BRPI0615563A2 - biodegradable microparticle pharmaceutical formulations exhibiting improved release rates - Google Patents

Abstract

PHARMACEUTICAL FORMULATIONS IN BIODEGRADABLE MICRO-PARTICLE DISPLAYING PERFECTED RELEASE RATES. The present invention relates to an apparatus and method for producing microparticles comprising pharmacologically active agents and biodegradable polymers. The apparatus (100) includes a rotating disk (105) containing a reservoir (708) in the center of it and a flat inclined surface. The apparatus optionally includes saws (712) and / or a flat surface below the periphery of the disc that is parallel to the rotational axis of the disc. The invention also relates to a method for producing microparticles containing pharmacologically active agents, using the rotating disk apparatus. Formulations containing ophthalmically active agents are provided. Formulations showing release rates on the order of zero are also described.

Description

Patent Descriptive Report for "PHARMACEUTICAL FORMULATIONS IN BIODEGRADABLE MICROPARTY AND EFFECTING PERFECT RELEASE RATES".

Cross-reference to related patent applications

The present patent application claims priority of United States Patent Applications Serial Nos. 11 / 221,337; 11 / 220,430; 11 / 220,431; 11 / 220,807; and 11 / 220,445, all filed September 7, 2005.

Field of the Invention

The present invention relates to the sustained release of pharmaceutically (i.e. pharmacologically) active agents. The invention relates specifically to a method and apparatus for manufacturing microcapsules and microspheres containing pharmaceutically active agents, especially ophthalmic active agents.

Background of the Invention

Pharmacologically active agents may be administered systemically, such as oral intravenously, or locally, such as topically or subcutaneously. In another case, it is often desirable to apply to a targeted site a dosage of these agents that is not greater than that which can be immediately metabolized, as excess dosages may be useless and / or harmful. This has traditionally required agent administration at regular time intervals, which can be laborious and / or impractical and can also lead to errors in administration.

As an alternative, pharmacologically active agent delivery systems have been developed whereby the active agent is applied (preferably in a sustained, consistent release amount) over a period of time. Specifically with respect to locally administered agents, sustained release has been performed using microparticles containing the active agent and one or more pharmaceutically inactive materials. Microparticles can be divided into "microspheres" and "microcapsules", which are different from each other. Microspheres generally refer to a monolithic formulation where drug molecules are dispersed in a polymeric matrix. On the other hand, microcapsules refer to reservoir devices where the core of the drug is surrounded by a continuous polymeric layer or shell. The drug core of a microcapsule may comprise the drug itself or a drug-containing microsphere.

The microparticles are applied to the desired location and the agent is released from them over an extended period of time. For ocular applications, the microparticles may be applied, for example, by injection to the posterior segment of the eye using a designed cannula or otherwise introduced as implants.

Release of the active agent from microspheres may involve fusion, solvation and / or biodegradation of the polymer matrix. In the case of microcapsules, the active agent must penetrate the shell to reach the target site. This may be accomplished by mechanical rupture, fusion, dissolution, blanking and / or biodegradation of the shell and / or diffusion of the active agent. through Dhaka.

In particular, biodegradable materials, such as polymers, which form a matrix with and / or encapsulate pharmaceutically active agents may be employed as a sustained application system. By "biodegradable" is meant that materials are degraded or broken under physiological conditions in the body such that degradation products are excretable or absorbable by the body. The use of biodegradable polymers can provide sustained release of an active agent using the biodegradability of the polymer to control release of the active agent thereby providing a more consistent, sustained level of application.

The prior art describes various methods of producing microparticles, including through solvent extraction, low temperature molding, coacervation, hot melting, interfacial crosslinking, interfacial polymerization, spray drying, supercritical fluid expansion, crystallization. anti-solvent in supercritical fluid and solvent evaporation. Solvent extraction involves the use of organic solvents to dissolve water-insoluble polymers. An insoluble or dispersed drug is added to the polymer solution, and the mixture is then emulsified into an aqueous phase containing a surfactant. The organic solvent diffuses into the water phase facilitating precipitation of solid polymer microspheres. An example of this technology can be found in U.S. Patent. No. 4,389,330 (to Tice et al.).

A process known as low temperature molding has been used to produce microparticles. In this process, which is described in US Patent No. 5,019,400 (issued to Gombotz et al.), A polymer is dissolved in a solvent together with an active agent that can either be dissolved in the solvent or dispersed in the solvent in the form of microparticles. . The polymer / active agent mixture is atomized into a container containing a non-solvent liquid and covered with a liquefied gas at a temperature below the freezing point of the polymer / active agent solution. Liquefied gas or cold liquid immediately freezes polymer exhaust. As the droplets and non-solvent for the polymer are heated, the solvent in the droplets thaws and is extracted into the co-solvent, resulting in hardened microspheres.

Coacervation is based on salting out or phase separation a homogeneous polymer solution of hydrophilic polymers into small droplets of a second, polymer rich liquid phase. When an aqueous polymer solution is particularly dehydrated or desolated by the addition of a strongly hydrophilic or a water-miscible non-solvent, the water-soluble polymer is concentrated in water to form the polymer rich phase. This is known as simple coacervation. If water-insoluble drug particles are present as a suspension or as an emulsion, the polymer rich phase is formed on the surface of the drug particle to form a capsule under suitable conditions. In "complex" coacervation, the polymer complex phase (coacervate) is induced by interaction between two dispersed hydrophilic polymers (colloids) of opposite electric charges. This process is described in a number of patents, including U.S. Patent No. 2,800,457 (issued to Green and others).

A hot melting or freezing process has been described where an active agent is mixed with a polymer, which is melted at high temperatures. The mixture is then transferred to a centrifugal atomizer and the formed droplets cooled and collected. This process is described in U.S. Patent No. 3,080,293 (issued to Koff). Alternatively, as described in US Patent No. 4,898,734 (issued to Mathio-witz et al.), The active agent is mixed with the molten polymer, and the molten mixture is suspended in a non-miscible solvent heated above. melting point of the polymer and stirred continuously. Once the emulsion is stabilized, it is cooled until the core material solidifies.

Interfacial cross-linking may be employed if the polymer has functional groups that can be cross-linked by ions or multifunctional molecules. As described in US Patent No. 4,138,362 (issued to Vasiliades et al.), For example, microparticle production by interfacial cross-linking involves mixing a non-water-miscible oily material containing a polyfunctional cross-linking agent, and an aqueous solution of a polymeric emulsifying agent. An oil-in-water emulsion is formed containing the dispersed polyfunctional crosslinking agent in the form of microscopic emulsion droplets in the aqueous continuous phase containing the emulsifying agent, and a solid capsule wall is formed by crosslinking the emulsifying agent by the polyfunctional crosslinking agent.

Interfacial polymerization requires monomers that can be polymerized at the interface of two non-miscible substances to form a membrane. US Patent No. 4,119,565 (issued to Baatz et al.) Re-sail a process for encapsulation where a polyfunctional compound is dissolved in a core material, or in an inert solvent or dissolving mixture, and subsequently mixed with the material. Core This homogeneous mixture is then introduced into a non-miscible liquid phase with it, for example, water, which contains a material that catalyzes polymerization of the polyfunctional compound. Another known microparticle process is atomization drying, where a solid forming material Such a polymer, which is intended to form the particle volume, is dissolved in a self-solvent to form a solution. Alternatively, the material may be suspended or emulsified in a non-solvent to form a suspension or emulsion. An active agent is then added and the solution is atomized to form a fine mist of droplets. The droplets then enter a drying chamber where they contact a drying gas. The solvent is evaporated from the droplets in the drying gas to solidify the droplets, thereby forming particles. The particles are then separated from the drying gas and collected. This process is described in U.S. Patent No. 6,308,434 (issued to Chickering, Ill and others) and references described herein.

