CA2304662C - Methods for fabricating polymer-based controlled release preparations - Google Patents

Methods for fabricating polymer-based controlled release preparations Download PDF

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Publication number
CA2304662C
CA2304662C CA002304662A CA2304662A CA2304662C CA 2304662 C CA2304662 C CA 2304662C CA 002304662 A CA002304662 A CA 002304662A CA 2304662 A CA2304662 A CA 2304662A CA 2304662 C CA2304662 C CA 2304662C
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polymer
active agent
solvent
continuous phase
sustained release
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CA2304662A1 (en
Inventor
Mark A. Tracy
John D. Herberger
Paul A. Burke
Paul F. Herbert
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Alkermes Controlled Therapeutics Inc
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Alkermes Controlled Therapeutics Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682Processes
    • A61K9/1694Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08Peptides having 5 to 11 amino acids
    • A61K38/09Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1641Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647Polyesters, e.g. poly(lactide-co-glycolide)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2984Microcapsule with fluid core [includes liposome]
    • Y10T428/2985Solid-walled microcapsule from synthetic polymer

Abstract

The present invention relates to a polymer-based sustained release device, a nd methods of forming and using the device for the sustained release of an active agent. The improved method of the invention f or forming a polymer-based sustained release device comprises forming a polymer/active agent solution by mixing a polymer, a continuous phase, and an active agent. The continuous phase can comprise one or more polymer solvents, a polymer solvent/polymer non-solvent mixture, or a polymer solvent/active agent non-solvent mixture. When the continuous phase comprises a polymer solvent/active agent non- solvent, the active agent can also be present as a microparticulate rather than in solution. The continuous phase is then removed from the polymer/active agent solution, thereby forming a solid polymer/active agent matrix.

Description

METHODS FOR FABRICATING POLYMER-BASED CONTROLLED RELEASE PREPARIONS
BACKGROUND OF THE INVENTION
Many illnesses or conditions require administration of a constant or sustained level of a medicament or biologically active agent to provide the most effective prophylactic or therapeutic effect. This may be accomplished through a multiple dosing regimen or by employing a system that releases the medicament in a sustained fashion.
Systems for delivering sustained levels of medication have employed biodegradable materials, such as polymers, encapsulating the medicament. The use of biodegradable polymers, for example, in the form of microparticles or microcarriers, provides a sustained release of medicaments, by utilizing the inherent biodegradability of the polymer to control the release of the medicament thereby providing a more consistent, sustained level of medication and improved patient compliance.
Certain methods of fabricating polymer-based sustained release devices comprise the steps of dissolving a polymer in a solvent, adding to the polymer solution the active agent to be incorporated and removing the solvent from the mixture thereby forming a matrix of the polymer with the active agent distributed throughout the matrix.

Many of these methods of fabricating polymer-based sustained release devices employ a solvent or mixture of solvents, which solubilizes the polymer, but are not capable of solubilizing the active agent to be incorporated. Hence, these methods have disadvantages, for example, in the lack of suitable solvents which are capable of dissolving both active agent and polymer and which are non-toxic, biocompatible and can be readily removed from the final product; in solubilizing of the active agent in an active form; and in optimizing encapsulation efficiency of the active agent to achieve a device with the desired release characteristics.
Therefore, a need exists for improved methods for fabricating a polymer-based sustained release device, particularly devices having a high load of active agent.

SUMMARY OF THE INVENTION
The present invention is based upon the discovery that an improved polymer-based sustained release device can be achieved when a continuous phase which is capable of solubilizing both the polymer and the active agent is employed in the method for fabricating the device. Unexpectedly, an advantage of the sustained release devices obtained thereby is that they can have a very high load of active agent. For example, the device can achieve a relative weight of active agent in excess of the total polymer weight (e.g., present at about 50% by weight or more of the total weight of the device) with improved encapsulation efficiency and improved sustained release characteristics.
An additional advantage of the invention is that it allows for the preparation of small microparticles which contain encapsulated drug and exhibit improved delivery characteristics. A further advantage is the ability to use solubility properties of the active agent to affect particle size of the active agent, further enabling improved delivery characteristics. Additionally, the process for preparing microparticles may be improved by permitting the ability to filter sterilize process components or facilitate atomization of the polymer/active agent solution or dispersion.

