosen from EDTA, potassiumsorbate, and ations thereof.
In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) ocin, wherein the carbetocin is present in a tration of about 1 mg/mL toabout 4 mg/mL;(b) nicotinamide, wherein the nicotinamide is present in a concentration ranging fromabout 50 mM to about 500 mM;1o» (c) HPMC, wherein the HPMC is t in an amount ranging from 0.01% to 0.05%w/v; and(d) sorbitol, wherein the sorbitol is present in a concentration ranging from about 100mM to about 287 mM.
In at least one embodiment, the pharmaceutical preparations ofthe presentdisclosure are administered intranasally daily for a period of time. In at least one embodiment, thepharmaceutical preparations are administered intranasally up to 3 times daily for chronic use. In at leastabout 200one embodiment, the pharmaceutical preparation is administered in a volume of about 50 uL touL into one nostril and then a volume of about 50 uL to about 200 uL into the second nostril, for acombined volume of about 100 uL to about 400 uL for both nostrils. In at least one embodiment, thepharmaceutical preparations are administered intranasally 3 times daily for 20 consecutive days. In atleast one embodiment, the pharmaceutical ation is administered in a volume of about 20 uL toabout 200 uL into one nostril and then a volume of about 20 uL to about 200 uL into the second l,for a combined volume of about 40 uL to about 400 uL for both nostrils. In at least one embodiment, thepharmaceutical preparation is administered in a volume of about 25 uL to about 35 uL into one nostriland then a volume of about 25 uL to about 35 uL into the second nostril, for a combined volume of about50 uL to about 70 uL for both nostrils. In one embodiment, the pharmaceutical preparation isadministered in a volume of 140 uL into one nostril and then a volume of 140 uL into the second nostrils,for a combined volume of 280 uL for both ls.
In at least one embodiment, the pharmaceutical preparations of the presentdisclosure may be for use in (or in the manufacture of medicaments for) the ent or prevention of aneurodevelopmental disorder or related symptoms in a t in need thereof. In at least oneembodiment, a therapeutically-effective amount of a pharmaceutical preparation of the present disclosureis administered to a t diagnosed with -Willi syndrome. In one embodiment, thepharmaceutical preparation is administered to the subject intranasally. In at least one embodiment, a totaldaily dose of carbetocin is from about 1 mg/day to about 30 . In at least one embodiment, a totaldaily dose of carbetocin is from about 8.0 mg/day to about 30.0 mg/day. In at least one embodiment, atotal daily dose of carbetocin is from about 9.0 mg/day to about 29.0 mg/day. In one embodiment, a totaldaily dose of carbetocin is chosen from about 8.0 mg/day, about 9.0 mg/day,10.0 mg/day, about 11.0WO 61414 mg/day, about 12.0 mg/day, about 13.0 mg/day, about 14.0 , 15.0 mg/day. 16.0 mg/day, 17.0mg/day, 18.0 mg/day, 19.0 mg/day, 20.0 mg/day, 21.0 mg/day, 22.0 mg/day, 23.0 mg/day, 24.0 mg/day,.0 mg/day, 26.0 mg/day, 27.0 mg/day, 28.0 mg/day, 29.0 mg/day, and about 30.0 mg/day. In anotherembodiment, a total daily dose of carbetocin is chosen from about 9.1 mg/day, about 9.2 mg/day, about9.3 mg/day, about 9.4 mg/day, about 9.5 mg/day, about 9.6 mg/day, about 9.7 mg/day, about 9.8 mg/day,and about 9.9 mg/day. In at least one ment, a total daily dose of carbetocin is 96 mg/day. In oneembodiment, a total daily dose of carbetocin is chosen from about 11.1 mg/day, about 11.2 mg/day, about11.3 mg/day, about 11.4 mg/day, about 11.5 mg/day, about 11.6 mg/day, about 11.7 mg/day, about 118mg/day, and about 11.9 mg/day. In at least one embodiment, a total daily dose of carbetocin is 11.4mg/day. In one embodiment, a total daily dose of carbetocin is chosen from about 28.1 mg/day, about28.2 mg/day, about 28.3 mg/day, about 28.4 mg/day, about 28.5 mg/day, about 28.6 mg/day, about 28.7mg/day, about 28.8 mg/day, and about 28.9 mg/day. In at least one ment, a total daily dose ofcarbetocin is 28.8 mg/day. In at least one embodiment, the total daily dose is d into 3 equal doses.
In another ment, the pharmaceutical ations disclosed show improved stability andbioavailability. In at least some embodiments, the pharmaceutical preparation is an aqueous solution ofabout 10 mg/mL to about 70 mg/mL carbetocin that includes a hydrotrope and a viscoelastic polymer insuch concentrations that the solution retains 75-125% of the bioavailability (as measured by the areaunder the curve and the maximum concentration) of an aqueous solution of carbetocin in .
In another aspect, the disclosure provides a method of administering carbetocin toof 3.2 mg/dosea subject diagnosed with Prader-Willi syndrome, wherein two or three doses per daycarbetocin are administered intranasally to the patient. According to this aspect, the disclosure provides amethod of administering carbetocin to a subject diagnosed with Prader—Willi syndrome, wherein threedoses per day of 3.2 mg/dose carbetocin are administered intranasally to the patient. The disclosure alsoprovides a method of administering carbetocin to a t diagnosed with Prader-Willi syndrome,wherein each dose is administered within 30 minutes of a meal or just before a meal. In another aspect,the disclosure provides a method of administering carbetocin to a subject diagnosed with Prader-Willisyndrome, wherein carbetocin is administered for at least one week, at least two weeks, at least threeweeks, at least four weeks, at least one month, at least two months, at least three , or .
The sure also provides a method of administering carbetocin to a subjectdiagnosed with Prader-Willi me, wherein the administration results in one or more of (a) decreasein hyperphagia behavior compared to placebo, optionally as measured by the Hyperphagia Questionnairefor Clinical Trials ) Total Score; (b) se in ive and compulsive behavior ed toplacebo, optionally as ed by the Children's rown ive—Compulsive Scale (CY-BOCS)Total Score; (c) decrease in anxiety compared to placebo, optionally as measured by the PWS Anxietyand Distress Questionnaire (PADQ) Total Score; and (d) improvement in global clinical impressioncompared to placebo, optionally as measured by the Clinical Global Impression of Change (CGI-C) score.
According to this aspect, the disclosure provides a method of administering carbetocin to a subjectdiagnosed with Prader-Willi syndrome, wherein the administration results in a decrease in hyperphagiabehavior. According to this aspect, the disclosure provides a method of administering carbetocin to asubject diagnosed with Pr'ader-Willi syndrome, wherein the administration results in a decrease inhyperphagia or and a se in obsessive and compulsive behavior.
In another aspect, the disclosure provides a method of administering carbetocin toa subject diagnosed with Prader-Willi syndrome, wherein the age of the subject is from seven (7) toeighteen (18) years old, inclusive. According to this aspect, the disclosure provides a method ofadministering ocin to a subject diagnosed with Prader-Willi me, wherein the subject is agedseven (7) years old, eight (8) years old, nine (9) years old, ten (10) years old, eleven (11) years old, twelve(12) years old, thirteen (13) years old, fourteen (14) years old, fifteen (15) years old, sixteen (16) yearsold, seventeen (17) years old, or eighteen (18) years old.
BRIEF DESCRIPTION OF GS The foregoing summary, as well as the following detailed description of thedisclosure, will be better understood when read in conjunction with the appended drawings. For theillustrate some, but not all, alternativepurpose of illustrating the present disclosure, the attached drawingsembodiments. It should be understood, however, that the disclosure is not limited to the precisearrangements and instrumentalities shown. These figures, which are orated into and constitute partof the specification, assist in explaining the principles of the disclosure.
Fig 1. ‘shows an e image comparing 400 mM and 200 mM sodiumsalicylate (left- and right—hand vials, respectively) samples after 6 days of continuous agitation. The 200mM sample contains more and larger particles than the 400 mM sample. Additionally, the 200 mMsample has a slight opalescent appearance.
Fig 2. shows an example image of various samples studied after 6 days ofcontinuous agitation. From left to right: 400 mM sodium salicylate, 200 mM sodium salicylate, 82 mMne, and 160 mM sodium benzoate after 6 days of uous ion.
[0050] Fig 3. shows A350 measurements for various samples. Fig 3.(a) shows A350measurements for samples having 80% headspace. Fig 3.(b) shows A350 measurements for shaving limited headspace.
Fig 4. shows an example image of “soft” precipitate for 2 HPMC containingsamples on the left vs. “hard” or significant precipitate for the two HPMC samples on the right.
[0052] Fig 5. shows an example image of “fine” precipitate, as found in 350 and 400 mMnicotinamide samples (19 hrs agitation).