Microparticle formation using supercritical fluid expansion involves rapidly dissolving a solid material in a supercritical fluid solution at a high pressure and then rapidly expanding the solution to a relatively low pressure region. This produces a molecular spray that is discharged into a collection chamber. Solvent is vaporized and pumped out, and the particles are collected.

An example of this process is described in U.S. Patent No. 4,734,451 (to Smith).

Crystallization of supercritical anti-solvent as described in US Patent No. 6,461,642 (issued to Bisrat et al.) Involves dissolution of the active agent, and optionally one or more carrier materials in a first solvent, introduction of the solution and a fluid. supercritical or subcritical in an apparatus where the fluid contains an anti-solvent (such as carbon dioxide) and a second solvent. The essentially crystalline particles formed contain the active agent in a solvated form. The particles may be further dried using a dry antisolvent in a supercritical or subcritical state.

A widely used process employs solvent evaporation to form microparticles containing active agents. In a solvent evaporation process, the active agent and matrix material are dissolved in a volatile organic solvent which is finally removed by increasing the temperature and / or decreasing the pressure. The most widely used apparatus for microparticle formation through solvent evaporation incorporates a rotating device, often referred to as a spinning disk. The spinning disk process was originally described in USN-3,015,128 (issued January 2, 1962 to GR Somerville1 Jr.), The description of which is pertinent to the spinning disk process is incorporated herein by reference in its to the extent not inconsistent with the descriptions in this patent application.

Since the advent of spinning disk technology, various modifications of the method and apparatus have been introduced; however, several problems associated with it have not been alleviated. For example, large particle size distributions are often obtained. Importantly, the smaller the particle size distribution, the more calculable and capable of repeating active agent dosing. In addition, "pure" coating material particles (placebo particles) are produced. This results in dosage dilution if the placebo particles were administered or additional manufacturing costs if the placebo particles had to be separated from the active agent containing microparticles. In addition, microparticle agglomeration occurs, which further affects particle size distribution. What is needed is an apparatus and method for producing microparticles having narrow particle size distribution, reduced placebo formation, lower particle agglomeration, and improved product yield.

Summary of the Invention

A spinning disk apparatus for microparticle production having these desired properties is provided, wherein the apparatus contains a substantially circular spinning disk comprising a substantially smooth annular disk surface comprising a substantially flat inclination, where an outer peripheral edge thereof defines a first diameter and an edge. Its inner peripheral edge defines a second diameter, and where the area circumscribed by the inner peripheral edge includes a reservoir comprising a top portion thereof defined by the inner peripheral edge of the annular disc surface, and where the reservoir is partially defined by a third diameter. , located between the bottom of the reservoir and the top end of the reservoir, where the third diameter is larger than the second diameter. The spinning disk apparatus may comprise a substantially flat surface below the surface of the annular disk and near the outer peripheral edge thereof, where the substantially flat surface lies in a plane that is substantially parallel to the rotational axis of the spinning disk. Further, the outer peripheral edge of the annular disc surface may comprise teeth.

A method for producing microparticles using the spinning disk apparatus described above is provided. In one embodiment thereof, microspheres are produced by combining an active agent with a matrix material to form a composition that is introduced into the spinning disk apparatus reservoir and operation of the apparatus for producing microspheres comprising the active agent and the matrix material. In another embodiment thereof, a method for producing microcapsules is also provided, wherein microspheres are combined with a coating material and translated into the reservoir of the spinning disk apparatus and its operation produces microcapsules comprising the coating material-coated microspheres. The active agent may comprise a pharmacologically active agent and the matrix and coating materials may comprise biodegradable polymers.

Formulations comprising microparticles containing biodegradable polymers and an ophthalmically active agent are also provided.The ophthalmically active agent may comprise anecortave acetate, a form of alcohol thereof, derivatives thereof and combinations thereof. In one embodiment, the formulation comprises microspheres containing the ophthalmically active agent. In another embodiment, the formulation comprises microcapsules containing the ophthalmically active agent.

Formulations comprising microcapsules which when introduced into a living organism release a pharmacologically active agent at a substantially zero order rate are provided. The microcapsules comprise microspheres comprising a biodegradable polymer and containing more than about 15% by weight of a pharmacologically active agent and a biodegradable polymer coating material. In one aspect, the release of the pharmacologically active agent at a substantially zero order rate extends over a period of at least about four weeks.

Microcapsules prepared by the methods described above are provided where the microcapsules, when introduced into a living organism, release a pharmacologically active agent at a substantially zero disorder rate. Such microcapsules comprise a biodegradable polymer coating material on a microsphere core comprising a biodegradable polymer and a pharmacologically active agent. The microsphere contains more than about 15% by weight of the pharmacologically active agent. In one aspect, the release of the pharmacologically active agent at a substantially zero order rate extends over a time period of at least about four weeks.

Brief Description of the Drawings

For a more complete understanding of the present invention, its advantages, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, where:

Figure 1 schematically illustrates a spinning disk apparatus in accordance with an embodiment of the present invention;

Figure 2 schematically illustrates a spinning disc according to prior art technology;

Figure 3 schematically illustrates a spinning disc according to prior art technology;

Figure 4 schematically illustrates a spinning disc according to the prior art technology;

Figure 4A schematically illustrates a prior art spinning disc;

Figure 4C schematically illustrates a prior art spinning disc;

Figure 5 schematically illustrates a spinning disc according to prior art technology;

Figure 6 schematically illustrates a conventional spinning disc according to the prior art technology;

Figure 7 schematically illustrates a side view of a rotary disk according to one embodiment of the present invention;

Fig. 8 schematically illustrates a top view of a spinning disc embodiment shown in Fig. 7

Figure 9 shows particle size distribution curves comparing a hypothetical population of microparticles produced with the spinning disk of the present invention and a conventional spinning disk;

Figure 10 shows an enlarged image of microcapsules produced in accordance with one embodiment of the present invention wherein a reduced number of placebo particles are formed;

Figure 11 shows an enlarged image of microcapsules produced according to an embodiment of the present invention wherein the microcapsules exhibit improved coating uniformity;

Figure 12 shows an enlarged image of microcapsules produced using a conventional spinning disk;

Figure 13 shows another enlarged image of microcapsules produced using a conventional spinning disk; and

Figure 14 shows a graph showing the amount of agent released over time from various microparticles produced by the present invention.

Detailed Description

Figure 1 shows a spinning disk apparatus 100 according to one embodiment of the present invention. The rotating disc apparatus 100 includes a rotating disc 105 which is coupled to a stirrer motor 115 via connecting rod 120. The rotating disc 105 is typically substantially circular and may have a diameter between about 10 mm and about 300 mm. As will be described in more detail below, the spinning disk105 may have a variety of surface features and various geometries. The agitator motor 115 is supported within the rotary dial 100 by a motor mounting frame 125. The hydraulically, pneumatically or electrically driven agitator motor 115 is adapted to rotate the rotary disc 105 through the connection rod 120. The motor The agitator 115 includes a speed control system (not shown) adapted to rotate the spinning disk 105 at various speeds, such as from about 60 rpm to about 25,000 rpm.

The rotary disc apparatus 100 also includes a sample application system 130 which includes one or more feed containers 135, one or more fluid pumps and a fluid delivery system 145. The fluid delivery system 145 typically comprises a tube whereby the materials to be processed within the disk apparatus 100 are introduced into the spinning disk 105. Fluid pumps 140 are typically adapted to apply fluids from the feed containers 135 to the spinning disk 105 through the system. of fluid application 145 at flow rates of about 0 to about 750 g / min. Feed containers 135 include one or more stirring devices 150 (such as a stirrer) adapted to facilitate mixing of materials introduced into feed containers 135 and may optionally include a temperature control system (not shown) adapted to control temperature. material contained therein.