The present invention thus relates to a polymer-based sustained release device, and methods of forming and using said device for the sustained release of an active agent. The improved method of the invention, for forming the polymer-based sustained release device, utilizes a continuous phase which comprises, for example, one or more polymer solvents, a polymer solvent/polymer non-solvent mixture or a polymer solvent/active agent non-solvent mixture, to dissolve the polymer and also solubilize the active agent in the polymer solution. Also embraced by the invention described herein is a process wherein the continuous phase comprises a polymer solvent/active agent non-solvent mixture and the active agent is present as a microparticulate. For purposes of the invention, the term "microparticulate"
describes the situation where the active agent is dispersed in the continuous phase at a concentration of the active agent approaching solubilization of the active agent or where the active agent is present as a combination of both dispersed particulate and solubilized active agent. Typically, the microparticulate is formed by mixing an active agent non-solvent with a solution containing the active agent which thereby leads to partial or complete precipitation of the active agent (also referred to as the "Microparticulate Method").
In one embodiment, the method comprises (a) forming a polymer/active agent solution by mixing a polymer, a continuous phase comprising one or more polymer solvents and an active agent wherein the polymer and active agent are present in relative concentrations such that the final product contains about 50% by weight or more of active agent; and (b) removing the continuous phase of step (a) thereby forming a solid polymer/active agent matrix.
The method can further comprise the step of forming droplets of the polymer/active agent solution prior to removal of the continuous phase.
Further, the method can comprise freezing the droplets prior to removal of the continuous phase.
According to the method of the invention the droplets can be microdroplets. In a specific embodiment wherein droplets are formed and then frozen, the continuous phase can be removed by an extraction process. Alternatively, the continuous phase can be removed by an evaporation process or a combination of an evaporation and extraction process.
When the continuous phase comprises one or more polymer solvents any combination of polymer solvents which is miscible and allows both the polymer and active agent to be dissolved, is suitable for use in the invention.
Dimethylsulfoxide (also referred to as DMSO) is preferred because it is a good solvent for many polymers and active agents, including water-soluble agents such as peptides, antigens, and small molecule drugs. Other suitable solvents, in particular for PLGA
polymers include, DMSO, ethyl acetate, methyl acetate, methylene chloride, chloroform, hexafluoroisopropanol, acetone, and combinations thereof.
Preferably, the polymer solvent is pharmaceutically acceptable.
In another embodiment, the method for forming a polymer-based sustained release device comprises the steps of: (a) forming a polymer/active agent solution by mixing a polymer, an effective amount of an active agent and a continuous phase comprising a polymer solvent/polymer non-solvent mixture wherein the amount of polymer non-solvent is dictated by achieving solubilization of the active agent without causing substantial precipitation of the polymer; and (b) removing the continuous phase of step (a) from the polymer/active agent solution, thereby forming a solid polymer/active agent matrix. In a further embodiment, the active agent is present at a concentration such that the final product or device contains about 50%
by weight or more of active agent.
The method can further comprise the step of forming droplets of the polymer/active agent solution prior to removal of the continuous phase.
Further, the method can comprise freezing the droplets prior to removal of the continuous phase. According to the method of the invention the droplets can be microdroplets.
In a specific embodiment wherein droplets are formed and then frozen, the continuous phase can be removed by an extraction process. Alternatively, the continuous phase can be removed by evaporation process or a combination of an evaporation and extraction process.
The polymer non-solvent can be selected such that it is miscible with the polymer solvent, does not cause substantial precipitation of the polymer and is not deleterious to the active agent. Preferably, the polymer solvent and the polymer non-solvent are pharmaceutically acceptable.
Suitable polymer non-solvents include, for example, ethanol, methanol, water, acetonitrile (MeCN), dimethylformamide (DMF), ethyl ether, alkanes such as pentane, isopentane, hexane, heptane and oils, such as mineral oils, fish oils, silicone oils, vegetable oils, or combinations thereof. Vegetable oils, such as olive oil, sesame oil, soybean oil, safflower oil, peanut oil, cottonseed oil, coconut oil, linseed oil, corn oil, castor oil, palm oil, or combinations thereof, are preferred for use in the invention. In particular embodiments, the polymer solvent is DMSO and the non-solvent is ethanol or water.
In another embodiment, the method for forming a polymer-based sustained release device comprises the steps of: (a) forming a polymer/active agent mixture by mixing a polymer, an effective amount of an active agent and a continuous phase comprising a polymer solvent/active agent non-solvent mixture wherein the amount of active agent non-solvent is dictated by achieving solubilization of the active agent, or alternatively achieving the active agent as a microparticulate in the continuous phase containing the polymer; and (b) removing the continuous phase of step (a) thereby forming a solid polymer/active agent matrix. In a further embodiment, the active agent is present at a concentration such that the final product or device contains about 50% by weight or more of active agent.
The method can further comprise the steps of forming droplets of the polymer/active agent solution prior to removal of the continuous phase.
Further, the method can comprise freezing the droplets prior to removal of the continuous phase.
According to the method of the invention the droplets can be microdroplets. In a specific embodiment wherein droplets are formed and then frozen, the continuous phase can be removed by an extraction process. Alternatively, the continuous phase can be removed by evaporation process or a combination of an evaporation and extraction process.
The active agent non-solvent can be selected such that it is miscible with the polymer solvent, does not substantially precipitate the polymer, and is not deleterious to the active agent. Suitable active agent non-solvents are dependent upon the properties of the active agent and for peptides can include, for example, acetone, ethanol and methylene chloride.
In another aspect, the invention relates to a polymer-based sustained release device prepared according to the method of the invention. The device comprises a polymeric matrix and an active agent dispersed within the matrix. The device formed by the method of the invention exhibits a unique microstructure, the porosity of which varies as a function of load, polymer concentration and the type of continuous phase employed.
The method of using the polymer-based sustained release device of the present invention comprises providing a sustained delivery of active agent, in a subject, over a therapeutically useful period of time, by administering to the subject a dose of said polymer-based sustained release device. The invention also provides methods for preparing microparticles of varying size and/or morphology for use in specific applications, for example, applications such as chemoembolization, vaccine delivery or cellular uptake where the size of the microparticles directly impacts performance.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a plot of the percent of animals per treatment group in diestrus for groups of rats treated with microparticles prepared using the Particulate Method, as described herein, and having the indicated load of azaline B versus time.
Figure 2 is a plot of the percent of animals per treatment group in diestrus for groups of rats treated with microparticles having the indicated load of azaline B
prepared using the method of the invention, according to Examples 1 and 3, as described herein, and having the indicated load of azaline B, versus time.
Figure 3 is a plot of serum concentrations (ng/ml) of azaline B for groups of animals treated with azaline B containing microparticles prepared by using the Particulate Method and the method of the invention, according to Examples 1 and 3, as described herein, and having the indicated load of azaline B, versus time.

DETAILED DESCRIPTION OF THE INVENTION
The features and other details of the invention will now be more particularly described and pointed out here as well as in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention.