DETAILED DESCRIPTION OF THE DISCLOSURE The present disclosure relates to a stable intranasal pharmaceutical preparation thatses an aqueous solution of ocin and a solubilizer and/or HPMC. The pharmaceuticalpreparations disclosed may include but do not require a surfactant. The pharmaceutical preparations of thepresent disclosure t ed ity despite their relatively high trations of carbetocin. Forexample, in certain embodiments, the pharmaceutical preparations show little to no visible solids afterextended periods of time at room temperature. In other embodiments, the ceutical preparations ofWO 61414 the present disclosure exhibit little to no e solids after shaking stress. The pharmaceuticalpreparations disclosed herein may be formulated in a container having d headspace, which mayinclude close to or ntially zero headspace to minimize, for example, the gas—water interface. Incertain embodiments, however, it is ssary to reduce headspace to maintain improved stability. Thepharmaceutical preparations disclosed exhibit improved stability despite their vely highconcentrations of ocin (e.g., 210 mg/mL). Certain embodiments are stable under conditions of, such as mechanical stress (e.g., shaking and stirring, pumping, freeze-thaw processes). Thepharmaceutical ations of the present disclosure also possess ageously extended in-use timeand/or shelf life for the patient. For example, the pharmaceutical preparation of the present disclosureexhibits an in-use time ranging from 1 day to 7 days, and includes ments wherein the contentuniformity of carbetocin remains consistent and high throughout the in-use period. In someembodiments, the pharmaceutical preparations of the present disclosure also possess good localtolerability after 14 days at room temperature. In at least some ments, the pharmaceuticalpreparations of the present disclosure possess good local tolerability for 3-7 days at room temperature.
[0054] In at least one embodiment, the t disclosure is directed to a stablepharmaceutical preparation comprising an aqueous solution of carbetocin and a solubilizer and/or alastic polymer, such as HPMC, wherein the concentration of carbetocin ranges from about1 mg/mL to about 70 mg/mL. In at least some embodiments, the addition ofHPMC to the preparationreduces aggregation of an aqueous solution of carbetocin compared to an aqueous solution of carbetocinthat doe-s not contain HPMC. In some embodiments, the HPMC in the carbetocin ation reducesaggregation of the carbetocin solution by at least 20% and up to 50% when ed to an aqueoussolution of carbetocin that does not contain HPMC. In other embodiments, the HPMC in the carbetocinpreparation reduces aggregation of the carbetocin solution by at least 20% compared to an aqueoussolution of carbetocin that does not contain HPMC. In some embodiments, the HPMC in the carbetocinpreparation s aggregation of the carbetocin solution by at least 30% compared to an aqueoussolution of carbetocin that does not contain HPMC. In some embodiments, the HPMC in the carbetocinpreparation reduces aggregation of the carbetocin solution by at least 40% compared to an aqueoussolution of carbetocin that does not n HPMC. In some embodiments, the HPMC in the carbetocin:preparation reduces aggregation of the carbetocin solution by at least 50% compared to an aqueoussolution of carbetocin that does not contain HPMC.
For example, the concentration of carbetocin ranges from 1 mg/mL to 70 mg/mL,such as from 5 to 65 mg/mL, from 10 mg/mL to 50 mg/mL, from 15 mg/mL to 35 mg/mL, or from 30mg/mL to 34 mg/mL. In at least one embodiment, the concentration of carbetocin in solution is about 40mg/mL. In another embodiment, the concentration of carbetocin ranges from about 10 mg/mL to about 45mg/mL. In at least one embodiment, the concentration of carbetocin ranges from about 20 mg/mL toabout 40 mg/mL. In at least one embodiment, the concentration of carbetocin may be, for example, aboutmg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 33 mg/mL,about 34 mg/mL, about 35 mg/mL, 36 mg/mL, about 37 mg/mL, about 38 mg/mL, about 39 mg/mL, or PCT/USZOl9/052090about 40 mg/mL. In another embodiment, the concentration of carbetocin may be, for example, 34.1mg/mL, 34.2 mg/mL, 34.3 mg/mL, 34.4 mg/mL, 34.5 mg/mL, 34.6 mg/mL, 34.7 mg/mL, 34.8 mg/mL,34.9 mg/mL, or 40 mg/mL. In one ment, the concentration of carbetocin is about 34.3 mg/mL.
For the pharmaceutical preparations of the present disclosure at least onesolubilizer and/or HPMC is included in the pharmaceutical preparation.
In at least one embodiment, the hydrotrope is an aromatic anionic nd, anaromatic cationic compound, or aliphatic and linear compounds. Examples of hydrotropes include but arenot limited to nicotinamide, sodium te, salicylate salts (e.g., sodium late, potassiumsalicylate, lithium late, ammonium salicylate, calcium salicylate, magnesium salicylate etc.), N,N—1O diethylnicotinamide, or N,N-dimethyl benzamide. In certain ments, the rope isnicotinamide, sodium benzoate, or sodium salicylate. The hydrotrope may also be an aromatic cationiccompound, such as caffeine and procaine hydrochloride. In other embodiments, the hydrotrope may be antic and linear compound chosen from N,N—dimethyl urea, urea, or sodium alkanoate.
If present in the pharmaceutical preparation, nicotinamide is present in atration g from 50 mM to 500 mM. In at least one embodiment, the nicotinamideconcentration ranges from about 50 mM to about 350 mM, such as from 100 mM to 220 mM, from 240mM to 260 mM, from 280 mM to 300 mM, or from 320 mM to 340 mM. In at least one embodiment, theconcentration of nicotinamide is, for example, about 200 mM, about 210 mM, about 220 mM, about 230mM, about 240 mM, about 250 mM, about 260 mM, about 270 mM, about 280 mM, about 290 mM,about 300 mM, about 310 mM, about 320 mM, about 330 mM, about 340 mM, about 350 mM, about 360mM, about 370 mM, about 380 mM, about 290 mM, or about 400 mM. In at least one embodiment, theconcentration of nicotinamide is about 400 mM. In at least one embodiment, the concentration ofnicotinamide is about 350 mM. In at least one embodiment, the concentration of nicotinamide is about300 mM. In at least one embodiment, the concentration of nicotinamide is about 250 mM. In anotherembodiment, the concentration of nicotinamide is about 200 mM.
If present in the pharmaceutical preparation, the sodium salicylate salt (e.g.,sodium late, potassium salicylate, lithium salicylate, ammonium salicylate, calcium salicylate,magnesium salicylate etc.) is present in a concentration ranging from 50 mM to 500 mM. In at least someembodiments, the salicylate salt is sodium salicylate which is present in a concentration ranging from 200mM to 400 mM. In at least one embodiment, the sodium salicylate tration ranges from about 200mM to about 300 mM, such as from 200 mM to 220 mM, from 240 mM to 260 mM, or from 280 mM to300 mM. In at least one embodiment, the concentration of sodium salicylate is about 400 mM. In at leastone embodiment, the concentration of sodium salicylate is about 300 mM. In another embodiment, thetration of sodium salicylate is about 200 mM.
[0060] If present in the pharmaceutical preparation, sodium benzoate is present in aconcentration ranging from 100 mM to 400 mM. In at least one embodiment, the sodium teconcentration ranges from about 160 mM to about 400 mM, such as from 160 mM to 200 mM, from 250mM to 300 mM, or from 350 mM to 400 mM. In at least one embodiment, the concentration of sodiumbenzoate is about 160 mM. In at least one embodiment, the concentration of sodium benzoate is about400 mM.
If present in the pharmaceutical ation, methyl-B—cyclodextrin is present in aconcentration ranging from 15 mM to 50 mM. In at least one embodiment, the methyl-B-cyclodextrintration ranges from about 17.5 mM to about 40 mM, such as from 17.5 mM to 25 mM, from 30mM to 35 mM, or from 35 mM to 40 mM. In at least one embodiment, the concentration of methyl-B—cyclodextrin is about 17 .5 mM. In at least one embodiment, the concentration of methyl—B-cyclodextrin isabout 2.5 mM. In at least one embodiment, the concentration of -B-cyclodextrin is about 35 mM.
If present in the pharmaceutical preparation, HPMC is present in an amountranging from 0.005% to 0.05% w/v. In at least one embodiment, HPMC is present in an amount gfrom 0.0075% to 0.0125% w/v. In another embodiment, HPMC is present in an amount ranging from0.0075% to 0.01% w/v. In at least one embodiment, HPMC is present in an amount of 0.01% w/v. In atleast one ment, the grade ofHPMC is chosen from low viscosity (e.g., 10—20 cP), mediumviscosity (e.g., 40-60 GP), and high viscosity (e.g., 80-120 CF, 4000 GP). In at least one embodiment,HPMC is high viscosity grade. In at least one ment, the high viscosity HPMC possesses aviscosity of 4000 CF.
The pharmaceutical preparations of the present sure may include asolubilizer and HPMC. Thus, in certain embodiments, nicotinamide, sodium benzoate, sodium salicylate,arginine, inethyl-B-cyclodextrin, and combinations thereof are present in the pharmaceutical preparationwith HPMC. Such preparations may optionally contain an additional excipient. Non-limiting examples ofadditional excipients include sorbitol, ethylenediaminetetraacetic acid (EDTA), ium sorbate,mannitol, and sodium or potassium acetate. These additional excipients may be included even if only asolubilizer or HPMC is present alone. Specifically, in at least one ment, the pharmaceuticalpreparation contains at least one solubilizer or HPMC with at least one additional excipient.
