NZ773548B2 - Stable intranasal formulations of carbetocin - Google Patents
Stable intranasal formulations of carbetocin Download PDFInfo
- Publication number
- NZ773548B2 NZ773548B2 NZ773548A NZ77354819A NZ773548B2 NZ 773548 B2 NZ773548 B2 NZ 773548B2 NZ 773548 A NZ773548 A NZ 773548A NZ 77354819 A NZ77354819 A NZ 77354819A NZ 773548 B2 NZ773548 B2 NZ 773548B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- carbetocin
- concentration
- mosm
- formulated
- hpmc
- Prior art date
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- HDTRYLNUVZCQOY-LIZSDCNHSA-N Trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- FXAGBTBXSJBNMD-UHFFFAOYSA-N acetic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound CC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O FXAGBTBXSJBNMD-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000004931 aggregating Effects 0.000 description 1
- 150000001294 alanine derivatives Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 125000000511 arginine group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 235000012970 cakes Nutrition 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 230000004059 degradation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 235000010944 ethyl methyl cellulose Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012520 frozen sample Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000007970 homogeneous dispersion Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229920003087 methylethyl cellulose Polymers 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000036220 oral bioavailability Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000004728 pyruvic acid derivatives Chemical class 0.000 description 1
- 229910052904 quartz Inorganic materials 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 230000003381 solubilizing Effects 0.000 description 1
- 230000001954 sterilising Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 150000003667 tyrosine derivatives Chemical class 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Classifications
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/095—Oxytocins; Vasopressins; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
- A61K47/551—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P3/04—Anorexiants; Antiobesity agents
Abstract
The application describes stable aqueous compositions comprising relatively high concentrations of carbetocin and a solubilizer and/or surface active agent. The disclosed carbetocin compositions are effective in the treatment of a neurodevelopmental disorder, such as Prder-Willi syndrome. Additionally, the disclosed carbetocin compositions show improved stability at room temperature and/or under accelerated conditions of stress. ly, the disclosed carbetocin compositions show improved stability at room temperature and/or under accelerated conditions of stress.
Description
(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, Christopher
US 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 concentraons
of carbetocin and a solubilizer and/or surface acve agent. The disclosed carbetocin composions
are effecve in the treatment of a neurodevelopmental disorder, such as Willi syndrome.
Addionally, the disclosed carbetocin composions show improved stability at room temperature
and/or under accelerated condions of stress.
773548 B2
PCT/USZOl9/052090
STABLE INTRANASAL FORMULATIONS OF CARBETOCIN
References 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 July
22, 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 of
ocin, including those that demonstrate improved stability under various long-term storage
conditions and/or under accelerated conditions of stress. The t disclosure also relates to methods of
preparing such pharmaceutical ations. The present disclosure r relates to kits and the use of
the 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 are
typically distinguished from ns as having a r amino acid sequence, such as, for example, less
than 50 amino acids. Because of this difference in size, peptides and proteins often possess different
three-dimensional structures, properties, and functions. Peptides are used to treat various diseases and
conditions. Owing to their low oral bioavailability, most peptides are administered parenterally. (Frokjaer
S. 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 is
nasal drug administration. (Pathak K. (2011) Int J Pharm Investig. 1(2): 62—63.) Nasal drug delivery has
several 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, intranasal
administration offers several practical advantages either from the viewpoint of ts (e.g.,
noninvasiveness, essentially painless, ease of drug delivery, and favorable tolerability profile) or
pharmaceutical ry (e.g., sterilization of nasal preparations is often unnecessary).
Depending on potency, it may be necessary to formulate a peptide at a high
concentration, but doing so may increase the likelihood of peptide aggregation. (Shire S.J. et al. (2004) J
Pharm Sci. 0-1402; Payne R. W. et al. (2006) Biopolymers 84:527-533.) One way to mitigate
peptide aggregation is to formulate the peptide at a pH far from its isoelectric point to generate a high net
charge. 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 since
peptides generally do not possess higher-order structure, and their physical ity thus primarily
depends 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 an
example of an uncharged peptide. Carbetocin is a long-acting tic oxytocin analog. The structure of
carbetocin is shown below.
NIH2
H21»: 0
>“‘% ‘i 0
o HN
o ‘a
o 0 NH HN‘
1 ‘2 3 a s 6 7 a 9
CHz—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 tertiary
structure. Carbetocin is currently used outside the U.S. to treat or t postpartum hemorrhage during
or following caesarean section. As such, carbetocin is administered by slow intravenous (IV) single
ion at a dose of 100 ug. This formulation (Duratocin®, Ferring) requires refrigeration and contains
0.1 mg/mL of carbetocin, 9 mg sodium chloride, acetic acid — glacial to pH 3.8 and water for injection to
1 mL. (Widmer M. et a1. (2016) Trials. 17:143.) Carbetocin (IV form) is currently registered in more than
1O 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 now
approved in the European Union; this variant differs from the current carbetocin formulation in its
ents. CARBETOCIN RTS contains 0.1 mg/mL of carbetocin, 1.19 succinic acid, 47.0 mg/mL
mannitol, 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 using
typical peptide excipients (e.g., surfactants); however, none of the studied excipients ted carbetocin
aggregation. (Hggstedt U. B. et al. (2018). J Pharm Sci. 107(3):838—847.) Only in the absence of
headspace was 15 mM sodium dodecyl e (SDS) capable of preventing shaking induced carbetocin
aggregation.
In addition, when aqueous carbetocin solutions are manufactured, packaged,
transported, stored, and d prior to administration to a patient, they are subject to mechanical and
chemical stresses. These types of stresses can be detrimental to various ations of carbetocin in
solution.
Given the propensity of carbetocin to aggregate in solution, a stable carbetocin
pharmaceutical formulation that optimizes and s carbetocin’s in-use period, as well as delivers
relatively high content uniformity is ble. For example, an asal formulation that can be thawed
by a patient and used for several days without aggregation or a change in the ocin content from one
dose to another would enhance patient compliance and safety.
Thus, given carbetocin’s strong propensity to aggregate in solution, there remains a
need for stable carbetocin pharmaceutical preparations, including those that are stable to stress, that show
relatively high content uniformity of carbetocin over long periods of time before and after one or more
freeze/thaw cycles, are suitable for intranasal administration, e enhanced convenience and t
compliance, and/or are highly concentrated.
Summary of the Disclosure
[0012] It has been surprisingly found that improved carbetocin pharmaceutical
preparations can be ed with n solubilizers and/or surface active agents, such as a viscoelastic
r, for example, hydroxypropyl cellulose (HPMC), including those that contain high
concentrations of carbetocin and that are stable under conditions of stress.
For example, the pharmaceutical ations of the present disclosure remain
unexpectedly stable even at relatively high trations of carbetocin (e.g., greater than about
mg/mL to about 70 mg/mL) and under accelerated stress conditions. In some embodiments of the
least 10
present disclosure, carbetocin is present in a pharmaceutical preparation in a concentration of at
mg/mL, which is 100 times greater than that of the DURATOCIN® and CARBETOCIN RTS products
referenced above. The carbetocin pharmaceutical preparations disclosed herein also t improved
stability even under conditions of mechanical stress and for extended periods of time. In addition, the
pharmaceutical ations of the present sure are suitable for intranasal administration.
In certain embodiments, the stable intranasal pharmaceutical preparation comprises
In at least one
an 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 one
embodiment, the pharmaceutical preparation does not have reduced headspace, i.e., the container is not
completely full.
In at least one embodiment, the present disclosure is directed to a stable intranasal
pharmaceutical ation comprising an aqueous solution of carbetocin and a solubilizer and/or surface
active 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 least
visual assessment,
some embodiments, the pharmaceutical preparation has little to no aggregates by
including photographs.
In at least one embodiment, the present disclosure is directed to a stable intranasal
pharmaceutical preparation comprising an aqueous solution of carbetocin and a solubilizer and/or surface
active agent, such as HPMC, wherein the resulting preparation exhibits a vely high content
uniformity of carbetocin for long periods of time at room temperature, and also after one or more
freeze/thaw .
For example, the disclosed preparations show content uniformity of carbetocin
after thawing for up to 7 days (longer shelf life and/or in-use ). In at least some ments, the
disclosed carbetocin preparation is stable and does not aggregate for a period of time after one or more
1O freeze/thaw cycles. In some ments, the pharmaceutical ation has little to no aggregates by
visual assessment, which may include photographs. In some embodiments, the carbetocin in the disclosed
preparation is evenly distributed throughout the preparation to ensure that ifthe preparation is, for
example, split in one or more preparations, each resulting preparation has an equal dose of carbetocin. In
which is
one embodiment, the disclosed carbetocin preparations have a consistent dose of carbetocin,
maintained between various preparation batches so that the patient receives the correct dose consistently
over various strations. In at least one embodiment, the disclosed carbetocin ations e
enhanced convenience and t compliance.
In at least one embodiment, the concentration of carbetocin
In at least one embodiment, the concentration of
ranges 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, the
concentration of carbetocin ranges from about 11 mg/mL to about 36 mg/mL. In at least one
embodiment, the concentration of carbetocin is about 34.3 mg/mL. In at least one embodiment, the
concentration of carbetocin is about 11.4 mg/mL. In some embodiments, the high tration
carbetocin 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 visible
solids for up to 3 years. In some embodiments, the carbetocin pharmaceutical preparation has no
visible solids for 2 years. In some embodiments, the carbetocin pharmaceutical preparation has no
visible solids for 1 year. In some embodiments, the carbetocin pharmaceutical preparation has no
visible solids for up to 3 years when the headspace is near zero. In one embodiment, the carbetocin
3O pharmaceutical preparation has no e solids for up to 3 years when the ace is substantially
zero.