A solution, as defined herein, is a mixture of one or more substances (referred to as the solute, for example, the polymer and the active agent) dissolved in one or more other substances (referred to as the solvent or solvents, for example, DMSO or a combination of DMSO and methylene chloride). For purposes of this invention, the "continuous phase" refers to the major component of a solution, such as a polymer solvent or a mixture thereof, and a mixture of a polymer solvent and a non-solvent.
The term "non-solvent," as used herein, refers to a material, which does not substantially dissolve a second or reference material. For purposes of this invention, the non-solvent can be a non-solvent for the active agent or the polymer.
The term "microdroplet," as used herein, refers to a droplet of any morphology which has a dimension less than or equal to about 1000 m.
The active agent, azaline B, used in many of the examples described herein is an LHRH peptide analog, the structure of which is described in, for example, Campen et al., Biochemical Pharmacology 40: 1313-1321, 1995, and which can be depicted as follows:
Ac-D-Nal' - D-CpaZ - D-Pa13 - Ser4 - Aphs(atz) -D-Aph6(atz) - Leu' - Ilysg - Pro9 - D-Ala10 (Ac=acetyl, Nal=3-(2'-naphthyl)-alanine, Cpa=4-chloro-phenylalanine, Pal=3-(3'-pyridyl)-alanine, Aph=4-amino-phenylalanine, atz= 5'-(3'-amino-IH-1',2',4'-triazolyl), Ilys=N'-isopropyl-lysine). The azaline B can also be in the form of salt, such as the acetate salt.
In one aspect, the invention provides an improved method for preparing a polymer-based sustained release device comprising the use of a continuous phase which comprises one or more polymer solvents, a mixture of one or more polymer solvents with one more polymer non-solvents or a mixture of one or more polymer solvents with one or more active agent non-solvents, to dissolve the polymer and also solubilize the active agent in the polymer solution. When the continuous phase comprises a polymer solvent/active agent non-solvent, the situation where the active agent is present as a microparticulate is also embraced within the invention described herein.
In one embodiment, the method comprises (a) forming a polymer/active agent solution by mixing a polymer, a continuous phase comprising one or more polymer solvents and an active agent wherein polymer and active agent are present in relative concentrations such that the final product or device contains about 50%
by weight or more of active agent; and (b) removing the continuous phase of step (a) thereby forming a solid polymer/active agent matrix.
The method can further comprise the step of forming droplets of the polymer/active agent solution prior to removal of the continuous phase.
Further the method can comprise freezing the droplets prior to removal of the continuous phase.
According to the method of the invention the droplets can be microdroplets. In a specific embodiment wherein droplets are formed and then frozen, the continuous phase can be removed by an extraction process. Alternatively, the continuous phase can be removed by evaporation process or a combination of an extraction and evaporation process.

When the continuous phase comprises one or more polymer solvents any combination of polymer solvents which is miscible and allows both the polymer and active agent to be dissolved, is suitable for use in the invention.
Dimethylsulfoxide (also referred to as DMSO) is a preferred solvent because it is a good solvent for many polymers and active agents, including peptides, antigens and small molecule drugs. Other suitable solvents, in particular for PLGA polymers, include, for example, DMSO, ethyl acetate, methyl acetate, methylene chloride, chloroform, hexafluoroisopropanol and acetone. Preferably, the polymer solvent is pharmaceutically acceptable.

The method wherein one or more polymer solvents can be used as the continuous phase can be referred to herein as the "Polymer Solvent Method"
indicating that the major component of the continuous phase of the method comprises, or consists essentially of, one or more polymer solvents. If more than one polymer solvent is employed, it is understood that one of the polymer solvents can also be a non-solvent for the active agent provided that the active agent remains soluble in the continuous phase.

In another embodiment, the method for forming a polymer-based sustained release device comprises the steps of: (a) forming a polymer/active agent solution by mixing a polymer, an effective amount of an active agent and a continuous phase comprising a polymer solvent/polymer non-solvent mixture wherein the amount of non-solvent is dictated by achieving solubilization of the active agent without causing substantial precipitation of the polymer; and (b) removing the continuous phase of step (a) from the polymer/active agent solution, thereby forming a solid polymer/active agent matrix. In a further embodiment, the active agent is present at a concentration such that the final product or device contains about 50% by weight or more active agent.
The method can further comprise the step of forming droplets of the polymer/active agent solution prior to removal of the continuous phase.
Further, the method can comprise freezing the droplets prior to removal of the continuous phase.
According to the method of the invention the droplets can be microdroplets. In a specific embodiment wherein droplets are formed and then frozen, the continuous phase can be removed by an extraction process. Alternatively, the continuous phase can be removed by evaporation process or a combination of an extraction and evaporation process.
The method wherein the continuous phase comprises a polymer solvent/polymer non-solvent mixture, can be referred to as the "Polymer Solvent/Polymer Non-Solvent Method." When the major component of the continuous phase comprises, or consists essentially of, a polymer solvent/polymer non-solvent mixture a combination or one or more polymer solvents with one or more polymer non-solvents can be employed. The amount and type of polymer non-solvent can be selected such that it is completely or substantially miscible with the polymer solvent, does not cause substantial precipitation of the polymer, and is not deleterious to the active agent. Preferably, the polymer solvent and the polymer non-solvent are pharmaceutically acceptable. It is understood that one or both solvents in the continuous phase can serve to solubilize the active agent.
Polymer non-solvents suitable for use in the invention include, for example, ethanol, methanol, water, acetonitrile (MeCN), dimethylformamide (DMF), ethyl ether, alkanes, such as pentane, isopentane, hexane or heptane, and oils, such as mineral oils, fish oils, silicone oil, vegetable oils, or any combination thereof.
Vegetable oils, such as olive oil, sesame oil, soybean oil, safflower oil, peanut oil, cottonseed oil, coconut oil, linseed oil, corn oil, castor oil, palm oil, or combinations thereof, are preferred for use in the invention. In particular embodiments, the polymer solvent is DMSO and the non-solvent is ethanol or water.
In another embodiment, the method for forming a polymer-based sustained release device comprises the steps of: (a) forming a polymer/active agent mixture by mixing a polymer, an effective amount of an active agent and a continuous phase comprising a polymer solvent/active agent non-solvent mixture wherein the amount of active agent non-solvent is dictated by achieving solubilization of the active agent, or alternatively achieving the active agent as a microparticulate, in the continuous phase containing the polymer; and (b) removing the continuous phase of step (a) thereby forming a solid polymer/active agent matrix. In a further embodiment, the active agent is present at a concentration such that the final product or device contains about 50% by weight or more of active agent.
The method can further comprise the step of forming droplets of the polymer/active agent solution prior to removal of the continuous phase.
Further, the method can comprise freezing the droplets prior to removal of the continuous phase.
According to the method of the invention the droplets can be microdroplets. In a specific embodiment wherein the droplets are formed and then frozen, the continuous phase can be removed by an extraction process. Alternatively, the continuous phase can be removed by an evaporation process or a combination of an extraction and evaporation process.
The amount and type of active agent non-sblvent can be selected such that it is miscible with the polymer solvent, does not substantially precipitate the polymer, and is not deleterious to the active agent. Suitable active agent non-solvents are dependent upon the properties of the active agent and for peptides can include, for example, acetone, ethanol and methylene chloride.
Other excipients can be present in the polymer/active agent solution, as described below. These excipients need not be soluble in the continuous phase, although, this is preferred.