[0064] In some embodiments, the presence of either HPMC or nicotinamide alone in the}carbetocin formulation may be sufficient to mitigate precipitation of carbetocin upon prolonged agitation.
This is possible because HPMC and nicotinamide have ndent mechanisms of action. It was foundthat HPMC associates to the glass e of the vial and because of this ation it can ze theinteraction of carbetocin with this interface. In contrast, it was surprisingly found that nicotinamide is abletoto solubilize aggregates formed during agitation, which in turn reduces carbetocin’s propensitythe addition ofaggregate and subsequently form small and large precipitates. It was further found thatboth namide and HPMC to a carbetocin preparation results in a istic effect that ,reduces, or prevents carbetocin from aggregating and subsequently precipitating in solution. The resultingocin ations comprising nicotinamide and HPMC are surprisingly stable under acceleratedconditions of stress for long periods of time.
In at least some embodiments, the present disclosure is directed to a stableintranasal pharmaceutical preparation comprising an aqueous solution of carbetocin and a solubilizerand/or surface active agent, such as HPMC, wherein the resulting preparation shows a surprising highcontent uniformity of carbetocin for long periods of time and after one or more freeze/thaw cycles.example, the sed preparations show content uniformity of carbetocin after one or more /thawcycles for a duration chosen from 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and 7 days. In at leastassessment aftersome embodiments, the pharmaceutical preparation has little to no aggregates by visualthawing for up to 7 days. In some embodiments, the carbetocin in the disclosed preparation is evenlybuted throughout the preparation to ensure that if the preparation is, for example, split in one or morepreparations, each resulting preparation has an equal dose of carbetocin. In one embodiment, thedisclosed carbetocin preparations have a consistent dose of ocin, which is maintained betweenvarious preparation batches so that the patient receives the correct dose consistently over variousstrations. In at least one embodiment, the disclosed carbetocin preparation provides enhancedconvenience and patient compliance.
A tonicity enhancer/modifier may be, but is not required, to provide isotonicformulations (e.g., 300 g). In at least one embodiment, the osmolality of a pharmaceuticalcomposition is preferably adjusted to maximize the active ingredient’s stability and/or to minimizefort to the patient upon stration. In at least one embodiment, the pharmaceuticalcomposition for direct stration to a patient is ic, which may be achieved by addition of aacidstonicity modifier, such as sorbitol. Other non—limiting examples of tonicity modifiers include amino(e.g., ne, arginine, histidine, glycine etc.), salts (e.g., sodium chloride, potassium chloride, sodiumcitrate etc.) or nonelectrolytes (e.g., sugars or polyols, such as, for e, sucrose, glucose andmannitol).
If present in the pharmaceutical preparation of the present disclosure, the tonicityenhancer/modifier is added to adjust the osmolality to, for example, about 225 mOsm/Kg, about 226mOsm/Kg, about 227 mOsm/Kg, about 228 mOsm/Kg, about 229 mOsm/Kg, about 230 mOsm/Kg, about231 mOsm/Kg, about 232 g, about 233 mOsm/Kg, about 234 mOsm/Kg, about 235 mOsm/Kg,about 236 mOsm/Kg, about 237 mOsm/Kg, about 238 mOsm/Kg, about 239 mOsm/Kg, about 240mOsm/Kg, about 241 mOsm/Kg, about 242 mOsm/Kg, about 243 mOsm/Kg, about 244 mOsm/Kg, about245 mOsm/Kg, about 246 mOsm/Kg, about 247 mOsm/Kg, about 248 mOsm/Kg, about 249 mOsm/Kg,about 250 mOsm/Kg, about 251 mOsm/Kg, about 252 mOsm/Kg, about 253 mOsm/Kg, about 254aboutmOsm/Kg, about 255 g, about 256 mOsm/Kg, about 257 mOsm/Kg, about 258 mOsm/Kg,259 mOsm/Kg, about 260 mOsm/Kg, about 261 g, about 262 mOsmfl<g, about 263 mOsm/Kg,about 264 mOsm/Kg, about 265 mOsm/Kg, about 266 mOsm/Kg, about 267 mOsm/Kg, about 268mOsm/Kg, about 269 mOsm/Kg, about 270 mOsm/Kg, about 271 mOsm/Kg, about 272 mOsm/Kg, about273 mOsm/Kg, about 274 mOsm/Kg, about 275 mOsm/Kg, about 276 mOsm/Kg, about 277 mOsm/Kg,about 278 mOsm/Kg, about 279 mOsm/Kg, about 280 mOsm/Kg, about 281 mOsm/Kg, about 282g, about 283 mOsm/Kg, about 284 mOsm/Kg, about 285 mOsm/Kg, about 286 g, about287 mOsm/Kg, about 288 mOsm/Kg, about 289 mOsm/Kg, about 290 mOsm/Kg, about 291 g,about 292 mOsm/Kg, about 293 mOsm/Kg, about 294 mOsm/Kg, about 295 mOsm/Kg, about 296mOsm/Kg, about 297 mOsm/Kg, about 298 mOsm/Kg, about 299 mOsm/Kg, about 300 mOsm/Kg, about310 mOsm/Kg, about 320 mOsm/Kg, about 330 mOsm/Kg, about 340 mOsm/Kg, about 350 mOsm/Kg,about 360 mOsm/Kg, about 370 mOsm/Kg, about 380 g, about 390 mOsm/Kg, about 400mOsm/Kg, about 410 mOsm/Kg, about 420 mOsm/Kg, about 430 mOsm/Kg, about 440 mOsm/Kg, about450 mOsm/Kg, about 460 mOsm/Kg, about 470 mOsm/Kg, about 480 mOsm/Kg, about 490 mOsm/Kg,about 500 mOsm/Kg, about 510 mOsm/Kg, about 520 mOsm/Kg, about 530 mOsm/Kg, about 540g, about 550 mOsm/Kg, about 560 mOsm/Kg, about 570 mOsm/Kg, about 580 mOsm/Kg, about600 mOsm/Kg, about 610 mOsm/Kg, about 620 mOsm/Kg, about 630 mOsm/Kg, about 640 g,about 650 mOsm/Kg, about 660 mOsm/Kg, about 670 mOsm/Kg, about 680 mOsm/Kg, about 700aboutmOsm/Kg, about 710 mOsm/Kg, about 720 mOsm/Kg, about 730 mOsm/Kg, about 740 mOsm/Kg,1O 750 mOsm/Kg, about 760 g, about 770 mOsm/Kg, about 780 mOsm/Kg, or about 800mOsm/Kg. In some embodiments, the osmolality may be in excess of 800 mOsm/Kg.
In some embodiments, sorbitol is present in a concentration ranging from 100mM to 300 mM. In some embodiments, sorbitol is t in a concentration ranging from 110 mM to287 mM. In some embodiments, sorbitol is added to adjust the lity to, for example, about 105mM, about 110 mM, about 115 mM, about 120 mM, about 125 mM, about 130 mM, about 135 mM,about 140 mM, about 145 mM, about 150 mM, about 155 mM, about 160 mM, about 165 mM, about 170mM, about 175 mM, about 180 mM, about 185 mM, about 190 mM, about 195 mM, about 200 mM, 205mM, about 210 mM, about 215 mM, about 220 mM, about 225 mM, about 230 mM, 235 mM, aboutmM, about 245 mM, about 250 mM, about 255 mM, about 260 mM, 265 mM, about 270 mM, about 275mM, about 280 mM, about 285 mM, about 290 mM, or about 300 mM. In at least one embodiment, theconcentration of sorbitol is chosen from about 110 mM, about 120 mM, about 150 mM, about 200 mM,:about 250 mM, or about 287 mM. In at least one embodiment, the concentration of sorbitol is about 110mM. In at least one embodiment, the concentration of sorbitol is about 130 mM.
This disclosure is also ed to achieving a stable lyophilized preparation ofocin. In at least one ment, a carbetocin lyophilisate is mixed with a solubilizer and/or HPMCin water to obtain a pharmaceutical preparation drug product. Without being bound to any particulartheory, the solubilizer and/or HPMC expedites dissolution of lyophilized ocin as compared to itstypically slow reconstitution with conventional diluents (e,g., bulking agents and sugar stabilizers). In atleast one embodiment, isotonic solutions sing a solubilizer and/or HPMC of the disclosure3O ntly solubilize carbetocin lyophilizate. In one embodiment, isotonic solutions of, for example,arginine and/or nicotinamide (a hydrotrope) efficiently lize carbetocin lyophilizate. In at least oneembodiment, the solubilizer and/or HPMC of the disclosure increases the dissolution rate of lizedcarbetocin. In at least one embodiment, the solubilizer is nicotinamide which improves the dissolutionrate of lyophilized carbetocin. The use of a solubilizer, such as nicotinamide and/or HPMC, reduceddissolution time of the lyophilized carbetocin (at 40 mg/mL) to only a few minutes, a time generallyconsidered acceptable for a lyophilized drug product.
