Intravitreal microsphere drug delivery and method of preparation
First Claim
1. A method of preparing microspheres encapsulating a pharmacologically active agent to enable delivery and sustained release of the agent, such method comprising the steps ofselecting a biodegradable polymer and a volatile non-aqueous solvent,adding the pharmacologically active agent suspended in a first oil to said polymer and non-aqueous solvent, and mixing them to produce an aqueous-free dispersion in which the drug is contained primarily in said first oil,selecting a second oil which is immiscible with said first oil and in which said solvent is at least partially soluble,mixing said aqueous-free dispersion in a volume of said second oil and solvent with an emulsifier, and drying the solvent therefrom to produce well-formed microspheres, andremoving said second oil from said microspheres with a second solvent, said second solvent being insoluble in said polymer and said first oil,wherein said pharmacologically active agent, is a hydrophilic agent and said first oil is selected to substantially hinder dissolution in an aqueous environment, so that release of the agent from microspheres occurs as the polymer degrades releasing said first oil to contact said environment at a surface and said agent diffuses from the surface.
2 Assignments
0 Petitions
Accused Products
Abstract
A method of forming microspheres containing a hydrophilic drug or agent for injection to provide localized treatment over a protracted time with sustained delivery in a therapeutically indicated rate band. The drug or agent is first dispersed or suspended as a micropulverized solid in an inert hydrophobic oil and sonicated with a non-aqueous solution of a biodegradable polymer. The dispersion is then stabilized in a second oil to remove solvent from the microspheres. Non-aqueous solvents are used throughout, and high drug concentrations are obtained simultaneously with enhanced control over a uniform and sustained delivery rate with extended duration of delivery. In vitro studies of ganciclovir in a silicone oil/fluorosilicone oil/PLGA system yield microsphere fractions that provide dose levels in a therapeutic range for CMV retinitis from only a single intravitreal injection that lasts substantially in excess of one month. The preparation method allows drug loading efficiencies above ninety percent. By protecting the drug in an inner phase carrier of biocompatible but not biodegradable oil, and forming biodegradable shells and pore-defining foliations within the microspheres, the rate of control of solvent erosion pathways into the microspheres is extended, and selection of the polymer and of the oils allow control over both the delivery rate and time.
-
Citations
18 Claims
-
1. A method of preparing microspheres encapsulating a pharmacologically active agent to enable delivery and sustained release of the agent, such method comprising the steps of
selecting a biodegradable polymer and a volatile non-aqueous solvent, adding the pharmacologically active agent suspended in a first oil to said polymer and non-aqueous solvent, and mixing them to produce an aqueous-free dispersion in which the drug is contained primarily in said first oil, selecting a second oil which is immiscible with said first oil and in which said solvent is at least partially soluble, mixing said aqueous-free dispersion in a volume of said second oil and solvent with an emulsifier, and drying the solvent therefrom to produce well-formed microspheres, and removing said second oil from said microspheres with a second solvent, said second solvent being insoluble in said polymer and said first oil, wherein said pharmacologically active agent, is a hydrophilic agent and said first oil is selected to substantially hinder dissolution in an aqueous environment, so that release of the agent from microspheres occurs as the polymer degrades releasing said first oil to contact said environment at a surface and said agent diffuses from the surface.
-
10. A method of preparing microspheres for delivering a pharmacologically active agent to the vitreous, such method comprising the steps of
mixing a biodegradable hardenable polymer in a non-aqueous solution with a mixture of said agent in a hydrophobic oil to form a non-aqueous two-phase dispersion containing said agent stabilizing the dispersion of said non-aqueous two-phase dispersion with an emulsifier in a second oil that is immiscible with the first oil to form microspheres of said polymer enclosing a multi-chambered interior defined by precipitated dividing walls formed of said polymer with inclusions of said hydrophobic oil carrying said agent, the step of stabilizing including drying said non-aqueous solution in said second oil, and washing said second oil from said microspheres to produce well-formed spheres with complex porosity that biodegrade to release said agent at a therapeutic rate.
-
11. A method of ocular treatment, such method comprising the steps of
preparing microspheres of an agent suspended in a hydrophobic oil, said oil being held as lacunae within foliations and shells of a hardenable biodegradable polymer, each microsphere being enclosed by a substantially spherical outer shell of said polymer drying said microspheres in an oil which is immiscible with said hydrophobic oil to remove solvent therefrom for a period effective to harden said foliations and shells as well as said outer shell, and selecting a quantity of said microspheres having a total volume less than one milliliter and having a diameter greater than approximately several hundred micrometers effective to release said agent at a rate above a minimum therapeutic rate for over one month.
-
14. A therapeutic preparation comprising
microspheres of a bioactive agent suspended in an oil, wherein an outer shell of a hardened biodegradable polymer encloses and defines each microsphere, said oil being a hydrophobic oil enclosed within said outer shell as lacunae between sheets and shells of said hardened biodegradable polymer, the microspheres being between approximately 300-500 μ - m in diameter and compounded with said agent suspended as a powder in said oil, and said microsphere being dried in a second oil which is immiscible with the hydrophobic oil so that substantially all of said agent remains in said hydrophobic oil and the microspheres are effective to release said agent for an extended period at a therapeutic rate to an aqueous environment as said polymer degrades.
Specification