Method for the production of polymerized nanoparticles and microparticles by ternary agent concentration and temperature alteration induced immiscibility

This patent application is a divisional application of, and claims priority under 35 U.S.C. § 120 to, patent application having Ser. No. 10/941,163, filed on Sep. 15, 2004.

The present invention relates to a method for producing polymerized or crosslinked nanoparticle- and microparticle-sized spherical particles potentially consisting of or including one or more active agents. More particularly, the present invention is a method for producing nanoparticle- and microparticle-sized spherical particles useful as pure entities and as drug delivery agents, and a method for incorporating one or more active therapeutic agents uniformly or non-uniformly within the spherical particles.

Medication of the eyes is done commonly for two purposes—to treat the exterior of the eyes for infections such as conjunctivitis, blepharitis and keratitis sicca, and to treat the interior of eyes, i.e., intraocular treatment, for diseases such as glaucoma or uveitis. Most ocular diseases are treated through topical applications of solutions administered as eye drops. One major problem encountered with topical delivery of ophthalmic drugs is the rapid and extensive loss of drug through drainage and high tear fluid turn over. After instillation of an eye-drop in an eye, typically less than 2 to 3 percent of the applied drug penetrates the cornea. A major fraction of such instilled doses are often absorbed systematically via the conjunctiva and nasolacrimal duct. Another limitation encountered with topical delivery is a relatively impermeable corneal barrier that limits ocular absorption.

Due to inherent problems associated with the delivery of conventional ophthalmic therapeutic agents, significant effort has been directed to the development of new delivery systems such as hydrogels, nanoparticles, microparticles, liposomes and collagen shields. Ocular drug delivery is an approach to controlling and ultimately optimizing the delivery of therapeutic agents or drugs to their target tissues within the eye. Most formulation efforts to date aim to maximize ocular therapeutic agent or drug absorption by prolonging residence time on the cornea and in the conjunctival sac. Methods of prolonging such residence time include slowing the therapeutic agent or drug release rate from the delivery system and minimizing precorneal drug loss.

Many methods for the production of non-polymerized microspherical- and nanospherical-sized particles and methods for incorporating therapeutically active agents evenly throughout and as central cores within the microspherical and nanospherical particles for ophthalmic delivery are known. One method for producing particles in the microspherical-size range uses monomer directly or a solvent as a polymer or matrix sphere-forming agent that is immiscible with a bulk non-solvent. A surfactant may also be used to stabilize the emulsion formed from the immiscibility of the monomer or solvent and bulk non-solvent. Immiscibility of the monomer or solvent and non-solvent induces a lower limit on the size of the particles that form. In a static state, the monomer or solvent and non-solvent separate into two layers with the less dense layer over the denser layer. Dispersion or emulsification of the two immiscible layers results from some form of agitation, such as ultrasonic waves, mechanical mixing or stirring, and/or vortexing. Polymerization or crosslinking reaction is effected by the addition of energy such as heat or light to form the particle. Where solvents are used to mediate particle formation, hardened microparticle spheres are then formed by removal of the solvent by evaporation. The very small amount of solvent dissolved in the non-solvent is evaporated, and solvent contained in the stable emulsion droplets dissolves into the non-solvent to again saturate the solution.

The addition of dispersive energy competes with the immiscibility of the two solvents or non-solvent and monomer, acting to reduce the solvent phase droplet dimension, causing the latter to reform larger droplets. The resulting size of the microspherical particles is the balance of the two tendencies. Increasing the amount of a particular type of dispersive energy will balance the tendencies at a smaller final microspherical particle size. However, addition of dispersive energy becomes exponentially less effective, while the tendency for smaller droplets to aggregate into larger ones increases exponentially as size decreases. Using an immiscible solvent/non-solvent system, it is difficult to obtain particles smaller than 500 nm in size. Because the energy spectrum used to disperse the solvent in the non-solvent is usually broad, a continuous range of size equilibriums exist. This creates a range of final particle sizes. Additionally, based on available means to introduce dispersive energy into the emulsion, the more energy that is added in an attempt to make smaller final particles, the greater the energy spectrum. Particle size distributions increase substantially as mean particle size decreases.