Next to the spinning disk 105 is a heating unit 155, which may be in contact with or integral with the spinning disk 105 as shown, or alternatively arranged in close, non-contact proximity with it. Suitable heating units 155 include, but are not limited to, capacitance heaters, impedance heaters, liquid circulation heaters, and hot air guns. The spinning disk apparatus 100 includes a process chamber 160, which hermetically seals a surrounding space The spinning disc 105e is operably connected to a gas source (not shown) adapted to maintain the environment within the process chamber 106 under a controlled atmosphere. Process chamber 106 may optionally include a vacuum source (not shown) adapted to control pressure within process chamber 160. The gaseous environment maintained within process chamber 160 may comprise air or some inert gases or gases that are supplied to the process chamber. 160 by a degass power supply (not shown). Process chamber 160 may comprise thermally controllable internal surfaces comprising a material such as, but not limited to, coated stainless steel. Alternatively or additionally, the process chamber 160 may include surfaces having low thermal conductivity, such as / but not limited to, plastic. In one embodiment, the plastic used is high density polyethylene (HDPE), however, the invention It is not limited to this material and other similarly suitable materials may be employed.

Process chamber 160 may include a flat bottom tank containing internal surfaces comprising the above-mentioned materials. The spinning disk apparatus 100 may additionally include a sample collection system 165 which is operably connected to the process chamber 160. Suitable sample collection systems 165 include, but are not limited to, cyclone separators. Operably connected to sample collection system 165 may be an exhaust system 170, which may include one or more filters 175, one or more blowers 180, one or more airflow control valves 185, and one or more outputs 190. One cyclone separator comprising sample collection systems 165 may also comprise a thermally controllable internal surface, such as, but not limited to, coated stainless steel, and / or surfaces having low thermal conductivity, such as, but not limited to, plastic. In one embodiment, the plastic used is high density polyethylene (HDPE), however, the invention is not limited to this material and other similarly suitable materials may be employed.

Even as will be described in more detail below, the sample collection system 165 can be activated continuously. The surfaces of the spinning disk apparatus 100 which contact the microparticles produced therein, including, but not limited to, process chamber surfaces 160 and sample collection systems 165, may be thermally controlled by temperature control devices (not shown) to reduce particle agglomeration. .

Figures 2-6 show spinning disks according to prior art technology. Figure 2 shows a substantially flat spinning disk as described in US Patent No. 3,015,128 (issued to Somerville, Jr.), with which microparticles are produced by introducing materials through line 221 to surface 223 of FIG. turntable 215 near its center. The rotary disk 215 is rotated by the drive shaft 217 using a motor (not shown) operably connected to it, thereby urging materials introduced on the surface 223 of the rotary disc 215 radially outwardly along the surface 223 to circumferentially approach the disc 224. 215 where materials are carried out from random points and then separated into different particles 228.

Figure 3 shows a prior art spinning disk contending around its periphery as described in U.S. Patent No. 4,256,667 (issued to Lee). As shown herein, the materials fed through the outlet 317 to the revolving scratch surface 321 which contain teeth 320 around their periphery. The outlet 317 is arranged so that the introduced materials then contact the surface of the decoder 321 near its periphery. The toothed disc 321 is convex with respect to the introduction of materials through the outlet 317 and is heated using heating element 324 disposed near the peripheral edge of the disc 321. Using conventional spinning disc methodology as previously described, microparticles are then produced.

Figures 4A-4C show spinning disks of the prior art concave geometry as described in U.S. Patent No. 4,675,140 (issued to Sparks et al.). Figure 4A shows an angled spinning disc 490 into which melted or dissolved coating material 421 and core material 427 are introduced, which may comprise solid particles or liquid droplets. Using conventional spinning disc methodology as described above, microparticles comprising core particles 427 with a liquid coating layer 427a, and gouticles 421A of excess unused coating material 421 are then produced. Figure 4B shows a parabolic spinning disc 492 and figure 4C shows a sigmoidal spinning disc 494 which form microparticles as described above.

Figure 5 shows a prior art rotary apparatus having a cup-shaped rotary limb as described in U.S. Patent No. 5,643,594 (issued to Dorian et al.). As described herein, co-po 512 receives a supply mixture 518 of a departments suspension in a solution of a coating polymer through a conduit or tube 519. Cup 512 includes a mixing chamber 520 extending to a wall. conically shaped, diverging toward top 522, and ending in an edge or edge 525. Cup 512 is made to project beads 514 radially outward along a generally horizontal path employing conventional spinning disc methodology as previously described.

Figure 6 shows a conventional prior art rotary apparatus ("conventional disk") as described in Johnson et al., DE et al., "A New Method for Coating Glass Beads for Use in Gas Chro-matography of Chloropromazine and Its Metabolites". "J. Gas. Chrom., 3,345-47 (1965), the description of which is pertinent to the spinning disk is hereby incorporated by reference in its entirety to the point not inconsistent with the descriptions in the present application. The conventional disk shown here includes a concave geometry where the surface of the disk curves sig- nally from the center to its periphery. For purposes of general description of the features and advantages of the present invention as discussed below, the conventional disk described in the above cited reference is the standard for comparison.

Figure 7 shows a spinning disk comprising a fashion of the present invention. The spinning disk 105 includes a substantially smooth annular surface 706 which is defined herein as the rotatable disc top face 105. The spinning disk 105 comprises an outer peripheral edge 707. The spinning disk 105 also includes a reservoir 708 partially defined by an inner peripheral edge 709 of the spinning disk 105e disposed in the center thereof. The reservoir 708 has a vertical displacementH1 which may be between about 5 mm and about 20 mm. A diameter D3 defines a maximum reservoir width 708, while a diameter D2 defines a minimum reservoir width 708. The diameter D3 may be in the range of about 1 mm to about 20 mm. The diameter D2 may be in the range from about 1 mm to about 20 mm. Diameter D2 is disposed closer to the open end of reservoir 708 than is diameter D3. That is, reservoir 708 has an opening that is narrower than at least some cross-sectional area below the opening. This geometry produces an opening 710 at the top of reservoir 708.

The annular surface 706 has a diameter D1 which may be about 10 mm to about 300 mm. Annular surface 706 comprises a flat inclination defining a fixed angle α, which may range from about 2 degrees to about 85 degrees, preferably from about 5 degrees to about 45 degrees and more. preferably from about 15 degrees to about 30 degrees. A further optional feature of the spinning disc 105 is a substantially flat surface 711 substantially parallel to the axis of the rotational disc below the annular surface 706 near the outer peripheral edge 707. The substantially flat surface 711 may range from about 1 mm to about 10 mm length. The inclusion of surface 711 having this geometry assists in more precise machining of disc 105 by providing a second reference surface to aid in refixing and significantly reducing vibration during the machining process. The rotary disc 105 may be composed of any suitable material that may be manufactured to meet specifications for it, such as a metallic or synthetic material. In certain embodiments, the swivel disk 105 has been made from 304 or 316 stainless steel, however, the present invention is not limited to discs comprising such materials. Annular surface 706 and reservoir surface 708 may be ground and polished to a mirror finish; However, one of skill in the art would understand that the surface characteristics of a spinning wheel affect its performance and can be optimized to achieve the desired results.

As shown in Figure 8, the spinning disk 105 may optionally include saws ("teeth") 712 comprising the outer peripheral edge 707. The teeth 712 may define an angle β, which may range from about 145 degrees to about 10 degrees, preferably from about 105 degrees to about 15 degrees, and more preferably from about 65 degrees to about 20 degrees. However, a skilled person would understand that the β angle would affect the performance of a discogiratory and could be optimized to achieve the desired results. Teeth 712 may define a horizontal displacement D4 of from about µm to about 5,000 µm.