In at least one embodiment, the solubilizer is an arginine salt (e.g., HCl salt). Inin’ a concentrationsome embodiments, the arginine salt is present in the pharmaceutical preparationranging from 50 mM to 300 mM. In at least one embodiment, the arginine concentration ranges fromabout 100 mM to about 300 mM, such as from 100 mM to 150 mM, from 200 mM to 250 mM, or from250 1nM to 300 mM. In at least one embodiment, the concentration of arginine salt is about 100 mM. In atleast one embodiment, the concentration of ne salt is about 200 mM.
In at least one ment, the solubilizer is nicotinimide. In some embodiments,the nimide is present in the pharmaceutical ation in a concentration ranging from 50 mM to500 mM. In at least one embodiment, the nicotinimide concentration ranges from about 50 mM to about350 mM, such as from 200 mM to 220 mM, from 240 mM to 280 mM, or from 300 mM to 350 mM. In atleast one embodiment, the concentration of nicotinimide is about 200 mM. In at least one embodiment,the concentration of nicotinamide is about 300 mM. In at least one embodiment, the concentration ofnicotinimide is about 400 mM.
In at least one embodiment, the solubilizer is -B—cyclodextrin. In someembodiments, the methyl-B-cyclodextrin is present in the pharmaceutical preparation in a concentrationranging from 10 mM to 40 mM. In at least one embodiment, the methyl-B-cyclodextrin concentrationsuch as from 17.5 mM to 19.5 mM, from 24 mM to 28 mM,ranges from about 15 mM to about 35 mM,or from 30 mM to 35 mM. In at least one embodiment, the concentration of methyl—B—cyclodextrinabout 35 mM. In at least one embodiment, the concentration of methyl-B—cyclodextrin is about 25 mM. Inat least one embodiment, the concentration of methyl-B-cyclodextrin is about 17.5 mM.
This disclosure is further ed to a pharmaceutical preparation comprising anand/or HPMC in a ner, wherein the headspace inaqueous solution of ocin and a lizerthe container is near zero (i.e., limited headspace). In another embodiment, such a ceuticalpreparation with reduced headspace does not include a surfactant. That is, the present disclosure esand/ora pharmaceutical preparation comprising an aqueous solution of ocin and a solubilizer,optionally HPMC in a container, wherein the headspace in the container is near zero, and wherein thepreparation is substantially free of a surfactant (e.g., non-ionic surfactant, such as n—dodecyl-B-D-maltoside (DDM), poloxamer 188, polysorbate 20 or polysorbate 80), for example, such that thepharmaceutical preparation does not include a surfactant. In at least one embodiment, a surface activeagent is not present in the preparation disclosed.
The term “headspace” is a term well understood in the art and refers to gas space3O within a sealed container containing a solution. The volume of the ace may vary depending on theentire inner volume of the container and the amount of solution it contains.
For example, in at least one embodiment, the headspace represents about 2.0 mL,1.9 mL, 1.8 mL, 1.7 mL, 1.6 mL, 1.5 mL, 1.4 mL, 1.3 mL, 1.2 mL, 1.1mL, 1.0 mL, 0.9 mL, about 0.8mL, about 0.7 mL, about 0.6 mL, about 0.5 mL, about 0.4 mL, about 0.3 mL, about 0.2 mL, about 0.18mL, about 0.15 mL, about 0.12 mL, about 0.1 mL, about 0.08 mL, about 0.07 mL, about 0.06 mL, about0.05 mL, about 0.04 mL, about 0.03 mL, about 0.020 mL, or about 0.01 mL ofthe volume ofthecontainer comprising the carbetocin solution. In at least one embodiment, the headspace represents about80%, about 70%, about 60%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%,about 20%, about 15%, about 12%, about 10%, about 9%, about 8%, about 7%, about 6%, about 5%,about 4%, about 3%, about 2%, about 1.5%, about 1%, about 0.75%, about 0.5%, about 0.25%, or about0.1% of the volume of the container comprising the carbetocin solution. In at least one embodiment, theheadspace ents less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1%, lessthan , or 0.0% of the total volume of the container. In at least one embodiment of the presentdisclosure, the container ace is substantially zero.
The pharmaceutical preparations of the present disclosure are advantageousbecause they may be stable even at high concentrations of carbetocin, such as at a concentration ranging:from about 10 mg/mL to about 70 mg/mL, including about 34 mg/mL.1O [0077] In at least one embodiment, the stability of the pharmaceutical preparation isevident because it resists aggregate ion, and the aqueous solution has little to no e solids (e.g.,particles). In some embodiments, the carbetocin in solution has little to no visible solids when stored atroom temperature (~25 °C) for a sustained period of time. For example, in some embodiments,carbetocin solution has little to no e solids for up to 5 years. In some embodiments, thecarbetocin solution has little to no visible solids for up to 4 years. In some embodiments, thecarbetocin solution has little to no visible solids for up to 3 years. In some embodiments, thetration of carbetocin in the aqueous solution does not change over time (e.g., over 3, 4, or 5 years).
The pharmaceutical preparations of the present sure remain stable toshaking stress. For example, the aqueous ocin solution is stable to g stress for a period oftime. In some embodiments, the preparation is subjected to constant shaking stress for 14 days at both 5:°C and 25 °C (e.g., 200 or more RPMs), and the s carbetocin solution remains clear with little tono visible particles. In some embodiments, the preparation is subjected to shaking stress 1, 2, 3, 4, 5,6, or 7 days at both 5 °C and 25 °C, and the aqueous carbetocin solution remains clear with little to novisible particles. In at least one embodiment, the preparation is subjected to shaking stress for 5 days, andthe aqueous carbetocin solution remains clear with little to no visible particles. In some embodiments, theation is subjected to shaking stress for at least 3 days, and the aqueous carbetocin solution remainsclear with little to no visible les. In at least one embodiment, the pharmaceutical preparations arestable to shaking stress for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9hours, 10 hour, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours,20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours 30hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours,41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, or 48 hours, and the aqueouscarbetocin solution remains clear with little to no visible particles.
The stability of the pharmaceutical preparations described herein may also bemeasured by the chromatographic purity of carbetocin. In at least one embodiment, controls at one orIn at least onemore days assure that chromatographic purity of carbetocin is greater than 95%.embodiment, controls at one or more days assure that chromatographic purity of carbetocin is greaterthan 96%. In at least one embodiment, ls at one or more days assure that chromatographicpurity of carbetocin is greater than 97%. In at least one embodiment, the chromatographic purity ofocin is greater than 98%. In at least one embodiment, the chromatographic purity of carbetocin isthangreater than 99%. In at least one embodiment, the chromatographic purity of carbetocin is greater99.4%. In at least one embodiment, the chromatographic purity of carbetocin is greater than 99.5%. In atleast one embodiment, the chromatographic purity of carbetocin is greater than 99.6%. In at least oneembodiment, the chromatographic purity of carbetocin is greater than 99.7%. In at least onement, the chromatographic purity of carbetocin is greater than 99.8%. In at least oneembodiment, the chromatographic purity of carbetocin is greater than 99.9%. In at least one embodiment,ocin is not subject to al degradation, i.e., there is minimal or no change in chromatographicpurity of carbetocin before or after shaking stress. In addition, the pharmaceutical preparations of thepresent disclosure exhibit stability in that the concentration of carbetocin in solution does not change overtime, including under conditions of g .
In at least one embodiment, the chromatographic purity of carbetocin in solutionwith a solubilizer and/or surface active agent disclosed is greater than 98% after 24 hours of stress. In atleast one embodiment, the chromatographic purity of carbetocin in solution with a solubilizer and/orsurface active agent disclosed is greater than 98% after 36 hours of stress. In at least one embodiment,the chromatographic purity of carbetocin in solution with a solubilizer and/or surface active agentdisclosed is greater than 98% at 48 hours of . In at least one embodiment, the chromatographicpurity of carbetocin in on a solubilizer and/or surface active agent disclosed is r than 98 % at72 hours of stress.
In at least one embodiment, the chromatographic purity of carbetocin in solutionwith a solubilizer and/or surface active agent disclosed is greater than 99% after 24 hours of stress. In atleast one ment, the chromatographic purity of carbetocin in solution with a solubilizer and/ore active agent disclosed is greater than 99% after 36 hours of stress. In at least one embodiment,the chromatographic purity of carbetocin in solution with a solubilizer and/or surface active agentdisclosed is greater than 99% at 48 hours of stress. In at least one embodiment, the chromatographicpurity of carbetocin in solution with a solubilizer and/or surface active agent disclosed is greater than 99% at 72 hours of stress.