In at least some embodiments, the pharmaceutical preparation of carbetocin
comprises a hydrotrope and/or HPMC, and the concentration of carbetocin in the ation ranges from
about 1 mg/mL to about 15 mg/mL. In at least one embodiment, the concentration of carbetocin ranges
from about 1 mg/mL to about 10 mg/mL. In at least one embodiment, the concentration of carbetocin
ranges from about 1 mg/mL to about 5 mg/mL. In at least one embodiment, the concentration of
carbetocin is about 1 mg/mL. In at least one ment, the concentration of carbetocin is about 11.4
mg/mL. In some embodiments, the ocin pharmaceutical preparation has no visible solids when
stored at room temperature (e.g., 25 °C) for a ned period of time. For example, the carbetocin
pharmaceutical preparation has no visible solids for up to 3 years. In some embodiments, the
carbetocin pharmaceutical ation has no e solids for up to 3 years when the headspace is
near zero. In one embodiment, the carbetocin pharmaceutical preparation has no visible solids for up
to 3 years when the headspace is ntially zero.
In some embodiments, the concentration of carbetocin in the ceutical
preparation does not change over time (e. g., storage at 40 °C for 1 week, 40 °C for 2 weeks, 40 °C for 3
weeks, 40 °C for 4 weeks, 40 0C for 5 weeks). In at least one embodiment, carbetocin is not subject to
chemical degradation as measured by HPLC. For example, the tographic purity of carbetocin is
1O than
r than 98%. In at least one embodiment, the chromatographic purity of carbetocin is greater
99%. In at least one embodiment, the chromatographic purity of carbetocin is greater than 99.4%. In at
least one embodiment, the chromatographic purity of carbetocin is greater than 99.5%.
In at least one embodiment, the ocin pharmaceutical preparation is stable to
shaking stress. In some embodiments, the preparation is subjected to shaking stress for at least 14 days
when the headspace is limited, and the aqueous carbetocin solution remains clear with little to no visible
particles. In some embodiments, the preparation is subjected to intermittent shaking stress for at least 14
days, and the aqueous carbetocin solution remains clear with little to no visible particles. In at least one
ment, carbetocin does not chemically degrade before or after shaking stress. For example, the
chromatographic purity of ocin is greater than 98%. In at least one embodiment, the
tographic purity of carbetocin is greater than 99%. In at least one embodiment, the
chromatographic purity of carbetocin is 2 99.4. In at least one embodiment, the chromatographic purity
of ocin is 2 99.5. Such chromatographic purity occurs with and without exposure to shaking stress.
The pharmaceutical preparations of carbetocin disclosed comprise a lizer
and/or HPMC. The solubilizer is chosen from an amino acid, an interfacial stabilizer, or a hydrotrope. In
at least one embodiment, the amino acid may be chosen from a natural or unnatural amino acid. In one
embodiment, the natural amino acid is arginine. In at least some ments, the unnatural amino acids
and pyruvic acid derivatives, 3-substituted
may be chosen from B-amino acids, homo-amino acids, proline
alanine derivatives, glycine derivatives, ring-substituted phenylalanine and tyrosine derivatives, linear
is an
core amino acids, or N-methyl amino acids. In some embodiments, the unnatural amino acid
3O 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, randomly
methylated-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, the
cyclodextrin is methyl-B-cyclodextrin. In at least one embodiment, the hydrotrope is an aromatic anionic
compound. In at least one embodiment, the rope is selected from the group consisting of
nicotinamide, sodium benzoate, and salicylate salts (e.g., sodium salicylate, potassium salicylate, lithium
salicylate, ammonium salicylate, calcium salicylate, and magnesium salicylate).
In at least one embodiment, the ceutical ation comprises
nicotinamide. In another embodiment, the pharmaceutical preparation comprises sodium salicylate. In
some embodiments, the pharmaceutical ation comprises nicotinamide, sodium benzoate, salicylate
salt (e.g., sodium salicylate), methyl—B—cyclodextrin, or arginine and HPMC. The pharmaceutical
ation of the present disclosure may also include additional excipients, such sorbitol, mannitol,
e, lactose, trehalose, ethylenediaminetetraacetic acid (EDTA), potassium sorbate, acetate, and
methyl-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 a
cyclodextrin 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 some
embodiments, the extrin derivative is methyl-B-cyclodextrin.
If present in the pharmaceutical preparation, the surface active agent may be
chosen from a viscoelastic r, for example, hydroxypropyl methylcellulose (HPMC). In at least
some embodiments, the surface active agent is a cellulose derivative. In at least one embodiment, the
cellulose derivative may be chosen from hydroxypropyl ose (HPC), hydroxypropyl methylcellulose
, and carboxy methyl ethyl cellulose (CMEC). In some embodiments, the cellulose derivative is
HPMC. 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% to
0.0125% w/v. And, in some embodiments, HPMC is present in an amount ranging from 0.0075% to
0.01% w/v. In at least one embodiment, HPMC is high viscosity grade. In at least one embodiment, the
high ity HPMC is 4000 CF.
If present in the pharmaceutical preparation, namide is present in a
concentration ranging from 50 mM to 500 mM. In at least one embodiment, the concentration of
nicotinamide is about 400 mM. In at least one embodiment, the concentration of nicotinamide is about
300 mM. In another embodiment, the concentration of nicotinamide is about 200 mM.
If present in the pharmaceutical preparation, sodium salicylate is present in a
concentration ranging from 50 mM to 500 mM. In at least one embodiment, the concentration of sodium
salicylate is about 400 mM. In at least one embodiment, the concentration of sodium salicylate is about
300 mM. In another embodiment, the concentration of sodium late is about 200 mM.
In some embodiments, the pharmaceutical preparation further comprises a tonicity
enhancer to adjust the osmolality from about 220 mOsm/Kg to about 370 mOsm/Kg. In at least one
embodiment, the osmolality is about 225 mOsm/Kg. In at least one embodiment, the lity is about
290 mOsm/Kg. In at least one ment, the osmolality is about 352 mOsm/Kg. In at least one
embodiment, the osmolality is about 370 mOsm/Kg. In at least one ment, the tonicity enhancer is
sorbitol. 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 ation
from 5.15 to 5.65, from 5.25 to 5.55, or 5.35 to
ranges 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 one
embodiment, the pH is about 5.4 i 0.1.
The stable pharmaceutical preparation of the present disclosure may be formulated
in 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 preparation
comprising an aqueous solution of carbetocin and a solubilizer and/or HPMC in a container, wherein the
concentration of carbetocin ranges from about 1 mg/mL to about 70 mg/mL, and wherein the headspace
1O in the container is near zero (i.e., limited headspace). In one embodiment, the headspace in the container
is substantially zero.
In at least one embodiment, a stable intranasal pharmaceutical preparation
comprises:
(a) an aqueous solution of carbetocin, wherein the tration of carbetocin ranges from
about 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 preparation
comprises:
(a) an aqueous solution of ocin, wherein the carbetocin is present in a concentration of
about 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 3
to about 5.8.
In at least one embodiment, a stable intranasal pharmaceutical preparation
ses:
(a) an s solution of carbetocin, wherein the carbetocin is present in a concentration of
about 1 mg/mL to about 70 mg/mL;
(b) a hydrotrope selected from the group consisting of nicotinamide, sodium benzoate, and
sodium salicylate; and
(c) optionally an onal excipient. In another embodiment, the preparation has a pH
ranging from about 3 to about 5.8.
[003 5] In at least one ment, a stable intranasal pharmaceutical preparation
comprises:
(a) an aqueous solution of ocin, wherein the carbetocin is present in a concentration of
about 1 mg/mL to about 70 mg/mL;
(b) hydroxypropyl methylcellulose (HPMC), wherein the HPMC is present in an amount
g from 0.005% to 0.05% w/v; and
(c) optionally an onal excipient, wherein the solution has a pH ranging from about 3 to
about 5.8.
[003 6] In at least one embodiment, a stable intranasal pharmaceutical preparation
comprises:
(a) an aqueous solution of carbetocin, wherein the carbetocin is
present 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 preparation
1O comprises:
(a) an s solution of carbetocin, wherein the ocin is
present 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 preparation
comprises:
(a) carbetocin, wherein the carbetocin is present in a concentration of about 25 mg/mL to
about 35 mg/mL;
(b) namide, wherein the nicotinamide is present in a concentration ranging from about
200 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 to
about 250 mM.
[003 9] In at least one embodiment, a stable intranasal pharmaceutical preparation
comprises:
(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 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 excipient chosen from EDTA, potassium sorbate, and
combinations thereof.
In at least one embodiment, a stable intranasal ceutical preparation
comprises:
(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 from
about 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, potassium
sorbate, and ations thereof.
In at least one embodiment, a stable intranasal pharmaceutical preparation
comprises:
(a) ocin, wherein the carbetocin is present in a tration of about 1 mg/mL to
about 4 mg/mL;
(b) nicotinamide, wherein the nicotinamide is present in a concentration ranging from
about 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 100
mM to about 287 mM.