The apparatus described in figures 1, 7 and 8 may be employed to produce microparticles according to embodiments of the present invention. In one aspect, the apparatus is used to produce microspheres.

In one embodiment, microspheres are produced by dispersing a pharmacologically active agent in solutions containing a biodegradable polymer. Referring again to Figure 1, the solution is prepared by introducing a biodegradable polymer and a solvent into the feed container 135. Suitable biodegradable polymers include, but are not limited to, polylactic acids (PLA), polyglycolic acid (PGA), acids polylactic glycols (PLGA), polycaprolactone (PCL), polyorthoesters, polyanhydrides, polyesters, cellulosics, triglycerides (such as Sterotex K and Sterotex NF), polyethylene glycols (PEG) and combinations thereof. Suitable solvents include any material where the biodegradable polymer will dissolve. Such solvents include, but are not limited to, methanol, ethanol, methylene chloride, chloroform, ethyl acetate, acetone and combinations thereof. Although less volatile solvents may be used according to the invention, it is a particular feature. of the present invention that lower boiling solvents may be employed.

The pharmacologically active agent is then dispersed in the biodegradable polymer solution by its introduction into the food container 135. Suitable pharmacologically active agents that may be used to advantage with the present invention include, but are not limited to, ophthalmically active agents, angiogenic inhibitors. , antiinflammatory agents (steroidal and non-steroidal), detirosin kinase inhibitors, antiinfectives (eg antibiotics, antivirals and antifungals), antiallergic agents (eg antihistamine and mast cell stabilizers), cyclooxygenase inhibitors (eg, Cox Ie Cox II inhibitors), decongestants, antiglaucoma agents (eg, adrenergic agents, beta-adrenergic blocking agents, alpha-adrenergic agonists, cholinesterase inhibitors, carbonic deanhydrase inhibitors and prostaglandin analogues), phosphatidyl inositol kinase, acid gamma-aminobutyric and its derivatives (including gaba-pentin and pregabalin), antioxidants, nutritional supplements, agents for the treatment of systemic macular edema (eg, non-steroidal anti-inflammatory agents), agents for the treatment of degeneration age-related macular disease (ARMD) (eg angiogenic inhibitors and nutritional supplements), agents for the treatment of herpes infections and cytomegalovirus (CMV) eye infections, agents for the treatment of vitreoretinopathy proliferative (eg, fibrinolytic antimetabolites), wound modulation agents (eg, decay factors), antimetabolites, neuroprotective drugs (eg eli-prodil), angiostatic steroids for the treatment of diseases or conditions of the posterior segment of the eye (eg ARDM, co-roidal neovascularization (CNV), retinopathies, retinitis, uveitis, macular edema and glaucoma) and their combinations. A suitable pharmacologically active agent for use with the present invention is the ophthalmically active agent deanecortave (4,9 (11) -pregnadien-17a, 21-diol-3,20-dione-21-acetate) acetate. may also be used in its alcohol form (4,9 (11) -pregnadien-17a, 21-diol-3,20-dione) or in other prodrug derivative forms.

Once the dispersion or solution containing the pharmacologically active agent, the biodegradable polymer and the solvent is prepared, the dispersion is transferred to the top face of a spinning disc 105 using fluid pump 140 and fluid delivery system 145. Although Dispersion can be introduced into the spinning disk 105 in any portion thereof (including annular surface 706), It is a feature of the present invention that the dispersion may be introduced into the reservoir 708. Prior to the manufacture of the microsphere, the process chamber 160 is maintained. conductive conditions to control evaporation of the solvent from the dispersion. This is accomplished by controlling the annular surface temperature 706 and reservoir 708 (using heating unit 155) and the temperature and / or pressure of the process chamber 160 (using a vacuum source not shown) so that the solvent evaporation rate increases the production of microspheres. One skilled in the art would understand the effects of temperature and pressure on solvent evaporation (and thus microsphere production) and understand that conditions can be optimized to produce the desired materials.

Upon introduction of the dispersion or solution into the reservoir708, the centrifugal force transferred to the dispersion from the spinning disk105 urges the dispersion as a liquid film upwardly on the inner surface of the reservoir 708. Before the liquid film advances outward to angular aporion of the annular surface 706 of the spinning disk 105 toward the outer peripheral edge 707, it must pass through the opening 710 of the reservoir 708. It is a feature of the present invention that the opening 710 is disposed between the reservoir 708 and the flat angular portion of the surface annular 706 extending to the outer peripheral edge 707. Once the liquid film has spread beyond aperture 710, the dispersion becomes more viscous as the solvent is evaporatively removed from it. It would be understood by one of skill in the art that the spinning speed of the spinning disk 105, in contemplation of the dispersion composition and environmental conditions of the process chamber 160, can be optimized to achieve the desired microsphere production.

The materials in the dispersion or solution may be atomized as they rotate urgently beyond the outer peripheral edge 707 and are ejectably ejected from the edge of the spinning disk 105. Solidification of the atomized material as it falls to the bottom of the process chamber 160 results in the formation of microspheres comprising the pharmacologically active agent and the biodegradable polymer. The microspheres then produced are collected using sample collection system 165. Microsphering a diameter from about 1 μιη to about 2,500 μηι can be produced by this process. The microspheres then produced may comprise about 0.0001 wt.% To about 99 wt.% Of the active agent, preferably about 0.001 wt.% To about 55 wt.% Of the active agent and more preferably about 0 0.01% by weight to about 30% by weight of active agent.

In another embodiment of the present invention, microspheres are produced using a hot melt process (as generally described in U.S. Patent No. 3,080,293 (issued to Koff)) which employs the apparatus of the present invention. In this embodiment, the biodegradable polymer is introduced to feed the container 135 and melted or partially melted therein. As previously described, the dispersion can then be introduced into reservoir 708 of the spinning disc 105 via fluid delivery system 145. Centrifugal force urges the dispersion as a liquid film upwardly on the inner surface of reservoir 708 and beyond opening 710 of reservoir 708. The dispersion may be maintained in a molten or partially melted state by the temperature of the annular surface 706 as it is spread outward to the peripheral edge707. The dispersion is rotationally ejected from spinner disk 105 and frozen spheres as they fall to the bottom of the process chamber160. The microspheres then produced may be collected using a sample collection system 165. Microspheres having a diameter of about 1 μηι at about 2,500 pm may be produced by this process. The microspheres then produced may comprise about 0.0001 wt.% to about 75 wt.% active agent, preferably about 0.001 wt.% to about 45 wt.% active agent and more preferably about 0.01 wt.% to about 30% by weight of active agent.

In additional embodiments of the present invention, microspheres may be produced comprising core materials other than pharmacologically active agents. Thus, the apparatus of the present invention may be employed to produce microspheres suitable for introduction into living organisms where sustained release materials do not cause pharmacological or pathological responses in vivo. Examples of such materials include, but are not limited to, dyes, radioactive compounds, imaging agents, quantum dots, contrast agents and combinations thereof. Further, the microspheres produced in accordance with the present invention may comprise agents which are developed to be non-physiologically active ex vivo. Examples include, but are not limited to, ultraviolet blocking or absorption compounds, deodorants or antiperspirants, emollients, cosmetics and combinations thereof. Furthermore, microspheres produced in accordance with the present invention may comprise matrix materials other than biodegradable polymers. Suitable materials include, but are not limited to, waxes, lipids, oils, gums, resins, cellulose, starches, non-biodegradable polymers and combinations thereof.