The active agent of the invention can be added either as a solid (such as in a fine powder) or neat liquid, or as a solution of the active agent in the polymer solvent or polymer non-solvent.
It can be desirable to add a polymer non-solvent which is a solvent for the active agent to the polymer solvent when forming the polymer/active agent solution if, for example, the polymer solvent does not solubilize the active agent to the desired degree.. The polymer non-solvent should be miscible with the polymer solvent, aid in solubilizing the active agent, not cause substantial precipitation of the polymer and not be deleterious to the active agent. An example of such an embodiment is in the formation of a solution of PLGA and tRNA. DMSO is a good solvent for PLGA but poorly solubilizes tRNA. The inclusion of, for example, water (a good solvent for tRNA, miscible with DMSO and a non-solvent for the polymer) results in an optically transparent solution comprising PLGA, tRNA, DMSO and water. Therefore, the continuous phase, in this embodiment, comprises a polymer solvent/non-solvent mixture, wherein the non-solvent is a non-solvent for the polymer. The amount of polymer non-solvent included is at least that amount necessary to achieve the desired level of solubilization of the active agent but not to exceed that amount which causes substantial precipitation of the polymer.
It can also be desirable to add a polymer non-solvent, which is a non-solvent for the active agent, to the polymer solvent when forming the polymer/active agent solution, if, for example, the polymer solvent solubilizes the active agent to a greater degree than desired. For example, in such an embodiment, the active agent may "leach" out of the microdroplet with the polymer solvent during the extraction step of the process. The addition of the active agent non-solvent can minimize this effect. The polymer non-solvent should be miscible with the polymer solvent and assist in decreasing the solubility of the active agent in the resulting polymer solvent/non-solvent mixture.

In summary, one aspect of the invention relates to maximizing polymer and active agent solubility properties in the continuous phase by selecting the appropriate solvent or combination of solvents. Thus, the addition or selection of appropriate solvents, co-solvents, or non-solvents results in the improved microparticles described herein.

The continuous phase can be formed prior to, following or simultaneous with the addition of the polymer to the polymer solvent. The active agent can be mixed with the polymer solution either as a solid, a neat liquid or in solution.
When the active agent is added in solution the solvent of the active agent solution can be a polymer non-solvent, polymer solvent or combinations thereof. Further, when the active agent is added as a solid or neat liquid, which is not soluble in the polymer solution, an additional polymer solvent, polymer non-solvent or combinations thereof can be added which solubilizes the active agent.
For example, poly(lactide-co-glycolide) was dissolved in DMSO and the active agent, ovalbumin, was predissolved in a minimum amount of water (a polymer non-solvent) and added to the polymer solution to form the polymer/active Wb 99/15154 PCTILTS98119603 _1,-agent solution, tliereby providing a continuous phase comprising a polymer solvent/polynler non-solvzmt mixture.
In another example, poly(lactide-co-glycolide) was dissolved in DMSO and the active agent, tRNA, was predissolved in a minimum amount of water and added to the polyrner solution to form the polymer/aetive agent solution.
In yet another embodiment, the active agent can be added as a solid, to a mixture of polymer solvent/polymer non-solvent having the polymer dissolved therein. The solid is soluble in the mixture. In a specific embod'zr,nent, the continuous phase comprising the polymer solvent/polymer non-solvent mixture, is ~ 10 DMSO and ethanol. In a more specific embodiment, the polymer of the polymer .r solution includes poly(lactide-co-glycolide) dissolved in a DMSQ/ethanol mixture and the active agent is azaline B. In each of these embodiments, the result was a single continuous phase in which both the polymer and active agent were solubilized, thereby avoiding prior art processes which are characterized by two or more phases. The solvents and/or non-solvents can be added in a wide range of = relative amounts, including for exump]e. about 1:10 to about 10:1 or about 1:3 to about 3:1, by volume, as is appropriate.
After the polymer/active agent solution is formed it can be processed to form microdroplets, These microdroplets can then be frozen by means suitable to form microparticles. Examples of ineans for processing the polymer/active agent solution to form droplets include directing the solution through an ultrasonic nozzle, pressure nozzle, R,ayleigh. jet, or by other means known for creating droplets from solution such as those described in U.S. Patent No. 5,019,400, issued to Gombotz et al., e;. a U.S. Patent No. 5,922,253 issued to Herbert et p1. and U.S. Pateat No.
5,817,343 issued to Burke et ad.

