Pharmaceutical formulations and systems for delivery of an androgenic agent and an aromatase inhibitor with sustained multi-phasic release profiles and methods of use
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Publication Number
US-12128055-B2
Publication Date
2024-10-29
Expiration Date
Abstract
The present disclosure is directed formulations, delivery systems and/or methods of use that have a novel a sustained release multi-phasic concentration pattern that may be used, among other things, for reducing mammographic breast density and/or breast stiffness in warm-blooded animals. For example, the formulation may comprise: the administration of an effective amount of androgenic agent and an effective amount of an aromatase inhibitor to a subject that provides a sustained release multi-phasic concentration pattern in the blood of the subject over time as measured by serum concentration for the androgen and plasma concentration for the aromatase inhibitor and improves, among other things, breast tissue stabilization and/or increases of the levels of androgen receptor expression. The present disclosure is also directed to the use of an effective amount of an androgenic agent in combination with an effective amount of an aromatase inhibitor for the prophylaxis or treatment of autoimmune inflammatory mastitis (AIM) in a patient in need thereof. Autoimmune inflammatory mastitis includes the conditions of idiopathic inflammatory macromastia, plasma cell mastitis, granulomatous mastitis.
Core Innovation
The invention provides a pharmaceutical formulation comprising an androgenic agent that is testosterone or a pharmaceutically acceptable salt or ester thereof, an aromatase inhibitor that is anastrozole, and a binding agent. The formulation is compressed into a pellet for subcutaneous administration to a subject and provides a sustained release multi-phasic concentration pattern in the blood measured as serum concentration for the androgenic agent and plasma concentration for the aromatase inhibitor over time.
The sustained release multi-phasic concentration pattern includes a first time period in which the androgenic agent has a first peak in concentration (Tmax) in the serum while the aromatase inhibitor is increasing in concentration in the plasma but remains below its Tmax concentration in the plasma. A second time period follows in which the androgenic agent initially has a decreasing serum level concentration and then an increasing serum level concentration, while the aromatase inhibitor has its Tmax concentration in the plasma.
In particular embodiments, the pellet includes defined amounts of testosterone (or an ester thereof) and anastrozole, together with stearic acid as a binding agent, and the pellet is defined by diameter and length ranges. Further embodiments add additional time periods so that the androgenic agent exhibits a second serum peak concentration that is less than the Tmax while the aromatase inhibitor gradually decreases and falls below the concentration of the testosterone (or an ester). The concentration decreases of the androgenic agent and aromatase inhibitor are defined to be approximately parallel in a fourth time period.
Claims Coverage
The document contains three independent claims directed to sustained-release, multi-phasic testosterone/anastrozole delivery via compressed subcutaneous pellets, with specified serum/plasma peak and time-period relationships.
Compressed pellet subcutaneous multi-phasic delivery for serum androgenic agent and plasma aromatase inhibitor
A pharmaceutical formulation comprising testosterone or a pharmaceutically acceptable salt or ester thereof, anastrozole, and a binding agent, compressed into a pellet for subcutaneous administration that provides a sustained release multi-phasic concentration pattern in the blood of a subject as measured by serum concentration for the androgenic agent and plasma concentration for the aromatase inhibitor.
First time period peak relationship between androgenic agent Tmax and aromatase inhibitor below its Tmax
The sustained release multi-phasic concentration pattern comprises a first time period in which the androgenic agent has a first peak in concentration (Tmax) in the serum and the aromatase inhibitor is increasing in concentration in the plasma but is below its Tmax concentration in the plasma.
Second time period transition with androgenic agent decreasing-then-increasing and aromatase inhibitor at its Tmax
The sustained release multi-phasic concentration pattern comprises a second time period in which the androgenic agent has initially a decreasing serum level concentration and then an increasing serum level concentration, and the aromatase inhibitor has its Tmax concentration in the plasma.
Defined dose amounts with stearic acid binding agent and defined pellet geometry
A pharmaceutical formulation comprising 60 mg to 120 mg of testosterone or an ester thereof, 2 mg to 6 mg of anastrozole, and stearic acid, compressed into a pellet having a diameter between 4.25 mm to 4.75 mm and a length between 4 mm to 7 mm, where subcutaneous administration provides the sustained release multi-phasic concentration pattern defined by the first and second time periods.
Additional third and fourth time periods with second androgenic agent peak below Tmax and approximately parallel declines
A pharmaceutical formulation where the sustained release multi-phasic concentration pattern further comprises a third time period in which the androgenic agent has a second peak concentration in the serum that is less than the Tmax and the aromatase inhibitor is gradually decreasing in concentration in the plasma and falls below the concentration of the testosterone or an ester, and a fourth time period in which the androgenic agent serum level gradually decreases and the aromatase inhibitor plasma concentration gradually decreases, with both decreasing levels approximately parallel each other.
Overall claim coverage centers on pellet-based subcutaneous sustained-release co-delivery of testosterone or esters and anastrozole via a binding agent, producing a multi-phasic serum/plasma pattern defined by specific peak and time-period relationships, with narrower embodiments specifying dose ranges, pellet geometry, and additional third and fourth time periods.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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