In at least one embodiment, the pharmaceutical preparations ofthe present
disclosure are administered intranasally daily for a period of time. In at least one embodiment, the
pharmaceutical preparations are administered intranasally up to 3 times daily for chronic use. In at least
about 200
one embodiment, the pharmaceutical preparation is administered in a volume of about 50 uL to
uL into one nostril and then a volume of about 50 uL to about 200 uL into the second nostril, for a
combined volume of about 100 uL to about 400 uL for both nostrils. In at least one embodiment, the
pharmaceutical preparations are administered intranasally 3 times daily for 20 consecutive days. In at
least one embodiment, the pharmaceutical ation is administered in a volume of about 20 uL to
about 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, the
pharmaceutical preparation is administered in a volume of about 25 uL to about 35 uL into one nostril
and then a volume of about 25 uL to about 35 uL into the second nostril, for a combined volume of about
50 uL to about 70 uL for both nostrils. In one embodiment, the pharmaceutical preparation is
administered 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 present
disclosure may be for use in (or in the manufacture of medicaments for) the ent or prevention of a
neurodevelopmental disorder or related symptoms in a t in need thereof. In at least one
embodiment, a therapeutically-effective amount of a pharmaceutical preparation of the present disclosure
is administered to a t diagnosed with -Willi syndrome. In one embodiment, the
pharmaceutical preparation is administered to the subject intranasally. In at least one embodiment, a total
daily dose of carbetocin is from about 1 mg/day to about 30 . In at least one embodiment, a total
daily dose of carbetocin is from about 8.0 mg/day to about 30.0 mg/day. In at least one embodiment, a
total daily dose of carbetocin is from about 9.0 mg/day to about 29.0 mg/day. In one embodiment, a total
daily dose of carbetocin is chosen from about 8.0 mg/day, about 9.0 mg/day,10.0 mg/day, about 11.0
WO 61414
mg/day, about 12.0 mg/day, about 13.0 mg/day, about 14.0 , 15.0 mg/day. 16.0 mg/day, 17.0
mg/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 another
embodiment, a total daily dose of carbetocin is chosen from about 9.1 mg/day, about 9.2 mg/day, about
9.3 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 one
embodiment, a total daily dose of carbetocin is chosen from about 11.1 mg/day, about 11.2 mg/day, about
11.3 mg/day, about 11.4 mg/day, about 11.5 mg/day, about 11.6 mg/day, about 11.7 mg/day, about 118
mg/day, and about 11.9 mg/day. In at least one embodiment, a total daily dose of carbetocin is 11.4
mg/day. In one embodiment, a total daily dose of carbetocin is chosen from about 28.1 mg/day, about
28.2 mg/day, about 28.3 mg/day, about 28.4 mg/day, about 28.5 mg/day, about 28.6 mg/day, about 28.7
mg/day, about 28.8 mg/day, and about 28.9 mg/day. In at least one ment, a total daily dose of
carbetocin 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 and
bioavailability. In at least some embodiments, the pharmaceutical preparation is an aqueous solution of
about 10 mg/mL to about 70 mg/mL carbetocin that includes a hydrotrope and a viscoelastic polymer in
such concentrations that the solution retains 75-125% of the bioavailability (as measured by the area
under the curve and the maximum concentration) of an aqueous solution of carbetocin in .
In another aspect, the disclosure provides a method of administering carbetocin to
of 3.2 mg/dose
a subject diagnosed with Prader-Willi syndrome, wherein two or three doses per day
carbetocin are administered intranasally to the patient. According to this aspect, the disclosure provides a
method of administering carbetocin to a subject diagnosed with Prader—Willi syndrome, wherein three
doses per day of 3.2 mg/dose carbetocin are administered intranasally to the patient. The disclosure also
provides 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-Willi
syndrome, wherein carbetocin is administered for at least one week, at least two weeks, at least three
weeks, 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 subject
diagnosed with Prader-Willi me, wherein the administration results in one or more of (a) decrease
in hyperphagia behavior compared to placebo, optionally as measured by the Hyperphagia Questionnaire
for Clinical Trials ) Total Score; (b) se in ive and compulsive behavior ed to
placebo, 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 Anxiety
and Distress Questionnaire (PADQ) Total Score; and (d) improvement in global clinical impression
compared 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 subject
diagnosed with Prader-Willi syndrome, wherein the administration results in a decrease in hyperphagia
behavior. According to this aspect, the disclosure provides a method of administering carbetocin to a
subject diagnosed with Pr'ader-Willi syndrome, wherein the administration results in a decrease in
hyperphagia or and a se in obsessive and compulsive behavior.
In another aspect, the disclosure provides a method of administering carbetocin to
a subject diagnosed with Prader-Willi syndrome, wherein the age of the subject is from seven (7) to
eighteen (18) years old, inclusive. According to this aspect, the disclosure provides a method of
administering ocin to a subject diagnosed with Prader-Willi me, wherein the subject is aged
seven (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) years
old, seventeen (17) years old, or eighteen (18) years old.
BRIEF DESCRIPTION OF GS
The foregoing summary, as well as the following detailed description of the
disclosure, will be better understood when read in conjunction with the appended drawings. For the
illustrate some, but not all, alternative
purpose of illustrating the present disclosure, the attached drawings
embodiments. It should be understood, however, that the disclosure is not limited to the precise
arrangements and instrumentalities shown. These figures, which are orated into and constitute part
of the specification, assist in explaining the principles of the disclosure.
Fig 1. ‘shows an e image comparing 400 mM and 200 mM sodium
salicylate (left- and right—hand vials, respectively) samples after 6 days of continuous agitation. The 200
mM sample contains more and larger particles than the 400 mM sample. Additionally, the 200 mM
sample has a slight opalescent appearance.
Fig 2. shows an example image of various samples studied after 6 days of
continuous agitation. From left to right: 400 mM sodium salicylate, 200 mM sodium salicylate, 82 mM
ne, and 160 mM sodium benzoate after 6 days of uous ion.
[0050] Fig 3. shows A350 measurements for various samples. Fig 3.(a) shows A350
measurements for samples having 80% headspace. Fig 3.(b) shows A350 measurements for s
having limited headspace.
Fig 4. shows an example image of “soft” precipitate for 2 HPMC containing
samples 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 mM
nicotinamide samples (19 hrs agitation).
DETAILED DESCRIPTION OF THE DISCLOSURE
The present disclosure relates to a stable intranasal pharmaceutical preparation that
ses an aqueous solution of ocin and a solubilizer and/or HPMC. The pharmaceutical
preparations disclosed may include but do not require a surfactant. The pharmaceutical preparations of the
present disclosure t ed ity despite their relatively high trations of carbetocin. For
example, in certain embodiments, the pharmaceutical preparations show little to no visible solids after
extended periods of time at room temperature. In other embodiments, the ceutical preparations of
WO 61414
the present disclosure exhibit little to no e solids after shaking stress. The pharmaceutical
preparations disclosed herein may be formulated in a container having d headspace, which may
include close to or ntially zero headspace to minimize, for example, the gas—water interface. In
certain embodiments, however, it is ssary to reduce headspace to maintain improved stability. The
pharmaceutical preparations disclosed exhibit improved stability despite their vely high
concentrations 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). The
pharmaceutical ations of the present disclosure also possess ageously extended in-use time
and/or shelf life for the patient. For example, the pharmaceutical preparation of the present disclosure
exhibits an in-use time ranging from 1 day to 7 days, and includes ments wherein the content
uniformity of carbetocin remains consistent and high throughout the in-use period. In some
embodiments, the pharmaceutical preparations of the present disclosure also possess good local
tolerability after 14 days at room temperature. In at least some ments, the pharmaceutical
preparations 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 stable
pharmaceutical preparation comprising an aqueous solution of carbetocin and a solubilizer and/or a
lastic polymer, such as HPMC, wherein the concentration of carbetocin ranges from about
1 mg/mL to about 70 mg/mL. In at least some embodiments, the addition ofHPMC to the preparation
reduces aggregation of an aqueous solution of carbetocin compared to an aqueous solution of carbetocin
that doe-s not contain HPMC. In some embodiments, the HPMC in the carbetocin ation reduces
aggregation of the carbetocin solution by at least 20% and up to 50% when ed to an aqueous
solution of carbetocin that does not contain HPMC. In other embodiments, the HPMC in the carbetocin
preparation reduces aggregation of the carbetocin solution by at least 20% compared to an aqueous
solution of carbetocin that does not contain HPMC. In some embodiments, the HPMC in the carbetocin
preparation s aggregation of the carbetocin solution by at least 30% compared to an aqueous
solution of carbetocin that does not contain HPMC. In some embodiments, the HPMC in the carbetocin
preparation reduces aggregation of the carbetocin solution by at least 40% compared to an aqueous
solution 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 aqueous
solution 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 30
mg/mL to 34 mg/mL. In at least one embodiment, the concentration of carbetocin in solution is about 40
mg/mL. In another embodiment, the concentration of carbetocin ranges from about 10 mg/mL to about 45
mg/mL. In at least one embodiment, the concentration of carbetocin ranges from about 20 mg/mL to
about 40 mg/mL. In at least one embodiment, the concentration of carbetocin may be, for example, about
mg/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/USZOl9/052090
about 40 mg/mL. In another embodiment, the concentration of carbetocin may be, for example, 34.1
mg/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 one
solubilizer and/or HPMC is included in the pharmaceutical preparation.