In at least one embodiment, the chromatographic purity of carbetocin in solutionwith a solubilizer and/or surface active agent disclosed is greater than 99.5% after 24 hours of stress. Inat least one ment, the chromatographic purity of carbetocin in solution with a solubilizer and/orsurface active agent disclosed is greater than 99.5%. after 36 hours of stress. In at least oneembodiment, the tographic purity of carbetocin in solution with a solubilizer and/or surface activeagent disclosed is r than 99.5% at 48 hours of stress. In at least one embodiment, thechromatographic purity of carbetocin in solution with a solubilizer and/or surface active agent sedis greater than 99.5 % at 72 hours of stress.
In general, the pharmaceutical preparations of the present disclosure will have apH from about 3.0 to about 5.8. In at least one embodiment, the pH of the aqueous carbetocin solutionfor e from 5.3 to 5.4. In somemay be from 3.5 to 5.7, for example from 4.2 to 5.6, orembodiments of the present disclosure, the pH of the pharmaceutical preparation is from about 5.3 toabout 5.5; about 5 .3 i 3; 5.4 i 3; or 5.5 i 3. In at least one embodiment, the pH of the aqueous carbetocinsolution is 5.4 i 0.5. In another embodiment, the pH of the s carbetocin solution is 5.4 i 0.3. Inanother embodiment, the pH of the aqueous carbetocin solution is 5 .4 i 0.1.
The pharmaceutical preparations of the present disclosure may include a container.
Non-limiting examples of a container e an ampoule, vial, pre—filled filed intranasal dispenser. In atleast one embodiment, the container is an e or a vial. In at least one ment, the container is avial.
Exemplary Pharmaceutical Preparations In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) an s solution of carbetocin, wherein the concentration of carbetocin ranges fromabout 10 mg/mL to about 70 mg/mL; and(b) a solubilizer and/or HPMC, wherein the solution has no visible solids.
In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) ofan aqueous solution of carbetocin, wherein the carbetocin is present in a concentrationabout 10 mg/mL to about 70 mg/mL;(b) an amino acid, hydrotrope, and/or HPMC; and(c) optionally an additional excipient, wherein the preparation has a pH ranging from about 3to about 5.8.
In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) an aqueous solution of carbetocin, wherein the carbetocin is t in a concentration ofabout 1 mg/mL to about 70 mg/mL;(b) a hydrotrope ed from the group consisting of nicotinamide, sodium benzoate, andsodium salicylate; and(c) optionally an additional excipient. In another embodiment, the preparation has a pHranging from about 3 to about 5.8.[008 8] In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) ofan s solution of carbetocin, wherein the carbetocin is present in a concentrationabout 1 mg/mL to about 70 mg/mL;(b) hydroxypropyl methylcellulose (HPMC), wherein the HPMC is present in an amountranging from 0.005% to 0.05% w/v; and(c) optionally an onal excipient, n the on has a pH ranging from about 3 toabout 5.8.
In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) ofan aqueous solution of carbetocin, wherein the carbetocin is present in a concentrationabout 1 mg/mL to about 70 mg/mL;(b) nicotinamide;(c) HPMC; and(d) sorbitol, wherein the solution has a pH g from about 5 to about 5.8.
In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) ofan s solution of carbetocin, wherein the ocin is t in a concentrationabout 1 mg/mL to about 70 mg/mL;(b) -B-cyclodextrin;(c) HPMC; and(d) sorbitol, wherein the solution has a pH ranging from about 5 to about 5.8.
[0091] In at least one embodiment, a stable intranasal pharmaceutical ationcomprises:(a) carbetocin, wherein the carbetocin is present in a concentration of about 25 mg/mL toabout 35 mg/mL;(b) nicotinamide, wherein the nicotinamide is present in a concentration ranging from about 50mM to about 500 mM; ..(c) HPMC, wherein the HPMC is present in an amount ranging from 0.0075% to 0.05% w/v;(d) sorbitol, wherein the sorbitol is t in a concentration g from about 110 mM toabout 250 mM.
[0092] In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) carbetocin, wherein the carbetocin is present in a concentration of about 34.3 mg/mL;(b) nicotinamide, wherein the nicotinamide is present in a tration ranging from about 50mM to about 500 mM;(c) HPMC, wherein the HPMC is present in an amount of about 0.01% w/v; and(d) sorbitol, and optionally an additional excipient chosen from EDTA, potassium sorbate, andcombinations thereof.
In at least one embodiment, a stable intranasal pharmaceutical preparationcomprises:(a) carbetocin, n the carbetocin is present in a concentration of about 11.4 mg/mL;(b) nicotinamide, wherein the nicotinamide is present in a concentration ranging from about 50mM to about 500 mM;(c) HPMC, wherein the HPMC is present in an amount of about 0.01% w/v; and(d) sorbitol, and optionally an onal excipient chosen from EDTA, potassium e, andcombinations thereof.
In at least one embodiment, a stable intranasal pharmaceutical ationcomprises:(a) carbetocin, wherein the carbetocin is present in a tration of about 1 mg/mL to about4 mg/mL;(b) nicotinamide, wherein the nicotinamide is present in a concentration ranging from about 50mM to about 500 mM;(c) HPMC, wherein the HPMC is present in an amount ranging from 0.01% to 0.05% w/v; and(d) sorbitol, wherein the sorbitol is present in a concentration ranging from about 100 mM toabout 287 mM.
In each of these exemplary embodiments, the headspace of the container mayally be reduced. In addition, the headspace may be substantially zero for each of these exemplaryembodiments.
[0096] The pharmaceutical preparations sed herein may optionally include one oror more solvents may bemore pharrnaceutically acceptable solvents. In at least one embodiment, the oneand water.present as a mixture with water, such as, for example, a pharrnaceutically acceptable alcohol The t disclosure also provides for a kit of parts comprising: a liquid (e.g.,aqueous) pharmaceutical ition sing carbetocin with a solubilizer and/or a surface activeagent, wherein the pH of the composition is from 3.0 to 5.8; and a container for the composition,optionally with separate injection means (e.g., if required for administration), ally with instructionsfor administration of the composition. The pH of the composition may be from 3.5 to 5.75, for examplefrom 4.0 to 5.65. The pH of the composition may be from 5.15 to 5.75, for example from 5.2 to 5.65. ThepH of the composition may be from 5.30 to 5.8, for example from 5.40 to 5.70, for example from 5.50 to5.6. In at least one embodiment, the pH of the composition is about 5.4. In at least one embodiment, thepH of the aqueous carbetocin solution is 5.4 i 0.5. In another embodiment, the pH of the aqueouscarbetocin on is 5.4 i 0.3. In another embodiment, the pH of the aqueous carbetocin solution is 5.4:1: 0.1. In at least one embodiment, the pH of the pharmaceutical composition is adjusted to the desired pH(e. g., 5.4) by addition of an appropriate amount of a base. In one ment the base is NaOH. In atleast one embodiment, the base is 5 M NaOH.
Methods of Preparation In at least one embodiment, the present disclosure provides a method to e apharmaceutical preparation of carbetocin that has a vely high concentration carbetocin and whichdemonstrates improved stability at room temperature and/or under conditions of stress. In at least oneembodiment, a stable pharmaceutical preparation of aqueous carbetocin is prepared, for e, in acontainer. In at least one embodiment, the disclosure provides a method for preparing a stableceutical preparation of aqueous carbetocin and a container, wherein the concentration ofcarbetocin ranges from about 10 mg/mL to about 70 mg/mL, comprising: (a) adding aqueous carbetocinsolution to the container, and optionally the added solution can be in an amount ent to reduceheadspace (e.g., 20% headspace, 10% headspace, 5% headspace, close to zero headspace (i.e., limitedheadspace)); and (b) adding a solubilizer and/or HPMC to the solution. In at least one embodiment, theceutical preparation of aqueous carbetocin prepared by the method disclosed herein has little to novisible solids after horizontal shaking for 24 hours. In at least one embodiment, the pharmaceuticalation of aqueous carbetocin prepared by the method sed herein has little to no visible solidsafter horizontal shaking for 48 hours. In at least one embodiment, the pharmaceutical preparation ofherein has little to no visible solids after horizontalaqueous carbetocin prepared by the method disclosedshaking for 72 hours. In at least one embodiment, the pharmaceutical preparation of aqueous carbetocinprepared by the method disclosed herein has little to no visible solids after horizontal shaking for 96hours. In at least one embodiment, carbetocin is not subject to chemical degradation before or after theshaking stress. In at least one embodiment, controls at one or more days assure that chromatographicpurity of carbetocin is r than 98%. In at least one embodiment, the chromatographic purity ofocin is greater than 99%. In at least one embodiment, the tographic purity of carbetocin is99.4 :: 0.0%. In at least one embodiment, the chromatographic purity of carbetocin is 99.4 :: 0.1%. In atleast one embodiment, the chromatographic purity of carbetocin is 99.4 :: 0.2%. In at least onement, the chromatographic purity of carbetocin is 99.5 i 0.0%. In at least one embodiment, thetographic purity of carbetocin is 99.5 i 0.1%. In at least one embodiment, the chromatographicpurity of carbetocin is 99.5 :: 0.2%. In at least one embodiment, the chromatographic purity ofcarbetocin is 99.8 i 0.3%. In at least one embodiment, the chromatographic purity of carbetocin is 99.9i 0.1%.s of ent In at least one embodiment, the disclosure provides a method of treating asubject suffering from, or susceptible to, a disease that is beneficially treated by a stable highconcentration ceutical preparation of carbetocin sing the step of stering to saidsubject an effective amount of a pharmaceutical preparation of the present disclosure.
