WO2024146964A1

WO2024146964A1 - Method of preparing microparticles, pharmaceutical polymeric compositions, active ingredient delivery medical device and implant

Info

Publication number: WO2024146964A1
Application number: PCT/EP2024/050246
Authority: WO
Inventors: Roland Bodmeier; Chenghao Zhang
Original assignee: Roland Bodmeier; Chenghao Zhang
Priority date: 2023-01-08
Filing date: 2024-01-06
Publication date: 2024-07-11

Abstract

The invention relates to microparticles containing nanosized active ingredient and/or nanosized excipient particles embedded in a polymer matrix for a continuing active ingredient release; pharmaceutical polymeric compositions useful as a controlled release delivery system comprise a) a nanosized active ingredient, b) a polymer, c) a pharmaceutically acceptable organic solvent, and d) optionally one or more nanosized excipients; an implantable coated medical device, comprising a substrate and a coating disposed on the substrate, wherein the coating comprises at least one polymer and at least one nanosized active ingredient and optionally, one or more nanosized excipients; implants comprising a rod shaped polymeric matrix with an elongated body and two ends, said matrix having nanosized solid particles of active ingredient and/or excipient dispersed throughout the polymeric matrix. The present invention also relates to methods of manufacturing the microparticles, pharmaceutical polymeric compositions, implantable coated medical devices, and implants, and methods of use thereof.

Description

METHOD OF PREPARING MICROPARTICLES, PHARMACEUTICAL POLYMERIC COMPOSITIONS, ACTIVE INGREDIENT DELIVERY MEDICAL DEVICE AND IMPLANT

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U. S. provisional patent application, Ser. No. 63/437,697, Ser. No. 63/437,699, Ser. No. 63/437,738, and Ser. No. 63/437,740, filed on Jan. 08, 2023. Priority to the provisional patent application is expressly claimed, and the disclosure of the provisional application is hereby incorporated herein by reference in its entirety and for all purposes.

FIELD OF THE INVENTION

The invention relates to the composition and manufacture of microparticles containing solid particles of a nanosized active ingredient and/or nanosized excipient for extended release of the active ingredient; to the composition and manufacture of pharmaceutical polymeric composition containing a nanosized active ingredient, a polymer, a pharmaceutically acceptable organic solvent, and optionally one or more nanosized excipients for the extended and uniform release of active ingredient; to the manufacture and composition of an implantable coated medical device, comprising a substrate and a coating disposed on the substrate, wherein the coating comprises at least one polymer and at least one nanosized active ingredient and optionally, one or more nanosized excipients for the extended and uniform release of active ingredient; to rod shaped implants for delivering an active ingredient over a prolonged or extended time period.

BACKGROUND OF THE INVENTION

The extended release of an active ingredient is desirable for the treatment of many different diseases, including cancers, cardiovascular diseases, vascular conditions, orthopedic disorders, dental disorders, wounds, autoimmune diseases, gastrointestinal disorders, and ocular diseases. Polymers as carrier materials for the controlled and extended delivery of active ingredients have been in use for decades. Biodegradable polymeric active ingredient delivery systems like microparticles, implants and coatings allow the delivery of active ingredients over weeks to months. The most popular biodegradable polymer for the preparation of these active ingredient delivery systems is PLGA (poly-lactide-co-glycolide).

In order to use microparticles as suitable delivery systems, it is important to design a formulation, which maximizes the therapeutic efficacy of an active ingredient, enhances patient compliance, and minimizes side effects. Polymeric microparticles can be manufactured by various methods including the solvent evaporation/extraction method, organic phase separation, spray-drying, and others. In these processes, the active ingredient is usually dissolved or dispersed in an organic polymer solution, which depends on the solubility of the active ingredient in the organic polymer solution. The physical state of the active ingredient (dissolved or dispersed) in the formulation can greatly affect its chemical stability, mechanical properties, and in vitro and in vivo release characteristics.

To obtain PLGA microparticles loaded with dispersed active ingredient, larger active ingredient particles in the µm size range are usually added to a PLGA solution to obtain a solid-in-oil dispersion. Subsequently, this active ingredient-PLGA dispersion/solution is emulsified, phase-separated, or spray-dried to obtain microparticles after precipitation of the polymer PLGA. To prepare PLGA microparticles loaded with dissolved active ingredient, active ingredient and PLGA are dissolved in a single solvent or co-solvent system first, followed by emulsification, phase separation, or spray-drying to prepare microparticles. The encapsulated active ingredient in the dried microparticles might be dissolved, dispersed, or a mixture of dissolved and dispersed in the solid PLGA matrix. However, the solid-state of dissolved active ingredient could be potentially unstable during storage. This unstable state may cause chemical degradation in the matrix during storage or even after in vivo administration. Moreover, uncontrolled recrystallization may occur during storage. Thus, the encapsulation of dispersed active ingredient is more desirable to ensure physicochemical stability during fabrication and storage.

In the case of dispersed active ingredient, micronized active ingredient can be prepared by conventional mechanical technologies such as jet and ball milling. Very fine particles (below 10 μm) can be produced, but preparing smaller particles in the nanometer range becomes difficult. Most active ingredients are supplied with a diameter greater than a few μm or even unmicronized. When encapsulating these active ingredient particles into microparticles, a heterogeneous distribution of large active ingredient crystals in the microparticle matrix happens, which in turn causes low active ingredient loading and high burst release. A pronounced burst is not desired since a high active ingredient plasma peak may lead to systemic toxicity and active ingredient loss in the burst phase is not available for later release.

Therefore, there is a need to improve storage stability, to increase encapsulation efficiency, to obtain a uniform particle distribution inside the matrix, and to achieve a continuous release. This surprisingly can be achieved with nanosized active ingredient and/or nanosized excipient encapsulated into microparticles.

Moreover, there is a significant need for extended release formulations to deliver active ingredients effectively over time with microparticles having a diameter of less than 5 μm. Since the diameter of micronized active ingredient particles is close to the diameter of microparticles, the encapsulation efficiency is low. Nanosized active ingredients can be efficiently encapsulated into these microparticles resulting in a high encapsulation efficiency.

Besides active ingredients, excipients can also be encapsulated into microparticles, for example to stabilize the active ingredient or to modify active ingredient release or to improve other properties of the microparticles (e.g., antisticking). Excipients can also exist in different physical states, such as in the dissolved state or the dispersed state. Nanosized excipients can also be of advantage to be uniformly distributed in the matrix.

Microparticles containing a nanosized active ingredient and/or nanosized excipient in accordance with the present invention solve/ improve the above-mentioned problems. Because nanosized active ingredient and/or excipient have high particle numbers and large surface area at the same amount, the resulting microparticles of the present invention can effectively improve stability, achieve continuous release, and even control PLGA matrix degradation/erosion/swelling behavior and the release of an active ingredient over a prolonged period. Hereinafter, the present invention is described in more detail.

To prepare nanosized active ingredients and/or nanosized excipients, normally, coarse particles are nanosized by aqueous wet milling with a water-soluble stabilizer to form aqueous nanosuspensions. Alternatively, nanosuspensions are prepared by nanoprecipitation. After nanosizing these particles, they are washed and dried. They are then redispersed as powders in the polymer solutions to be encapsulated into microparticles. This is a time- and energy-consuming process. Additionally, a small amount of residual stabilizer, which covers the large surface of nanosized active ingredients is introduced into the microparticle matrix; this may impact the release profile and even cause toxicity for injectable active ingredient delivery.

In this invention, active ingredients and/or excipients were directly wet milled in organic solvent to prepare nanosized active ingredient suspensions with or without a potential stabilizer (e.g., PLGA). Therefore, nanosized active ingredients were encapsulated directly into PLGA microparticles avoiding tedious milling, drying and redispersion procedures and potentially bioincompatible stabilizers.

In another approach, the polymer and the active ingredients are dissolved in a biocompatible organic solvent to provide a liquid composition. When the liquid composition is injected into the body, the solvent dissipates into the surrounding aqueous environment, and the polymer forms a solid or gel depot from which the active ingredient is released over a long period of time. Notwithstanding some success, those methods have not been entirely satisfactory for a large number of active ingredients that may be effectively delivered by such an approach.

It is well recognized in the art that active ingredient containing basic functional groups interacts with polymer to catalyze (or expedite) the degradation of the polymer and form conjugate with the polymer and/or its degradation products.

Since the controlled release delivery system is commonly fabricated through a step that involves dissolving/dispersing active ingredient into polymer solution in an organic solvent, the stabilization of all the components in the composition at this step represents a very significant formulation challenge. One common approach that has been used to overcome the challenge of manufacturing and storage stability of active ingredient and polymer in solution or suspension is to keep the active ingredient and the polymer solution in two separate containers and mix them just before use. However, because of the viscous nature of the polymer formulations, it is often difficult to mix the contents in two separated syringes. Therefore, there is a need to develop a pharmaceutical composition that will minimize or prevent the interaction/reaction between the active ingredient and the polymer in an organic solution by dispersing the active ingredient in the organic solution. There is a further need to develop a pharmaceutical composition that is stable with a satisfactory storage shelf life in a ready-to-use product configuration.

In the case of dispersed active ingredient, micronized active ingredient can be prepared by conventional mechanical technologies such as jet and ball milling. Very fine particles (below 10 μm) can be produced, but preparing smaller particles in the nanometer range becomes difficult. Active ingredients are normally supplied with a diameter greater than a few μm or even unmicronized. When adding these active ingredient particles into polymer solution, sedimentation of large active ingredient crystals happens during preparation, storage, and application, which in turn causes non-continuous active ingredient release.

Besides active ingredients, excipients can also be loaded into polymer solution, for example to stabilize the active ingredient or to modify active ingredient release or to improve other properties of the polymer solution. Excipients can also exist in different physical states, such as in the dissolved state or the dispersed state.

Therefore, there is a need to improve physical and chemical stability, to obtain a uniform particle distribution in the polymer solution, and to achieve a continuous release. This can be achieved by using nanosized active ingredients and/or nanosized excipients.

The pharmaceutical compositions containing nanosized active ingredients and/or nanosized excipients in accordance with the present invention solve/improve the above-mentioned problems. Because nanosized active ingredient and/or nanosized excipient have high particle numbers and large surface area at the same amount, the resulting pharmaceutical compositions of the present invention can effectively improve stability, achieve continuous release, and even control polymer matrix degradation/erosion/swelling behavior and the release of an active ingredient over a prolonged period. Hereinafter, the present invention is described in more detail.

To prepare nanosized active ingredients and/or nanosized excipients, normally, coarse particles are nanosized by aqueous wet milling with a water-soluble stabilizer to form aqueous nanosuspensions. Alternatively, nanosuspensions are prepared by nanoprecipitation. After nanosizing these particles, they are washed and dried. They are then redispersed as powders into polymer solution. This is a time- and energy-consuming process. Additionally, a small amount of residual stabilizer, which covers the large surface of nanosized active ingredients is introduced into the polymeric composition; this may impact the release profile and even cause toxicity for injectable active ingredient delivery.

In this invention, active ingredients and/or excipients are directly wet milled in a pharmaceutically acceptable organic solvent to prepare nanosized active ingredient suspensions with or without a stabilizer (e.g., PLGA (poly(lactide-co-glycolide)). Therefore, nanosized active ingredients were loaded directly into polymer solutions avoiding tedious milling, drying and redispersion procedures and potentially bioincompatible stabilizers.

There is a need for medical device technology that can efficiently, reproducibly and safely transfer an active ingredient delivery formulation from the surface of a medical device (a coating) onto/into a specific site in the body.

Implantable medical devices having thin polymeric coatings containing active ingredients that are released from the coating to provide a local therapeutic effect in the vicinity of the coated device have been shown to be valuable for the treatment of various medical conditions, in particular those conditions involving diseases of the cardiovascular system. For example, delivery of an active ingredient from the device surface can prevent cellular responses initiated by the presence of the implantable device. The active ingredient that is released from the coating can prevent conditions that would otherwise shorten the functional life of the device following implantation. Active ingredients released from the coating may also be directed at treating a diseased area of the body. For example, stents having a coating containing an active ingredient can provide localized release of the active ingredient at the site of administration. Local administration of active ingredients via polymeric coatings on stents has shown favorable results in reducing restenosis.

Polymeric coatings can be manufactured by various methods including dip coating, spray coating, and others. In these processes, the active ingredient is usually either dissolved or dispersed in an organic polymer solution, depending on the solubility of the active ingredient in the organic polymer solution. The physical state of the active ingredient (dissolved or dispersed) in the formulation can greatly affect its chemical stability, mechanical properties, and in vitro and in vivo release characteristics.

To obtain coatings loaded with dispersed active ingredient, larger active ingredient particles in the µm size range are usually added to a polymer solution to obtain a dispersion. Subsequently, this active ingredient-polymer dispersion/solution is coated. To prepare coatings loaded with dissolved active ingredient, active ingredient and polymer are dissolved in a single solvent or co-solvent system first, following a coating process. The encapsulated active ingredient in the dried coatings might be dissolved, dispersed, or a mixture of dissolved and dispersed in the solid PLGA matrix. However, solid-state of dissolved active ingredient could be potentially unstable during storage. This unstable state may cause chemical degradation in the matrix during storage or even after in vivo administration. Moreover, uncontrolled recrystallization may occur during storage. Thus, the encapsulation of dispersed active ingredient is more desirable to ensure physicochemical stability during fabrication and storage.

In the case of dispersed active ingredient, micronized active ingredient can be prepared by conventional mechanical technologies such as jet and ball milling. Very fine particles (below 10 μm) can be produced, but preparing smaller particles in the nanometer range becomes difficult. Most active ingredients are supplied with a diameter greater than a few μm or even unmicronized. When encapsulating these active ingredient particles into coatings, a heterogeneous distribution of large active ingredient crystals in the polymer matrix happens, which in turn causes high burst release and noncontinuous release. A pronounced burst is not desired since a high active ingredient plasma peak may lead to systemic toxicity and active ingredient loss in the burst phase is not available for later release. In addition, the coating films are usually very thin and larger active ingredient particles might result in less smooth film surfaces.

Moreover, there is a significant need for extended release coatings to deliver active ingredients effectively over time with coatings having a thickness of less than 5 μm. If the diameter of micronized active ingredient particles is close to the thickness of coatings, the larger particles cannot be efficiently encapsulated. Nanosized active ingredients can be efficiently encapsulated into these coatings resulting in a homogenous distribution.

