Claims for Patent: 12,491,163

Summary for Patent: 12,491,163

Title:	Stabilized microcapsules, method of their preparation and uses thereof
Abstract:	The present application is directed to stabilized core-shell microcapsules comprising a core of benzoyl peroxide (BPO) or all trans retinoic acid (ATRA) and a metal-oxide shell; and to pharmaceutical compositions and methods of use thereof.
Inventor(s):	Ofer Toledano, Karine Neimann, Danil FINKEL-MOISEEV, Maya Erlich, Dorit Marco
Assignee:	Mayne Pharma LLC
Application Number:	US17/327,732
Patent Claims:	1. A method for treating acne, said method comprising topically administering to a subject in need thereof a pharmaceutical composition comprising microcapsules comprising tretinoin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient, wherein said microcapsules comprising tretinoin or a pharmaceutically acceptable salt thereof, wherein the tretinoin is the only active agent in said microcapsules; each comprise a core encapsulated by a shell, wherein said core comprises a dispersion, wherein said dispersion comprises: an oil phase comprising tretinoin in a solid form at a concentration of from 17% to 25% w/w in said oil phase; and optionally at least one phase changing material; wherein said at least one phase changing material is not liquid at room temperature, wherein the tretinoin or a pharmaceutically acceptable salt thereof is in an amount of 0.1% by weight of said composition and the composition further comprises microcapsules comprising benzoyl peroxide, wherein the benzoyl peroxide is in an amount of 3% by weight of said composition, wherein the benzoyl peroxide is the only active agent in said microcapsules; wherein said phase changing material is selected from the group consisting of natural or synthetic paraffin having a molecular formula of CnH2n+2, C10-C100 alkane, C10-C100 alkene, C10-C100 alkyne, waxes, aliphatic alcohols having a molecular formula of CH3(CH2)nOH, fatty acids having a molecular formula of CH3(CH2)nCOOH, and any combination thereof, wherein n is an integer from 10 to 100. 2. The method according to claim 1, wherein the shell is a silicon dioxide shell. 3. The method according to claim 1, wherein the shell is a metal oxide shell. 4. The method according to claim 3, wherein a thickness of said metal oxide shell is ranging from 50 nm to 5000 nm according to the energy selective backscattered-detector. 5. The method according to claim 1, wherein an average diameter of said microcapsules comprising tretinoin or a pharmaceutically acceptable salt thereof in the range of from 5 micrometers to 50 micrometers according to the energy selective backscattered-detector. 6. The method according to claim 1, wherein the microcapsules comprising encapsulated tretinoin provide a dissolution rate of the tretinoin from 5% to 35% weight/h as measured in a medium of 30%:70% v/v mixture of water:isopropyl alcohol at 32° C. 7. The method according to claim 1, wherein said microcapsules comprising tretinoin or a pharmaceutically acceptable salt thereof are stable for a period of from 2 weeks to 2 years at room temperature. 8. The method according to claim 1, wherein the carrier is in a form of an ointment, a cream, a lotion, an oil, a solution, an emulsion, a gel, a paste, a milk, an aerosol, a powder or a foam. 9. The method according to claim 1, wherein the microencapsulation efficiency of the tretinoin is at least 90% by weight, wherein up to 10% by weight of the tretinoin is not encapsulated. 10. The method according to claim 1, wherein in said pharmaceutical composition after two weeks of storage at 40° C. and 75% relative humidity a concentration of all-trans 5,6-epoxy retinoic acid is less than 1% by weight of the initial tretinoin amount prior to storage. 11. The method according to claim 1, wherein the microcapsules comprising encapsulated tretinoin provide a dissolution rate of the tretinoin from 5% to 35% weight/h as measured in a medium of 30%:70% v/v mixture of water:isopropyl alcohol at 32° C. and wherein the microcapsules comprising encapsulated benzoyl peroxide provide a dissolution rate of the benzoyl peroxide from 10% to 60% weight/h as measured in a medium of 55%:45% mixture of water:acetonitrile at ambient temperature. 12. The method according to claim 1, wherein the benzoyl peroxide has microencapsulation efficiency of at least 75% by weight, wherein up to 25% by weight of the benzoyl peroxide is not encapsulated and the tretinoin has microencapsulation efficiency of at least 90% by weight, wherein up to 10% by weight of the tretinoin is not encapsulated. 13. The method according to claim 1, wherein in said pharmaceutical composition after two weeks of storage at 40° C. and 75% relative humidity a concentration of all-trans 5,6-epoxy retinoic acid is less than 1% by weight of the initial tretinoin amount prior to storage. 14. The method according to claim 1, wherein the benzoyl peroxide has microencapsulation efficiency of at least 85% by weight, wherein up to 15% by weight of the benzoyl peroxide is not encapsulated and the tretinoin has microencapsulation efficiency of at least 90% by weight, wherein up to 10% by weight of the tretinoin is not encapsulated. 15. The method according to claim 1, wherein the benzoyl peroxide has microencapsulation efficiency of at least 90% by weight, wherein up to 10% by weight of the tretinoin is not encapsulated, and the tretinoin has microencapsulation efficiency of at least 90% by weight, wherein up to 10% by weight of the tretinoin is not encapsulated.