In at least one ment, the pharmaceutical preparations of the presentdisclosure may be for use in (or in the manufacture of medicaments for) the treatment or prevention ofneurodevelopmental disorders, including Prader-Willi syndrome, or related symptoms in a mammalian3O subject in need thereof. In at least one embodiment, a therapeutically-effective amount of apharmaceutical preparation of the present disclosure is administered to a subject suffering from Prader-Willi syndrome.
Examples The present disclosure may be better understood by reference to es. Thefollowing examples are intended for illustration purposes only and should not be construed as limiting thethe section headings used herein are for organizationalscope of the disclosure in any way. Further,the subject matter described.purposes only and are not to be construed as limiting Methods: Visual Inspection Storage ity and agitation samples were analyzed for particles in a light boxagainst both a white and black background. es were taken to document any particles/precipitateformed in these samples.
A350 Absorbance at 350 nm was monitored to track formation of large, solubleaggregates in storage stability and agitation samples. For these measurements, 300 uL of solution wasmeasured in a reduced volume, 1 cm path-length quartz cuvette. MQ water was used as the blank for allements. Note, A350 is a light scattering technique, so it is most effective for measuring scatteringin solutions containing large, soluble aggregates, or solutions with a homogeneous dispersion of non-soluble particles.
Example 1 Carbetocin was obtained as a powder and was stored at S 20 °C until ready for use.ations were ed by dissolving 40 mg/mL or 20 mg/mL of carbetocin in an s oncontaining a lizer and/or HPMC. The pH of each formulation was adjusted to 5.4 and :: 0.1 byaddition of an appropriate amount of 5 M NaOH. All preparations were ed using multi—compendialgrade excipients and reagents, and ultra-pure water (Millipore MilliQ, 18MQ). The osmolality of eachpreparation was measured before preparing the final formulation to ensure it was r to that of thetheoretically determined value. Each formulation (bulk material) was sterile filtered using a MilliporeMillex-GV syringe filter (022 um). 1.2 mL of each sterile filtered formulation was filled into a 3 mLglass vial, stoppered with a 13 mm Fluorotec coated serum r, and crimped. All materials (i.e., vials,stoppers, etc.) were sterilized before filling. For samples with reduced or limited headspace, a 1 mL vialwas used instead of a 3 mL vial. After sterile preparation, samples were placed ntally on an orbitalplate shaker (Labnet, 3 mm orbit) and shaken continuously at 200 rpm for a prescribed period of time (seeTable 1). Samples were shielded from ambient light during ion. All samples used in this study wereagitated at room temperature. The results of this experiment are summarized below in Table 1.
TABLE 1Visual ation Results of Agitated Carbetocin FormulationsCarbetocin HPMCSolubilizer Headspace Orientation Observations(rn /mL) % (w/v50 mM Arg HCl 40 0.05 d Horizontal 1 piece of soft precipitate after 4 daysNo precipitation after 5 hrs of200 mM Arg HCl 40 None 30% Horizontal agitation, but significant precipitationafter 24 hrssome piftldes at? daysiw1th a few200 mM Arg HCl 40 0.05 30% Horizontallarge, soft prec1p1tate partlcles400 mM Proline 40 None 30% Horizontal Significant precipitation after 1 dayNilg‘gnralrlillide 40 None 30% Horizontal Significant precipitation after 1 daySome very fine particles after 2 days,300 mM40 None 30% Horizontal but not obvious; same appearance at 4NicotinamidedaysVisual Observation Results of Agitated Carbetocin FormulationsCarbetocin HPMCSolubilizer oAifll/‘Qieadspace Orientation ations(mg/m—L)Niiggnnmde 4O 0'05 30% Horizontal Sfrfilgeefigdftligzipif:t:;”vpiz:fti:lfe:wNigggnnarlh/Iide 40 0'005 30% Horizontal Sfefilgeegztdftlfr:ipiftiieigpifiti:1::va The results presented in Table 1 show that these high carbetocin concentrationpreparations (Le, 40 mg/mL, 20 mg/mL) in pure water (pH 5.4) with various ents show visual signsof precipitation, but differences in the precipitation behavior were ed dependent on the excipientand excipient tration. Under the selected conditions (see Table 1 above), it can be seen that botharginine and e were not effective at suppressing particle formation in the concentration rangesexamined. In contrast, 300 mM nicotinamide significantly helped to ss particle formation whenused as the sole formulation ent. onally, nicotinamide was more effective at ssingparticle formation when the concentration of carbetocin in the formulation was reduced from 40 mg/mLto 20 mg/mL. However, under the tested conditions, nicotinamide was not effective at suppressingparticle ion when its concentration was reduced to 100 mM.
It was also observed that the morphology of the particles formed in 300 mMnamide solutions were different than those seen in the other carbetocin formulations studied. Theparticles generated in agitated nicotinamide formulations were granular/fine in nature, and their formationdid not seem to progress substantially with prolonged agitation of the solution.[011 l] The results show that nicotinamide alone, or in combination with hydroxypropylmethylcellulose , was effective at mitigating precipitation of carbetocin upon prolongedagitation. While particles/precipitate may form with both of these excipients, the amounts formed aresignificantly less than that of the other excipients studied.
[0112] Example 2 Samples were prepared using the general procedure provided in Example 1. It isnoted that the hydrotropes d in this example were formulated at the following concentrations: 160mM (isotonic) and 400 mM sodium te, 200 mM (isotonic) and 400 mM sodium salicylate, and 82mM caffeine (near solubility limit), and 35 mg/mL carbetocin. Again, as in Example 1, an agitation studywas conducted to evaluate the y of these solutions to suppress particle formation upon agitation.
Observations were made after both 14 and 24 hours of agitation.
After 14 hours, the following was observed: the benzoate preparations/samples(160 mM and 400 mM) formed a hard precipitate. The caffeine preparation formed a carbetocin skin onthe vial wall. The late preparations formed a few fine particles, but were otherwise generally clear.
After 24 hrs of agitation, the 200 mM salicylate preparation had slightly more particles/precipitate than its400 mM counterpart. Additionally, the 200 mM salicylate ation had a slight opalescent appearance.
WO 61414 [01 15] It was further observed that the ne preparation had a similar appearance to the400 mM salicylate preparation. As a result, the sample agitation was continued. After five days ofadditional agitation, the samples were once again observed for particle formation. Both latepreparations were minimally changed from their earlier (i.e., their 24 hr appearance) (see Figure 1), whilethe ne sample had formed a hard itate. An image ing the salicylate, caffeine, andbenzoate samples after 6 days of agitation is shown in Figure 2.
The result of this agitation study showed that salicylate may behave similarly tonicotinamide in suppressing particle ion with agitation. It is noted that nicotinamide can be utilizeddue to itsat much higher concentrations (i.e., 400 mM is isotonic) than salicylate (200 mM is ic),tonicity properties.
Example 3 Formulations were prepared according to the method described in Example 1 bydissolving the desired amount of 40 mg/mL of ocin in an aqueous solution ning differentexcipients or HPMC. The pH of each formulation was adjusted to 5.4 and :I: 0.1 by addition of anriate amount of 5 M NaOH. After sterile preparation according to the same method described inExample 1, samples were placed horizontally on an orbital plate shaker (Labnet, 3 mm orbit) and shakencontinuously at 200 rpm for prescribed periods of time. Samples were shielded from ambient light duringagitation. All samples used in this study were agitated at room temperature. The results of this experimentare summarized below in Tables 2 and 3.
TABLE 2Visual Observation Results for Agitated Carbetocin FormulationsCarbetocin Vial. . Agitation Observations. Ex01pientConcentration Orientation Time (hrs)40 mg/mL DS Hydroxypropyl B—Cyclodextrin Horizontal 17 Significant precipitation1 A) (W/V) Hydroxypropyl040 mg/mL DS ntal l7 GelledcelluloseOnly a few particles0.1% (w/v) Hydroxypropyl . (“soft precipitate”) and40 mg/mL DS Hor1zontal 17methyl cellulose (HPMC) some gel pieces on theglass40 mg/mL DS 0.02% (w/v) Poloxamer 188 Horizontal 17 Significant precipitation40 mg/mL DS 0.1% (w/v) Poloxamer 188 Horizontal 17 Significant precipitation As can be seen from Table 2, poloxamer 188 (a nonionic block co-polymersurfactant) and ypropyl-B-cyclodextrin, both of which have been shown to be effective atsuppressing acial damage of proteins in solution, failed to stabilize carbetocin. itation ofcarbetocin occurred within 17 hours of agitation when formulated with both of these excipients. Inaddition, hydroxypropyl cellulose (HPC) caused the solution to gel after 17 hrs of agitation. Conversely,HPMC appeared to be relatively effective at mitigating precipitation, with only a few pieces of larger,“soft” precipitate being present in the vial after 17 hrs of agitation.
