Stable intranasal formulations of carbetocin

a technology of intranasal formulation and carbetocin, which is applied in the direction of drug composition, peptide/protein ingredient, metabolic disorder, etc., can solve the problems of increasing the likelihood of peptide aggregation, difficult to maintain a sufficient stability at high peptide concentration, and inability to optimize ph, etc., to achieve the effect of high concentration

Inactive Publication Date: 2020-03-26
ACADIA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]It has been surprisingly found that improved carbetocin pharmaceutical preparations can be prepared with certain solubilizers and / or surface active agents, such as a viscoelastic polymer, for example, hydroxypropyl methylcellulose (HPMC), including those that contain high concentrations of carbetocin and that are stable under conditions of stress.

Problems solved by technology

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.
But for peptides without ionizable groups, pH optimization may not be possible.
Consequently, maintaining a sufficient stability at high peptide concentrations may be challenging, especially since peptides generally do not possess higher-order structure, and their physical stability thus primarily depends on the nature of their peptide-peptide interactions.
It is also known that carbetocin lacks a stable and well-defined tertiary structure.
Other prior attempts to develop a heat-stable oxytocin formulation for injection have been unsuccessful.
Other attempts have been made to make stable high carbetocin formulations using typical peptide excipients (e.g., surfactants); however, none of the studied excipients prevented carbetocin aggregation.
In addition, when aqueous carbetocin solutions are manufactured, packaged, transported, stored, and handled prior to administration to a patient, they are subject to mechanical and chemical stresses.
These types of stresses can be detrimental to various formulations of carbetocin in solution.

Method used

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  • Stable intranasal formulations of carbetocin
  • Stable intranasal formulations of carbetocin
  • Stable intranasal formulations of carbetocin

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0177]Carbetocin was obtained as a powder and was stored at ≤20° C. until ready for use. Formulations were prepared by dissolving 40 mg / mL or 20 mg / mL of carbetocin in an aqueous solution containing a solubilizer 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 prepared using multi-compendial grade excipients and reagents, and ultra-pure water (Millipore MilliQ, 18 MΩ). The osmolality of each preparation was measured before preparing the final formulation to ensure it was similar to that of the theoretically determined value. Each formulation (bulk material) was sterile filtered using a Millipore Millex-GV syringe filter (0.22 μm). 1.2 mL of each sterile filtered formulation was filled into a 3 mL glass vial, stoppered with a 13 mm Fluorotec coated serum stopper, and crimped. All materials (i.e., vials, stoppers, etc.) were sterilized before filling. For samples with reduced or limited headsp...

example 2

[0181]Samples were prepared using the general procedure provided in Example 1. It is noted that the hydrotropes studied in this example were formulated at the following concentrations: 160 mM (isotonic) and 400 mM sodium benzoate, 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 ability of these solutions to suppress particle formation upon agitation. Observations were made after both 14 and 24 hours of agitation.

[0182]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 salicylate 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...

example 3

[0185]Formulations were prepared according to the method described in Example 1 by dissolving the desired amount of 40 mg / mL of carbetocin in an aqueous solution containing different excipients 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. 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 2Visual Observation Results for Agitated Carbetocin FormulationsCarbetocinVialAgitation TimeConcentrationExcipientOrientation(hrs)Observations40 mg / mL DSHydroxypropyl β-CyclodextrinHorizontal17Significant precipitation40 mg / mL DS1% (w / v) Hydroxypropyl cellulos...

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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 Präder-Willi syndrome. Additionally, the disclosed carbetocin compositions show improved stability at room temperature and/or under accelerated conditions of stress.

Description

DESCRIPTION OF THE DISCLOSURE[0001]This application claims priority from U.S. Provisional Patent Application No. 62 / 734,152, filed Sep. 20, 2018, and U.S. Provisional Patent Application No. 62 / 876,857, filed Jul. 22, 2019, both of which are hereby incorporated by reference in their entirety.FIELD OF THE DISCLOSURE[0002]The present disclosure relates to stable intranasal pharmaceutical preparations of carbetocin, including those that demonstrate improved stability under various long-term storage conditions and / or under accelerated conditions of stress. The present disclosure also relates to methods of preparing such pharmaceutical preparations. The present disclosure further relates to kits and the use of the intranasal pharmaceutical preparations for the treatment of neurodevelopmental disorders, such as Präder-Willi syndrome, and related symptoms.BACKGROUND OF THE DISCLOSURE[0003]Although both peptides and proteins are composed of amino acids, peptides are typically distinguished f...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/095A61K47/38A61K9/08A61K9/00A61K47/55
CPCA61K47/38A61K38/095A61K9/0043A61K47/551A61K9/08A61K47/22A61P3/04A61P43/00A61K47/183A61K47/26A61K47/18A61P25/00A61K47/12
Inventor MANNING, MARK C.HOLCOMB, RYAN E.KATAYAMA, DERRICK S.BRYANT, CHRISTOPHER
Owner ACADIA PHARMA INC
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