In another aspect of the present invention, microcapsules comprising a coated microsphere may be produced. The formation of microcapsules involves applying a coating to microspheres using the apparatus of the present invention. In one embodiment, the microcapsule production according to the present invention involves applying a biodegradable coating to microspheres comprising a pharmaceutically active agent and biodegradable polymer matrix. In this embodiment, a solution comprising a coating material and a solvent may be prepared in feed container 135. Suitable solvents include any material where the coating material will dissolve but where the microspheres are substantially insoluble. Such solvents include, but are not limited to, methanol, ethanol, methylene chloride, chloroform, ethyl acetate, acetone and combinations thereof. Although volatile solvents may be used according to the invention, it is a feature of the present invention that lower boiling solvents may be used. It is also a feature of the present invention that the solvent used for microcapsule formation may be one unable to extract significant amounts of the active agent from the microsphere matrix. Suitable coating materials include, but are not limited to, poly-lactic acids (PLA), polyglycolic acids (PGA), polylactic glycolic acids (PLGA), polycaprolactone (PCL), polyorthoesters, polyanhydrides, polyesters, celluloses, triglycerides ( such as Sterotex K and Sterotex NF), polyethylene glycols (PEG) and combinations thereof.

A microsphere comprising a pharmacologically active agent and a biodegradable polymer may be dispersed in the coating material solution. The dispersion then formed may be introduced as previously described with reference to the noreservatory microsphere production 708 of the spinning disk 105 through the fluid delivery system 145. As described above, the centrifugal force transferred to adispersion from the spinning disk 105 may be urgent. the dispersion as an upward liquid film on the inner surface of reservoir 708 beyond aperture 710. As described above, once the liquid film has spread beyond aperture 710, the dispersion becomes more viscous as the solvent is evaporatively removed from it. It would be understood by one skilled in the art that the rotational speed of the spinning disk 105, in contemplation of the dispersion composition and ambient conditions of the process chamber 160, can be optimized to achieve the desired microcapsule production.

The materials in the dispersion may be atomized by rotating urgently beyond the outer peripheral edge 707 and ejected from the discogiratory 105. Solidification of the atomized material as it falls into the process chamber 160 results in the formation of microcapsules comprising an outer layer of the material. biodegradable coating on the core of the microsphere. The microcapsules then produced can be collected using sample collection system 165. Microcapsules having a diameter of about 1 μηη to about 2,500 μμ can be produced through this process. The microcapsules then produced have a coating of from about 0.002 volume% to about 96 volume%, preferably about 0.003 volume% to about 50 volume%, and more preferably about 0.004 volume% about. 5% by volume. The microcapsules then produced may comprise from about 0.0001% by weight to about 99% by weight of active agent, preferably from about 0.001% by weight to about 50% by weight of active agent and more. preferably about 0.01% by weight to about 30% by weight of active agent.

In a further embodiment, microencapsulation using the apparatus of the present invention may comprise a hot melt process. In this embodiment, a biodegradable polymer coating material is introduced to feed the container 135 and partially or partially melted therein. Once the coating material exists in the melted or partially melted state, a microsphere comprising a pharmacologically active agent and a biodegradable polymer is introduced into it. As previously described, the dispersion is then introduced into the reservoir 708 of the spinning disk 105 by rotating through the fluid delivery system 145. The centrifugal force urges the dispersion as a liquid film onto the inner surface of the reservoir 708 and beyond the opening. 710 of reservoir 708. The dispersion is maintained in a melted or partially melted state by the temperature of the annular surface 706 as it is spread out to the outer peripheral edge 707. The dispersion is rotatably ejected from the spinning disk 105 and freezes as microcapsules. comprising an outer layer of biodegradable coating material on the microsphere core as it extends to the bottom of the process chamber 160. The then produced microcapsules are collected using sample collection system 165. Microcapsules having a diameter of about 1 µm. pm to about 2,500 μηι can be produced through this process. The microcapsules then produced have a coating of from about 0.002% by volume to about 96% by volume. The microcapsules then produced may comprise from about 0.0001% by weight to about 99% by weight of active agent, preferably about 0.001% by weight to about 50% by weight of active agent and more preferably about 0.01%. by weight to about 30% by weight of active agent.

Embodiments of the present invention comprise microcapsule production using the apparatus described herein. Microspheres employed to produce microcapsules according to the present invention may be produced using the apparatus described herein as described above or produced by another suitable process. In addition, microspheres according to the present invention may comprise non-pharmacologically active agents and / or matrix materials that do not comprise biodegradable polymers, such as the microspheres previously described herein. In additional embodiments, microcapsule production may be achieved in accordance with the present invention whereby the coating material does not comprise a biodegradable polymer. Suitable materials include, but are not limited to, waxes, lipids, oils, gums, resins, cellulose, starches, non-biodegradable polymers and combinations thereof.

The following Examples are provided to demonstrate particular features of the present invention. It should be understood by those skilled in the art that the methods described in the following Examples represent only exemplary embodiments of the present invention. However, those skilled in the art should, in light of the present description, understand that many changes may may be made in the specific embodiments described and still obtain a similar or similar result without departing from the spirit and scope of the present invention.

In one embodiment of the above microspheres manufacturing process, 312 g of a 50:50 solution of 8% poly lactide-co-glycolide (PLGA) in 60:40 acetone / methylene chloride were prepared in the feed container. 135. To this solution was added 9.7 g of anecortave acetate and the resulting dispersion was transferred at a rate of about 120 g / min through the fluid delivery system 145 to the reservoir 708 of a spinning disk 105 having a diameter of ca. -ca 76.2 mm, running at a rate of about 3,000-4,000 rpm. Using a process chamber 160 comprising a high density polyethylene (HDPE) inner surface, microspheres were formed by evaporative removal of the solvent with a process chamber 160 outlet temperature of about 48-50 ° C. An 88% yield (30.6g) of microspheres was collected as a free flowing powder using a cyclone separator.

Comparative Example 1

In an example comparable to Example 1 above, a stainless steel process chamber 160 was used instead of the less thermally conductive plastic material. In it, 250 grams of a 50:50 solution of 8% poly lactide-co-glycolide (PLGA) in 60:40 acetone / methylene chloride were prepared in feed vessel 135. To this solution was added 7.8 g. of anecortave acetate and the resulting dispersion was transferred at a rate of about 125 g / min through a fluid delivery system 145 to reservoir 708 of a spinning disk 105 having a diameter of about 76.2 mm, running at a rate of about 3,000-4,000 rpm. The microspheres were formed by evaporative removal of the solvent with a stainless steel process chamber outlet temperature of 48-50 ° C. The microspheres agglomerated on the sides of the stainless steel process chamber 160 and any separate microspheres were collected.

Example 2

In one embodiment of the microspheres fabrication process described here, 200 g of a 90% 10% poly lactide-co-glycolide (PLGA) solution in acetone was prepared in feed vessel 135. To this solution was added 6.7 g of acetate. from anecortave. The resulting dispersion was transferred at a rate of about 180 g / min through fluid application system 145 to reservoir 708 of a spinning disk105 having a diameter of about 76.2 mm, rotating at a rate around 4,000-5,000 rpm. Using a process chamber 160 comprising an inner surface of high density polyethylene (HDPE), the microspheres were formed by evaporative removal of aceton with an external temperature of the process chamber 160 of about 45 ° C. A 90% yield (15.0 g) of microspheres was collected as a free flowing powder using a cyclone separator.