The microdroplets are then frozen by rneans suitable to form uZicroparticles.
Means suitable for fxeeziilg droplets to form microparticles include directing Che droplets into or near a liquified gas, such as liquid argon and liquid nitrogen to form frozen microdroplets which are then separated from the liquid gas: The frozen microdroplets are then exposed to an extractiou solvent or curing solvent or phase, which is generally a poor solvent for the polymer, which has a lower melting point WO 99/15154 PCT/ClS9$/19603 . -1.~- . .

than the continuous phase ax,d wliich has sufficient miscibility with Che continuous phase to extract solid andlor thawed oontinuous phase from a frozen micropartiele.
In one niethod the liquified gas overlays frozen extraction solvent, as described in U.S. Patent No. 5,0 19,400, issued to Gombotz et al..
.In a second method, the liquified gas and cold extraction solvent are maintained in a distinct "freezing zone" and "extraction zone," as described inU.S. Patent No. 5,922,253, issued to Herbert et al.

As stated above, the purpose of the extraction solvent is to remove or extract, as solid and/or a liquid, atry continuous phase in the frozen microdroplets, thereby forming active agent containing mieropartieles. Typically, the extraction solvent or curing phase is selected from one or more of the polymer non-solvents discussed above. It can be the same or different as any polymer non-solvent employed in the continuous phase, as described herein. It can optionally further include an active agent non-solvent as well. Typical extraction solvents inchide, for example, ethanol, metlzanol, ethyl ether, alkanes such as pentane, isopentane, hexane, heptane, and oils such as mineral oils, fish oils, silicone oil, vegetable oils, or combinationa thereof. Vegetable oils, such as olive oil, sesame oil, soybean oil, safflower oil, peanut oil, cottonseed oil, coconut oil, palm oil or combinations thereof, are preferred. It is generally desirable that the extraation solvent(s) or curing phase possess a melting point the sanie or, preferably, lower than the continuous phase. Thus, the extraction step can be conducted or initiated at -a temperature at which the extraction solvent(s) or curing phase is a liquid and the microdroplets (including the continuous phase) are frozen. Mixing ethanol with other suitable extraction solvents, such as an alkane, including hexane, heptane or pentane, can directly impact the encapsulation efficiency, morphology, and eonsistency therein of the resulting microspheres as well as cause an unexpected increase in the rate of solvent extraction, above that achieved by ethanol alone, from certain polymers, sucb as poly(lactide-co-glycolide) polymers.
In another method the polymer/aetive agent matrix, as formed above, is fragmented at a temperature below the glass transition temperature of the polymer/active agent matrix, thereby forrning polymerlactive agent microparticles, " WO 99/15154 _ PCTI(1S98/19603 as described in U.S. PatentNo. 5,817,343, isstxed to Burlce=et al.

A wide range of sizes of polymer-based sustained release devices can be made by varying the droplet size, for example, by changing the ultrasonic nozzle frequency or diameter. If larger devices are desired, the polymer/active agent solution can be processed by passage through a syringe or the likc directly into the cold liquid. Alternatively, the solution can be dripped or otherwise added to the cold ;ry liquid. Increasing, the viscosity of the polymer/active agent solution can also '='~ increase device size. The size o]'the devices which can be produced by the method of the inventxon are, for example, mieroparticles ranging from greater than about 1000 to about 1 micrometer in diameter.
The tez= "polymer-based sustained release device," as defined herein, comprises a polymerand an active agent (also referred to herein as a "polyrnerlactive agent matrix"). The polymers of the preseni invention are generally biocompatible. Suitable biocompatible polymers can be either biodegradable or non-biodegradable polymers, or blends or copolymers thereof.
A polymer is biocornpatible if the polymer, and any degradatioa products of the polymer, are substantially non-toxic to the recipient, and also presents no unacceptable, deleterious or untoward effects on the recipient's body, such as a significaut immunological reaction at the site of administration.