In at least one embodiment, the hydrotrope is an aromatic anionic nd, an
aromatic cationic compound, or aliphatic and linear compounds. Examples of hydrotropes include but are
not limited to nicotinamide, sodium te, salicylate salts (e.g., sodium late, potassium
salicylate, lithium late, ammonium salicylate, calcium salicylate, magnesium salicylate etc.), N,N—
1O diethylnicotinamide, or N,N-dimethyl benzamide. In certain ments, the rope is
nicotinamide, sodium benzoate, or sodium salicylate. The hydrotrope may also be an aromatic cationic
compound, such as caffeine and procaine hydrochloride. In other embodiments, the hydrotrope may be an
tic and linear compound chosen from N,N—dimethyl urea, urea, or sodium alkanoate.
If present in the pharmaceutical preparation, nicotinamide is present in a
tration g from 50 mM to 500 mM. In at least one embodiment, the nicotinamide
concentration ranges from about 50 mM to about 350 mM, such as from 100 mM to 220 mM, from 240
mM to 260 mM, from 280 mM to 300 mM, or from 320 mM to 340 mM. In at least one embodiment, the
concentration of nicotinamide is, for example, about 200 mM, about 210 mM, about 220 mM, about 230
mM, 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 360
mM, about 370 mM, about 380 mM, about 290 mM, or about 400 mM. In at least one embodiment, the
concentration of nicotinamide is about 400 mM. In at least one embodiment, the concentration of
nicotinamide is about 350 mM. In at least one embodiment, the concentration of nicotinamide is about
300 mM. In at least one embodiment, the concentration of nicotinamide is about 250 mM. In another
embodiment, 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 some
embodiments, the salicylate salt is sodium salicylate which is present in a concentration ranging from 200
mM to 400 mM. In at least one embodiment, the sodium salicylate tration ranges from about 200
mM to about 300 mM, such as from 200 mM to 220 mM, from 240 mM to 260 mM, or from 280 mM to
300 mM. In at least one embodiment, the concentration of sodium salicylate is about 400 mM. In at least
one embodiment, the concentration of sodium salicylate is about 300 mM. In another embodiment, the
tration of sodium salicylate is about 200 mM.
[0060] If present in the pharmaceutical preparation, sodium benzoate is present in a
concentration ranging from 100 mM to 400 mM. In at least one embodiment, the sodium te
concentration ranges from about 160 mM to about 400 mM, such as from 160 mM to 200 mM, from 250
mM to 300 mM, or from 350 mM to 400 mM. In at least one embodiment, the concentration of sodium
benzoate is about 160 mM. In at least one embodiment, the concentration of sodium benzoate is about
400 mM.
If present in the pharmaceutical ation, methyl-B—cyclodextrin is present in a
concentration ranging from 15 mM to 50 mM. In at least one embodiment, the methyl-B-cyclodextrin
tration ranges from about 17.5 mM to about 40 mM, such as from 17.5 mM to 25 mM, from 30
mM 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 is
about 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 amount
ranging from 0.005% to 0.05% w/v. In at least one embodiment, HPMC is present in an amount g
from 0.0075% to 0.0125% w/v. In another embodiment, HPMC is present in an amount ranging from
0.0075% to 0.01% w/v. In at least one embodiment, HPMC is present in an amount of 0.01% w/v. In at
least one ment, the grade ofHPMC is chosen from low viscosity (e.g., 10—20 cP), medium
viscosity (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 a
viscosity of 4000 CF.
The pharmaceutical preparations of the present sure may include a
solubilizer and HPMC. Thus, in certain embodiments, nicotinamide, sodium benzoate, sodium salicylate,
arginine, inethyl-B-cyclodextrin, and combinations thereof are present in the pharmaceutical preparation
with HPMC. Such preparations may optionally contain an additional excipient. Non-limiting examples of
additional excipients include sorbitol, ethylenediaminetetraacetic acid (EDTA), ium sorbate,
mannitol, and sodium or potassium acetate. These additional excipients may be included even if only a
solubilizer or HPMC is present alone. Specifically, in at least one ment, the pharmaceutical
preparation 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 found
that HPMC associates to the glass e of the vial and because of this ation it can ze the
interaction of carbetocin with this interface. In contrast, it was surprisingly found that nicotinamide is able
to
to solubilize aggregates formed during agitation, which in turn reduces carbetocin’s propensity
the addition of
aggregate and subsequently form small and large precipitates. It was further found that
both 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 resulting
ocin ations comprising nicotinamide and HPMC are surprisingly stable under accelerated
conditions of stress for long periods of time.
In at least some embodiments, the present disclosure is directed to a stable
intranasal pharmaceutical preparation comprising an aqueous solution of carbetocin and a solubilizer
and/or surface active agent, such as HPMC, wherein the resulting preparation shows a surprising high
content 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 /thaw
cycles for a duration chosen from 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and 7 days. In at least
assessment after
some embodiments, the pharmaceutical preparation has little to no aggregates by visual
thawing for up to 7 days. In some embodiments, the carbetocin in the disclosed preparation is evenly
buted throughout the preparation to ensure that if the preparation is, for example, split in one or more
preparations, each resulting preparation has an equal dose of carbetocin. In one embodiment, the
disclosed carbetocin preparations have a consistent dose of ocin, which is maintained between
various preparation batches so that the patient receives the correct dose consistently over various
strations. In at least one embodiment, the disclosed carbetocin preparation provides enhanced
convenience and patient compliance.
A tonicity enhancer/modifier may be, but is not required, to provide isotonic
formulations (e.g., 300 g). In at least one embodiment, the osmolality of a pharmaceutical
composition is preferably adjusted to maximize the active ingredient’s stability and/or to minimize
fort to the patient upon stration. In at least one embodiment, the pharmaceutical
composition for direct stration to a patient is ic, which may be achieved by addition of a
acids
tonicity 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, sodium
citrate etc.) or nonelectrolytes (e.g., sugars or polyols, such as, for e, sucrose, glucose and
mannitol).
If present in the pharmaceutical preparation of the present disclosure, the tonicity
enhancer/modifier is added to adjust the osmolality to, for example, about 225 mOsm/Kg, about 226
mOsm/Kg, about 227 mOsm/Kg, about 228 mOsm/Kg, about 229 mOsm/Kg, about 230 mOsm/Kg, about
231 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 240
mOsm/Kg, about 241 mOsm/Kg, about 242 mOsm/Kg, about 243 mOsm/Kg, about 244 mOsm/Kg, about
245 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 254
about
mOsm/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 268
mOsm/Kg, about 269 mOsm/Kg, about 270 mOsm/Kg, about 271 mOsm/Kg, about 272 mOsm/Kg, about
273 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 282
g, about 283 mOsm/Kg, about 284 mOsm/Kg, about 285 mOsm/Kg, about 286 g, about
287 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 296
mOsm/Kg, about 297 mOsm/Kg, about 298 mOsm/Kg, about 299 mOsm/Kg, about 300 mOsm/Kg, about
310 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 400
mOsm/Kg, about 410 mOsm/Kg, about 420 mOsm/Kg, about 430 mOsm/Kg, about 440 mOsm/Kg, about
450 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 540
g, about 550 mOsm/Kg, about 560 mOsm/Kg, about 570 mOsm/Kg, about 580 mOsm/Kg, about
600 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 700
about
mOsm/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 800
mOsm/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 100
mM to 300 mM. In some embodiments, sorbitol is t in a concentration ranging from 110 mM to
287 mM. In some embodiments, sorbitol is added to adjust the lity to, for example, about 105
mM, 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 170
mM, about 175 mM, about 180 mM, about 185 mM, about 190 mM, about 195 mM, about 200 mM, 205
mM, about 210 mM, about 215 mM, about 220 mM, about 225 mM, about 230 mM, 235 mM, about
mM, about 245 mM, about 250 mM, about 255 mM, about 260 mM, 265 mM, about 270 mM, about 275
mM, about 280 mM, about 285 mM, about 290 mM, or about 300 mM. In at least one embodiment, the
concentration 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 110
mM. In at least one embodiment, the concentration of sorbitol is about 130 mM.
This disclosure is also ed to achieving a stable lyophilized preparation of
ocin. In at least one ment, a carbetocin lyophilisate is mixed with a solubilizer and/or HPMC
in water to obtain a pharmaceutical preparation drug product. Without being bound to any particular
theory, the solubilizer and/or HPMC expedites dissolution of lyophilized ocin as compared to its
typically slow reconstitution with conventional diluents (e,g., bulking agents and sugar stabilizers). In at
least one embodiment, isotonic solutions sing a solubilizer and/or HPMC of the disclosure
3O 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 one
embodiment, the solubilizer and/or HPMC of the disclosure increases the dissolution rate of lized
carbetocin. In at least one embodiment, the solubilizer is nicotinamide which improves the dissolution
rate of lyophilized carbetocin. The use of a solubilizer, such as nicotinamide and/or HPMC, reduced
dissolution time of the lyophilized carbetocin (at 40 mg/mL) to only a few minutes, a time generally
considered acceptable for a lyophilized drug product.