Besides active ingredients, excipients can also be encapsulated into coatings, for example to stabilize the active ingredient or to modify active ingredient release or to improve other properties of the coatings. Excipients can also exist in different physical states, such as in the dissolved state or the dispersed state. Nanosized excipients can also be of advantage to be uniformly distributed in the matrix.

Coatings containing a nanosized active ingredient and/or nanosized excipient in accordance with the present invention solve/improve the above-mentioned problems. Because nanosized active ingredient and/or nanosized excipient have high particle numbers and large surface area at the same amount, the resulting coatings of the present invention can effectively improve stability, achieve continuous release, and even control polymer matrix degradation/erosion/swelling behavior and the release of an active ingredient over a prolonged period. Hereinafter, the present invention is described in more detail.

In this invention, active ingredients and/or excipients were directly wet milled in organic solvent to prepare nanosized active ingredient suspensions with or without a potential stabilizer (e.g., PLGA). Therefore, nanosized active ingredients were encapsulated directly into polymer coatings avoiding tedious milling, drying and redispersion procedures and potentially bioincompatible stabilizers.

The use of implant is becoming important with regard to the administration of active ingredients to patients. In general, these implants containing the active ingredients to be administered are implanted in the patient and the active ingredients are administered to the patient over a prolonged period of time in a predetermined and controlled quantity. By use of implants, it is not necessary to repeatedly administer the active ingredient daily to the patient. In this way, patients can be simultaneously implanted with an implant containing an active ingredient so that implant releases the active ingredient over a prolonged period of time.

It has been difficult to construct implants with a continuous of release or high content uniformity. A continuous release occurs when a controlled amount of the active ingredient is released daily to the patient. In most cases, implants provide an initial burst of active ingredient release which slowly tapers off with time, which may due to poor content uniformity. Such variable rates of release are extremely disadvantageous, since they do not provide the proper controlled dosing to be administered to the patient. Therefore, it has been long desired to provide an active ingredient delivery implant for implantation, which can release the active ingredient with minimum initial burst and at a controlled rate which does not significantly vary with time.

Depending on the solubility of the active ingredient in the polymer, the active ingredient can exist in different physical states in the formulation, such as in the dissolved state or the dispersed state. The physical state of the active ingredient (dissolved or dispersed) in the formulation can greatly affect its chemical stability, mechanical properties, and in vitro and in vivo release characteristics.

To obtain implants loaded with dispersed active ingredient, larger active ingredient particles in the µm size range are dispersed into a polymer solution to obtain a dispersion. Subsequently, solvent in this active ingredient-polymer dispersion/solution is removed and implant loaded with micronized active ingredient is prepared by extrusion methods, compression methods, molding methods, injection molding methods, heat press methods, and the like. Alternatively larger active ingredient particles in the µm size range are mixed with polymer first and implants loaded with micronized active ingredient is prepared by extrusion methods, compression methods, molding methods, injection molding methods, heat press methods, and the like. To prepare PLGA (poly-lactide-co-glycolide) implants loaded with dissolved active ingredient, active ingredient and PLGA are dissolved in a single solvent or co-solvent system first, following extrusion methods, compression methods, molding methods, injection molding methods, heat press methods, and the like to prepare implants loaded with dissolved active ingredient. Alternatively active ingredient particles are mixed with polymer first and implants loaded with dissolved active ingredient is prepared by extrusion methods, compression methods, molding methods, injection molding methods, heat press methods, and the like with a manufacturing temperature above the melting temperature of the active ingredient. The encapsulated active ingredient in the final implants might be dissolved, dispersed, or a mixture of dissolved and dispersed. However, the solid-state of the dissolved active ingredient could be potentially unstable during storage. This unstable state may cause chemical degradation in the matrix during storage or even after in vivo administration. Moreover, uncontrolled recrystallization may occur during storage. Thus, the encapsulation of dispersed active ingredient is more suitable to ensure physicochemical stability during fabrication and storage.

Most active ingredients are supplied with a diameter greater than a few μm or even unmicronized. When loading these active ingredient particles into implants, a heterogeneous distribution of large active ingredient crystals in the implant matrix happens, which in turn could cause high burst release and non-continuous release. A pronounced burst is not desired since a high active ingredient plasma peak may lead to systemic toxicity and active ingredient loss in the burst phase is not available for later release.

Therefore, there is a need to obtain a uniform particle distribution inside the matrix, and a more continuous release. This can be achieved with nanosized active ingredient and/or nanosized excipient loaded into implants when compared to the commonly used dispersed drug with larger particle sizes in the µm size range.

Implants containing a nanosized active ingredient and/or nanosized excipient in accordance with the present invention solve/improve the above-mentioned problems. Because nanosized active ingredient and/or excipient have high particle numbers and large surface area at the same amount, the resulting implants of the present invention can effectively improve stability, achieve continuous release, and even control PLGA matrix degradation/erosion/swelling behavior and the release of an active ingredient over a prolonged period. Hereinafter, the present invention is described in more detail.

In this invention, active ingredients and/or excipients were directly wet milled in organic solvent to prepare nanosized active ingredient suspensions with or without a potential stabilizer (e.g., PLGA). Therefore, nanosized active ingredients were loaded directly into PLGA implants avoiding tedious milling, drying and redispersion procedures and potentially bioincompatible stabilizers.

Applicants have discovered and herein disclose and claim compositions and methods of manufacturing for: microparticles containing solid particles of a nanosized active ingredient and/or nanosized excipient embedded in a polymer matrix, which results in higher encapsulation efficiencies, and in releasing an active ingredient effective amount of the active ingredient more uniformly over an extended period of time; a polymeric composition comprises a) a nanosized active ingredient; b) a polymer; c) a pharmaceutically acceptable organic solvent; and d) optionally one or more nanosized excipients, which results in better stability, and in releasing an active ingredient effective amount of the active ingredient more uniformly over an extended period of time; an implantable coated medical device, comprising: a substrate and a coating disposed on the substrate, wherein the coating comprises at least one polymer and at least one nanosized active ingredient and optionally, one or more nanosized excipients, which results in releasing an active ingredient effective amount of the active ingredient more uniformly over an extended period of time; implants containing solid particles of a nanosized active ingredient and/or nanosized excipient embedded in a polymer matrix, which results in releasing an active ingredient effective amount of the active ingredient more uniformly over an extended period of time.

SUMMARY OF THE INVENTION

One objective of the present invention is to provide microparticles containing a nanosized active ingredient and/or nanosized excipient, and a polymer matrix.

The nanosized active ingredient and/or nanosized excipient have an average particle size (according to photon correlation spectroscopy (PCS)) of less than 1 µm, preferably in the range from 10 to 800 nm.

The particle diameter of the individual microparticles may be 0.1 to 5,000 μm, preferably 1 to 200 μm, most preferably 1 to 50 μm.

Another objective of the present invention is to provide a simple and efficient method of preparing a microparticle containing a nanosized active ingredient and/or nanosized excipient dispersed throughout the polymer matrix.

In accordance with embodiments of the present invention, a method of preparing a microparticle containing nanosized solid particles of active ingredient and/or excipient, which comprises the following steps of:

(a) active ingredient and/or excipient were dispersed into the organic medium;

(b) wet milling this mixture to reduce the particle size of the active ingredient and/or excipient to an average particle size of less than 1µm;

(c) further processing this organic nanosuspension into microparticles by solvent extraction/evaporation method, phase separation method, spray drying method, or other methods.

Another objective of the present invention provides an injectable polymeric composition for forming an economical, practical, and efficient controlled release delivery system for active ingredients. The present invention also provides a method of manufacturing and a method of use thereof. According to the present invention, the active ingredient delivery system is produced easily and delivered conveniently to a subject such as a mammal or human. The compositions deliver therapeutic amount of active ingredients over a desired, extended period of time, preferably from several weeks to one year.

The compositions in accordance with the present invention comprise a) a nanosized active ingredient; b) a polymer; c) a pharmaceutically acceptable organic solvent. According to the invention, the pharmaceutical composition may optionally include nanosized excipients to achieve optimal delivery of the active ingredient. The pharmaceutical composition may be a viscous or non-viscous liquid, gel or semisolid so that it may be injected using a syringe. The pharmaceutical composition may be pre-filled into one syringe to form a product in a ready-to-use configuration.

The present invention further provides methods of making and using such compositions.

In accordance with embodiments of the present invention, a method of preparing a polymeric composition comprises a) a nanosized active ingredient; b) a polymer; c) a pharmaceutically acceptable organic solvent; and d) optionally one or more nanosized excipients., which comprises the following steps of:

(a) adding an active ingredient and/or an excipient into a pharmaceutically acceptable organic solvent;

(b) wet milling this mixture to reduce the particle size of the active ingredient and/or excipient to an average particle size of less than 1 µm;

(c) further processing this organic nanosuspension into polymeric composition by the combination of this organic nanosuspension with other components.

The present invention further provides a kit for administration of the injectable composition to form a consistent and controlled release depot system, the kit comprises: a polymer dissolved in a pharmaceutically acceptable solvent; a nanosized active ingredient dispersed in the polymeric vehicle; and optionally one or more nanosized excipients dispersed in the polymeric vehicle. The uniform mixture of all the components is packaged into one container. Preferably, the container is a syringe.

The present invention further provides a method for in situ forming implant capable of functioning as a controlled release delivery system of the nanosized active ingredient in a subject. The nanosized active ingredient is preferably incorporated into the in situ formed implant, and subsequently released into the surrounding tissue fluids and to the pertinent body tissue or organ. The method comprises: administration of the injectable compositions of the present invention to an implant site by any suitable method for applying a liquid, for example, employing a syringe, needle, cannula, catheter, pressure applicator, and the like.

Another objective of the present invention is to provide a coating to at least a portion of a medical device comprising a balloon, a stent, and the like, thereby forming on the medical device a coating comprising at least one polymer and at least one nanosized active ingredient and optionally, one or more nanosized excipients.

Another objective of the present invention is to provide a simple and efficient method of preparing an implantable coated medical device containing a coating comprising at least one polymer and at least one nanosized active ingredient and optionally, one or more nanosized excipients.

In accordance with embodiments of the present invention, a method of preparing an implantable coated medical device containing a coating comprising at least one polymer and at least one nanosized active ingredient and optionally, one or more nanosized excipients, which comprises the following steps of:

(a) active ingredient and/or excipient were added into the organic medium;

(c) further coating this organic nanosuspension to the substrate by dip coating or spray coating.

Another objective of the present invention is to provide compositions for implants formulated to provide a controlled, sustained active ingredient release. The release rate is modulated by loading nanosized solid particles of active ingredient and/or excipient.

The implants may have a regular and preferably cylindrical pellet (e.g., rod) shape. The dimensions of the implants are 10 to 3,000 μm in diameter, 0.050 to 100 mm in length, and 0.05 to 10,000 mg in total weight. The implants may be of any geometry including fibers, sheets, films, spheres, circular discs, plaques, and the like.

Another objective of the present invention is to provide a simple and efficient method of preparing an implant containing nanosized solid particles of active ingredient and/or excipient active ingredient dispersed throughout the polymer matrix.

In accordance with embodiments of the present invention, a method of preparing an implant containing nanosized solid particles of active ingredient and/or excipient, which comprises the following steps of:

(a) active ingredient and/or excipient were added into the organic medium;

(c) further processing this organic nanosuspension into implants employing various techniques may include extrusion methods, compression methods, pellet pressing, solvent casting, wet granulation, print technology, hot embossing, soft lithography molding methods, injection molding methods, heat press methods, and combinations thereof.

Brief Description of the Drawings

is a graph showing the in vitro active ingredient release behavior of dexamethasone from 0 - 5 μm PLGA 503H microparticles containing nanosized dexamethasone.

is a graph showing the in vitro active ingredient release behavior of dexamethasone from 10 % dexamethasone PLGA 503H microparticles and porous PLGA 503H microparticles using nanosized sucrose as porogen.

is a graph showing the in vitro active ingredient release from 20 - 50 μm dexamethasone PLGA 502H microparticles containing nanosized dexamethasone and micronized dexamethasone.

is a graph showing the macroscopic pictures of (a) micronized dexamethasone injectable polymeric compositions and (b) nanosized dexamethasone injectable polymeric compositions stored at room temperature for 3 months.

is a graph showing the in vitro active ingredient release from PLGA 502 injectable polymeric compositions loaded with nanosized and micronized dexamethasone sodium phosphate.

is a graph showing the in vitro active ingredient release from PLGA 503H implant containing nanosized dexamethasone and nanosized sucrose.

DETAILED DESCRIPTION

The present invention is explained in greater detail below. This description is not intended to be a detailed catalog of all the different ways in which the invention may be implemented, or all the features that may be added to the instant invention. For example, features illustrated with respect to one embodiment may be incorporated into other embodiments, and features illustrated with respect to a particular embodiment may be deleted from that embodiment. In addition, numerous variations and additions to the various embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention. Hence, the following specification is intended to illustrate some particular embodiments of the invention, and not to exhaustively specify all permutations, combinations, and variations thereof.

Definitions

As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

The singular forms “a” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an organic medium” includes a single organic medium as well as a mixture of two or more different organic mediums, reference to “an excipient” includes a single excipient as well as two or more different excipients in combination, and the like.

The term “nanosized” used herein means that these particles have an average particle size (according to photon correlation spectroscopy (PCS)) of less than 1 μm, preferably in the range of 10 to 800 nm.

The term “microparticle” used herein may have an irregular and preferably essentially spherical shape and comprises different structures like matrix or reservoir structure, microspheres and microcapsules. The particle diameter of the individual microparticles may be 0.1 to 5,000 μm, preferably 1 to 200 μm, most preferably 1 to 50 μm. The particle size may be controlled, for example, by adjusting the process parameters and by selecting solvents, polymers and the molecular weight of the polymers employed. Depending on the preparation process and the composition, the microparticles may be compact and essentially pore-free particles, or porous particles.

The term “solid particles” as used herein includes active ingredient and/or excipient particles.

The term “average particle size (also referred to as Z-average)” used herein is defined as an average diameter based on the intensity of light scattered by the particle, which was obtained by measuring the particle size distribution through a wet process with a dynamic light scattering particle size distribution analyzer.

The term “controlled release delivery”, as defined herein, is intended to refer to the delivery of an active ingredient in vivo over a desired, extended period of time following administration, preferably from at least several weeks to one year.