Biodegradable, as defined herein, means the composition will degrade or erode iyt viva to form smaller cherrmical species which are biometabolizable and/or excretable. Degradation can result, for exaznple, by enzymatic, chemical and/oz physical processes. Suitabla. biocompatible, biodegradable polymers include, for example, poly(lactides), poly(glycolides), po].y(lactide-co-glyco]ides), poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polycaprolacloue, polyoarbonates, polyesteramides, polyanh.ydrides, poly(amino acids), polyorthoesters, polyacetals, polycyanoacrylates, polyetheresters, poly(dioxanone)s, poly(alkylena a.lkylates)s, copolymers of polyethylene glycol and polyorthoester, biodegradable polyurethanes, blends and copolymers thereof.
Bioeompatible, non-biodegradable polymers suitable for a sustained release device include non-biodegradable polymers selected from the group consisting of polyacrylates, polymers of ethylene-vinyl acetates and acyl substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole), chlorosulphonate polyolefins, polyethylene oxide, blends and copolymers thereof.
Further, the terminal functionalities or pendant groups of the polymers can be modified, for example, to modify hydrophilicity, hydrophobicity and/or provide, remove or block moieties which can interact with the active agent (via, for example, ionic or hydrogen bonding).
Acceptable molecular weights for polymers used in this invention can be determined by a person of ordinary skill in the art taking into consideration factors such as the desired polymer degradation rate, physical properties such as mechanical strength, and rate of dissolution of polymer in solvent. Typically, an acceptable range of molecular weights is between about 2,000 Daltons to about 2,000,000 Daltons. In a preferred embodiment, the polymer is a biodegradable polymer or copolymer. In a more preferred embodiment, the polymer is a poly(lactide-co-glycolide) (hereinafter "PLGA").
The term "active agent," as defined herein, is an agent, or its pharmaceutically acceptable salt, which when released in vivo, possesses the desired biological activity, for example therapeutic, diagnostic and/or prophylactic properties in vivo. Examples of suitable biologically active agents include proteins such as immunoglobulins, antibodies, cytokines (e.g., lymphokines, monokines, chemokines), interleukins, interferons, erythropoietin, nucleases, tumor necrosis factor, colony stimulating factors, insulin, enzymes (e.g. superoxide dismutase, a plasminogen activator), tumor suppressors, blood proteins, hormones and hormone analogs (e.g., growth hormone, adrenocorticotropic hormone, luteinizing hormone releasing hormone (LHRH) and azaline B), vaccines (e.g., tumoral, bacterial and viral antigens), antigens, blood coagulation factors; growth factors; peptides such as protein inhibitors, protein antagonists, and protein agonists; nucleic acids, such as antisense molecules; oligonucleotides; and ribozymes. Small molecular weight agents suitable for use in the invention include, antitumor agents such as bleomycin hydrochloride, methotrexate and adriamycin; antibiotics such as gentamicin, tetracycline hydrochloride and ampicillin; antipyretic, analgesic and anti-inflammatory agents; antitussives and expectorants such as ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride and codeine phosphate;
sedatives such as chlorpromazine hydrochloride, prochlorperazine hydrochloride and atropine sulfate; muscle relaxants such as tubocurarine chloride;
antiepileptics such as sodium phenytoin and ethosuximide; antiulcer agents such as metoclopramide;
antidepressants such as clomipramine; antiallergic agents such as diphenhydramine;
cardiotonics such as theophillol; antiarrhythmic agents such as propranolol hydrochloride; vasodilators such as diltiazem hydrochloride and bamethan sulfate;
hypotensive diuretics such as pentolinium and ecarazine hydrochloride;
antidiuretic agents such as metformin; anticoagulants such as sodium citrate and sodium heparin; hemostatic agents such as thrombin, menadione sodium bisulfite and acetomenaphthone; antituberculous agents such as isoniazide and ethanbutol;
honnones such as prednisolone sodium phosphate and methimazole; and narcotic antagonists such as nalorphine hydrochloride.
The amount of active agent which is contained in the polymer-based sustained release device is a therapeutically or prophylactically effective amount which can be determined by a person of ordinary skill in the art taking into consideration factors such as body weight, condition to be treated, type of device used, and release rate from the device.
A polymeric drug delivery device of the invention can contain from about 0.01 %(w/w) to about 90% (w/w) of active agent (total weight of polymer/active agent). The amount of agent can vary depending upon the desired effect of the agent, the planned release levels, and the time span over which the agent is to be released. A low range of agent loading can be from about 0.1 % (w/w) to about 30%
(w/w). In treatments where a low range of agent loading is desired a preferred range is from about 0.5% (w/w) to about 20% (w/w). A high range of agent loading is that greater than or equal to about 50%. In treatments where a high range of agent loading is employed a preferred range is from about 50% (w/w) to about 85%
(w/w) and more preferably from about 50% (w/w) to about 70% (w/w).
A sustained release of active agent is a release which occurs over a period of time longer than that which would be obtained following similar administration of the active agent as a dispersion or solution in a carrier. Generally, the sustained release device can deliver the active agent for at least about seven days and, preferably, up to about three months.
The polymer-based sustained release device of this invention can be formed into many shapes such as a film, a pellet, a cylinder, a wafer, a disc or a microparticle. A microparticle, generally has a diameter of less than about one millimeter. A microparticle can have a generally spherical, non-spherical or irregular shape. Typically, the microparticle will be of a size suitable for injection.
A preferred size range for microparticles is from about 1 to about 250 microns in diameter. The sustained release device in the form of a wafer or disc, for example, will typically be of a size suitable for implantation and, for example, can be manufactured by compressing microparticles.
The present invention can be used to incorporate and deliver a wide variety of active agents. Most often, the composition of the present invention will be used to deliver an active agent to a human or other animal for purposes of therapy, prophylaxis, hygiene, analgesics, cosmetics or the like. Such uses where the compositions are delivered to a human or other animal will generally be referred to as in vivo uses. The composition of the present invention will also have in vitro uses where an active substance is being delivered to an environment or system other than a human or animal such as in the sustained release of agrochemicals or in diagnostics. One of the major in vivo uses for the composition of the present invention will be for the delivery of drugs and other pharmaceutical agents in human and veterinary applications. For both in vivo and in vitro uses, the compositions will deliver the active substance to a surrounding environment.
Unexpectedly, the above process resulted in the ability to form sustained delivery devices even at very high loads (greater than or equal to at least about 50%
(w/w)) with improved release characteristics and duration of release, as illustrated, for example, in Figures 1 and 2. It was also found that the morphology of the device changed with the amount, or load, of the active agent. The device, or microparticle, was porous at low loads (e.g, 10% to 30%), similar to the microparticles obtained in the known processes. However, at high loads (e.g. 50% to 90%), the microparticles were dense. Thus, the invention includes microparticles or sustained release devices manufactured by the process of the invention.