WO 61414 TABLE 3Carbetocin HPMC, Potassium Vial Fill Shake Observations(mg/mL) % (w/v) Sorbate, Position Volume Time% (W/VL40 0.05 0.5 Horizontal 30% 24 hrs Some “soft”precipitate40 0.01 0.5 Horizontal 30% 24 hrs Some “soft”precipitate40 0.005 0.5 Horizontal 30% 24 hrs Some “soft”itate40 0.05 None Horizontal 30% 24 hrs Some “soft”precipitate40 0.01 None Horizontal 30% 24 hrs Some “soft”precipitate40 0.005 None Horizontal 30% 24 hrs Some “soft”itate40 0.05 0.5 Horizontal 67% 24 hrs Some “soft”precipitate40 0.01 0.5 Horizontal 67% 24 hrs Some “sof ”precipitate40 0.005 0.5 Horizontal 67% 24 hrs Some “soft”precipitate Inspection of the agitation results in Table 3 shows that all formulations formedsoft precipitate within 24 hours of ion. The amount of precipitate was essentially the same for allconcentrations ofHPMC investigated, with each formulation containing a few pieces of “soft” precipitateat 24 hrs. Additionally, it appeared as if the amount of precipitate was slightly less for the samples withreduced headspace (67% fill volume). The presence of the preservative potassium sorbate did not appearto negatively impact particle ion. Continued agitation of these samples (up to a week) resulted in =only a slow increase in the amount of soft precipitate present.1O [0121] It was also found that 0.005% (w/v) HPMC is the practical lower limit of thisexcipient in terms of providing a tive benefit during agitation. Concentrations of 0.001% (w/v)HPMC were shown to be less effective than 0.005% in suppressing particle formation.
Example 4 For this study, carbetocin was formulated at 15, 25, and 35 mg/mL in an aqueoussolution of 400 mM nicotinamide at a pH of 5.4 i 0.1 according to the method described in Example 1.
A350 ements and visual ations were made over a ourse of 14 days. Samples wereagitated (horizontal orientation) at both 5 °C and 25 °C, and ements were taken at time-zero, 3days, and 14 days. A corresponding set of controls (no agitation) were measured at the conclusion of thestudy. The results of the A3 50 measurements at time-zero, 3 days, and 14 days are listed below in Table4, while visual observations are given in Table 5. Graphical depictions of the A350 values for samples -with and without headspace are given in Figure 3(a) and Figure 3(b), respectively. 2019/052090TABLE 4A350 values measured for samples stored at 5 °Cand 25 0C for zero (t=0), 3 days (dl,_a_nd 14 daysQ)Sample Headspace t0 14d ctrl 3d 5 OC 3d 25 °C 14d 5 OC 14d 25 0Cmg/mL 80% 0.011 0.010 0.014 0.014 0.022 0.025mg/mL 80% 0.017 0.017 0.018 0.025 0.058 0.042mg/mL 80% 0.023 0.023 0.026 0.046 0.037 0.081mg/mL Limited 0.011 0.014 N.M. 0.019 0.016 0.013mg/mL Limited 0.017 0.019 N.M. 0.022 0.030 0.024mg/mL Limited 0.023 0.030 N.M. 0.031 0.049 0.037NM. = not measuredTABLE 5Visual inspection s of samples stored at 5 °C and°C for zeroit=0L3 daLsgd), and 14 @s (dLSample Head Space t0 14d ctrl 3d 5 OC 3d 25 OC 14d 5 OC 14d 25 °Cmg/mL 80% x x x x precipitate precipitatemg/mL 80% x x x x precipitate precipitatemg/mL 80% x x x x precipitate precipitatemg/mL Limited x x x x x xmg/mL Limited x x x x precipitate xmg/mL d x x x x precipitate precipitatex = no evidence ble les/precipitate in these samples The A3 50 data in Table 4, as well as s 3(a) & 3(b), shows that A3 50 valuestend to increase with sing carbetocin concentration. Additionally, for the headspace samples,propensity to form aggregates/precipitate has both a concentration and temperature dependence, with the°C, 35 mg/mL sample showing the largest increase in A350 versus time—zero. The effect of limitingthe headspace to near zero appears to have a measurable benefit from the A350 measurements, althoughmultiple samples at both the 5 OC and 25 OC agitation condition had visible particles/precipitate afterdays of agitation. After 5 days of continuous agitation, no visible signs of precipitate were seen for thepreparations studied; as a result, the final time-point was extended to 14 days. Only after 7 days ofagitation were visible particles/precipitate evident in these samples.1 5 [0125] The effects of ocin g/concentration, temperature, and vial headspaceit was found that the propensityon the precipitation behavior of carbetocin were studied. From this studyto precipitate was concentration ent, with higher concentration samples precipitating more readilythan lower concentration samples. Additionally, for samples containing headspace, it appeared as if thepropensity to precipitate increased with sing temperature. Limiting vial headspace may decreaseamount of aggregates/precipitate formed during agitation.
Example 5 Formulations were prepared according to the method described in Example 1. Thecarbetocin concentration for all formulations was 35 mg/mL, and the pH was adjusted to 5.4 :: 0.1. Theformulations investigated in Example 5 are listed below in Table 6.
TABLE 6Example 5 formulation designArg amldZnClz Citrate Acetate Sorbitol EDTA Sorbate HPMC Me-[3-CyFm HCI 6(mM)<mM> <mM> <mM> (mM) (% w/v) (% w/v) (% w/v) (mM)(mM)1 0 0 10 225 0 0 0.1 0.12 0 02 35 35 7.4 0 0 0 0 0 0 03 25 0 25 0 0 0 0 0.12 0 04 25 12.5 7.4 0 0 0 0 0 0 17.50 0 7.4 0 0 200 0.1 0.12 0 06 0 7.4 227 0 0 0 0 0 07 0 0 7.4 0 50 200 0.1 0.12 0 08 0 0 7.4 200 0 0 0 0 0 359 35 17.5 7.4 0 0 200 0 0 0 00 0 7.4 0 0 0 0.1 0.12 0.05 011 0 0 50 200 0 0 0 0 0.05 012 0 0 7.4 0 0 200 0 0 0.01 013 0 0 7.4 0 0 0 0.1 0.12 0 3514 0 0 25 0 0 0 0 0 0 350 0 7.4 0 50 200 0 0 0.01 016 0 0 7.4 0 0 300 0.1 0.12 0 017 0 0 7.4 200 50 0 0 0 0 018 0 0 7.4 270 25 0 0 0 0 17.5Me-fl—Cy = -fl—cyclodexn'in; sorbate = potassium sorbate Freeze/ Thaw (F/T) Agitation StudyA F/T agitation study was conducted with the formulations listed in Table 6. For this study,two different headspace configurations were tested (12% and 70%). For this study, samples were frozenfor Z 24 hrs at —20 °C before thawing. After thawing, samples were allowed to brate to roomtemperature and then gently swirled to mix (freeze concentration was evident) before starting ion.
Samples were agitated in a horizontal orientation and monitored for particle/precipitate formation at 5 and19 hrs. Visual observation results from this agitation study are given below in Table 7.
TABLE 7Appearance of freeze thaw samples after 5 and 19 hrs. of agitationForm 70% Headspace, 5 12% Headspace, 5 70% Headspace, 12% Headspace,hrs. hrs. 19 hrs. 19 hrs.1 Precipitation Precipitation Significant cantprecipitation precipitation2 Fine precipitate on Precipitation Significant Significantvial wall itation precipitation3 None Precipitation Significant Significantprecipitation precipitation4 Fine precipitate on Fine precipitate on Fine precipitate on Fine precipitate onvial wall vial wall and vial wall vial wall andsome fine some fineparticles particlesMaybe a few Fine precipitate Fine precipitate Fine precipitateles, notdefinitive6 Precipitation Precipitation Significant Significantprecipitation precipitationAppearance of freeze thaw sampfl after 5 and 19 hrs. of ionForm 70% ace, 5 12% Headspace, 5 70% Headspace, 12% Headspace,hrs. hrs. 19 hrs. 19 hrs.7 Maybe a few None Small amount of Fine precipitateparticles, not fine and softdefinitive precipitate8 Maybe a few Fine precipitate Some soft Fine precipitateparticles, not precipitatedefinitive9 None None Fine precipitate Fine precipitate onvial wall somefine particlesSome soft Some soft and Some soft Some soft and .precipitate fine precipitate precipitate fine precipitate11 None None Some soft Some soft andprecipitate fine precipitate12 None None Some soft Some softprecipitate precipitate13 Maybe a few Fine precipitate Some soft Fine precipitateparticles, not precipitatedefinitive14 Maybe a few Maybe a few Some fine Some fine andparticles, not particles, not precipitate soft precipitatedefinitive definitiveNone None Some soft Soft precipitateprecipitate16 Fine itate Maybe some fine Fine precipitate on Fine precipitateparticles, not vial wall anddefinitive some fineparticles17 Fine precipitate on None Significant Significantvial wall and precipitate precipitatesome particles18 Fine precipitate on Some fine Significant Fine itate onvial wall and precipitate precipitate vial wall and finesome fine precipitatefirticles As can be seen from Table 7, the majority of samples/preparations demonstratedprecipitation after only 5 hours of agitation. Furthermore, there was no noticeable difference in theprecipitation or of the two different headspace samples. Non—frozen control samples (stored at 5°C) demonstrated the same type of precipitation behavior as the frozen samples.