The term “biodegradable” refers to a material that gradually decomposes, dissolves, hydrolyzes and/or erodes in situ. Generally, the “biodegradable polymers” herein are polymers that are hydrolyzable, and/or bioerode in situ primarily through hydrolysis and/or enzymolysis.

The term “biodegradable polymer” as used herein is meant to include any biocompatible and/or biodegradable synthetic and natural polymers that can be used in vivo, provided the polymer is at least hardens, precipates or solidifies in aqueous medium or body fluid. When the polymer solution in a water miscible or dispersible organic solvent is mixed with an aqueous solution, the polymer will precipitate to form a solid or gelled matrix as the organic solvent dissipates.

The term “pharmaceutically acceptable organic solvent” is meant to include any biocompatible organic solvents that are miscible or dispersible in aqueous or body fluid. The term “dispersible” means that the solvent partially soluble or miscible in water. The suitable organic solvent should be able to diffuse into body fluid so that the liquid composition coagulates or solidifies. Examples of pharmaceutically acceptable organic solvent include, but not limited to, N-methyl-2-pyrrolidone, methoxypolyethylene glycol, alkoxypolyethylene glycol, polyethylene glycol esters, glycofurol, glycerol formal, methyl acetate, ethanol, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, benzyl benzoate, ethyl benzoate, triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, triethyl phosphate, diethyl phthalate, diethyl tartrate, ethyl lactate, propylene carbonate, ethylene carbonate, butyrolactone, and 1-dodecylazacyclo-heptan-2-one, and combinations thereof. The pharmaceutically acceptable organic solvent may contain a small amount of water. It may be advantageous to combine different solvents to obtain a desirable delivery system. The solvents of low and high water miscibility may be combined to improve the solubility of the polymer, modify the viscosity of the composition, optimize the diffusion rate, and reduce the initial burst release.

As used herein, the term “administered to a subject” is intended to refer to dispensing, delivering or applying a composition (e.g., pharmaceutical formulation) to a subject by any suitable route for delivery of the composition to the desired location in the subject. Preferably, the composition of the present invention can be administered by injection and/or implantation subcutaneously, intramuscularly, intraperitoneally, intradermally, or orally to provide the desired dosage based on the known parameters for treatment of the various medical conditions with the active ingredient.

As used herein, the term “implantable polymeric matrices” is intended to include particles, films, pellets, cylinders, discs, microcapsules, microspheres, nanospheres, microparticles, wafers, and other known polymeric configurations used for active ingredient delivery.

The term “implantable” comprises insertable, implacable, embeddable and the like, and refers to any medical device placed partially or wholly inside a living, for example a human or animal body, usually by surgery.

The term “substrate” as used herein, refers to any surface upon which it is desirable to deposit a coating. Biomedical implants are of particular interest to the present invention; however, the present invention is not intended to be restricted to this class of substrates. Examples of substrates that can be coated using the methods of the invention include surgery devices or medical devices, e.g., a catheter, a balloon, a cutting balloon, a wire guide, a cannula, tooling, an orthopedic device, a structural implant, stent, stent-graft, graft, vena cava filter, a heart valve, cerebrospinal fluid shunts, pacemaker electrodes, axius coronary shunts, endocardial leads, an artificial heart, and the like.

The term “biomedical implant” as used herein refers to any implant for insertion into the body of a human or animal subject, including but not limited to stents (e.g., coronary stents, vascular stents including peripheral stents and graft stents, urinary tract stents, urethral prostatic stents, rectal stent, oesophageal stent, biliary stent, pancreatic stent), electrodes, catheters, leads, implantable pacemaker, cardioverter or defibrillator housings, joints, screws, rods, ophthalmic implants, femoral pins, bone plates, grafts, anastomotic devices, perivascular wraps, sutures, staples, shunts for hydrocephalus, dialysis grafts, colostomy bag attachment devices, ear drainage tubes, leads for pace makers and implantable cardioverters and defibrillators, vertebral disks, bone pins, suture anchors, hemostatic barriers, clamps, screws, plates, clips, vascular implants, tissue adhesives and sealants, tissue scaffolds, various types of dressings (e.g., wound dressings), bone substitutes, intraluminal devices, vascular supports, etc.

The term “intervention site” as used herein refers to the location in the body where the coated device is intended to be delivered. The intervention site can be any substance in the medium surrounding the device, e.g., tissue, cartilage, body fluid, etc. The intervention site can be the same as the treatment site, i.e., the substance to which the coating is delivered is the same tissue that requires treatment. Alternatively, the intervention site can be separate from the treatment site, requiring subsequent diffusion or transport of the pharmaceutical or other agent away from the intervention site.

The term “coating” as used herein refers to a material covering a surface or forming an overlying part or segment.

While coatings defined by uniform thickness and/or regular shape are contemplated herein, several embodiments described herein relate to coatings having varying thickness and/or irregular shape.

The term “dip coating” and “spray coating” as used herein refer to methods of coating substrates that have been described at length in the art. These processes can be used for coating medical devices with active ingredients. Spray coating, described in, e.g., U.S. Pat. No. 7,419,696, “Medical devices for delivering a therapeutic agent and method of preparation” and elsewhere herein, can involve spraying or airbrushing a thin layer of solubilized coating or dry powder coating onto a substrate. Dip coating involves, e.g., dipping a substrate in a liquid, and then removing and drying it. Dip coating is described in, e.g., U.S. Pat. No. 5,837,313 “Drug release stent coating process,” incorporated herein by reference in its entirety.

The term “implant” used herein may have a regular and preferably cylindrical pellet (e.g., rod) shape. The implants may be of any geometry including fibers, sheets, films, spheres, circular discs, plaques, and the like. The upper limit for the implant size will be determined by factors such as toleration for the implant, size limitations on insertion, ease of handling, etc. Where sheets or films are employed, the sheets or films will be in the range of at least about 0.5 mm x 0.5 mm, usually about 3 - 10 mm x 5-10 mm with a thickness of about 0.25 - 1.0 mm for ease of handling. Where fibers are employed, the diameter of the fiber will generally be in the range of 0.05 to 3 mm. The length of the fiber will generally be in the range of 0.5 - 10 mm. Spheres will be in the range of 2 μm to 3 mm in diameter.

The term “balloon” as used herein refers to a flexible sac that can be inflated within a natural or non-natural body lumen or cavity, or used to prepare a cavity, or used to enlarge an existing cavity. The balloon can be used transiently to dilate a lumen or cavity and thereafter may be deflated and/or removed from the subject during the medical procedure or thereafter.

The term “copolymer” as used herein refers to a polymer being composed of two or more different monomers. A copolymer may also and/or alternatively refer to random, block, graft, copolymers known to those of skill in the art.

The terms “biocompatible” and “biocompatibility” when used herein are art-recognized and mean that the referent is neither itself toxic to a host (e.g., an animal or human), nor degrades (if it degrades) at a rate that produces byproducts (e.g., monomeric or oligomeric subunits or other byproducts) at toxic concentrations, causes inflammation or irritation, or induces an immune reaction in the host.

Suitable active ingredients for the present invention may include drugs, nutrients, agricultural agents, and other chemicals used in chemical applications. Suitable drugs are described below. Suitable nutrients include amino acids, fatty acids, vitamins, minerals, choline, and the like. Suitable agriculture agents include fertilizer, insecticides, pesticides, and the like.

Suitable drugs for the present invention may include among others peptide or protein drugs, therapeutic nucleic acids, antiinflammatory drugs, anticancer agents, antiviral agents, sex hormones, antibiotics, antimicrobial agents, antifungal agents, antineoplastic agents, immunosuppressive agents, and compounds. Representative examples thereof may include peptide or protein drugs such as bone morphogenic proteins, insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic hormone, follicle stimulating hormone, chorionic gonadotropin, gonadotropin releasing hormone, bovine Somatotropin, porcine somatotropin, oxytocin, vasopressin, GRF, Somatostatin, lypressin, pancreozymin, luteinizing hormone, LHRH, LHRH agonists and antagonists, leuprolide, interferons such as interferon alpha-2a, interferon alpha-2b, and consensus interferon, interleukins, growth hormones such as human growth hormone and its derivatives such as methionine-human growth hormone and des-phenylalanine human growth hormone, parathyroid hormone, bovine growth hormone and porcine growth hormone, fertility inhibitors such as the prostaglandins, fertility promoters, growth factors such as epidermal growth factors (EGF), platelet-derived growth factors (PDGF), fibroblast growth factors (FGF), transforming growth factors-O. (TGF-C.), transforming growth factors-B (TGF-3) erythropoietin (EPO), insulin-like growth factor-I (IGF-I), insulin-like growth factor-fi (IGF-B), interleukin-ω, interleukin-2, interleukin-6, interleukin-8, tumor necrosis factor-α (TNF-α), tumor necrosis factor-β (TNF-β), Interferon-α (INF-α), Interferon-β (INF-β), Interferon-γ (INF-γ), Interferon-ω (INF-ω), colony stimulating factors (CGF), vascular cell growth factor (VEGF), thrombopoietin (TPO), stromal cell-derived factors (SDF), placenta growth factor(PlGF), hepatocyte growth factor (HGF), granulocyte macrophage colony stimulating factor (GM-CSF), glial-derived neurotropin factor (GDNF), granulocyte colony stimulating factor (G-CSF), ciliary neurotropic factor (CNTF), bone growth factor, transforming growth factor, bone morphogeneic proteins (BMP), coagulation factors, human pancreas hormone releasing factor, botulinum toxin, analogs and derivatives of these compounds, and pharmaceutically acceptable salts of these compounds, or their analogs or derivatives; therapeutic nucleic acids such as siRNA, miRNA, antisense oilgonucleotides, antisense RNA and the like; antiinflammatory drugs such as dexamethasone, dexamethasone sodium phosphate, hydrocortisone, indomethacin, ibuprofen, ketoprofen, piroxicam, flurbiprofen, diclofenac and the like: anticancer agents such as paclitaxel, doxorubicin, carboplatin, camptothecin, 5-fluorouracil, cisplatin, cytosine arabinoside, methotrexate and the like; antiviral agents such as acyclovir, ganciclovir, cidofivir, entecavir and the like; sex hormones such as testosterone, estrogen, progesterone, estradiol and the like; antibiotics such as tetracycline, minocycline, doxycycline, ofloxacin, levofloxacin, ciprofloxacin, clarithromycin, erythromycin, cefaclor, cefotaxime, imipenem, penicillin, gentamicin, streptomycin, vancomycin and the like; antifungal agents such asketoconazole, itraconazole, fluconazole, amphotericin-B, griseofulvin and the like; antineoplastic agents include adriamycin, cyclophosphamide, actinomycin, bleomycin, duanorubicin, doxorubicin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), methyl-CCNU, cisplatin, etoposide, interferons, camptothecin and derivatives thereof, phenesterine, taxol and derivatives thereof, taxotere and derivatives thereof, vinblastine, Vincristine, tamoxifen, etoposide, piposulfan, cyclophosphamide, and flutamide, and derivatives thereof; immunosuppressive agents include cyclosporine, azathioprine, tacrolimus, and derivatives thereof.

The term “excipient” means any useful ingredient in the formulation besides the active ingredients and polymer matrix used to form the microparticle vehicle. For example, excipients are useful for increasing the encapsulation efficiency, modulating the drug release, stabilizing the active ingredient, and positively affecting the manufacturing process or properties of the microparticles, polymeric compositions, coatings and implants.

Excipients that can be used in the present invention include but are not limited to release modifiers, pH modifiers, preservatives, antioxidant agents, reducing agents, anticaking agents, dispersed polymers and the like. Suitable release modifiers include sugars such as glucose, fructose, galactose, sucrose, lactose, trehalose, maltose, and the like, and salts such as sodium chloride, magnesium chloride, calcium chloride, and the like, and ice, dry ice, and the like. Suitable pH modifiers include, without limitation, alkali and alkaline earth hydroxide, carbonates, phosphates, bicarbonates, citrates, borates, acetates, succinates, and the like, such as magnesium hydroxide, phosphate, citrate, borate, acetate, bicarbonate, carbonate and the like. Suitable preservatives include sodium bisulfite, sodium bisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, parabens, methylparaben, polyvinyl alcohol, benzyl alcohol, phenyl ethanol and the like and mixtures thereof. Suitable antioxidant agents include ascorbate, alphatocopherol, mannitol, reduced glutathione, various carotenoids, cysteine, uric acid, taurine, tyrosine, superoxide dismutase, lutein, Zeaxanthin, cryptoxanthin, astazanthin, lycopene, N-acetyl-cysteine, carnosine, gamma-glutamylcysteine, quercitin, lactoferrin, dihydrolipoic acid, citrate, Ginkgo Biloba extract, tea catechins, bilberry extract, vitamins E or esters of vitamin E, retinyl palmitate, and derivatives thereof. Suitable reducing agents can be cysteine or methionine. Suitable anticaking agents include tricalcium phosphate, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, calcium phosphate, sodium silicate, silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, polydimethylsiloxane and the like. Suitable dispersed polymers are insoluble in organic medium and include water-soluble polymers, among others cellulose derivatives like HPMC, PVP, acrylate derivatives, polysaccharides like chitosan or sodium alginate, and water-insoluble polymers like ion-exchange resin and the like.

The excipient may leach out partially or completely during the manufacturing process resulting in a porous structure.

Suitable polymers can be biodegradable polymers including, but not limited to poly(lactide-co-glycolide) (PLGA), PLGA-PEG, polylactide, polyglycolide, polycaprolactone, orother polyesters, poly(orthoesters), poly(aminoesters), polyanhydrides, polyorganophosphazenes, polydioxanone, polyacetal, polyketal, polycarbonate, polyphosphoester, polyester, polybutylene terephthalate, polyorthocarbonate, polysuccinate, poly(malic acid), poly(amino acid), polyvinylpyrrolidone, poly (ethylene glycol), polyhydroxycellulose, polysaccharide, chitin, chitosan, hyaluronic acid, or any combination thereof. Other biodegradable polymers known to those skilled in the art may also be applied and selected.