In at least one embodiment, the solubilizer is an arginine salt (e.g., HCl salt). In
in’ a concentration
some embodiments, the arginine salt is present in the pharmaceutical preparation
ranging from 50 mM to 300 mM. In at least one embodiment, the arginine concentration ranges from
about 100 mM to about 300 mM, such as from 100 mM to 150 mM, from 200 mM to 250 mM, or from
250 1nM to 300 mM. In at least one embodiment, the concentration of arginine salt is about 100 mM. In at
least 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 to
500 mM. In at least one embodiment, the nicotinimide concentration ranges from about 50 mM to about
350 mM, such as from 200 mM to 220 mM, from 240 mM to 280 mM, or from 300 mM to 350 mM. In at
least 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 of
nicotinimide is about 400 mM.
In at least one embodiment, the solubilizer is -B—cyclodextrin. In some
embodiments, the methyl-B-cyclodextrin is present in the pharmaceutical preparation in a concentration
ranging from 10 mM to 40 mM. In at least one embodiment, the methyl-B-cyclodextrin concentration
such 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—cyclodextrin
about 35 mM. In at least one embodiment, the concentration of methyl-B—cyclodextrin is about 25 mM. In
at least one embodiment, the concentration of methyl-B-cyclodextrin is about 17.5 mM.
This disclosure is further ed to a pharmaceutical preparation comprising an
and/or HPMC in a ner, wherein the headspace in
aqueous solution of ocin and a lizer
the container is near zero (i.e., limited headspace). In another embodiment, such a ceutical
preparation with reduced headspace does not include a surfactant. That is, the present disclosure es
and/or
a 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 the
preparation 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 the
pharmaceutical preparation does not include a surfactant. In at least one embodiment, a surface active
agent is not present in the preparation disclosed.
The term “headspace” is a term well understood in the art and refers to gas space
3O within a sealed container containing a solution. The volume of the ace may vary depending on the
entire 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 0.8
mL, 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 0.18
mL, about 0.15 mL, about 0.12 mL, about 0.1 mL, about 0.08 mL, about 0.07 mL, about 0.06 mL, about
0.05 mL, about 0.04 mL, about 0.03 mL, about 0.020 mL, or about 0.01 mL ofthe volume ofthe
container comprising the carbetocin solution. In at least one embodiment, the headspace represents about
80%, 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 about
0.1% of the volume of the container comprising the carbetocin solution. In at least one embodiment, the
headspace ents less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1%, less
than , or 0.0% of the total volume of the container. In at least one embodiment of the present
disclosure, the container ace is substantially zero.
The pharmaceutical preparations of the present disclosure are advantageous
because 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 is
evident 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 at
room 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, the
carbetocin solution has little to no visible solids for up to 4 years. In some embodiments, the
carbetocin solution has little to no visible solids for up to 3 years. In some embodiments, the
tration 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 to
shaking stress. For example, the aqueous ocin solution is stable to g stress for a period of
time. 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 to
no 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 no
visible particles. In at least one embodiment, the preparation is subjected to shaking stress for 5 days, and
the aqueous carbetocin solution remains clear with little to no visible particles. In some embodiments, the
ation is subjected to shaking stress for at least 3 days, and the aqueous carbetocin solution remains
clear with little to no visible les. In at least one embodiment, the pharmaceutical preparations are
stable to shaking stress for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9
hours, 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 30
hours, 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 aqueous
carbetocin solution remains clear with little to no visible particles.
The stability of the pharmaceutical preparations described herein may also be
measured by the chromatographic purity of carbetocin. In at least one embodiment, controls at one or
In at least one
more 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 greater
than 96%. In at least one embodiment, ls at one or more days assure that chromatographic
purity of carbetocin is greater than 97%. In at least one embodiment, the chromatographic purity of
ocin is greater than 98%. In at least one embodiment, the chromatographic purity of carbetocin is
than
greater than 99%. In at least one embodiment, the chromatographic purity of carbetocin is greater
99.4%. In at least one embodiment, the chromatographic purity of carbetocin is greater than 99.5%. In at
least one embodiment, the chromatographic purity of carbetocin is greater than 99.6%. In at least one
embodiment, the chromatographic purity of carbetocin is greater than 99.7%. In at least one
ment, the chromatographic purity of carbetocin is greater than 99.8%. In at least one
embodiment, 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 chromatographic
purity of carbetocin before or after shaking stress. In addition, the pharmaceutical preparations of the
present disclosure exhibit stability in that the concentration of carbetocin in solution does not change over
time, including under conditions of g .
In at least one embodiment, the chromatographic purity of carbetocin in solution
with a solubilizer and/or surface active agent disclosed is greater than 98% after 24 hours of stress. In at
least one embodiment, the chromatographic purity of carbetocin in solution with a solubilizer and/or
surface 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 agent
disclosed is greater than 98% at 48 hours of . In at least one embodiment, the chromatographic
purity of carbetocin in on a solubilizer and/or surface active agent disclosed is r than 98 % at
72 hours of stress.
In at least one embodiment, the chromatographic purity of carbetocin in solution
with a solubilizer and/or surface active agent disclosed is greater than 99% after 24 hours of stress. In at
least one ment, the chromatographic purity of carbetocin in solution with a solubilizer and/or
e 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 agent
disclosed is greater than 99% at 48 hours of stress. In at least one embodiment, the chromatographic
purity 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 solution
with a solubilizer and/or surface active agent disclosed is greater than 99.5% after 24 hours of stress. In
at least one ment, the chromatographic purity of carbetocin in solution with a solubilizer and/or
surface active agent disclosed is greater than 99.5%. after 36 hours of stress. In at least one
embodiment, the tographic purity of carbetocin in solution with a solubilizer and/or surface active
agent disclosed is r than 99.5% at 48 hours of stress. In at least one embodiment, the
chromatographic purity of carbetocin in solution with a solubilizer and/or surface active agent sed
is greater than 99.5 % at 72 hours of stress.
In general, the pharmaceutical preparations of the present disclosure will have a
pH from about 3.0 to about 5.8. In at least one embodiment, the pH of the aqueous carbetocin solution
for e from 5.3 to 5.4. In some
may be from 3.5 to 5.7, for example from 4.2 to 5.6, or
embodiments of the present disclosure, the pH of the pharmaceutical preparation is from about 5.3 to
about 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 carbetocin
solution is 5.4 i 0.5. In another embodiment, the pH of the s carbetocin solution is 5.4 i 0.3. In
another 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 at
least one embodiment, the container is an e or a vial. In at least one ment, the container is a
vial.
Exemplary Pharmaceutical Preparations
In at least one embodiment, a stable intranasal pharmaceutical preparation
comprises:
(a) an s solution of carbetocin, wherein the concentration of carbetocin ranges from
about 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 preparation
comprises:
(a) of
an aqueous solution of carbetocin, wherein the carbetocin is present in a concentration
about 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 3
to about 5.8.
In at least one embodiment, a stable intranasal pharmaceutical preparation
comprises:
(a) an aqueous solution of carbetocin, wherein the carbetocin is t in a concentration of
about 1 mg/mL to about 70 mg/mL;
(b) a hydrotrope ed from the group consisting of nicotinamide, sodium benzoate, and
sodium salicylate; and
(c) optionally an additional excipient. In another embodiment, the preparation has a pH
ranging from about 3 to about 5.8.
[008 8] In at least one embodiment, a stable intranasal pharmaceutical preparation
comprises:
(a) of
an s solution of carbetocin, wherein the carbetocin is present in a concentration
about 1 mg/mL to about 70 mg/mL;
(b) hydroxypropyl methylcellulose (HPMC), wherein the HPMC is present in an amount
ranging from 0.005% to 0.05% w/v; and
(c) optionally an onal excipient, n the on has a pH ranging from about 3 to
about 5.8.
In at least one embodiment, a stable intranasal pharmaceutical preparation
comprises:
(a) of
an aqueous solution of carbetocin, wherein the carbetocin is present in a concentration
about 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 preparation
comprises:
(a) of
an s solution of carbetocin, wherein the ocin is t in a concentration
about 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 ation
comprises:
(a) carbetocin, wherein the carbetocin is present in a concentration of about 25 mg/mL to
about 35 mg/mL;
(b) nicotinamide, wherein the nicotinamide is present in a concentration ranging from about 50
mM 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 to
about 250 mM.
[0092] In at least one embodiment, a stable intranasal pharmaceutical preparation
comprises:
(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 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 excipient chosen from EDTA, potassium sorbate, and
combinations thereof.
In at least one embodiment, a stable intranasal pharmaceutical preparation
comprises:
(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 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 onal excipient chosen from EDTA, potassium e, and
combinations thereof.
In at least one embodiment, a stable intranasal pharmaceutical ation
comprises:
(a) carbetocin, wherein the carbetocin is present in a tration of about 1 mg/mL to about
4 mg/mL;
(b) nicotinamide, wherein the nicotinamide is present in a concentration ranging from about 50
mM 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 to
about 287 mM.
In each of these exemplary embodiments, the headspace of the container may
ally be reduced. In addition, the headspace may be substantially zero for each of these exemplary
embodiments.
[0096] The pharmaceutical preparations sed herein may optionally include one or
or more solvents may be
more pharrnaceutically acceptable solvents. In at least one embodiment, the one
and 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 active
agent, 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 instructions
for administration of the composition. The pH of the composition may be from 3.5 to 5.75, for example
from 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. The
pH of the composition may be from 5.30 to 5.8, for example from 5.40 to 5.70, for example from 5.50 to
5.6. In at least one embodiment, the pH of the composition is about 5.4. In at least one embodiment, the
pH of the aqueous carbetocin solution is 5.4 i 0.5. In another embodiment, the pH of the aqueous
carbetocin 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 at
least one embodiment, the base is 5 M NaOH.