To produce particles smaller than 500 nm, the constraint of the tendency for droplets to aggregate is removed by using a solvent for the monomer, polymer, or matrix that is miscible with a non-solvent bulk phase. Because the formation process is not dependent on the initial formation of stable emulsion droplets, surfactants can be eliminated. Variations of this method have been named nanoprecipitation and spontaneous emulsification solvent diffusion (SESD), which includes of all such methods characterized by a miscible Solvent non-solvent system used with or without surfactant. Additionally, prior art also describes using a second solvent that serves as a solvent for the polymer or matrix and a second agent, but is immiscible with the non-solvent. A solution is made of the first two solvents and subsequently added to the non-solvent. This represents a combined approach where the first solvent, miscible in the bulk non-solvent, immediately diffuses out of the spontaneous emulsion, but the second solvent, immiscible in the bulk non-solvent, is removed more slowly.

The advantage of methods involving some portion of a miscible solvent is the reduced capacity of aggregation, thus producing narrow size distributions of particles having a mean size less than 500 nm. The limitation with nanoprecipitation lies in the formation of a narrow size distribution of particles with a mean size from 500 nm to 1 mm in diameter. The terms “nanoprecipitation” and “spontaneous emulsification” highlight the functional aspects of these methods. It is the polymer or matrix that emulsifies in the solvent/non-solvent solution, that then precipitates on the addition of the polymer- or matrix-containing solvent to the non-solvent. The precipitation is caused by the insolubility of the polymer or matrix in the solvent/non-solvent system. Emulsification refers to the ability of the solvent to act as a plasticizer in allowing the polymer or matrix to behave as a fluid. Such enables reorganization on the same time scale as that of solvent diffusion. Hardened particles smaller than 500 nm are thus formed.

The limitation in nanoprecipitation/SESD methods arises from the practically instantaneous rate of nanoparticle formation. This places extreme requirements on the rate of the polymeriziation or crosslinking reaction.

A third method for formation of microparticles and nanoparticles involves using a monomer, monomer solution, or functionalized polymer or matrix solvent solution. Microspherical or nanospherical particles are made by initiating the reaction of monomer or functionalized polymer or matrix. The increase in molecular originates insolubility of the resulting polymer or crosslinked polymer or matrix, causing particle precipitation. The limitation of this particular method is that the solvent must be a solvent for unreacted precursor, not reacted material. Such limits the selection of polymers from which one may choose as well as ultimate molecular weight or particle size. The advantage of this method is the seamless transition of a narrow distribution of particle sizes from 1 nm up to 10 μm achieved by “growing” spheres.

Clearly, it is preferable that any ocular drug delivery system does not impair vision and reliably delivers the desired amount of therapeutic agent or drug to the targeted tissues within the eye. Therefore, the materials used to produce oclular drug delivery systems should be biocompatible, non-irritating to ocular tissues and not cause blurring or visual impairment upon use thereof.

The present invention relates to polymerized drug delivery devices, methods for the production of such drug delivery devices and uses for the drug delivery devices in the ophthalmic field. Polymerization of monomers or crosslinking of macromonomers allows for formation of particles that are insoluble in a bulk fluid regardless of solubility of starting material. Additionally, the presence of crosslinks can control release rate directly by altering diffusivity of therapeutic agent through the particle material or indirectly by increasing particle stability. Polymerized drug delivery devices of the present invention in the form of polymeric particles are useful for the delivery of therapeutically effective amounts of one or more therapeutically active agents such as but not limited to ophthalmic therapeutic agents. Polymeric spherical particles of the present invention are particularly useful in the field of ophthalmology due to the fact that the size of the subject particles may be controlled so as to not alter or only temporarily minimally alter visual acuity. Unaltered visual acuity during use leads to higher user compliance and greater universal appeal than traditional therapeutic treatments, which may temporarily blur or obscure vision.

The subject polymeric spherical particles are effective in the delivery of therapeutically effective amounts of one or more therapeutically active agents. Additionally, the subject polymeric spherical particles are biocompatible and cause little or no tissue irritation.

Accordingly, it is an object of the present invention to provide a method for the production of polymerized particles useful as drug delivery agents.

Another object of the present invention is to provide a method for the production of drug delivery agents useful in ophthalmic applications.

Another object of the present invention is to provide a method for the production of polymeric spherical particles containing a therapeutically effective amount of a therapeutically active agent.

Another object of the present invention is to provide a method for the production of biocompatible particles for ophthalmic drug delivery.