In another embodiment, the suitable polymer is non-degradable. For example, the polymer of the active ingredient-release material may be poly(ethylene-co-vinyl acetate) (PEVA), cellulose derivatives like ethyl cellulose or cellulose acetate, poly(butyl acrylate), poly(urethanes), silicone resins, nylon, ammonium polyacrylate, acrylamide copolymers, acrylate/acryl amide copolymers, acrylate/ammonium acrylate copolymers, acrylate/alkyl acrylate copolymers, acrylate/carbamate copolymers, acrylate/dimethylamino ethyl methacrylate copolymers, ammonium acrylate copolymers, styrene acrylate copolymers, vinyl acetate/acrylate copolymers, aminomethyl propanol/acrylate/dimethylamino ethyl methacrylate copolymers, or any combination thereof. Other non-degradable polymers known to those skilled in the art may also be applied and selected.

The polymers may be linear, branched, and optionally crosslinked. According to the invention, star polymers may also be used, in which polymer chains are bonded to the functional groups (for example hydroxyl, amino and/or carboxyl groups) of a core monomer, such as saccharides. Such polymers are known and are partly commercial.

Poly(lactide), and copolymers of lactide and glycolide (PLGA), including poly(D, L-lactide-co-glycolide) and poly(L-lactide-co-glycolide) are preferably used in the present invention. The polymers (or thermoplastic polyesters) have various monomer ratios of lactide to glycolide and average molecular weights. Many suitable PLGAs are available commercially, and the PLGAs of specific compositions can be readily prepared according to the prior art. The selection of the type, molecular weight, and amount of biodegradable polymer present in the compositions to achieve desired properties of the controlled release implant can be determined by simple experimentations.

The amount of active ingredient in the microparticles may be 0.1 wt% to 80.0 wt% by weight, preferably 1 wt% to 50 wt%, most preferably 1 wt% to 30 wt%, based on the weight of the microparticles.

The amount of excipient in the microparticles may be 0.01 wt% to 80 wt% by weight, preferably 0.01 wt% to 50 wt%, most preferably 0.01 wt% to 30 wt%, based on the weight of the microparticles.

The amount of polymer may be, for example, 10 wt% to 99.99 wt% by weight, preferably 50 wt% to 95 wt% by weight, based on the composition of the microparticles.

The method of preparing microparticles containing nanosized solid particles of active ingredient and/or excipient according to the present invention comprises:

(a) active ingredient and/or excipient were added and dispersed into the organic medium with or without milling stabilizers;

(b) then wet milling this mixture by mechanical force to obtain nanosized active ingredient and/or excipient with an average particle size (according to photon correlation spectroscopy (PCS)) of less than 1µm;

In step (a), the type of organic medium used as milling medium may vary according to the type of the active ingredient and/or excipient used and may include organic solvents, such as methylene chloride, chloroform, carbon tetrachloride, acetone, methanol, ethanol, ethyl acetate, dioxane, tetrahydrofuran, hexafluoroisopropanol, triacetin, dimethylsulfoxide, N-methyl-2-pyrrolidone, propylene glycol, polyethylene glycol, glycerol, natural and synthetic oils, and the like. It is desirable to use methylene chloride, ethyl acetate, chloroform, and acetone. The organic medium may contain a small amount of water.

The active ingredient and excipient can be wet milled together, or can be wet milled separately.

The organic medium may contain no or a small amount of milling stabilizer of about 0.01 wt % to about 3 wt % based on the weight of the organic medium, or a larger amount of milling stabilizer of about 3 wt % to about 150 wt % based on the weight of the organic medium.

Milling stabilizers are soluble in organic medium and can avoid the aggregation of active ingredient and/or excipient particles: a polymer stabilizer is PLGA and PLGA derivatives.

In step (b), for the preparation of nanosized active ingredient and/or excipient particles, wet milling methods can be employed as described in the literature and include size reduction methods such as cavitation milling, ball milling, medium milling, or high-pressure homogenization.

Particle size analysis was performed using photon correlation spectroscopy (PCS, Zetasizer Nano-ZS, Malvern Instruments, United Kingdom). The PCS yields an average particle diameter (Z-average) and a polydispersity index (PDI). The samples were diluted with the corresponding solvent to reach an appropriate concentration for the measurement, as indicated by the PCS instrument. Three measurement runs were conducted, each consisting of 10 single measurements, and then a mean was calculated. The PDI is a measure of the width of the size distribution. The nanosuspensions produced had mean PCS diameters in the range of approximately 100 nm to 800 nm. The PDI for relatively narrow distributions is between 0.0 - 0.3, and values greater than 0.5 and higher indicate a broad particle size distribution.

In step (c), the organic nanosuspension obtained in step (b) can be directly used as polymer suspension to prepare microparticles. Alternatively, polymer suspension can be prepared by adding extra organic medium to the resulting organic nanosuspension to dilute the nanosized active ingredient and/or nanosized excipient to a targeted concentration, and/or dissolving extra polymer to a specific polymer concentration, and/or dissolving or dispersing an extra active ingredient in this organic nanosuspension. The polymer suspension should be homogeneously mixed.

In step (c), the detailed process to transfer the polymer suspension into microparticles can be either c1, c2, c3 or c4 as described below.

(c1) solvent extraction/evaporation method: the above polymer dispersion was dispersed by known dispersion means into a stabilizer solution and then organic medium was removed by extraction and evaporation. In the present invention, the external phase consists of an aqueous solution with a surfactant, preferably polyvinyl alcohol (PVA). Examples of other surfactants that optionally can be employed include one or more anionic surfactants (such as sodium oleate, sodium stearate or sodium lauryl sulfate), non-ionic surfactants (such as Poloxamers, Tweens), polyvinylpyrrolidone, carboxymethyl cellulose sodium, and gelatin, used independently or in combination. PVA, preferably has an average molecular weight from about 10, 000 to about 150, 000 Da and 85 - 89 % degree of hydrolysis. Selected PVA grades that are used in the present invention include PVA 4 - 88 (Mw 25, 000 - 30, 000). The amount of the surfactant added to the aqueous phase is preferably up to 5.0 % (w/w, based on the weight of the aqueous phase) relative to mass of the aqueous solution. More preferably the amount of surfactant (optimally the PVA amount) is from about 0.1 to about 2.5 %.

(c2) organic phase separation method: the above polymer dispersion was phase separated through the addition of a solvent, in which the polymer is insoluble, at high agitation speeds, and then organic medium was removed from the microparticles by extraction, evaporation, lyophilization, and the like. Examples of solvents that cause phase separation include silicone oil, vegetable oil, low molecular weight methacrylic polymers hexane, petroleum ether, and the like. In the present invention, solvent may include a stabilizer, for example Tween 80.

(c3) spray drying method: the above polymer dispersion was sprayed into an airflow, and then organic solvent was removed by evaporation, lyophilization, and the like. The spray process is by atomizing polymer suspension through a nozzle.

(c4) film casting method. the above polymer dispersion was cast into a mold. Then the films containing active ingredient and/or excipient can be prepared after the organic medium was removed by extraction, evaporation, or lyophilization. The microparticles containing nanosized solid particles have a particle size in the range of 0.1 μm to about 5,000 μm can be obtained by cutting or cryogenic grinding of films.

The above prepared microparticles containing a nanosized active ingredient and/or nanosized excipient can be easily collected, dried, and then stored in a particle form. And the above-prepared microparticles can directly be stored for further usage.

The present invention has several advantages: it is possible to adjust the particle size of active ingredient and/or excipient in the microparticles to the nanosized range, making a homogeneous distribution of these particles in the microparticles and a more continuous active ingredient release possible compared to microparticles prepared with dispersed but not nano-sized solid particles; nanosized solid particles are still in the dispersed state and it is more stable than dissolved active ingredient and/or excipient during storage. Nanosized particles can result in microparticles (smaller than 5 μm) with high active ingredient loading and high encapsulation efficiency compared to larger dispersed active ingredient particles. A simplified successive fabrication method was found to fabricate microparticles loaded with nanosized active ingredient and/or nanosized excipient avoiding complicated manufacturing processes and unwanted water-soluble milling stabilizers.

The microparticles are analyzed with respect to particle size, encapsulation efficiency, and in vitro release.

Particle sizes of microparticles were determined using an optical microscope (Axioskop, Carl Zeiss Jena GmbH, Jena, Germany). Diameters of at least 300 particles were measured using an image processing program (Image J 1.53a, National Institutes of Health, Maryland, USA).

Approximately 10 mg microparticles were dissolved in 10 mL acetonitrile. 0.2 mL of this solution was added to 0.8 mL water to precipitate PLGA, followed by vortexing for 1 min and then by centrifugation (15000 rpm and 30 min; Heraeus Biofuge Stratus Centrifuge, Thermo Fisher Scientific GmbH, Darmstadt, Germany). The supernatant was analyzed by UV. The actual active ingredient loading was determined using a UV spectrophotometer (Agilent HP 8453, Agilent Technologies Inc., Santa Clara, USA) at 242 nm for dexamethasone. The encapsulation efficiency (%) was calculated as (actual active ingredient loading/theoretical active ingredient loading) * 100%.

The microparticles were released in 50 mL of 10 mM phosphate buffer (pH 7.4 and incubated at 37 °C in a horizontal shaker (80 rpm, New Brunswick Scientific, Edison, USA). At pre-determined time points, release medium was removed and replaced. Sink conditions were maintained throughout. The samples were passed through 0.45 μm syringe filters and the concentration of active ingredient in each sample was determined spectrophotometrically (Agilent HP 8453, Agilent Technologies Inc., Santa Clara, US) at 242 nm.

The present invention also provides an injectable polymeric composition for forming an economical, practical, and efficient controlled release delivery system for active ingredients. The present invention also provides a method of manufacturing and a method of use thereof.

The injectable polymeric compositions of the present invention comprise a) a nanosized active ingredient; b) a polymer; c) a pharmaceutically acceptable organic solvent. According to the invention, the pharmaceutical composition may optionally include one or more nanosized excipients to achieve optimal delivery of the active ingredient. The injectable polymeric composition of the present invention may be a viscous or non-viscous liquid, gel or semisolid. The injectable polymeric composition may be pre-filled into one syringe to form a product kit in a ready-to-use configuration.

The controlled release delivery system of the present invention may be formed as an implantable polymeric matrix in vitro, or alternatively, it may be formed in situ in the forms of a gel or a solid implant. When administered to a subject, the controlled release of the active ingredient can be sustained for a desired period of time depending upon the composition of the implant. With the selection of the polymer and other components, the duration of the sustained release of the active ingredient can be controlled over a period of time from several weeks to one year.

The injectable polymeric compositions of the present invention may contain active ingredient in a range of 0.01 to 80% by weight. In general, the optimal active ingredient loading depends upon the period of release desired and the potency of the active ingredient. Obviously, for active ingredient of low potency and longer period of release, higher levels of incorporation may be required.

The injectable polymeric compositions of the present invention may contain polymer in a range of 1% to 70% by weight. The viscosity of the injectable compositions of the invention depends on the molecular weight of the polymer and organic solvent used. Typically, when the same solvent is used, the higher the molecular weight and the concentration of the polymer, the higher the viscosity. More preferably concentration of the polymer in the compositions is between 20 to 60% by weight.

The amount of excipient in the polymeric composition may be 0.1 wt% to 80 wt%, preferably 0.1 wt% to 30 wt%, based on the weight of the polymeric composition.

In one aspect the present invention provides an injectable polymeric composition for forming an economical, practical, and efficient controlled release delivery system for active ingredients comprises a) a nanosized active ingredient; b) a polymer; c) a pharmaceutically acceptable organic solvent; and d) optionally one or more nanosized excipients to achieve optimal delivery of the active ingredient. Preferably, the injectable composition is packaged into a kit comprising a step to fill the composition into a syringe in a ready-to-use configuration. The composition in the kit is stable for a reasonable period of time, preferably at least one year, to have a suitable storage shelf-life under controlled storage conditions. The composition is preferably injected into a subject to form in situ an implant, from which the active ingredient is released in a therapeutic effective amount over a desired, extended period of time.

The injectable polymeric composition of the present invention can be prepared by appropriately combining a nanosized active ingredient, a polymer, a pharmaceutically acceptable organic solvent, and an optional nanosized excipient. The composition for administration may conveniently be presented in dosage unit form and may be prepared by any of the methods known in the art of pharmacy.

The method of preparing the composition of the present invention according to the present invention comprises:

In step (a), the type of pharmaceutically acceptable organic solvents used as milling medium may vary according to the type of the active ingredient and/or excipient used and may include solvents, such as N-methyl-2-pyrrolidone, methoxypolyethylene glycol, alkoxypolyethylene glycol, polyethylene glycol esters, glycofurol, glycerol formal, methyl acetate, ethanol, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, benzyl benzoate, ethyl benzoate, triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, triethyl phosphate, diethyl phthalate, diethyl tartrate, ethyl lactate, propylene carbonate, ethylene carbonate, butyrolactone, and 1-dodecylazacyclo-heptan-2-one, and combinations thereof. The organic medium may contain a small amount of water.

Milling stabilizers are soluble in pharmaceutically acceptable organic solvents and can avoid the aggregation of active ingredient and/or excipient particles: a polymer stabilizer is PLGA or PLGA derivatives.

In step (c), the organic nanosuspension obtained in step (b) can be directly used as polymeric composition. Alternatively, polymeric composition can be prepared by adding extra organic medium to the resulting organic nanosuspension to dilute the nanosized active ingredient and/or nanosized excipient to a targeted concentration, and/or dissolving extra polymer to a specific polymer concentration, and/or dissolving or dispersing an extra active ingredient in this organic nanosuspension. The polymeric composition should be homogeneously mixed.

In step (c), preferably, the nanosized active ingredients and optionally one or more nanosized excipients are formed first, and then combined with the polymer dissolved in an organic solvent and/or an extra active ingredient dissolved or dispersed in an organic solvent.

In step (c), the components are thoroughly mixed using any proper means to obtain a uniform nanosuspension.

Such injectable injectable polymeric compositions are physicochemically stable during preparation, storage, and subsequent administration to a subject and form consistent and controlled release implants upon administration to a tissue site.

The level of incorporation of the active ingredient and polymer in the injectable polymeric composition of the invention will naturally vary, depending upon the potency of the active ingredient component, the period of time over which delivery of the agent is desired, the solubility of the polymer in the solvent, and the volume and viscosity of the injectable composition which is desired to administer.

In certain preferred embodiments of the present invention, the injectable polymeric composition for forming an economical, practical, and efficient controlled release delivery system for active ingredients contains about 0.1% to 40% of the active ingredient and about 10% to 70% of a poly(lactide-co-glycolide) polymer. The composition further contains about 30% to 70% of a pharmaceutically acceptable organic solvent.