The invention also includes an improved sustained release device which has incorporated therein an amount of active agent greater than or equal to at least about '50% by weight (w/w) of the polymer-based sustained release device (also referred to as a "high load"). A preferred range is from about 50% (w/w) to about 85%
(w/w) and more preferably from about 50% (w/w) to about 70% (w/w). In general, these high load microparticles are difficult to manufacture employing the prior art processes and the high encapsulation efficiency observed is unexpected. In addition, the high load microparticles would not be expected to exhibit improved sustained release of active agent over lower active agent loads. In a specific embodiment, the polymer-based sustained release device has a high load of azaline B. In a more specific embodiment, the polymer of the sustained release device is poly(lactide-co-glycolide) having a high load of azaline B.
In a further embodiment, the improved polymer-based sustained release device has an increased period of sustained release and/or increased bioavailability over that achieved with a device prepared by a method which does not solubilize the active agent in the polymer solution. For example, when microparticles containing azaline B are prepared employing methylene chloride as the sole polymer solvent the active agent is not solubilized (referred to herein as the "Particulate Method").
Comparison of active agent release from these microparticles with those prepared employing DMSO as the continuous phase (active agent solubilized) can be achieved by comparing Figures 1 and 2. Clearly, the polymer-based sustained release devices prepared by the process wherein the active agent is solubilized (Figure 2), demonstrate an increased period of sustained release over those devices wherein a single polymer solvent which does not solubilize the active agent is employed (Figure 1).
Without being bound by a particular theory it is believed that the release of the biologically active agent can occur by at least two different mechanisms.
First, release can occur due to degradation of the polymer. Second, biologically active agent can be released by diffusion through the channels generated in the polymer-based sustained release device, such as by the dissolution of the active agent or by voids or pores created by the removal of the polymer/active agent solvent during the synthesis of the drug delivery device.

The rate of degradation can be controlled by changing polymer properties that influence the rate of hydration and/or degradation of the polymer. These properties include, for instance, the ratio of different monomers, such as lactide and glycolide, comprising a polymer; the use of the L- or D- isomer or racemic mixture of a chiral monomer; a polymer, such as a poly(lactide-co-glycolide) polymer that has, for instance, a hydrophobic or a hydrophilic end group; the morphology of the particle as impacted for example, by choice of solvents for polymer during preparation; and the molecular weight of the polymer. These properties can affect hydrophilicity and crystallinity, which control the rate of hydration of the polymer.
Hydrophilic excipients such as salts, carbohydrates and surfactants can also be incorporated to increase hydration and which can alter the rate of erosion of the polymer.
In addition, the active agent in the sustained release device of the present invention can also contain other excipients, such as stabilizers, bulking agents or aggregation-stabilizing agents. Stabilizers are added to maintain the potency of the biologically active agent during device fabrication, storage and over the duration of the agent's release. Suitable stabilizers include, for example, carbohydrates, amino acids, fatty acids and surfactants which are known to those skilled in the art. For amino acids, fatty acids and carbohydrates, such as sucrose, lactose, mannitol, inulin, maltose, dextran and heparin, the mass ratio of carbohydrate to biologically active agent is typically between about 1:10 and about 20:1. For surfactants, such as polysorbates (e.g., TweenT"') and poloxamers and poloxamines (e.g., PluronicTM), the mass ratio of surfactant to agent is typically between about 1:1000 and about 1:2.
Aggregation-stabilizing agents are agents which stabilize the biologically active agent against significant aggregation in vivo over the sustained release period.
Typically an aggregation stabilizer reduces the solubility of the biologically active agent, precipitates out a salt of the agent or forms a complex of the agent.
The aggregation stabilizer and the biologically active agent can be separately contained within the drug delivery device, such as a device containing particles of aggregation stabilizer and separate particles of biologically active agent, and/or can be combined together in complexes or particles which contain both the aggregation stabilizer and the biologically active agent.

W 0 99/151 S4 = PCT/U89811960.

The use of aggregation-stabilizing agents is also described inU.S. Patent No.
5,716,644, issued to Zale et ala attd U.S. Patent No. 5,674,534, issued to ?ale et a.l.
.E . , Metal cations can be suitable as aggregation-stabilizing agents. These rnetal cations include cations of transition metals, such as Zn=hz, CutZ, Co+', re*l and Ni''.
The use ofinetal cations as aggregation-stabilizing agents, is aLso described in U.S. Patent No. 5,711,968, issued to Traay et alõ p ixblished International Application WO 96/03116, U.S. Patent No. 5,654,010,issued to Johnson et al.
aiid U.S. Patent No. 5,667,800 issued to rohnson et al.

The polymer-based sustained release device can also contain a metal cation component which is dispersed within the polymer. This metal cation component acts to modulate the release of biologically active agent from the polymeric matrix.
A metal cation component used in modulating release typically contains at least one-type of multivalent metal cation. 'Examples of metal cation components suitable to modtilate release of biologically active agent, include, or contain, for instance, Mg(OH)z,1VTgCO3 (such as 4MgCO,.Mg(OH)2=514ZO), ZnCO3 (such as 3Zaa(pH),'2ZnCO3), CaCO3, Zna(CsHsO7)z, Mg(OAc)Z, MgSOO Zn(OAc)2, ZnSOa, ZnClz , MgC1z and MgXbHsQ7)2. A suitable ratio of metal cation pornponent-to-device is betvVeen about 1:99 to about 1:1 by weight. The optizaum ratio depends -apon the polymer and the metal cation utilized.
A polymeric matrix containing a dispersed metal cation compouent to modulate the release of a biologically active agent from the polymeric matrix is further described in U.S. Patent No. 5,656,297 issued to Dernstein ei al, and p,itblished Internatxonal Application WO 95/29644.

In a tltird aspect, the present invention provides a method of using the polymer-based sustained release device comprising providing a sustained delivery rate of active agent, in a subject, over a thera.psutically useful period of time, by administering to the subject a dose of said polymer-based sustained release device.

I =,.