Example 3

In one embodiment of the microspheres fabrication process described here, 200 g of a 5% poly lactide-co-glycolide (PLGA) 90:10 solution in acetone was prepared in feed vessel 135. To this solution was added 0.5 g of polyethylene. glycol (PEG 400) and 3.5 g anecortave deacetate. The resulting dispersion was transferred at a rate of about 200 g / min through the fluid delivery system 145 to the reservoir 708 of a spinning disc 105 having a diameter of about 76.2 mm, rotating at a rate of about 4,000-5,000 rpm. Using a process chamber 160 comprising an inner surface of high density polyethylene (HDPE), the microspheres were formed by evaporative removal of acetone with a process chamber 160 outlet temperature of about 45 ° C. A 77% yield (10.8 g) of microspheres was collected as a free flowing powder using a cyclone separator.

Example 4

In one embodiment of the microspheres fabrication process described here, 100 g of 75:25 5% poly lactide-co-glycolide (PLGA) solution in acetone was prepared in feed vessel 135. To this solution was added 0.56 g of Isopropyl. (Z) -7 - [(1R, 2R, 3R, 5R) -5-chloro-3-hydroxy-2 - [(3R) - [3-cyclohexyl-3-hydroxy] -1-propyl] cyclopentyl] -5 -heptanoate. The resulting solution was transferred at a rate of about 85 g / min through fluid delivery system 145 to reservoir 708 of a spinning disk 105 having a diameter of about 76.2 mm, rotating at a rate about 5,500 rpm. Using a process chamber 160 comprising an inner surface of high density polyethylene (HDPE), the microspheres were formed by evaporative removal of acetone with a process chamber 160 outlet temperature of about 45 ° C. 56% yield (3.09 g) of microspheres was collected as a free flowing powder using a cyclone separator.

Example 5

In one embodiment of the microspheres fabrication process described here, 489 g of a 45% poly lactide-co-glycolide (PLGA) solution in acetone (85:15) was prepared in feed vessel 135. To this solution was added 0.396 g of 5-Fluoruridine. (5-FUD). The resulting solution was transferred at a rate of about 55 g / min through fluid application system 145 to reservoir 708 of a spinning disc 105 having a diameter of about 76.2 mm, rotating at a rate of about 5 g / min. 5,000 rpm. Using a process chamber 160 comprising a high density polyethylene (HDPE) inner surface, the microspheres were formed by evaporative removal of acetone with a process chamber 160 outlet temperature of about 45 ° C. A 70% yield (15.55 g) of microspheres was collected as a free flowing powder using a cyclone separator.

Example 6

In one embodiment of the microspheres fabrication process described here, 100 g of a 90% 10% poly lactide-co-glycolide (PLGA) solution in acetone was prepared in feed vessel 135. To this solution was added 0.56 g of Isopropyl. (Z) -7 - [(1R, 2R, 3R, 5S) -3,5-dihydroxy-2 - [(1 E, 3R) - [3-hydroxy-4 - [(α, aa-trifluoro-m- tolyl) oxy]] -1-butenyl] cyclopentyl] -5-heptanoate. The resulting solution was transferred at a rate of about 71 g / min through fluid delivery system 145 to reservoir 708 of a spinning disc 105 having a diameter of about 76.2 mm, rotating at a rate of about 5,500 rpm. Using a process chamber 160 comprising an inner surface of high density polyethylene (HDPE), the microspheres were formed by evaporative acetone removal with a process chamber 160 outlet temperature of about 46 ° C. A 68% yield (3.8 g) of microspheres was collected as a free flowing powder using a cyclone separator.

Example 7

In one embodiment of the microcapsule manufacturing process described herein, 42.7 g of a triglyceride (Sterotex NF, available from AbitecCorp., Janesville, WI) was melted in the feed container 135 at a temperature of about 90-95 ° C. To the melted material was added 15.0 g of anecortave acetate and the resulting dispersion was transferred at a rate of about 50-60 g / min through the fluid delivery system 145 to reservoir 708 of a spinning disk. 105 having a diameter of about 76 mm, rotating at a rate of about 7,500-8,500 rpm. The spinning disc was kept at a temperature of about 90-100 ° C. Microspheres were formed by cooling the hot melt with a process chamber 160 outlet temperature of about 22-28 ° C. An 80% yield (46.5 g) of microspheres was collected as a free-flowing powder using a cyclone separator. A coating was applied to a portion of the then produced microspheres. This was accomplished by preparing 100 g of a 75% poly lactide-co-glycolide (PLGA) 75:25 solution in 60: 40 acetone / ethyl acetate in the feed vessel 135 and then dispersing 20.0 g of the microspheres therein. . The resulting dispersion was transferred at a rate of about 120 g / min through the fluid delivery system 145 to the reservoir 708 of a spinning disk 105 having a diameter of about 76.2 mm, rotating at a rate of about 3000-4000 rpm. The microspheres were formed by evaporative removal of the solvent with a process chamber 160 outlet temperature of about 45-50 ° C. A yield of 71% (17.9 g) of microcapsules was collected using a cyclone separator. In the above-mentioned Examples, the spinning disk 105 included substantially flat surface 711 substantially parallel to the spinning disk axis below the annular surface. 706 near the outer peripheral rim 707, and the teeth 712 disposed at the outer peripheral edge 707. The inclusion of the surface 711 having this geometry facilitates the production of discs which have less surface variability and thus exhibit less vibration during rotation. rotation. A conventionally manufactured disc had substantial horizontal and vertical displacement, which resulted in measurable "vibration" during rotation, but could be "adjusted" for narrow particle size distributions by optimizing parameters such as flow rate. fluid, disc rotation speed and other variables known to those skilled in the art. However, although conventional disk operation could then be optimized, these optimal processing conditions were extremely limited and processing outside these conditions resulted in significantly broader particle size distributions. By comparison, conventional disc manufacturing including a flat surface 711 reduced vertical and horizontal displacement to about 5-10 pm and the disc exhibited slightly reduced levels of vibration during operation. Studies indicate that lower vibrational levels have resulted in reduced particle size variability compared to conventional "vibrating" discs over a wide range of operating conditions.

Further studies conducted indicate that the same phenomenon happens with discs having the spinning disc design 105 described herein. A spinning disc 105 prepared without including a substantially flat surface 711 and having a disc variability of about 38 pm generally exhibited shorter particle size distributions than a similar disc 105 made with a substantially flat surface 711e having a surface variation of about 7.6 pm. However, analogous to the performance observed for the conventional disk, the overall variability under a variety of operating conditions was lower for the spinning disk 105 comprising substantially flat surface 711 than for similar disk 105 made without a substantially flat surface 711. . Without being limited by theory, it is believed that the absence of disc vibration allows for better controlled particle breakage to occur on the disc surface resulting in narrower particle size distributions.

Particle formation on a disc periphery is known to be influenced by the presence of evenly spaced conical tips or cones. See, for example, Babu, S.R., "Analysis of Drop Formation at Conical Tips", J. Colloid Interface Sci., 116 [2], 350-372 (1987). The inclusion of saws or teeth 712 in the spinning disk 105 greatly narrows the particle size distribution. Studies performed comparing the particle size distribution of microparticles produced using a discogiratory 105 comprising a substantially flat surface 711, with and without teeth 712, indicate that the first particle size distribution is considerably narrower than for the latter. Although the result is not necessarily unexpected, what is surprising is the magnitude of the decrease in particle size variability achieved with the "saw" spinning disk 105.