In a preferred embodiment of the present invention, the injectable polymeric composition further contains about 0.1% to 40% of a suitable excipient including include release modifiers, pH modifiers, preservatives, antioxidant agents, reducing agents, and the like as defined above.

The amount of the injectable composition administered will typically depend upon the desired properties of the controlled release implant. For example, the amount of the injectable composition can influence the length of time in which the active ingredient is released from the controlled release implant.

The present invention further provides a method for in situ forming an implant in a subject comprising administering to a subject an effective amount of the injectable composition comprising: a) a nanosized active ingredient; b) a polymer; c) a pharmaceutically acceptable organic solvent; and d) optionally one or more nanosized excipients to achieve optimal delivery of the active ingredient; and allowing the solvent to dissipate into the surrounding aqueous environment to transform the liquid composition into a depot by phase separation. The depot may be a viscous gel, a semi-solid, or a solid matrix. The depot may also be porous or non-porous. The depot serves as the delivery system from which the active ingredient is released over a desired and extended period of time.

In another preferred embodiment, the injectable polymeric composition of the present invention may be administered to fit into a body cavity to form a depot system. Such cavities include the cavities created after a surgery or natural body cavity such as vagina, anus, and the like.

In another aspect, the present invention provides a liquid polymeric composition for forming an economical, practical, and efficient controlled release delivery system for active ingredients comprises: a) a nanosized active ingredient; b) a polymer; c) an organic solvent; and d) optionally one or more nanosized excipients to achieve optimal delivery of the active ingredient. The liquid polymeric composition may be fabricated into implantable polymeric matrices.

Thus, according to the present invention, these implantable polymeric matrices can be administered to a subject where sustained controlled release delivery of an active ingredient is desired. Preferably, the implantable polymeric matrices of the invention can be administered by injection and/or implantation subcutaneously, intramuscularly, intraperitoneally, or intradermally to provide the desired dosage based on the known parameters for treatment of the various medical conditions with the active ingredient.

All books, articles and patents referenced herein are fully incorporated by reference.

It was surprisingly discovered that injectable polymeric compositions comprising nanosized active ingredients exhibit higher physical stability and better release profiles than micronized active ingredients and higher chemical stability than those in the form of dissolved state. Such beneficial nanosized active ingredients may be formed through nanosizing solid particles.

The final polymeric compositions are analyzed with respect to in vitro release.

The polymeric compositions were released in 50 mL of 10 mM phosphate buffer (pH 7.4 and incubated at 37 °C in a horizontal shaker (80 rpm, New Brunswick Scientific, Edison, USA). At pre-determined time points, release medium was removed and replaced. Sink conditions were maintained throughout. The samples were passed through 0.45 μm syringe filters and the concentration of active ingredient in each sample was determined spectrophotometrically (Agilent HP 8453, Agilent Technologies Inc., Santa Clara, US) at 260 nm.

The biomedical implants may be formed from any suitable material, including but not limited to polymers (including stable or inert polymers, organic polymers, organic-inorganic copolymers, inorganic polymers, and biodegradable polymers), metals, metal alloys, inorganic materials such as silicon, and composites thereof, including layered structures with a core of one material and one or more coatings of a different material.

Subjects into which biomedical implants of the invention may be applied or inserted include both human subjects as well as animal subjects (including but not limited to pig, rabbit, mouse, dog, cat, horse, monkey, etc.) for veterinary purposes and/or medical research.

As used herein, a biological implant may include a medical device that is not permanently implanted. A biological implant in some embodiments may comprise a device which is used in a subject on a transient basis. For non-limiting example, the biomedical implant may be a balloon, which is used transiently to dilate a lumen and thereafter may be deflated and/or removed from the subject during the medical procedure or thereafter.

Suitable active ingredients for the coatings of medical device may include drugs, nutrients, agricultural agents, and other chemicals used in chemical applications. Suitable drugs are described below. Suitable nutrients include amino acids, fatty acids, vitamins, minerals, choline, and the like. Suitable agriculture agents include fertilizer, insecticides, pesticides, and the like.

Suitable drugs that are especially useful in the coatings of medical device are for example water-insoluble drugs, such as dexamethasone, paclitaxel, rapamycin, daunorubicin, doxorubicin, lapachone, vitamin D2 and D3 and analogues and derivatives thereof.

Other drugs that may be useful in the coatings of medical device include, without limitation, glucocorticoids (e.g., dexamethasone, betamethasone), hirudin, angiopeptin, aspirin, growth factors, antisense agents, anti-cancer agents, anti-proliferative agents, oligonucleotides, and, more generally, anti-platelet agents, anti-coagulant agents, anti-mitotic agents, antioxidants, anti-metabolite agents, anti-chemotactic, and anti-inflammatory agents.

Photosensitizing agents for photodynamic or radiation therapy, including various porphyrin compounds such as porfimer, for example, are also useful as drugs in the coatings of medical device.

Drugs for use in the coatings of medical device also include everolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan, ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, treosulfan, temozolomide, thiotepa, daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate, fludarabine, fludarabine-5’-dihydrogenphosphate, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, aldesleukin, tretinoin, asparaginase, pegaspargase, anastrozole, exemestane, letrozole, formestane, aminoglutethimide, adriamycin, azithromycin, spiramycin, cepharantin, smc proliferation inhibitor-2w, epothilone A and B, mitoxantrone, azathioprine, mycophenolatmofetil, c-myc-antisense, b-myc-antisense, betulinic acid, camptothecin, lapachol, beta.-lapachone, podophyllotoxin, betulin, podophyllic acid 2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b, lenograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab, daclizumab, selectin (cytokine antagonist), CETP inhibitor, cadherines, cytokinin inhibitors, COX-2 inhibitor, NFkB, angiopeptin, ciprofloxacin, camptothecin, fluroblastin, monoclonal antibodies, which inhibit the muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one, scopoletin, colchicine, NO donors such as pentaerythritol tetranitrate and syndnoeimines, S-nitrosoderivatives, tamoxifen, staurosporine, beta.-estradiol, a-estradiol, estriol, estrone, ethinylestradiol, fosfestrol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids, which are applied in the therapy of cancer, verapamil, tyrosine kinase inhibitors (tyrphostines), cyclosporine A, 6-a-hydroxy-paclitaxel, baccatin, taxotere and other macrocyclic oligomers of carbon suboxide (MCS) and derivatives thereof, mofebutazone, acemetacin, diclofenac, lonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol, celecoxib, .beta.-sitosterin, ademetionine, myrtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, ellipticine, D-24851 (Calbiochem), colcemid, cytochalasin A-E, indanocine, nocodazole, S 100 protein, bacitracin, vitronectin receptor antagonists, azelastine, guanidyl cyclase stimulator tissue inhibitor of metal proteinase-1 and -2, free nucleic acids, nucleic acids incorporated into virus transmitters, DNA and RNA fragments, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotides, VEGF inhibitors, IGF-1, active agents from the group of antibiotics such as cefadroxil, cefazolin, cefaclor, cefotaxim, tobramycin, gentamycin, penicillins such as dicloxacillin, oxacillin, sulfonamides, metronidazol, antithrombotics such as argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, enoxaparin, desulphated and N-reacetylated heparin, tissue plasminogen activator, GpIIb/IIIa platelet membrane receptor, factor Xa inhibitor antibody, heparin, hirudin, r-hirudin, PPACK, protamin, prourokinase, streptokinase, warfarin, urokinase, vasodilators such as dipyramidole, trapidil, nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin, ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan, thiol protease inhibitors, prostacyclin, vapiprost, interferon a, .beta and y, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators such as p65 NF-kB or Bcl-xL antisense oligonucleotides, halofuginone, nifedipine, tranilast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, Boswellic acids and derivatives thereof, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone, mutamycin, procainamide, retinoic acid, quinidine, disopyramide, flecainide, propafenone, sotalol, amidorone, natural and synthetically obtained steroids such as bryophyllin A, inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, non-steroidal substances (NSAIDS) such as fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviral agents such as acyclovir, ganciclovir and zidovudine, antimycotics such as clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprozoal agents such as chloroquine, mefloquine, quinine, moreover natural terpenoids such as hippocaesculin, barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostistachin, ovatodiolids, 4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and B7, tubeimoside, bruceanol A, B and C, bruceantinoside C, yadanziosides N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, C and D, ursolic acid, hyptatic acid A, zeorin, iso-iridogermanal, maytenfoliol, effusantin A, excisanin A and B, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13,18-dehydro-6-a-senecioyloxychaparrin, taxamairin A and B, regenilol, triptolide, moreover cymarin, apocymarin, aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburin chloride, cictoxin, sinococuline, bombrestatin A and B, cudraisoflavone A, curcumin, dihydronitidine, nitidine chloride, 12-beta-hydroxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic acid, helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol, glycoside 1a, podophyllotoxin, justicidin A and B, larreatin, malloterin, mallotochromanol, isobutyrylmallotochromanol, maquiroside A, marchantin A, maytansine, lycoridicin, margetine, pancratistatin, liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-All, bisparthenolidine, periplocoside A, ghalakinoside, ursolic acid, deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, sphatheliachromen, stizophyllin, mansonine, strebloside, akagerine, dihydrousambarensine, hydroxyusambarine, strychnopentamine, strychnophylline, usambarine, usambarensine, berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, umbelliferon, afromoson, acetylvismione B, desacetylvismione A, and vismione A and B.

A combination of active ingredients can also be used in the coatings of medical device. Some of the combinations have additive effects because they have a different mechanism, such as paclitaxel and rapamycin, paclitaxel and active vitamin D, paclitaxel and lapachone, rapamycin and active vitamin D, rapamycin and lapachone. Because of the additive effects, the dose of the active ingredient can be reduced as well. These combinations may reduce complications from using a high dose of the active ingredient.

The amount of active ingredient in the coatings may be 0.1 wt% to 99.9 wt% by weight, preferably 1 wt% to 70 wt%, most preferably 1 wt% to 30 wt%, based on the weight of the coatings.

The amount of excipient in the coatings may be 0.1 wt% to 99.9 wt% by weight, preferably 1 wt% to 70 wt%, most preferably 1 wt% to 30 wt%, based on the weight of the coatings.

The amount of polymer may be, for example, 0. 1 wt% to 99.9 wt% by weight, preferably 10 wt% to 95 wt% by weight, based on the composition of the coatings.

Coatings are prepared having a targeted coating thickness in the range from 0.1 to 1000 μm, preferably 0.5 to 100 μm.

The method of preparing coatings containing at least one polymer and at least one nanosized active ingredient and optionally, one or more nanosized excipients according to the present invention comprises:

(a) active ingredient and/or excipient were added into an organic medium with or without milling stabilizers;

(b) wet milling this mixture to reduce the particle size of the active ingredient and/or excipient to an average particle size (according to photon correlation spectroscopy (PCS)) of less than 1 µm;

(c) further coating this organic nanosuspension to the medical device by dip coating or spray coating.

In step (a), the type of organic medium used as milling medium may vary according to the type of the active ingredient and/or excipient used and may include organic solvents, such as methylene chloride, chloroform, carbon tetrachloride, acetone, methanol, ethanol, ethyl acetate, dioxane, tetrahydrofuran, hexafluoroisopropanol, triacetin, dimethylsulfoxide, N-methyl-2-pyrrolidone, propylene glycol, polyethylene glycol, glycerol, natural and synthetic oils, and the like; It is desirable to use methylene chloride, ethyl acetate, chloroform, and acetone. The organic medium may contain a small amount of water.

The organic medium may contain no or a milling stabilizer.

Milling stabilizers are soluble in organic medium and can avoid the aggregation of active ingredient and/or excipient particles: a polymer stabilizer is PLGA or PLGA derivatives.

In step (c), the organic nanosuspension obtained in step (b) can be directly used as polymer suspension to prepare coatings. Alternatively, polymer suspension can be prepared by adding extra organic medium to the resulting organic nanosuspension to dilute the nanosized active ingredient and/or nanosized excipient to a targeted concentration, and/or dissolving extra polymer to a specific polymer concentration, and/or dissolving or dispersing an extra active ingredient in this organic nanosuspension. The polymer suspension should be homogeneously mixed.

The size and form of the implant can be used to control the rate of release, period of treatment, and active ingredient concentration at the site of implantation. Larger implants will deliver a proportionately larger dose, but depending on the surface to mass ratio, may have a slower release rate. The particular size and geometry of an implant will be chosen to best suit the site of implantation. The chambers, e.g. anterior chamber, posterior chamber and vitreous chamber, are able to accommodate relatively large implants of varying geometries, having diameters of 1 to 3 mm. A sheet or circular disk is preferable for implantation in the suprachoroidal space. The restricted space for intraretinal implantation requires relatively small implants, having diameters from 0.2 to 1 mm.

In some situations, mixtures of implants may be utilized employing the same or different pharmacological agents. In this way, a cocktail of release profiles, giving a biphasic or triphasic release with a single administration is achieved, where the pattern of release may be greatly varied.

The implants may be monolithic, i.e. having the active agent or agents homogenously distributed through the polymeric matrix.

The amount of active ingredient in the implants may be 0.1 wt% to 80 wt% by weight, preferably 1 wt% to 50 wt%, most preferably 1 wt% to 30 wt%, based on the weight of the implants.

The amount of excipient in the implants may be 0.1 wt% to 80 wt% by weight, preferably 0.1 wt% to 50 wt%, most preferably 0.1 wt% to 30 wt%, based on the weight of the implants.

The amount of polymer may be, for example, 10 wt% to 99.9 wt% by weight, preferably 50 wt% to 95 wt% by weight, based on the composition of the implants.

The implants of the present invention may be sterilized by gamma or by electron–beam radiation and inserted or placed into the body by a variety of methods and devices, including needle-equipped delivery devices capable of ejecting the implant into body. An effective dose of radiation for sterilization may be about 20-30 kGy.

The method of preparing implants containing a nanosized active ingredient and/or nanosized excipient according to the present invention comprises:

(a) active ingredient and/or excipient were added and dispersed into the organic medium with or without milling stabilizers or polymers;

(c) further processing this organic nanosuspension into implants.

The organic medium may contain a milling stabilizer.