Methods of Preparation
In at least one embodiment, the present disclosure provides a method to e a
pharmaceutical preparation of carbetocin that has a vely high concentration carbetocin and which
demonstrates improved stability at room temperature and/or under conditions of stress. In at least one
embodiment, a stable pharmaceutical preparation of aqueous carbetocin is prepared, for e, in a
container. In at least one embodiment, the disclosure provides a method for preparing a stable
ceutical preparation of aqueous carbetocin and a container, wherein the concentration of
carbetocin ranges from about 10 mg/mL to about 70 mg/mL, comprising: (a) adding aqueous carbetocin
solution to the container, and optionally the added solution can be in an amount ent to reduce
headspace (e.g., 20% headspace, 10% headspace, 5% headspace, close to zero headspace (i.e., limited
headspace)); and (b) adding a solubilizer and/or HPMC to the solution. In at least one embodiment, the
ceutical preparation of aqueous carbetocin prepared by the method disclosed herein has little to no
visible solids after horizontal shaking for 24 hours. In at least one embodiment, the pharmaceutical
ation of aqueous carbetocin prepared by the method sed herein has little to no visible solids
after horizontal shaking for 48 hours. In at least one embodiment, the pharmaceutical preparation of
herein has little to no visible solids after horizontal
aqueous carbetocin prepared by the method disclosed
shaking for 72 hours. In at least one embodiment, the pharmaceutical preparation of aqueous carbetocin
prepared by the method disclosed herein has little to no visible solids after horizontal shaking for 96
hours. In at least one embodiment, carbetocin is not subject to chemical degradation before or after the
shaking stress. In at least one embodiment, controls at one or more days assure that chromatographic
purity of carbetocin is r than 98%. In at least one embodiment, the chromatographic purity of
ocin is greater than 99%. In at least one embodiment, the tographic purity of carbetocin is
99.4 :: 0.0%. In at least one embodiment, the chromatographic purity of carbetocin is 99.4 :: 0.1%. In at
least one embodiment, the chromatographic purity of carbetocin is 99.4 :: 0.2%. In at least one
ment, the chromatographic purity of carbetocin is 99.5 i 0.0%. In at least one embodiment, the
tographic purity of carbetocin is 99.5 i 0.1%. In at least one embodiment, the chromatographic
purity of carbetocin is 99.5 :: 0.2%. In at least one embodiment, the chromatographic purity of
carbetocin is 99.8 i 0.3%. In at least one embodiment, the chromatographic purity of carbetocin is 99.9
i 0.1%.
s of ent
In at least one embodiment, the disclosure provides a method of treating a
subject suffering from, or susceptible to, a disease that is beneficially treated by a stable high
concentration ceutical preparation of carbetocin sing the step of stering to said
subject an effective amount of a pharmaceutical preparation of the present disclosure.
In at least one ment, the pharmaceutical preparations of the present
disclosure may be for use in (or in the manufacture of medicaments for) the treatment or prevention of
neurodevelopmental disorders, including Prader-Willi syndrome, or related symptoms in a mammalian
3O subject in need thereof. In at least one embodiment, a therapeutically-effective amount of a
pharmaceutical 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. The
following examples are intended for illustration purposes only and should not be construed as limiting the
the section headings used herein are for organizational
scope 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 box
against both a white and black background. es were taken to document any particles/precipitate
formed in these samples.
A350
Absorbance at 350 nm was monitored to track formation of large, soluble
aggregates in storage stability and agitation samples. For these measurements, 300 uL of solution was
measured in a reduced volume, 1 cm path-length quartz cuvette. MQ water was used as the blank for all
ements. Note, A350 is a light scattering technique, so it is most effective for measuring scattering
in 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 on
containing a lizer and/or HPMC. The pH of each formulation was adjusted to 5.4 and :: 0.1 by
addition of an appropriate amount of 5 M NaOH. All preparations were ed using multi—compendial
grade excipients and reagents, and ultra-pure water (Millipore MilliQ, 18MQ). The osmolality of each
preparation was measured before preparing the final formulation to ensure it was r to that of the
theoretically determined value. Each formulation (bulk material) was sterile filtered using a Millipore
Millex-GV syringe filter (022 um). 1.2 mL of each sterile filtered formulation was filled into a 3 mL
glass 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 vial
was used instead of a 3 mL vial. After sterile preparation, samples were placed ntally on an orbital
plate shaker (Labnet, 3 mm orbit) and shaken continuously at 200 rpm for a prescribed period of time (see
Table 1). Samples were shielded from ambient light during ion. All samples used in this study were
agitated at room temperature. The results of this experiment are summarized below in Table 1.
TABLE 1
Visual ation Results of Agitated Carbetocin Formulations
Carbetocin HPMC
Solubilizer Headspace Orientation Observations
(rn /mL) % (w/v
50 mM Arg HCl 40 0.05 d Horizontal 1 piece of soft precipitate after 4 days
No precipitation after 5 hrs of
200 mM Arg HCl 40 None 30% Horizontal agitation, but significant precipitation
after 24 hrs
some piftldes at? daysiw1th a few
200 mM Arg HCl 40 0.05 30% Horizontal
large, soft prec1p1tate partlcles
400 mM Proline 40 None 30% Horizontal Significant precipitation after 1 day
Nilg‘gnralrlillide 40 None 30% Horizontal Significant precipitation after 1 day
Some very fine particles after 2 days,
300 mM
40 None 30% Horizontal but not obvious; same appearance at 4
Nicotinamide
days
Visual Observation Results of Agitated Carbetocin Formulations
Carbetocin HPMC
Solubilizer oAifll/‘Qieadspace Orientation ations
(mg/m—L)
Niiggnnmde 4O 0'05 30% Horizontal Sfrfilgeefigdftligzipif:t:;”vpiz:fti:lfe:w
Nigggnnarlh/Iide 40 0'005 30% Horizontal Sfefilgeegztdftlfr:ipiftiieigpifiti:1::va
The results presented in Table 1 show that these high carbetocin concentration
preparations (Le, 40 mg/mL, 20 mg/mL) in pure water (pH 5.4) with various ents show visual signs
of precipitation, but differences in the precipitation behavior were ed dependent on the excipient
and excipient tration. Under the selected conditions (see Table 1 above), it can be seen that both
arginine and e were not effective at suppressing particle formation in the concentration ranges
examined. In contrast, 300 mM nicotinamide significantly helped to ss particle formation when
used as the sole formulation ent. onally, nicotinamide was more effective at ssing
particle formation when the concentration of carbetocin in the formulation was reduced from 40 mg/mL
to 20 mg/mL. However, under the tested conditions, nicotinamide was not effective at suppressing
particle ion when its concentration was reduced to 100 mM.
It was also observed that the morphology of the particles formed in 300 mM
namide solutions were different than those seen in the other carbetocin formulations studied. The
particles generated in agitated nicotinamide formulations were granular/fine in nature, and their formation
did not seem to progress substantially with prolonged agitation of the solution.
[011 l] The results show that nicotinamide alone, or in combination with hydroxypropyl
methylcellulose , was effective at mitigating precipitation of carbetocin upon prolonged
agitation. While particles/precipitate may form with both of these excipients, the amounts formed are
significantly less than that of the other excipients studied.
[0112] Example 2
Samples were prepared using the general procedure provided in Example 1. It is
noted that the hydrotropes d in this example were formulated at the following concentrations: 160
mM (isotonic) and 400 mM sodium te, 200 mM (isotonic) and 400 mM sodium salicylate, and 82
mM caffeine (near solubility limit), and 35 mg/mL carbetocin. Again, as in Example 1, an agitation study
was 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 on
the 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 its
400 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 the
400 mM salicylate preparation. As a result, the sample agitation was continued. After five days of
additional agitation, the samples were once again observed for particle formation. Both late
preparations were minimally changed from their earlier (i.e., their 24 hr appearance) (see Figure 1), while
the ne sample had formed a hard itate. An image ing the salicylate, caffeine, and
benzoate samples after 6 days of agitation is shown in Figure 2.
The result of this agitation study showed that salicylate may behave similarly to
nicotinamide in suppressing particle ion with agitation. It is noted that nicotinamide can be utilized
due to its
at 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 by
dissolving the desired amount of 40 mg/mL of ocin in an aqueous solution ning different
excipients or HPMC. The pH of each formulation was adjusted to 5.4 and :I: 0.1 by addition of an
riate amount of 5 M NaOH. After sterile preparation according to the same method described in
Example 1, samples were placed horizontally on an orbital plate shaker (Labnet, 3 mm orbit) and shaken
continuously at 200 rpm for prescribed periods of time. Samples were shielded from ambient light during
agitation. All samples used in this study were agitated at room temperature. The results of this experiment
are summarized below in Tables 2 and 3.