It was found that the samples containing HPMC, nicotinamide, and methyl-[5-cyclodextrin were less prone to precipitation than samples that did not contain these excipients. Theprecipitation behavior of s ated with methyl—B-cyclodextrin and namide appeared to besimilar, with both types of samples forming fine/granular itate upon prolonged agitation.
Additionally, these solutions l-B—cyclodextrin and nicotinamide) had an opalescent tinge after 19hrs of agitation. The ce of opalescence suggests that these solutions may contain larger, solubleaggregates which are yet to precipitate. The results of this study show that the effectiveness ofnicotinamide at suppressing particle formation was concentration dependent, with 300 mM being moreeffective than 200 mM. Additional agitation s conducted with nicotinamide demonstrated that 400:mM > 350~3 00 mM > 200 mM at suppressing particle formation. The visual rank ordering for thesamples highlighted in gray in Table 7 is as follows: (F11, F12) 2 (F10, F14, F15) > (F5, F8, F13, F16) >(F7, F9). This rank ordering is based on visual observations.
The best performing formulations from the F/T agitation study were used assolubilizers to reconstitute pure, lyophilized carbetocin at 35 mg/mL. Reconstitution times of lyophilizedcarbetocin using these lizers are listed in Table 8.
TABLE 8Reconstitution time of lized carbetocin using theformulation samples in Table 7Solubilizer/Blank (no solubilizer) Solubilizer Recon TimeF5 200 mM Nicotinamide 2 min 20 sF7 50 mM Arg/200 mM Nicotinamide l min 50 5F8 35 mM Me-B-CD 4 min 30 5F9 200 mM Nicotinamide 4 minF11 None > 30 minF12 200 mM Nicotinamide 5 minF13 35 mM Me-B-CD l min 30 sF14 35 mM Me-B—CD 2 min 20 5F15 50 mM Arg/200 mM Nicotinamide 2 minF16 300 mM Nicotinamide 1 minRecon = reconstitution; D = Methyl—B-Cyclodextrin
[0132] As can be observed from Table 8, all samples containing a solubilizer hadreconstitution times of 5 minutes or less. But samples without a solubilizer (i.e., F11) had very longreconstitution times (i.e., > 30 min).
Following titution, these samples were subjected to an identical agitationstudy as described previously for the F/T samples. The visual observation results from this agitation studyare given below in Table 9.
TABLE 9Appearance of tituted lyo samples after 2, 5, and 19 hrs of agitationSolubilizer/Blank (no lizer) itate at 2hrs Precipitate at 5 hrs Precipitate at 19 hrsF5 No No YesF7 No No YesF8 No No YesF9 No No YesF1 1 No Maybe YesF12 No No YesF13 No No YesF14 No No YesF15 No No YesF16 No Maybe Yes A visual rank ordering of the reconstituted lyo samples after 19 hours of agitation> (F05, F07, F09, F16, 350was as follows: F15> (F13, F14) 2 (F12, F8) 2 (Fl 1, 400 mM nicotinamidemM nicotinamide). This rank was made using visual observations.
It was found that formulations containing HPMC, methyl—B—cyclodextrin, andnicotinamide were the most resistant to precipitation upon ion, but do eventually form someprecipitate. The morphologies of the precipitate formed with these excipients are ent, with HPMCg a few, large “soft” particles (see Figure 4) while nicotinamideland methyl-B-cyclodextrin form-'smaller, more granular particles. Concentration ranging experiments for nicotinamide ted that theeffectiveness of this solubilizer at suppressing precipitation increases with increasing nicotinamideconcentration (see Figure 5).
Example 6
[0137] Additional reconstitution examples are provided in Table 10. Arginine, as well ashydrotropes like proline and nicotinamide, were selected to improve the dissolution times. In on, theeffect of solids content on dissolution rate was examined. The results of these reconstitution studies aregiven in Table 10.
TABLE 10titution time of pure carbetocin lyophilisate withvarious ents and at various reconstitution volumes1 Final Recon.ent Lyo Sample Recon. Volume Recon. TimeConc. (mg/111EmM Arg HC1 40 mg/mL carbetocin Full 40 18 min50 mM Arg HC1 40 mg/mL carbetocin Full 40 8 min50 mM Arg/Glu 40 mg/mL carbetocin Full 40 16 min100 mM Arg HC1 40 mg/mL carbetocin Full 40 3 min200 mM Arg HC1 40 mg/mL carbetocin Full 40 1 min, 50 s200 mM Lysine HC1 40 mg/mL carbetocin Full 40 > 10 min400 mM Proline 40 mg/mL carbetocin Full 40 5 hrs300 mM Nicotinamide 40 mg/mL carbetocin Full 40 1 min, 30 s100 mM Nicotinamide 40 mg/mL carbetocin Full 40 5 min, 50 s0.5% ium Sorbate 40 mg/mL carbetocin Full 40 Z 25 minWater 40 mg/mL carbetocin 1/2 20 30 minWater 5 mg/mL carbetocin 1/4 20 3 minWater 10 mg/mL ocin 1/4 40 5 min, 30 s50 mM Arg HC1 10 mg/mL carbetocin 1/4 40 4 min200 mM Arg HC1 10 mg/mL carbetocin 1/4 40 2 min, 20 sRecon. = reconstitution; Conc. = carbetocin concentration Conditions which expedited the dissolution of pure carbetocin lyo material (re—lyophilized carbetocin, cake form) are ed in Table 10. It was found that 200 mM arginine and 300mM nicotinamide both dramatically improved the dissolution rate of lyophilized carbetocin. Utilizingthese solubilizers, dissolution times of the re-lyophilized carbetocin (at 40 mg/mL) were reduced to only afew minutes. The solubilizing power of these particular excipients was concentration dependent, withincreasing concentrations of the excipient decreasing dissolution time. Proline was not effective as asolubilizer at the concentration (400 mM) examined in this study.
The results r indicate (see Table 10) that while potassium sorbate did notexpedite dissolution of lyophilized carbetocin, it did not negatively impact dissolution either.
Regarding the effect of solids content on dissolution rate, it was found that areduced volume for reconstitution of carbetocin lyophilized at a lower solids content yielded fasterdissolution rates than ocin lyophilized at a higher solids content (see Table 10). It was further foundthat the dissolution rates for the lower solids content material were r to those of the solubilizers(like namide or arginine), although they were not superior.
It was found that isotonic solutions of arginine and nicotinamide could efficientlylize carbetocin lisate, and thus could ially be utilized as a solubilizer for lyophilized1 0 carbetocin.
Example 7 Exemplary Stable Pharmaceutical Preparations ofCarbetocin Exemplary pharmaceutical preparations of ocin are provided in Tables 11-1 5 TABLE 1 1Pharmaceutical Preflations of CarbetocinForm pH Carbetocin Acetate Sodium Sorbitol HPMC Nicotinamide K+ EDTA(mg/ml) (mM) Benzoate (mM) (%, (mM) Sorbate (%,(mM) w/V) (%, w/v) WW)1 5.4 l 5 0 0 0 400 0 02 5.4 l 5 0 110 0.01 200 0 03 5.4 l 5 160 0 0 0 0 04 5.4 1 5 0 287 0.01 0 0 05.4 1 5 0 287 0.05 0 0 06 5.4 1 5 0 0 0.05 400 0 0*HPMC = hydroxypropyl methylcellulose; K+ = ium; EDTA = ethylenediaminetetraacetic acidTABLE 12Pharmaceutical PrepLations of CarbetocinForm pH Carbetocin NaCl Sorbitol Nicotinamide Acetate HPMCmemo (mM) (mM) (mML M) 9/), w/v)1 5.4 34.3 0 250 0 0 02 5.4 34.3 0 250 0 0 0.053 5.4 34.3 0 110 200 0 0.014 5.4 34.3 0 0 400 0 05.4 25 0 110 200 1.6 0.01*HPMC = hydroxypropyl methylcelluloseTABLE 13Pharmaceutical Preparations of CarbetocinForm pH Carbetocin EDTA (%, K+Sorbate HPMC Nicotinamide(rag/1111) w/v) 4% w/v) 4wt%, ML @ML1 5.4 34.3 0 0 0.01 4002 5.4 34.3 0.1 0.12 0.01 4003 5.4 34.3 0 0 0 0*HPMC = hydroxypropyl methylcellulose; K+ = potassium; EDTA = ethylenediaminetetraacetic acid