In step (c), the organic nanosuspension obtained in step (b) can be directly used as polymer suspension to prepare implants. Alternatively, polymer suspension can be prepared by adding extra organic medium to the resulting organic nanosuspension to dilute the nanosized active ingredient and/or nanosized excipient to a targeted concentration, and/or dissolving extra polymer to a specific polymer concentration, and/or dissolving or dispersing an extra active ingredient in this organic nanosuspension. The polymer suspension should be homogeneously mixed.

In step (c), implants can be manufactured by removing the organic medium and forming implants at the same time using techniques including solvent casting, wet granulation, print technology, phase separation methods, interfacial methods, extrusion methods, molding methods, injection molding methods, heat press methods, and combinations thereof.

In step (c) alternatively, the organic medium was removed by evaporation, extraction, or lyophilization first, and the formed polymer matrix was transferred into implants by various techniques including extrusion methods (for example, hot melt extrusion), compression methods, pellet pressing, hot embossing, soft lithography molding methods, heat press methods and combinations thereof.

Various techniques may be employed to make implants. Useful techniques include extrusion methods (for example, hot melt extrusion), compression methods, pellet pressing, solvent casting, wet granulation, print technology, hot embossing, soft lithography molding methods, injection molding methods, heat press methods, and combinations thereof. As previously discussed, an implant according to this disclosure may be configured as a rod, wafer, sheet, film, or compressed tablet.

In one embodiment, the method for making the implants involves solvent casting. Solvent selection will depend on the polymers and active ingredients chosen. For the implants described herein, dichloromethane (DCM) is an appropriate solvent. Polymer suspension cast into a mold of an appropriate shape. Once cast, the solvent used to dissolve the polymers is evaporated at a temperature between 20 °C and 30 °C, preferably about 25 °C. The polymer can be dried at room temperature or even in a vacuum. For example, the cast polymers containing nanosized active ingredients and/or nanosized excipients can be dried by evaporation in a vacuum. Based on casting mold, once the cast polymers are dried, they can be processed into an implant of particular shape.

Alternatively, once the cast polymers are dried, they can be processed into an implantusing any method known in the art to do so. In an example embodiment, the dried casted polymer can be cut and/or ground into small pieces or particles and extruded into rounded or squared rod shaped structures at a temperature between 50 °C and 180 °C.

Preferably the implant of this disclosure is a solid rod-shaped implant formed by an extrusion process (an extruded rod) and is sized for placement in body. Choice of technique, and manipulation of technique parameters employed to produce the implants can influence the release rates of the active ingredient. Extrusion methods may result in implants with a progressively homogenous dispersion of the nanosized active ingredients and excipients within a continuous polymer matrix, as the production temperature is increased. The use of extrusion methods may allow for large-scale manufacture of implants and result in implants with a homogeneous dispersion of the active ingredient within the polymer matrix

The temperature used during an extrusion method should be high enough to soften the polymer but low enough to avoid substantial loss of activity. In this regard, extrusion methods may use temperatures of 50 °C to 130 °C, but more preferably the extrusion temperature is between 50 °C and 80 °C, or even more preferably from 55 °C to 70 °C.

Different extrusion methods may yield implants with different characteristics, including but not limited to the homogeneity of the dispersion of the active agent within the polymer matrix. For example, using a piston extruder, a single screw extruder, and a twin screw extruder may produce implants with progressively more homogeneous dispersion of the active agent. When using one extrusion method, extrusion parameters such as temperature, feeding rate, circulation time, pull rate (if any), extrusion speed, die geometry, and die surface finish will affect the release profile of the implants produced.

In one variation of producing implants by a piston or twin-screw extrusion method, the dried casted polymer heated to an appropriate temperature to soften the polymer matrix or transform it to a semi-molten state for a time period of 0 to 1 hour. The implants are then extruded at a temperature of between 50 °C and 170 °C. In some screw extrusion methods, the dried casted polymer is added to a single or twin screw extruder preset at a temperature of 50 °C to 170 °C, and directly extruded as a filament or rod with minimal residence time in the extruder.

The extruded filament is then cut to a length suitable for placement in the body. The total weight of the implant will of course be proportional to the length and diameter of the implant, and implants may be cut to a desired target weight and therefore dosage of the active ingredients.

Compression methods may also result in an implant with discrete particles. Compression methods may use pressures of 50-150 psi, more preferably 70-80 psi, even more preferably about 76 psi, and use temperatures of 0 °C to 170 ºC, more preferably about 25 °C.

Another popular method for making implants involves wet granulation. In this method, wet granulating the PLGA (or a mixture of PLGA and active ingredient and/or excipient) with the organic nanosuspension obtained in step (b), then drying the wet granulated mixture, and finally processing the dried granulated mixture to implants with extrusion methods or compression methods as described above.

Wet granulation may take place under standard conditions and using standard equipment, well known to those skilled in the art (e.g., high shear granulators, fluidized bed granulators). Standard mixing equipment may be employed to ensure homogeneous mixing. The wet granules may thereafter be dried using standard techniques to acceptable residual solvent levels, such as under a current of dry air or, preferably, under vacuum at an elevated temperature.

The dried granules may be alternatively ground prior to extrusion. This separate grinding step could be performed by milling the dried granules in a ball mill, though any apparatus may be employed which results in the granules being broken down into particles of a smaller size.

The present invention has several advantages: it is possible to adjust the particle size of active ingredient and/or excipient in the implants to the nanosized range, making a homogeneous distribution of these particles in the implants and a more continuous active ingredient release possible compared to implants prepared with dispersed but not nano-sized solid particles; nanosized solid particles are still in the dispersed state and it is more stable than dissolved active ingredient and/or excipient during storage.

The final implants are analyzed with respect to in vitro release.

The implants were released in 50 mL of 10 mM phosphate buffer (pH 7.4 and incubated at 37 °C in a horizontal shaker (80 rpm, New Brunswick Scientific, Edison, USA). At pre-determined time points, release medium was removed and replaced. Sink conditions were maintained throughout. The samples were passed through 0.45 μm syringe filters and the concentration of active ingredient in each sample was determined spectrophotometrically (Agilent HP 8453, Agilent Technologies Inc., Santa Clara, US) at 242 nm.

EXAMPLES

The following examples are provided to further elucidate the advantages and features of the present disclosure but are not intended to limit the scope of the disclosure. The examples are for illustrative purposes only. Pharmaceutical grade ingredients were used in preparing the formulations described below. The quantitative composition of these examples is presented in Table 1 below.

Example A1

Nanosized dexamethasone without stabilizer was produced by adding 15.0 g milling beads, 250.0 mg micronized dexamethasone, 5.0 g dichloromethane, and a magnetic stirrer in a 15 mL glass bottle with a polypropylene cap. The sealed glass bottle was put in an ice bath and the milling speed was set to 1500 rpm. Samples were milled for 4 h. The suspensions were separated from the beads by filtration through a 10 μm stainless sieve.

This method can reduce the particle size of dexamethasone from 7 μm to less than 2 μm (Table 1).

Example A2

Nanosized dexamethasone was produced according to the same method as described in Example A1 except that 50.0 mg PLGA 502H (acid end groups, 0.16 - 0.24 dl/g inherent viscosity; Evonik, Darmstadt, Germany) was added as the milling stabilizers instead of without any milling stabilizers.

This method can reduce the particle size of dexamethasone from 7 μm to around 1 μm (Table 1).

Example A3

Nanosized dexamethasone was produced according to the same method as described in Example A1 except that 1000.0 mg PLGA 502H (acid end groups, 0.16 - 0.24 dl/g inherent viscosity; Evonik, Darmstadt, Germany) was added as the milling stabilizers instead of without any milling stabilizers.

This method can reduce the particle size of dexamethasone from 7 μm to less than 1 μm (Table 1).

Example A4

Nanosized dexamethasone was produced according to the same method as described in Example A1 except that 50.0 mg poloxamer 188 (BASF SE, Ludwigshafen, Germany) was added as the milling stabilizers instead of without any milling stabilizers.

Example A5

Nanosized dexamethasone sodium phosphate was produced according to the same method as described in Example A2 except that the active ingredient changed from dexamethasone to dexamethasone sodium phosphate. The dexamethasone sodium phosphate particle size is listed in Table 1.

Example A6

Dual centrifugation was used to nanosize bovine serum albumin (BSA. After weighing 10.0 g milling beads, 0.5 g BSA, 50.0 mg PLGA 502H (acid end groups, 0.16 - 0.24 dl/g inherent viscosity; Evonik, Darmstadt, Germany), and 10.0 g dichloromethane were added to a 15 mL Twist-Top-Vial, wet bead milling was performed using a ZentriMix 380 R (0 °C, 1500 rpm, and 2 h; Andreas Hettich GmbH & Co. KG, Tuttlingen, Germany). The suspensions were separated from the beads by filtration through a 10 μm stainless sieve. The BSA particle size is listed in Table 1.

Example A7

Nanosized leuprolide was produced according to the same method as described in Example A6 except for changing the active ingredient from BSA to leuprolide. The leuprolide particle size is listed in Table 1.

Table 1 Particle size and polydispersity index of various active ingredients.

Active ingredients	Initial particle size, D50, μm	Milling stabilizers	Particle size, z-average, nm	Polydispersity index
Dexamethasone	7	-	1135	0.33
Dexamethasone	7	50 mg PLGA 502H	271	0.16
Dexamethasone	7	1000 mg PLGA 502H	311	0.18
Dexamethasone	7	50 mg Poloxamer 188	295	0.20
Dexamethasone sodium phosphate	6	50 mg PLGA 502H	207	0.20
BSA	35	50 mg PLGA 502H	768	0.21
leuprolide	30	50 mg PLGA 502H	197	0.19

Example A8

Nanosized sucrose was produced by adding 15.0 g milling beads, 250.0 mg sucrose, 5.0 g dichloromethane, and a magnetic stirrer in a 15 mL glass bottle with a polypropylene cap. The sealed glass bottle was put in an ice bath and the milling speed was set to 1500 rpm. Samples were milled for 8 h. The suspensions were separated from the beads by filtration through a 10 μm stainless sieve. Around 400 nm particles with a low polydispersity index were obtained for sucrose by organic wet bead milling (Table 2).

Table 2 Particle size and polydispersity index of nanosized excipients.

Excipients	Initial particle size, D50, μm	Particle size, z-average, nm	Polydispersity index
Sucrose	20	374	0.12
Mg(OH)₂	40	445	0.17

Example A9

Dual centrifugation was used to nanosize Mg(OH)₂. After weighing 10.0 g milling beads, 0.5 g Mg(OH)₂, 50.0 mg PLGA 502H (acid end groups, 0.16 - 0.24 dl/g inherent viscosity; Evonik, Darmstadt, Germany), and 10.0 g dichloromethane were added to a 15 mL Twist-Top-Vial, wet bead milling was performed using a ZentriMix 380 R (0 °C, 1500 rpm, and 2 h; Andreas Hettich GmbH & Co. KG, Tuttlingen, Germany). The suspensions were separated from the beads by filtration through a 10 μm stainless sieve.

This method can effectively reduce the particle size of Mg(OH)₂ from 10 – 50 μm to less than 1 μm (Table 2).

Example A10

Dual centrifugation was used to nanosizing dexamethasone. After weighing 10.0 g milling beads, 0.5 g micronized dexamethasone, and 10.0 g triacetin were added to a 15 mL Twist-Top-Vial, wet bead milling was performed using a ZentriMix 380 R (0 °C, 1500 rpm and 2 h; Andreas Hettich GmbH & Co. KG, Tuttlingen, Germany). The suspensions were separated from the beads by filtration through a 10 μm stainless sieve. 7 μm dexamethasone can be nanosized to 372 nm particles with a low polydispersity index by organic wet bead milling (Table 3).

Example A11

Nanosized bovine serμm albμmin (BSA) was produced according to the same method as described in Example A10 except that the active ingredient changed from dexamethasone to BSA. The BSA particle size is listed in Table 3.

Example A12

Nanosized leuprolide was produced according to the same method as described in Example A10 except that the active ingredient changed from dexamethasone to leuprolide. The leuprolide particle size is listed in Table 3.

Example A13

Nanosized dexamethasone sodium phosphate was produced according to the same method as described in Example A10 except that the active ingredient changed from dexamethasone to dexamethasone sodium phosphate and the milling medium changed from triacetin to N-methyl-2-pyrrolidone. The dexamethasone sodium phosphate particle size is listed in Table 3.

Table 3 Particle size and polydispersity index of various active ingredients.

Active ingredients	Initial particle size, D50, μm	Particle size, z-average， nm	Polydispersity index
Dexamethasone	7	372	0.17
BSA	35	368	0.20
leuprolide	30	180	0.11
Dexamethasone sodium phosphate	6	294	0.24

Example A14

Dual centrifugation was used to nanosizing sucrose. After weighing 10.0 g milling beads, 0.5 g micronized sucrose, and 10.0 g triacetin were added to a 15 mL Twist-Top-Vial, wet bead milling were performed using a ZentriMix 380 R (0 °C, 1500 rpm and 2 h; Andreas Hettich GmbH & Co. KG, Tuttlingen, Germany). The suspensions were separated from the beads by filtration through a 10 μm stainless sieve. Around 400 nm particles with a low polydispersity index were obtained for sucrose by organic wet bead milling (Table 4).

Table 4 Particle size and polydispersity index of nanosized excipient.

Excipients	Initial particle size, D50, μm	Particle size, z-average， nm	Polydispersity index
Sucrose	20	354	0.21
Mg(OH)₂	40	445	0.27

Example A15

Dual centrifugation was also used to nanosizing Mg(OH)₂ according to the same method as described in Example A14 except that Mg(OH)₂ was used as the raw material instead of sucrose.

This method can effectively reduce the particle size of Mg(OH)₂ from 10 – 50 μm to less than 1 μm (Table 4).

B) Preparation examples of microparticles , polymeric compositions , coated medical device , and implants containing nanosized active ingredient and/or nanosized excipient

Example B1

Preparation of microparticles

a) Preparation of the active ingredient suspension

Nanosized dexamethasone suspension was produced according to the method as described in Example A2.

b) Preparation of the PLGA suspension

270 mg of PLGA 503H was dissolved in 630 mg of nanosized dexamethasone suspension. 400 mg of extra dichloromethane was added. Then, this PLGA nanosuspension was mixed.

c) Preparation of microparticles

Subsequently, the PLGA suspension was homogenized into a 5 mL 1.0 % (w/v) PVA solution (8000 rpm and 30 s). The emulsion was diluted in 200 mL 0.25 % (w/v) PVA solution and stirred at 300 rpm.

d) Removal of organic medium and drying of microparticle

Dichloromethane was evaporated whilst stirring for 4 h. After 4 h, hardened microparticles were passed through 50 μm and 20 μm sieves. Microparticles were transferred to 50 ml centrifuge tubes and washed three times with deionized water (25 mL each time), recollected using centrifugation (2500 rpm and 5 min), and dried via freeze-drying (- 30 °C and 0.37 mbar). A free-flowing powder of microparticles with an average diameter of 28 - 40 μm was obtained.