TABLE 2
Visual Observation Results for Agitated Carbetocin Formulations
Carbetocin Vial
. . Agitation Observations. Ex01pient
Concentration Orientation Time (hrs)
40 mg/mL DS Hydroxypropyl B—Cyclodextrin Horizontal 17 Significant precipitation
1 A) (W/V) Hydroxypropyl0
40 mg/mL DS ntal l7 Gelled
cellulose
Only a few particles
0.1% (w/v) Hydroxypropyl . (“soft precipitate”) and
40 mg/mL DS Hor1zontal 17
methyl cellulose (HPMC) some gel pieces on the
glass
40 mg/mL DS 0.02% (w/v) Poloxamer 188 Horizontal 17 Significant precipitation
40 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-polymer
surfactant) and ypropyl-B-cyclodextrin, both of which have been shown to be effective at
suppressing acial damage of proteins in solution, failed to stabilize carbetocin. itation of
carbetocin occurred within 17 hours of agitation when formulated with both of these excipients. In
addition, 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 3
Carbetocin HPMC, Potassium Vial Fill Shake Observations
(mg/mL) % (w/v) Sorbate, Position Volume Time
% (W/VL
40 0.05 0.5 Horizontal 30% 24 hrs Some “soft”
precipitate
40 0.01 0.5 Horizontal 30% 24 hrs Some “soft”
precipitate
40 0.005 0.5 Horizontal 30% 24 hrs Some “soft”
itate
40 0.05 None Horizontal 30% 24 hrs Some “soft”
precipitate
40 0.01 None Horizontal 30% 24 hrs Some “soft”
precipitate
40 0.005 None Horizontal 30% 24 hrs Some “soft”
itate
40 0.05 0.5 Horizontal 67% 24 hrs Some “soft”
precipitate
40 0.01 0.5 Horizontal 67% 24 hrs Some “sof ”
precipitate
40 0.005 0.5 Horizontal 67% 24 hrs Some “soft”
precipitate
Inspection of the agitation results in Table 3 shows that all formulations formed
soft precipitate within 24 hours of ion. The amount of precipitate was essentially the same for all
concentrations ofHPMC investigated, with each formulation containing a few pieces of “soft” precipitate
at 24 hrs. Additionally, it appeared as if the amount of precipitate was slightly less for the samples with
reduced headspace (67% fill volume). The presence of the preservative potassium sorbate did not appear
to 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 this
excipient 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 aqueous
solution 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 were
agitated (horizontal orientation) at both 5 °C and 25 °C, and ements were taken at time-zero, 3
days, and 14 days. A corresponding set of controls (no agitation) were measured at the conclusion of the
study. The results of the A3 50 measurements at time-zero, 3 days, and 14 days are listed below in Table
4, 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.
2019/052090
TABLE 4
A350 values measured for samples stored at 5 °C
and 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 0C
mg/mL 80% 0.011 0.010 0.014 0.014 0.022 0.025
mg/mL 80% 0.017 0.017 0.018 0.025 0.058 0.042
mg/mL 80% 0.023 0.023 0.026 0.046 0.037 0.081
mg/mL Limited 0.011 0.014 N.M. 0.019 0.016 0.013
mg/mL Limited 0.017 0.019 N.M. 0.022 0.030 0.024
mg/mL Limited 0.023 0.030 N.M. 0.031 0.049 0.037
NM. = not measured
TABLE 5
Visual inspection s of samples stored at 5 °C and
°C for zeroit=0L3 daLsgd), and 14 @s (dL
Sample Head Space t0 14d ctrl 3d 5 OC 3d 25 OC 14d 5 OC 14d 25 °C
mg/mL 80% x x x x precipitate precipitate
mg/mL 80% x x x x precipitate precipitate
mg/mL 80% x x x x precipitate precipitate
mg/mL Limited x x x x x x
mg/mL Limited x x x x precipitate x
mg/mL d x x x x precipitate precipitate
x = 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 values
tend 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 limiting
the headspace to near zero appears to have a measurable benefit from the A350 measurements, although
multiple samples at both the 5 OC and 25 OC agitation condition had visible particles/precipitate after
days of agitation. After 5 days of continuous agitation, no visible signs of precipitate were seen for the
preparations studied; as a result, the final time-point was extended to 14 days. Only after 7 days of
agitation were visible particles/precipitate evident in these samples.
1 5 [0125] The effects of ocin g/concentration, temperature, and vial headspace
it was found that the propensity
on the precipitation behavior of carbetocin were studied. From this study
to precipitate was concentration ent, with higher concentration samples precipitating more readily
than lower concentration samples. Additionally, for samples containing headspace, it appeared as if the
propensity to precipitate increased with sing temperature. Limiting vial headspace may decrease
amount of aggregates/precipitate formed during agitation.
Example 5
Formulations were prepared according to the method described in Example 1. The
carbetocin concentration for all formulations was 35 mg/mL, and the pH was adjusted to 5.4 :: 0.1. The
formulations investigated in Example 5 are listed below in Table 6.
TABLE 6
Example 5 formulation design
Arg amld
ZnClz Citrate Acetate Sorbitol EDTA Sorbate HPMC Me-[3-Cy
Fm 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 0
2 35 35 7.4 0 0 0 0 0 0 0
3 25 0 25 0 0 0 0 0.12 0 0
4 25 12.5 7.4 0 0 0 0 0 0 17.5
0 0 7.4 0 0 200 0.1 0.12 0 0
6 0 7.4 227 0 0 0 0 0 0
7 0 0 7.4 0 50 200 0.1 0.12 0 0
8 0 0 7.4 200 0 0 0 0 0 35
9 35 17.5 7.4 0 0 200 0 0 0 0
0 0 7.4 0 0 0 0.1 0.12 0.05 0
11 0 0 50 200 0 0 0 0 0.05 0
12 0 0 7.4 0 0 200 0 0 0.01 0
13 0 0 7.4 0 0 0 0.1 0.12 0 35
14 0 0 25 0 0 0 0 0 0 35
0 0 7.4 0 50 200 0 0 0.01 0
16 0 0 7.4 0 0 300 0.1 0.12 0 0
17 0 0 7.4 200 50 0 0 0 0 0
18 0 0 7.4 270 25 0 0 0 0 17.5
Me-fl—Cy = -fl—cyclodexn'in; sorbate = potassium sorbate
Freeze/ Thaw (F/T) Agitation Study
A 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 frozen
for Z 24 hrs at —20 °C before thawing. After thawing, samples were allowed to brate to room
temperature 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 and
19 hrs. Visual observation results from this agitation study are given below in Table 7.
TABLE 7
Appearance of freeze thaw samples after 5 and 19 hrs. of agitation
Form 70% Headspace, 5 12% Headspace, 5 70% Headspace, 12% Headspace,
hrs. hrs. 19 hrs. 19 hrs.
1 Precipitation Precipitation Significant cant
precipitation precipitation
2 Fine precipitate on Precipitation Significant Significant
vial wall itation precipitation
3 None Precipitation Significant Significant
precipitation precipitation
4 Fine precipitate on Fine precipitate on Fine precipitate on Fine precipitate on
vial wall vial wall and vial wall vial wall and
some fine some fine
particles particles
Maybe a few Fine precipitate Fine precipitate Fine precipitate
les, not
definitive
6 Precipitation Precipitation Significant Significant
precipitation precipitation
Appearance of freeze thaw sampfl after 5 and 19 hrs. of ion
Form 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 precipitate
particles, not fine and soft
definitive precipitate
8 Maybe a few Fine precipitate Some soft Fine precipitate
particles, not precipitate
definitive
9 None None Fine precipitate Fine precipitate on
vial wall some
fine particles
Some soft Some soft and Some soft Some soft and .
precipitate fine precipitate precipitate fine precipitate
11 None None Some soft Some soft and
precipitate fine precipitate
12 None None Some soft Some soft
precipitate precipitate
13 Maybe a few Fine precipitate Some soft Fine precipitate
particles, not precipitate
definitive
14 Maybe a few Maybe a few Some fine Some fine and
particles, not particles, not precipitate soft precipitate
definitive definitive
None None Some soft Soft precipitate
precipitate
16 Fine itate Maybe some fine Fine precipitate on Fine precipitate
particles, not vial wall and
definitive some fine
particles
17 Fine precipitate on None Significant Significant
vial wall and precipitate precipitate
some particles
18 Fine precipitate on Some fine Significant Fine itate on
vial wall and precipitate precipitate vial wall and fine
some fine precipitate
firticles
As can be seen from Table 7, the majority of samples/preparations demonstrated
precipitation after only 5 hours of agitation. Furthermore, there was no noticeable difference in the
precipitation 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. The
precipitation behavior of s ated with methyl—B-cyclodextrin and namide appeared to be
similar, 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 19
hrs of agitation. The ce of opalescence suggests that these solutions may contain larger, soluble
aggregates which are yet to precipitate. The results of this study show that the effectiveness of
nicotinamide at suppressing particle formation was concentration dependent, with 300 mM being more
effective 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 the
samples 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 as
solubilizers to reconstitute pure, lyophilized carbetocin at 35 mg/mL. Reconstitution times of lyophilized
carbetocin using these lizers are listed in Table 8.
TABLE 8
Reconstitution time of lized carbetocin using the
formulation samples in Table 7
Solubilizer/Blank (no solubilizer) Solubilizer Recon Time
F5 200 mM Nicotinamide 2 min 20 s
F7 50 mM Arg/200 mM Nicotinamide l min 50 5
F8 35 mM Me-B-CD 4 min 30 5
F9 200 mM Nicotinamide 4 min
F11 None > 30 min
F12 200 mM Nicotinamide 5 min
F13 35 mM Me-B-CD l min 30 s
F14 35 mM Me-B—CD 2 min 20 5
F15 50 mM Arg/200 mM Nicotinamide 2 min
F16 300 mM Nicotinamide 1 min
Recon = reconstitution; D = Methyl—B-Cyclodextrin
[0132] As can be observed from Table 8, all samples containing a solubilizer had
reconstitution times of 5 minutes or less. But samples without a solubilizer (i.e., F11) had very long
reconstitution times (i.e., > 30 min).