For each of the tested sawless spinning discs that included a substantially flat surface 711 or the equivalent thereof, the discogiratory 105 produced particle distributions that were on average 72% wider than the particle populations produced by the conventional disc. The 105 saw spinning disc produced the narrowest particle size distributions, which on average were 58% smaller than the particle size distributions produced by the conventional disc. Figure 9 graphically shows generated particle size distribution curves comparing a hypothetical population of particles having a mean diameter of 250 μπι. As shown by graph 900 in Figure 9, particles produced by conventional disk would range in size from about 75 to 1000 pm (curve 901), particles produced by spinning disk 105 without saw would range in size from about from 25 to 2,500pm (curve 902), and saw blade spinner particles 105 would range in size from about 175 to 500 pm (curve 903). Disk measurement is another factor influencing microparticle formation, and so studies were performed to determine its effects on microparticle formation. Although the spinning disc 105 may be manufactured from any suitable material, the microparticle production examples described herein were made using a stainless steel disc. A stainless steel disc surface is expected to have high free energy, leading to limited humidification conditions. A conventional disc surface made of 30-4 stainless steel was initially conditioned by washing it with soapy water, then rinsing it with water followed by acetone and finally air drying the disc at 60 ° C for one hour. The disc was then stored under nitrogen. Contrary to the base crack, the disc surface was treated with a variety of materials, including Tergitol® TMN-100 surfactant (available from Dow Corporati-on, Midland, M1), methanol and water. Contact angle measurements were made when applying various process solutions to the disc surface and observations were made as fluid was allowed to flow through the disc surface during rotation of the spinning disc.

Studies indicate that repeatable microparticle formation is most readily obtained when fluid flow through the disc surface reaches complete wetting therein. The results indicate that the overall surface tension of the process solution liquid to be toned over the spinning disk must generally be less than 40 dynes / cm to ensure wetting of the surface of a dry, clean stainless steel disk. Alternatively, the free energy of the disc surface may be reduced by means of specific adsorption low free energy species or by making the disc from intrinsically low free energy materials.

Although reduced particle size variation is an object of the present invention, another object is to reduce "pure" shell material particles (satellite or placebo particles) produced during microcapsule formation. One skilled in the art would know that by manipulating the viscosity of the polymer solution used in the coating process, a person can reduce the amount of satellite particles produced. However, high polymer solution viscosity leads to some extent to the aggregation of microsphere (coating of multiple microspheres to form a large microcapsule). Using the apparatus of the present invention to produce microcapsules, lower levels of spot particles are typically formed and thicker, even coatings may be applied. Microcapsule formation using a saw disk 105 comprising a substantially flat surface 711 can produce microcapsules containing significantly lower levels of satellite particles (Figures 10 and 11) as compared to a process using a conventional disk (Figures 12 and 11). 13). The reduction in placebo particles translates into improved yield of the microcapsules. Also, as mentioned above, thicker coating can be applied using the apparatus of the invention compared to a conventional one (Fig. 11 versus Fig. 13).

Another advantage of the present invention is reduced particle agglomeration. Although as described above the design of the spinning disk 105 allows the production of microparticles having a narrow particle distribution, agglomeration of produced and collected microparticles causes problems in handling. The design features described above, such as thermally controlled surfaces and / or low thermal conductivity, reduce particle agglomeration.

The apparatus of the present invention may be operated continuously as opposed to normal batch manufacture of microparticles. The following is given as an example of a continuous 3 day operation. About 400 g of a 5% polycaprolactone solution in methylene chloride was prepared in feed vessel 135. To this solution was added 6.67 kg of anecortave acetate (25% payload) and the resulting dispersion was transferred at a rate. 90 g / min through fluid delivery system 145 to the rotary disc reservoir 708 having a diameter of about 76.2 mm, rotating at a rate of 3,000-4,000 rpm. The microspheres were formed by evaporative solvent removal with an outlet temperature of about 42-45 ° C within the plastic process chamber (HDPE) 160. A yield of 93% (24.8 kg) of microspheres was obtained. It is collected as a free flowing powder using a cyclone separator.

A further advantage of the present invention is that produced microcapsules then exhibit improved active agent release properties. In one embodiment of the present invention, microcapsule-containing microspheres containing anecortave acetate as the active agent are prepared according to the methods described herein. The produced microparticles were sterilized by exposure to gamma radiation at a dose level of 18-25 kGy. To measure agent release rates for them, about 5.0 mg of microparticles were weighed into glass bottles containing about 50 mL of a 5% sodium dodecyl sulfate / phosphate buffer solution (SDS / PBS). ). The sample bottles were then placed in a shaking water bath at 37 ° C. At various time intervals, 100 µl aliquots were removed for analysis and an equal volume of 5% SDS / PBS solution was replaced.

As shown graphically in Figure 14, a high payload (> 20% by weight active agent) microcapsule formulation provides near zero order release and reduced abrupt release compared to microsphere formulations. In Figure 14, graph 1400 shows the amount of active agent, anecortave acetate, released from various microparticles produced by the present invention and maintained in 5% SDS / PBS at 37 ° C. Curve 1401 shows the release profile of microcapsules (75:25 PLGA coating covering microspheres comprising glyceride matrix) containing 23.8% by weight of active agent. Curve 1402 shows the release profile of microcapsules (PL-GA 75:25 coating covering microspheres comprising glyceride matrix) containing 23.5% by weight of active agent. Curve 1403 shows the microspheres clearance profile comprising PLGA 75: 25 / PEG (95: 5) and containing 23.8% by weight of active agent. Curve 1404 shows the release profile of microspheres comprising PLG 75: 25 / PEG (95: 5) and containing 25.7% by weight of active agent. Curve 1405 shows the release profile of microspheres comprising PLGA 50: 50 / PEG (95: 5) and containing 25.8% by weight of active agent. Curve 1406 shows the release profile of non-sterile microspheres comprising PLGA 50: 50 / PEG (95: 5) and containing 24.6% by weight of active agent. Microcapsules and microspheres containing low payloads may exhibit zero order release, however, on payloads above about 15%, especially where the encapsulated agent is highly soluble in the release medium, microspheres and microcapsulastipically release most of the active agent. very quickly (<1 day). Microcapsules of the present invention with> 20% loading of activating agent do not show a rapid initial release in vitro, but in contrast a slow zero order release up to 4 weeks. (See curves 1401 and 1402 in Figure 14). Release rate control is a very important component of the formulation where a rapid initial release could waste the active agent or, worse, be toxic to the container.

All patents and publications referred to herein, to the extent not previously incorporated herein by reference, are hereby incorporated by reference in their entirety to the extent not inconsistent with the descriptions in the present Application. It will be understood that certain of the above described structures, functions and operations of the above described embodiments are not necessary for practicing the present invention and are included in the description simply for the integrity of an exemplary embodiment or embodiments. Further, it will be understood that specific structures, functions and operations shown in the above-described patents and publications may be practiced in conjunction with the present invention, but they are not essential to their practice. It should then be understood that the invention may be practiced otherwise than as specifically described without actually departing from the spirit and scope of the present invention as defined by the appended claims.

It is then understood that the claims will cover any such modifications or embodiments that fall within the true scope of the invention.

Claims (31)