Example B2

Preparation of microparticles: adjustment of the particle size of the microparticle

Steps a) to b) were carried out as described in example B1.

Step c) was carried out as described in example B1, except increasing the homogenization speed from 8000 rpm to 13500 rpm.

Step d) was carried out as described in example B1, except passing through 5 μm sieves instead of 50 μm and 20 μm sieves. Thus, a free-flowing powder consisting of microparticles with an average diameter of 1 – 4 μm was obtained.

Example B3

Preparation of microparticles: BSA microparticles

The biodegradable PLGA microparticles in which nanosized BSA encapsulated were prepared according to the same method as described in Example B1 except that A6 was used as the active ingredient suspension instead of A2. Thus, a free-flowing powder of microparticles with an average diameter of 28 - 40 μm was obtained.

Example B4

Preparation of microparticles: Leuprolide microparticles

The biodegradable PLGA microparticles in which nanosized leuprolide was encapsulated were prepared according to the same method as described in Example B1 except that A7 was used as the active ingredient suspension instead of A2. Thus, a free-flowing powder of microparticles with an average diameter of 28 - 40 μm was obtained.

Example B5

Preparation of microparticles: Addition of micronized active ingredient and nanosized excipient

a) Preparation of the active ingredient suspension

30 mg micronized dexamethasone powder was dispersed in 950 mg dichloromethane.

b) Preparation of the PLGA suspension

270 mg of PLGA 503H was dissolved in the active ingredient suspension. 50 mg nanosized sucrose suspension was added, which was produced according to the same method as described in Example A8. Then, this PLGA suspension was mixed (8000 rpm and 1 min).

Step c) was carried out as described in example B1.

Step d) was carried out as described in example B1, except the drying method changed from freeze-drying to vacuum-drying (24 h and room temperature).

A free-flowing powder of microparticles with an average diameter of 28 - 40 μm was obtained.

Example B6

Preparation of microparticles: Addition of dissolved active ingredient and nanosized excipient

a) Preparation of the active ingredient suspension

30 mg micronized risperidone powder was dispersed in 950 mg dichloromethane.

b) Preparation of the PLGA suspension

Step c) was carried out as described in example B1.

Step d) was carried out as described in example B1, except the drying method changes from freeze-drying to vacuum-drying (24 h and room temperature).

Example B7

Preparation of microparticles: Adjustment of nanosized excipient

The dexamethasone PLGA microparticles in which nanosized Mg(OH)₂ was encapsulated were prepared according to the same method as described in Example B5, except that A9 was used as the nanosized excipient solution instead of A8.

Example B8

Preparation of Microparticles: Adjustment of manufacturing process

a) Preparation of the active ingredient suspension

Nanosized dexamethasone sodium phosphate suspension was produced according to the same method as described in Example A5.

b) Preparation of the PLGA suspension

270 mg PLGA was dissolved in 4.4 g dichloromethane and mixed with 0.63 g nanosized dexamethasone sodium phosphate suspension. Then, this PLGA nanosuspension was mixed (8000 rpm and 1 min).

c) Preparation of microparticles

Subsequently, adding 1 g polydimethylsiloxane under homogenizing (8000 rpm and 30 s) to induce phase separation. The emulsion was injected under stirring with a propeller stirrer (300 rpm) into the hardening bath containing 100 g n-heptane and stirred at room temperature (300 rpm).

d) Removal of organic medium and drying of microparticle

Dichloromethane was evaporated whilst stirring for 1 h. After 1 h, hardened microparticles were passed through 50 μm and 20 μm sieves. Microparticles were transferred to 50 ml centrifuge tubes and washed three times with n-heptane (25 mL each time), recollected using centrifugation (2500 rpm and 5 min), and dried via freeze-drying (- 30 °C and 0.37 mbar).

Example B9

Preparation of Microparticles: Adjustment of manufacturing process

Steps a) and b) were carried out as described in example B5.

c) Preparation of microparticles

Instead of emulsifying into water phase, the PLGA suspension was spray-dried using a Buchi B290 benchtop spray-drier and collected as a dry powder. The polymer suspension was fed to a two-fluid nozzle (diameter 0.7 mm) at the top of the spray dryer.

d) Removal of organic medium and drying of microparticle

The microparticles were further dried via vacuum (24 h and room temperature)

A free-flowing powder of microparticles with an average diameter of 5 - 100 μm was obtained.

Example B10

Preparation of Microparticles: Combination of nanosized active ingredient and nanosized excipient

a) Preparation of the active ingredient suspension

Nanosized dexamethasone suspension was produced according to the same method as described in Example A2.

b) Preparation of the PLGA suspension

270 mg of PLGA 503H was dissolved in 630 mg of nanosized dexamethasone suspension. 420 mg nanosized sucrose suspension was added, which was produced according to the same method as described in Example A8. Then, this polymer suspension was mixed (8000 rpm and 1 min).

Steps c) and d) were carried out as described in example B9.

Example B11

Preparation of microparticles: adjustment of the polymer matrix

Steps a) to d) were carried out as described in example B1, except replacing PLGA 503H with ethyl cellulose (ETHOCEL™ Standard 20 premium, DuPont, Delaware, USA).

A free-flowing powder consisting of microparticles with an average diameter of 20 – 50 μm was obtained.

Example B12

Preparation of microparticles: adjustment of the polymer matrix

Steps a) to d) were carried out as described in example B1, except replacing PLGA 503H with PLGA 502H.

Example B13

Preparation of microparticles: comparative example

a) Preparation of the active ingredient suspension

30 mg micronized dexamethasone powder was dispersed in 1000 mg dichloromethane.

b) Preparation of the PLGA suspension

270 mg of PLGA 503H was dissolved in the active ingredient suspension. Then, this PLGA suspension was mixed (8000 rpm and 1 min).

Steps c) and d) were carried out as described in example B2.

A free-flowing powder consisting of microparticles with an average diameter of 1 – 5 μm was obtained.

Example B14

Preparation of microparticles: comparative example

a) Preparation of the active ingredient suspension

30 mg micronized dexamethasone powder was dispersed in 1000 mg dichloromethane.

b) Preparation of the PLGA suspension

Steps c) to d) were carried out as described in example B5.

Example B15

Preparation of microparticles: comparative example

a) Preparation of the active ingredient suspension

30 mg micronized dexamethasone powder was dispersed in 1000 mg dichloromethane.

b) Preparation of the PLGA suspension

270 mg of PLGA 502H was dissolved in the active ingredient suspension.

Steps c) to d) were carried out as described in example B1.

Example B16

Preparation of injectable polymeric compositions

a) Preparation of the active ingredient suspension

Nanosized dexamethasone suspension was produced according to the same method as described in Example A10.

b) Preparation of the polymer suspension

180 mg of PLGA 502H (acid end groups, 0.16 - 0.24 dl/g inherent viscosity; Evonik, Darmstadt, Germany) was dissolved in 600 mg triacetin and mixed with 420 mg of nanosized dexamethasone suspension to obtain a uniform PLGA nanosuspension.

c) Preparation of injectable compositions

The injectable compositions were filled into 1.2 mL polypropylene syringes with luer-lock tips. Then the pre-filled syringes were sealed using luer-lock caps. The capped syringes were packaged in a container and sealed in a plastic bag under vacuum and then stored at 4° C.

Example B17

Preparation of injectable polymeric compositions: adjustment of the model active ingredient

The biodegradable PLGA injectable polymeric compositions in which nanosized BSA loaded were prepared according to the same method as described in Example B16 except that A11 was used as the active ingredient suspension instead of A10.

Example B18

The biodegradable PLGA polymeric composition in which nanosized leuprolide loaded was prepared according to the same method as described in Example B16 except that A12 was used as the active ingredient suspension instead of A10.

Example B19

Preparation of injectable polymeric compositions: adjustment of the organic solvent and active ingredient

a) Preparation of the active ingredient suspension

Nanosized dexamethasone sodium phosphate suspension was produced according to the same method as described in Example A13.

b) Preparation of the polymer suspension

270 mg of PLGA 502 (ester end groups, 0.16 - 0.24 dl/g inherent viscosity; Evonik, Darmstadt, Germany) was dissolved in 400 mg N-methyl-2-pyrrolidone and mixed with 630 mg of nanosized dexamethasone sodium phosphate suspension to obtain a uniform PLGA nanosuspension.

c) Preparation of injectable compositions

The injectable compositions were filled into 1.2 mL polypropylene syringes with luer-lock tips. Then the pre-filled syringes were sealed using luer-lock caps. The capped syringes were packaged in a container and sealed in a plastic bag under vacuum.

Example B20

Preparation of injectable polymeric compositions: addition of nanosized excipient

Step a) was carried out as described in example B16.

b) Preparation of the polymer suspension

180 mg of PLGA 502H was dissolved in 600 mg triacetin and mixed with 420 mg of nanosized dexamethasone suspension produced according to the same method as described in Example A10 and 50 mg nanosized sucrose suspension produced according to the same method as described in Example A14 to obtain a uniform PLGA nanosuspension (8000 rpm and 1 min).

Step c) was carried out as described in example B16.

Example B21

The dexamethasone PLGA injectable polymeric compositions in which nanosized Mg(OH)₂ was loaded were prepared according to the same method as described in Example B20, except that A15 was used as the nanosized excipient solution instead of A14.

Example B22

Preparation of injectable polymeric compositions: comparative examples

a) Preparation of the active ingredient suspension

20 mg micronized dexamethasone was dispersed in 1000 mg triacetin.

b) Preparation of the polymer suspension

180 mg of PLGA 502H was dissolved in the active ingredient suspension to obtain a uniform PLGA suspension.

c) Preparation of injectable compositions

Example B23

Preparation of injectable polymeric compositions: comparative examples

a) Preparation of the active ingredient suspension

30 mg micronized dexamethasone sodium phosphate was dispersed in 1000 mg N-methyl-2-pyrrolidone.

b) Preparation of the polymer suspension

270 mg of PLGA 502 was dissolved in the active ingredient suspension to obtain a uniform PLGA suspension.

c) Preparation of injectable compositions

Example B24

Preparation of an implantable coated medical device: dip coating

a) Preparation of the active ingredient suspension

b) Preparation of the polymer solution

c) Coating

Subsequently, the implantable medical device was then dipped into the polymer suspension, and then dried in a vacuum oven overnight to form a dry coating.

Example B25

Preparation of an implantable coated medical device: adjustment of the model active ingredient

The coating in which nanosized BSA loaded was prepared according to the same method as described in Example B24 except that A6 was used as the active ingredient suspension instead of A2.

Example B26

The coating in which nanosized leuprolide was loaded was prepared according to the same method as described in Example B24 except that A7 was used as the active ingredient suspension instead of A2.

Example B27

Preparation of an implantable coated medical device: addition of nanosized Mg(OH)₂

The coating in which nanosized Mg(OH)₂ was embedded was prepared according to the same method as described in Example B24, except that A9 was used as the nanosized excipient suspension instead of A8.

Example B28

Preparation of an implantable coated medical device: Adjustment of manufacturing process (spray coating)

Steps a) and b) were carried out as described in example B24.

c) Coating

Subsequently, the implantable medical device was then spray-coated with the polymer suspension.

Example B29

Preparation of an implantable coated medical device: adjustment of the polymer

The coating in which nanosized dexamethasone loaded was prepared according to the same method as described in Example B24 except that poly(ethylenevinylacetate) (PEVA (ELVAX™ 40W) was used as the polymer matrix instead of PLGA 503H.

Example B30

Preparation of implants – solvent casting

a) Preparation of the active ingredient suspension

b) Preparation of the polymer suspension

c) Preparation of implant

Subsequently, the polymer solution was then cast into a suitable container (e.g., a TEFLON® dish, 1 mm width x 20 mm length), and then dried in a vacuum oven overnight to form a dry implant.

Example B31

Preparation of implants: adjustment of the model active ingredient

The biodegradable PLGA implant in which nanosized BSA encapsulated was prepared according to the same method as described in Example B30 except that A6 was used as the active ingredient suspension instead of A2.

Example B32

Preparation of implants: adjustment of the model active ingredient

The biodegradable PLGA implant in which nanosized leuprolide was encapsulated was prepared according to the same method as described in Example B30 except that A7 was used as the active ingredient suspension instead of A2.

Example B33

Preparation of implants: addition of nanosized Mg(OH)₂

The dexamethasone PLGA implant in which nanosized Mg(OH)₂ was encapsulated was prepared according to the same method as described in Example B30, except that A9 was used as the nanosized excipient solution instead of A8.

Example B34

Preparation of implants: addition of dispersed active ingredient

a) Preparation of the active ingredient suspension

20 mg micronized dexamethasone powder was dispersed to the 950 mg dichloromethane.

b) Preparation of the polymer suspension

Step c) was carried out as described in example B30.

Example B35

Preparation of implants: addition of dissolved active ingredient

a) Preparation of the active ingredient suspension

20 mg micronized risperidone powder was dissolved to the 950 mg dichloromethane.

b) Preparation of the polymer suspension

Step c) was carried out as described in example B30.

Example B36

Preparation of implants: Adjustment of manufacturing process (solvent casting – extrusion method)

Steps a) and b) were carried out as described in example B30.

c) Preparation of implant

Subsequently, the polymer solution was then cast into a suitable container (e.g., a TEFLON® dish), and then dried in a vacuum oven overnight to form a dry film. The film was then ground into particles, which were collected and extruded by hot melt extrusion (using, for example, a piston extruder) to prepare a filament. The filament may be cut to a length and thereby weight suitable for placement in the body. The extrusion temperature for this process may range from 45 °C to 85 °C.

Manufacture of implants using a piston extruder

The film was ground into particles which were then placed into the heated well of a piston extruder and extruded into 200 - 250 μm diameter filaments using a piston extruder at a temperature range of 45 – 85 °C. through a 200 μm nozzle and a speed setting number of 0.0025. Extruded filaments were cut into 5-inch lengths and collected into a storage tube.