Following titution, these samples were subjected to an identical agitation
study as described previously for the F/T samples. The visual observation results from this agitation study
are given below in Table 9.
TABLE 9
Appearance of tituted lyo samples after 2, 5, and 19 hrs of agitation
Solubilizer/Blank (no lizer) itate at 2hrs Precipitate at 5 hrs Precipitate at 19 hrs
F5 No No Yes
F7 No No Yes
F8 No No Yes
F9 No No Yes
F1 1 No Maybe Yes
F12 No No Yes
F13 No No Yes
F14 No No Yes
F15 No No Yes
F16 No Maybe Yes
A visual rank ordering of the reconstituted lyo samples after 19 hours of agitation
> (F05, F07, F09, F16, 350
was as follows: F15> (F13, F14) 2 (F12, F8) 2 (Fl 1, 400 mM nicotinamide
mM nicotinamide). This rank was made using visual observations.
It was found that formulations containing HPMC, methyl—B—cyclodextrin, and
nicotinamide were the most resistant to precipitation upon ion, but do eventually form some
precipitate. The morphologies of the precipitate formed with these excipients are ent, with HPMC
g 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 the
effectiveness of this solubilizer at suppressing precipitation increases with increasing nicotinamide
concentration (see Figure 5).
Example 6
[0137] Additional reconstitution examples are provided in Table 10. Arginine, as well as
hydrotropes like proline and nicotinamide, were selected to improve the dissolution times. In on, the
effect of solids content on dissolution rate was examined. The results of these reconstitution studies are
given in Table 10.
TABLE 10
titution time of pure carbetocin lyophilisate with
various ents and at various reconstitution volumes
1 Final Recon.
ent Lyo Sample Recon. Volume Recon. Time
Conc. (mg/111E
mM Arg HC1 40 mg/mL carbetocin Full 40 18 min
50 mM Arg HC1 40 mg/mL carbetocin Full 40 8 min
50 mM Arg/Glu 40 mg/mL carbetocin Full 40 16 min
100 mM Arg HC1 40 mg/mL carbetocin Full 40 3 min
200 mM Arg HC1 40 mg/mL carbetocin Full 40 1 min, 50 s
200 mM Lysine HC1 40 mg/mL carbetocin Full 40 > 10 min
400 mM Proline 40 mg/mL carbetocin Full 40 5 hrs
300 mM Nicotinamide 40 mg/mL carbetocin Full 40 1 min, 30 s
100 mM Nicotinamide 40 mg/mL carbetocin Full 40 5 min, 50 s
0.5% ium Sorbate 40 mg/mL carbetocin Full 40 Z 25 min
Water 40 mg/mL carbetocin 1/2 20 30 min
Water 5 mg/mL carbetocin 1/4 20 3 min
Water 10 mg/mL ocin 1/4 40 5 min, 30 s
50 mM Arg HC1 10 mg/mL carbetocin 1/4 40 4 min
200 mM Arg HC1 10 mg/mL carbetocin 1/4 40 2 min, 20 s
Recon. = 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 300
mM nicotinamide both dramatically improved the dissolution rate of lyophilized carbetocin. Utilizing
these solubilizers, dissolution times of the re-lyophilized carbetocin (at 40 mg/mL) were reduced to only a
few minutes. The solubilizing power of these particular excipients was concentration dependent, with
increasing concentrations of the excipient decreasing dissolution time. Proline was not effective as a
solubilizer at the concentration (400 mM) examined in this study.
The results r indicate (see Table 10) that while potassium sorbate did not
expedite dissolution of lyophilized carbetocin, it did not negatively impact dissolution either.
Regarding the effect of solids content on dissolution rate, it was found that a
reduced volume for reconstitution of carbetocin lyophilized at a lower solids content yielded faster
dissolution rates than ocin lyophilized at a higher solids content (see Table 10). It was further found
that 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 efficiently
lize carbetocin lisate, and thus could ially be utilized as a solubilizer for lyophilized
1 0 carbetocin.
Example 7
Exemplary Stable Pharmaceutical Preparations ofCarbetocin
Exemplary pharmaceutical preparations of ocin are provided in Tables 11-
1 5 TABLE 1 1
Pharmaceutical Preflations of Carbetocin
Form 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 0
2 5.4 l 5 0 110 0.01 200 0 0
3 5.4 l 5 160 0 0 0 0 0
4 5.4 1 5 0 287 0.01 0 0 0
5.4 1 5 0 287 0.05 0 0 0
6 5.4 1 5 0 0 0.05 400 0 0
*HPMC = hydroxypropyl methylcellulose; K+ = ium; EDTA = ethylenediaminetetraacetic acid
TABLE 12
Pharmaceutical PrepLations of Carbetocin
Form pH Carbetocin NaCl Sorbitol Nicotinamide Acetate HPMC
memo (mM) (mM) (mML M) 9/), w/v)
1 5.4 34.3 0 250 0 0 0
2 5.4 34.3 0 250 0 0 0.05
3 5.4 34.3 0 110 200 0 0.01
4 5.4 34.3 0 0 400 0 0
5.4 25 0 110 200 1.6 0.01
*HPMC = hydroxypropyl methylcellulose
TABLE 13
Pharmaceutical Preparations of Carbetocin
Form pH Carbetocin EDTA (%, K+Sorbate HPMC Nicotinamide
(rag/1111) w/v) 4% w/v) 4wt%, ML @ML
1 5.4 34.3 0 0 0.01 400
2 5.4 34.3 0.1 0.12 0.01 400
3 5.4 34.3 0 0 0 0
*HPMC = hydroxypropyl methylcellulose; K+ = potassium; EDTA = ethylenediaminetetraacetic acid
Claims (19)
1. Use of carbetocin in the manufacture of a medicament for treating Prader-Willi syndrome in a subject, wherein the medicament is formulated for intranasal administration at three doses per day of 3.2 mg/dose carbetocin, for at least one month, and wherein the medicament is formulated to decrease hyperphagia compared to placebo.
2. The use of claim 1, wherein the medicament is formulated for the dose to be administered before a meal.
3. The use of claim 2, wherein each dose is to be administered within 30 minutes of a meal.
4. The use of claim 1, wherein the ment is formulated for the carbetocin to be administered for at least two months.
5. The use of claim 2, wherein the medicament is ated for the carbetocin to be administered for at least two months.
6. The use of claim 1, wherein the medicament is formulated for the administration of carbetocin to further result in one or more of: (a) decrease in ive and compulsive behavior compared to placebo; (b) decrease in anxiety compared to placebo; or (c) improvement in global clinical impression compared to placebo.
7. The use of claim 2, wherein the ment is formulated for the administration of carbetocin to further result in one or more of: (a) decrease in obsessive and compulsive behavior compared to placebo; (b) decrease in anxiety compared to placebo; or (c) ement in global clinical impression compared to placebo.
8. The use of claim 2, wherein the medicament is formulated for the administration of carbetocin to result in a decrease in y.
9. The use of claim 2, wherein the ment is formulated for the stration of carbetocin to result in a decrease in obsessive and compulsive behavior.
10. The use of claim 1, wherein the ment is formulated for the stration of carbetocin to result in a decrease in hyperphagia or and a decrease in obsessive and compulsive behavior.
11. The use of claim 1, wherein the medicament is formulated for the administration of carbetocin to result in a decrease in anxiety.
12. The use of claim 1, wherein the subject has an age ranging from seven (7) to eighteen (18) years old, inclusive.
13. The use of claim 1, wherein the subject is aged seven (7) years old.
14. The use of claim 1, wherein the medicament is formulated for the administration of carbetocin to result in a decrease in measurement of Hyperphagia onnaire for Clinical Trials (HQ-CT) Total Score.
15. The use of claim 1, wherein the medicament is formulated for the administration of carbetocin to result in a decrease in measurement of the PWS Anxiety and Distress Questionnaire (PADQ) Total Score.
16. The use of claim 1 wherein the medicament is formulated for the carbetocin to be administered in an aqueous solution comprising: (a) carbetocin or a pharmaceutically acceptable salt thereof, wherein the ocin is present in a concentration of about 10 mg/mL to about 70 mg/mL; and (b) a hydrotrope, and wherein the solution has little to no visible solids.
17. The use of claim 16, wherein the pharmaceutical preparation has little to no visible solids after shaking for 1, 2, or 3 days at 5oC and/or 25oC.
18. The use of claim 16, wherein the hydrotrope is namide.
19. The use of claim 1 wherein the medicament is formulated for the carbetocin to be administered in an aqueous solution comprising: (a) ocin or a ceutically acceptable salt thereof, wherein the carbetocin is present in a concentration of about 10 mg/mL to about 70 mg/mL; (b) nicotinamide; (c) HPMC; and (d) one or more additional excipients.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201862734152P | 2018-09-20 | 2018-09-20 | |
US62/734,152 | 2018-09-20 | ||
US201962876857P | 2019-07-22 | 2019-07-22 | |
US62/876,857 | 2019-07-22 | ||
PCT/US2019/052090 WO2020061414A1 (en) | 2018-09-20 | 2019-09-20 | Stable intranasal formulations of carbetocin |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ773548A NZ773548A (en) | 2021-08-27 |
NZ773548B2 true NZ773548B2 (en) | 2021-11-30 |
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