A formulation comprising microcapsules, wherein the microcapsules comprise: (A) a core material comprising microspheres, wherein the microspheres comprise (i) a biodegradable polymer; and (ii) a pharmacologically active agent comprising more than about 15 wt% of the microsphere; and (B) a coating material comprising a biodegradable polymer, wherein the microcapsules are constituted such that when introduced into a living organism they release the pharmacologically active agent at a substantially zero order rate. The formulation of claim 1, wherein the release of the pharmacologically active agent at a substantially zero rate extends over a period of at least about two weeks. The formulation of claim 1, wherein the biodegradable polymers comprise materials selected from the group consisting of polylactic acids, polyglycolic acids, polylactic glycolic acids, polycaprolactone, triglycerides, polyethylene glycols, polyorthoesters, polyanhydrides, polyesters, cellulosics and combinations thereof. A formulation according to claim 1, wherein the microcapsules have diameters substantially between about 1 pm and about 2,500 pm. A formulation according to claim 1, wherein the microcapsules have a coating comprising from about 0.003% by volume to about 50% by volume. The formulation according to claim 1, wherein the pharmacologically active agent comprises a material selected from the group consisting of: angiogenic inhibitors; antiinflammatory agents; tyrosine kinase inhibitors; antiinfectants; antiallergic agents; cyclooxygenase inhibitors; decongestants; antiglaucoma agents ; phosphatidyl inositol kinase inhibitors; gamma-aminobutyric acid and derivatives thereof; antioxidants; nutritional supplements; agents for the treatment of cystoid macular edema; agents for the treatment of age-related macular degeneration; agents for the treatment of herpetic infections; agents for the treatment of cytomega lovirus eye infections; agents for the treatment of proliferative vitreoretinopathy; wound modulation agents; antimetabolites; neuroprotective drugs; angiostatic steroids; ecombinations of the same. The formulation according to claim 1, wherein the pharmacologically active agent comprises more than about 20% by weight of the microsphere. A microcapsule comprising a microsphere and a coating material, wherein: (A) the microsphere comprises a biodegradable polymer and a pharmacologically active agent comprising more than about 15% by weight of the microsphere; (B) the coating material comprises (C) the microcapsule is prepared by a process comprising: (i) combining a material comprising the microsphere with the coating material to form a composition comprising the microsphere and the coating material, (ii) introducing the composition into a spinning disk apparatus, wherein the spinning disk apparatus comprises a substantially circular spinning disk comprising: (a) a substantially smooth annular disk surface, wherein (I) the annular disk surface has an inner peripheral edge and an edge; peripheral periphery, wherein the outer peripheral edge defines a first diameter of the annular disc surface, (II) the the annular disc surface has a second diameter defined by the area circumscribed by the inner peripheral edge, wherein the area circumscribed by the inner peripheral edge is disposed substantially on a central portion of the spinning disk, and (III) the annular disk surface between the inner peripheral edge and the outer peripheral edge comprise a substantially flat inclination, and (b) a reservoir disposed in the area circumscribed by the inner peripheral edge of the annular disc surface, wherein (I) the reservoir comprises a top portion defined therein by the edge. peripheral surface of the annular disc surface, and (II) the reservoir is partially defined by a third diameter, located between the bottom of the reservoir and the top portion of the reservoir, wherein the third diameter is larger than the second diameter, wherein said introducing the composition into the apparatus comprises introducing the composition into the reservoir, and (iii) operating apparatus for producing microcapsules comprising microspheres having a coating comprising the coating material; and (D) the microcapsule is constituted such that when introduced into a living organism it releases the pharmacologically active agent in a taxed substantially zero order. A microcapsule according to claim 8, wherein the biodegradable polymers comprise materials selected from the group consisting of polylactic acids, polyglycolic acids, lactic-polyglycolic acids, polycaprolactone, triglycerides, polyethylene glycols, poly orthoesters, polyanhydrides. , polyesters, cellulosics and combinations thereof. A microcapsule according to claim 8, wherein the pharmacologically active agent comprises a material selected from the group consisting of: angiogenic inhibitors; antiinflammatory agents; tyrosine kinase inhibitors; antiinfectives; cyclooxygenase inhibitors; decongestants; antiglaucoma inhibitors; phosphatidyl inositol kinase; gamma-aminobutyric acid and derivatives thereof; antioxidants; nutritional supplements; agents for the treatment of cystoid macular edema; agents for the treatment of age-related macular degeneration; agents for the treatment of herpes infections; treatment of cytomega lovirus eye infections; agents for the treatment of proliferative vitreoretinopathy; wound modulation agents; antimetabolites; neuroprotective drugs; angiostatic steroids; ecombinations of the same. A microcapsule according to claim 8, wherein the pharmacologically active agent comprises an ophthalmic active agent. A microcapsule according to claim 8, wherein the microcapsules have diameters substantially between about 1 µη and about 2,500 µm. A microcapsule according to claim 8, wherein the microcapsules have a coating comprising from about 0.003% by volume to about 50% by volume. Microcapsule according to claim 8, wherein the outer peripheral aspect of the annular disc surface comprises saws. A microcapsule according to claim 8, wherein the rotatable disk comprises a substantially flat surface lower than the annular disc surface and near the outer peripheral edge thereof, wherein the substantially flat surface is in a plane which is substantially parallel to the one. rotational axis of the spinning disk and wherein the substantially flat surface has a length between about -1 mm and about 10 mm. A microcapsule according to claim 8, wherein the rotary disc apparatus comprises a process chamber, wherein the process chamber comprises a material selected from the group consisting of a thermally controllable material, a low thermal conductivity material. and combinations thereof; and wherein the process chamber comprises a cone bottom tank, wherein the cone bottom tank comprises a material selected from the group consisting of a thermally controllable material, a low thermal conductivity material and combinations thereof. A microcapsule according to claim 8, wherein the rotary disc apparatus comprises a sample collection system comprising a cyclone separator, wherein the cyclone separator comprises a material selected from the group consisting of a thermally controllable material, a low thermal conductivity material and combinations thereof. Microcapsule according to claim 8, wherein the third diameter of the reservoir is arranged near the bottom of the reservoir. The microcapsule of claim 8, wherein the microcapsule is formulated such that when introduced into a living organism, the pharmacologically active agent is released in a substantially zero order extending over a period of at least us about two weeks. A formulation comprising microparticles, wherein the microparticles comprise microspheres comprising: (A) a biodegradable polymer; and (B) an ophthalmically active agent, wherein the ophthalmically active agent comprises a material selected from the group consisting of deanecortave acetate, a form of anecortave acetate alcohol, derivatives thereof and combinations thereof. A formulation according to claim 20, wherein the microparticles consist essentially of the microspheres. The formulation according to claim 20, wherein the microparticles consist essentially of microcapsules comprising: (A) a core material comprising the microspheres; and (B) a coating material coating the core material, wherein the coating material comprises a second biodegradable polymer, wherein the second biodegradable polymer is selected from the group consisting of: (i) the biodegradable polymer comprising the microspheres; (ii) a biodegradable polymer other than the biodegradable polymer comprising the microspheres; and (iii) a combination thereof. A formulation according to claim 20, wherein the biodegradable polymers comprise materials selected from the group consisting of polylactic acids, polyglycolic acids, polylactic glycolic acids, polycaprolactone, triglycerides, polyethylene glycols, polyorthoesters, polyanhydrides, polyesters, cellulosics and combinations thereof. The formulation according to claim 21, wherein the biodegradable polymer comprises materials selected from the group consisting of polylactic acids, polyglycolic acids, polylactic glycolic acids, polycaprolactone, triglycerides, polyethylene glycols, polyorthoesters, polyanhydrides, polyesters, cellulosics and combinations thereof. The formulation of claim 21, wherein the ophthalmic active agent in the microspheres is substantially between about 0.001 wt% and about 50 wt%. The formulation according to claim 21, wherein the microspheres have diameters substantially between about 1 pm and about 2,500 pm. A formulation according to claim 22, wherein the biodegradable polymers comprise materials selected from the group consisting of polylactic acids, polyglycolic acids, polylactic glycolic acids, polycaprolactone, triglycerides, polyethylene glycols, polyorthoesters, polyanhydrides, polyesters, cellulosics and combinations thereof. The formulation of claim 22, wherein the ophthalmically active agent in the microcapsules is substantially between about 0.001 wt% and about 50 wt%. A formulation according to claim 22, wherein the microcapsules have a diameter substantially between about 1 pm and about 2,500 pm. A formulation according to claim 22, wherein the microcapsules have a coating comprising from about 0.003% by volume to about 50% by volume. A formulation according to claim 22, wherein the microcapsules are constituted such that when introduced into a living organism they release the ophthalmically active agent at a substantially zero orderly rate, and where the release of the ophthalmic active agent at a substantially zero order rate. extends over a period of time of at least about two weeks.