Example B37

Preparation of implants: Adjustment of manufacturing process (wet granulation – extrusion method)

Step a) was carried out as described in example B30.

b) Wet granulation

30 g PLGA 503H powder was wet granulated with 10 g organic nanosuspension obtained in step a) by fluidized bed granulators to obtain granulate with granulometric distribution in 90 % of cases between 5 and 5000 μm. Then the granulate was dried for 12 hours at a temperature of 25 °C in a current of dry air.

c) Preparation of implant

The dried granulated mixture obtained in step b) was extruded into implants with the extrusion method as described example B36.

C) Characterization examples

Example C1

Encapsulation efficiency

The encapsulation efficiency of the microparticle according to example B2 is greater than 60 %, but the encapsulation efficiency of the microparticle according to example B13 is less than 20 %. This confirmed that nanosized active ingredients can be more efficiently encapsulated into small microparticles (smaller than 5 μm).

In vitro active ingredient release

10 mg of the microparticle according to example B2 was added to a phosphate buffer (pH 7.4 and 10 mM) and the mixture was incubated at 37° C and 80 rpm. Then, at certain intervals, the dexamethasone content in the phosphate buffer is determined. The results are presented in .

Example C2

Encapsulation efficiency

The encapsulation efficiencies of the microparticles according to examples B5 and B14 are greater than 90 %. This confirmed that a small amount of nanosized sucrose did not impact dexamethasone encapsulation.

In vitro active ingredient release

10 mg of the microparticle according to examples B5 and B14 were added to a phosphate buffer (pH 7.4 and 10 mM) and the mixture was incubated at 37° C and 80 rpm. Then, at certain intervals, the dexamethasone content in the phosphate buffer was determined. The results are presented in . showed that a small amount of nanosized sucrose can eliminate the lag phase (day 1 to day 7) and achieve a more continuous release.

Example C3

Encapsulation efficiency

The encapsulation efficiencies of the microparticles according to examples B12 and B15 are greater than 90 %. This confirmed that nanosizing dexamethasone did not significantly impact dexamethasone encapsulation.

In vitro active ingredient release

10 mg of the microparticle according to examples B12 and B15 were added to a phosphate buffer (pH 7.4 and 10 mM) and the mixture was incubated at 37° C and 80 rpm. Then, at certain intervals, the dexamethasone content in the phosphate buffer was determined. The results are presented in and indicate that encapsulating nanosized dexamethasone can eliminate the lag phase (day 1 to day 3) and achieve a more continuous release.

Example C4

Physical stability of injectable polymeric compositions

2000 mg of the injectable polymeric compositions according to examples B16 and B22 was added to a glass bottle and stands at room temperature for 3 months. Their particle sizes were measured (Table 5) and sedimentation phenomenon was observed ( ). Micronized active ingredient in Example B22 started sedimenting immediately after 3 day, while the uniformity of Example B16 can maintain for at least 3 months. Additionally, there is no significant particle size change of nanosized dexamethasone drug after 3 months of storage.

Table 5. Particle size of nanosized dexamethasone in injectable polymeric compositions (18 % PLGA 502H and 2 % active ingredient loading) stored at room temperature.

Time, month	Particle size, nm	Polydispersity index
0	372	0.17
1	368	0.17
3	398	0.20

Example C5

Physical stability of injectable polymeric compositions

2000 mg of the injectable polymeric compositions according to examples B19 and B23 was added to a glass bottle and stands at room temperature for 3 months. Their particle sizes were measured (Table 6) and the sedimentation phenomenon was also observed as in Example C4. Micronized active ingredient in Example B23 started sedimenting immediately after 3 day, while the uniformity of Example B19 can maintain for at least 3 months. Additionally, there is no significant particle size change of nanosized dexamethasone sodium phosphate drug after 3 months of storage.

Table 6. Particle size of nanosized dexamethasone sodium phosphate in injectable polymeric compositions (27 % PLGA 502 and 3 % active ingredient loading) stored at room temperature.

Time, month	Particle size, nm	Polydispersity index
0	294	0.24
1	292	0.27
3	308	0.28

In vitro active ingredient release

100 mg of the injectable polymeric compositions according to examples B19 and B23 were added to a phosphate buffer (pH 7.4 and 10 mM) and the mixture was incubated at 37° C and 80 rpm. Then, at certain intervals, the dexamethasone sodium phosphate content in the phosphate buffer was determined. The results are presented in . The results indicate that encapsulating nanosized dexamethasone sodium phosphate can reduce the burst release, increase drug release at the lag phase (day 1 to day 40), and achieve a more continuous release.

Example C 6

In vitro active ingredient release

The implant according to example B30 was added to a phosphate buffer (pH 7.4 and 10 mM) and the mixture was incubated at 37 °C and 80 rpm. Then, at certain intervals, the dexamethasone content in the phosphate buffer was determined. The results are presented in . A small burst release and a continuous release were achieved.

Claims

A method for preparing microparticles comprising: (a) adding an active ingredient and/or an excipient into an organic medium; (b) wet milling this mixture to reduce the particle size of the active ingredient and/or excipient to an average particle size of less than 1µm; (c) further processing this organic nanosuspension into microparticles.
The method according to claim 1, wherein the organic nanosuspension is processed into microparticles by a solvent extraction/evaporation method.
The method according to claim 1, wherein the organic nanosuspension is processed into microparticles by an organic phase separation method.
The method according to claim 1, wherein the organic nanosuspension is processed into microparticles by a spray drying method.
The method according to claim 1, wherein the organic medium comprises one or more organic solvents comprising methylene chloride, chloroform, carbon tetrachloride, acetone, methanol, ethanol, ethyl acetate, dioxane, tetrahydrofuran, hexafluoroisopropanol, triacetin, dimethylsulfoxide, N-methyl-2-pyrrolidone, propylene glycol, polyethylene glycol or glycerol.
The method according to claim 1, wherein the organic medium comprises a polymer.
The method according to claim 6, wherein the organic medium comprises a biodegradable polymer.
The method according to claim 7, wherein the polymer comprises one or more polymers from the group of poly(lactide-co-glycolide) (PLGA), PLGA-PEG, polylactide, polyglycolide, polycaprolactone, or other polyesters.
The method according to claim 1, wherein the active ingredient is a drug comprising peptide or protein drugs, therapeutic nucleic acids, antiinflammatory drugs, anticancer agents, antiviral agents, sex hormones, antibiotics, antimicrobial agents, antifungal agents, antineoplastic agents, immunosuppressive agents, and the like.
Microparticles prepared according to claim 1.
A formulation comprising microparticles of claim 10 for oral, parenteral, or pulmonary application, and in the form of a suppository, an aerosol, a powder, a cream, a gel, a suspension, a nasal drop, an ophthalmic drop, or as part of a transdermal system.
A pharmaceutical composition comprising: (a) a nanosized active ingredient;
(b) a polymer; (c) a pharmaceutically acceptable organic solvent; and (d) optionally one or more nanosized excipients.
The pharmaceutical composition of claim 12, wherein the average particle size of nanosized active ingredients and/or nanosized excipient is less than 1 µm.
The pharmaceutical composition of claim 12, wherein the active ingredient is a drug comprises therapeutic protein drugs, therapeutic nucleic acids, antiinflammatory drugs, anticancer agents, antiviral agents, sex hormones, antibiotics, antimicrobial agents, antifungal agents, antineoplastic agents, immunosuppressive agents, and compounds.
The pharmaceutical composition of claim 12, wherein the polymer comprises one or more polymers from the group of poly-lactide-co-glycolide (PLGA), PLGA-PEG, polylactide, polyglycolide, polycaprolactone (PCL), PLGA and PCL derivatives, or other polyesters.
The pharmaceutical composition of claim 12, wherein the nanosized excipient comprises release modifiers, pH modifiers, preservatives, antioxidant agents, reducing agents, and the like.
The pharmaceutical composition of claim 12, comprising pharmaceutically acceptable organic solvents such as N-methyl-2-pyrrolidone, methoxypolyethylene glycol, alkoxypolyethylene glycol, polyethylene glycol esters, ethanol, glycofurol, glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decylmethylsulfoxide, benzyl benzoate, ethyl benzoate, triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerides, triethyl phosphate, diethyl phthalate, diethyl tartrate, ethyl lactate, propylene carbonate, ethylene carbonate, butyrolactone, 1-dodecylazacyclo-heptan-2-one, water and combinations thereof.
A method for manufacturing the pharmaceutical composition of claim 12 comprising the steps of: (a) adding an active ingredient and/or an excipient into a pharmaceutically acceptable solvent; (b) wet milling this mixture to reduce the particle size of the active ingredient and/or excipient to an average particle size of less than 1 µm; (c) further processing this organic nanosuspension into a polymeric composition.
The method according to claim 18, wherein the pharmaceutically acceptable solvent comprises a polymer.
The method according to claim 19, wherein the polymer comprises one or more polymers from the group of poly(lactide-co-glycolide) (PLGA), PLGA-PEG, polylactide, polyglycolide, polycaprolactone, or other polyesters.
A kit comprising a syringe comprising the pharmaceutical composition of claim 12.
A method of forming an implant in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of claim 12.
The method of claim 22, wherein the pharmaceutical composition is administered to the subject subcutaneously, intramuscularly, intraperitoneally, intradermally, or orally.
The method of claim 23, wherein the pharmaceutical composition is administered to fit into a body cavity of the subject to form a depot.
An implantable coated medical device, comprising: a substrate and a coating disposed on the substrate, wherein the coating comprises at least one polymer and at least one nanosized active ingredient and, optionally, one or more nanosized excipients.
The medical device of claim 25, wherein the substrate is a medical device, e.g., a catheter, a balloon, a cutting balloon, a wire guide, a cannula, tooling, an orthopedic device, a structural implant, stent, stent-graft, graft, vena cava filter, a heart valve, cerebrospinal fluid shunts, pacemaker electrodes, axius coronary shunts, endocardial leads, an artificial heart, and the like.
The medical device of claim 25, wherein the average particle size of nanosized active ingredients and/or nanosized excipient is less than 1 µm.
The medical device of claim 25, wherein the active ingredient is a drug comprising therapeutic protein drugs, therapeutic nucleic acids, antiinflammatory drugs, anticancer agents, antiviral agents, sex hormones, antibiotics, antimicrobial agents, antifungal agents, antineoplastic agents, immunosuppressive agents, and compounds.
The medical device of claim 25, wherein the polymer comprises one or more biodegradable polymers from the group of poly-lactide-co-glycolide (PLGA), PLGA-PEG, polylactide, polyglycolide, polycaprolactone (PCL), PLGA and PCL derivatives, or other polyesters.
The medical device of claim 25, wherein the polymer comprises one or more non degradable polymers from the group of poly(ethylene-co-vinyl acetate) (PEVA), cellulose derivatives, poly(butyl acrylate), poly(urethanes), silicone resins, nylon, ammonium polyacrylate, or acrylamide copolymers.
The medical device of claim 25, wherein the nanosized excipient comprises release modifiers, pH modifiers, preservatives, antioxidant agents, reducing agents, and the like.
A method for manufacturing the medical device of claim 25 comprising the steps of: (a) adding an active ingredient and/or an excipient into an organic medium; (b) wet milling this mixture to reduce the particle size of the active ingredient and/or excipient to an average particle size of less than 1 µm; (c) further coating this organic nanosuspension to the substrate.
The method according to claim 32, wherein the coating is by dip or spray coating.
The method according to claim 32, wherein the organic medium comprises a polymer.
The method according to claim 32, wherein the polymer comprises one or more polymers from the group of poly-lactide-co-glycolide (PLGA), PLGA-PEG, polylactide, polyglycolide, polycaprolactone (PCL), PLGA and PCL derivatives, or other polyesters.
The method according to claim 32, wherein the organic medium comprises an organic solvent from the group consisting of methylene chloride, chloroform, carbon tetrachloride, acetone, ethanol, methanol, ethyl acetate, dioxane, tetrahydrofuran, hexafluoroisopropanol, triacetin, dimethylsulfoxide, N-methyl-2-pyrrolidone, propylene glycol, polyethylene glycol, glycerol, and the like.
A method for preparing a solid implant comprising: (a) adding an active ingredient and/or an excipient into an organic medium; (b) wet milling this mixture to reduce the particle size of the active ingredient and/or excipient to an average particle size of less than 1µm; (c) further processing this organic nanosuspension into an implant.
The method according to claim 37, wherein the organic nanosuspension is processed into an implant by a solvent casting method.
The method according to claim 37, wherein the organic nanosuspension is processed into an implant by a combination of solvent casting and extrusion methods.
The method according to claim 37, wherein the organic nanosuspension is processed into an implant by a combination of solvent casting and compression methods.
The method according to claim 37, wherein the organic nanosuspension is processed into an implant by a combination of wet granulation and extrusion methods.
The method according to claim 37, wherein the organic medium comprising one or more organic solvents comprising methylene chloride, chloroform, carbon tetrachloride, acetone, methanol, ethanol, ethyl acetate, dioxane, tetrahydrofuran, hexafluoroisopropanol, triacetin, dimethylsulfoxide, N-methyl-2-pyrrolidone, propylene glycol, polyethylene glycol or glycerol.
The method according to claim 37, wherein the organic medium comprises a polymer.
The method according to claim 43, wherein the polymer comprising one or more biodegradable polymers from the group of poly-lactide-co-glycolide (PLGA), PLGA-PEG, polylactide, polyglycolide, polycaprolactone (PCL), PLGA and PCL derivatives, or other polyesters.
The method according to claim 43, wherein the polymer comprising one or more non-degradable polymers from the group of poly(ethylene-co-vinyl acetate) (PEVA), cellulose derivatives, poly(butyl acrylate), poly(urethanes), silicone resins, nylon, ammonium polyacrylate, or acrylamide copolymers.
The method according to claim 37, wherein the active ingredient comprising peptide or protein drugs, therapeutic nucleic acids, antiinflammatory drugs, anticancer agents, antiviral agents, sex hormones, antibiotics, antimicrobial agents, antifungal agents, antineoplastic agents, immunosuppressive agents, and the like.
Implants prepared according to claim 37.
A formulation or device comprising an implant of claim 47 administered to a subject subcutaneously, intramuscularly, intraperitoneally, or intradermally.