The sustained release device of this invention can be administered to a human, or other animal, by injection, implantation (e.g, subcutaneously, intramuscularly, intraperitoneally, intracranially, intraocularly, intravaginally and intradermally), administration to mucosal membranes (e.g., intranasally or by means of a suppository), or in situ delivery (e.g. by enema or aerosol spray) to provide the desired dosage of an agent based on the known parameters for treatment with that agent of the various medical conditions.
Even though the invention has been described with a certain degree of particularity, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art in light of the foregoing disclosure.
Accordingly, it is intended that all such alternatives, modifications, and variations which fall within the spirit and scope of the invention be embraced by the defined claims.
The invention will now be further and specifically described by the following examples.

EXEMPLIFICATION
METHODS
The polymers employed in the following examples are described below:
Purchased from Boehringer Ingelheim RG 502H: 10K MW, 50:50 Poly(D,L-lactide-co-glycolide) (PLGA), hydrophilic end groups RG 501H: 5K MW, 50:50 Poly(D,L-lactide-co-glycolide) (PLGA), hydrophilic end groups R 104: 5K MW, Poly(D,L-lactide) Purchased from Binningham Polymers, Inc., Birmingham Alabama Lot 112-43-1: 5K MW, Poly(D,L-lactic acid) EXAMPLE 1: POLYMER SOLVENT METHOD
A polymer/active agent solution can be formed by dissolving an appropriate amount of polymer and active agent in a continuous phase comprising one or more polymer solvents which also solubilize the active agent. If more than one polymer solvent is employed both need not solubilize the active agent. The polymer/active agent solution can then be atomized into droplets which can be frozen. The solvent is then removed from the frozen droplets to form a polymer/active agent matrix by diffusion of the polymer solvent into a polymer non-solvent phase, the cure phase.
The cure phase can be comprised of a single solvent or a mixture of solvents.
The particles are collected from the polymer non-solvent by filtration and residual polymer solvent and non-solvent are removed by evaporation. The dry product is sieved through an appropriately sized mesh so as to produce an injectable product.
The process can be summarized as follows:
= Formation of a polymer/active agent solution by dissolving PLGA
copolymer (3-28%(w/v)) and active agent in DMSO.
= Atomization of the polymer active agent solution by sonication, and freezing of the droplets by contact with liquid nitrogen.
= Extraction of the polymer/active agent solvent in 80 C ethanol cure solvent, thereby forming a polymer active agent matrix.
= Isolation of the particles from the cure solvent by filtration.
= Removal of remaining solvents by evaporation.
= Sizing of particles by passage through an appropriately sized mesh so as to produce an injectable product.

The "Particulate Method," refen:ed to in Figures 1 and 3, is a process similar to that summarized above, but where the active agent is added to the polymer solution as a solid and remains in the solid or particulate form (i.e., does not dissolve) throughout the process.

EXAMPLE 1.1: 63% (w/w) PEPTIDE LOADED, PLGA
MICROPARTICLES, ETHANOL CURE PHASE.
High load microparticles comprising PLGA and azaline B were prepared as follows:
1) A solution comprising DMSO (0.701 ml), PLGA (0.043 g) (10K MW, hydrophilic end groups) and azaline B acetate (0.185 g) was prepared by mixing the components at room temperature.

2) The solution from step 1 was atomized by an ultrasonic atomizing probe (Sonics & Materials #630-0507) at a constant flow rate of 0.3 ml/minute.
3) The atomized droplets were frozen upon passage through a cold nitrogen gas phase and then into liquid nitrogen. The liquid nitrogen layer was placed over a frozen non-solvent phase (100% ethanol).
4) The liquid nitrogen layer containing the frozen droplets was allowed to evaporate at -80 C and the polymer/active agent solvent (DMSO) was extracted from the frozen droplets over an 18 hour incubation time at -80 C employing ethanol as the cure phase.
5) The microparticles were separated from the cure phase by filtration and freeze-dried.
6) The dry product was sieved through a 180 m mesh sieve.
EXAMPLE 1.2: 63% (w/w) PEPTIDE LOADED, PLGA
MICROPARTICLES, HEPTANE/ETHANOL CURE
PHASE
1) A solution comprising DMSO (50.0 ml) and PLGA (5.0 g)(10K MW, hydrophilic end groups) copolymer was prepared at room temperature. To 3.0 ml of the polymer solution was added 0.233 g of azaline B acetate, and allowed to dissolve.
2) The solution from step I was atomized by an ultrasonic atomizing probe (Sonics & Materials #630-0507) at a constant flow rate of 0.3 ml/minute.
3) The atomized droplets were frozen upon passage through a cold nitrogen gas phase and then into liquid nitrogen. The liquid nitrogen layer was placed over a frozen non-solvent phase (75% heptane; 25% ethanol, v/v).
4) The liquid nitrogen layer containing the frozen droplets was allowed to evaporate at -80 C. The frozen non-solvent phase was allowed to melt at -80 C and the polymer/active agent solvent (DMSO) was extracted from the frozen droplets over an 18 hour incubation time at -80 C employing a mixture of heptane/ethanol (75:25) as the cure phase.
5) The microparticles were separated from the cure phase by filtration and freeze-dried.

6) The dry product was sieved through a 180 m mesh sieve.

Microparticles containing a 49% and a 41 % load of azaline B (Figure 3) were also prepared employing the process of Example 1.1.

EXAMPLE 2: POLYMER SOLVENT/POLYMER NON-SOLVENT
The general procedure for the formation of microparticles using a mixture of polymer solvent/polymer non-solvent, is similar to the Polymer Solvent Method, described above, with the exception that the continuous phase comprises a polymer solvent/polymer non-solvent mixture. This method provides for the solubilization of active agents such as tRNA and ovalbumin, which are not readily soluble in polymer solvents. In the example described below the polymer non-solvent employed was water.

The polymer solvent/water mixture was formulated such that the addition of water to the system increased the solubility of the active agent, but did not exceed the concentration at which substantial precipitation of the polymer would result. In addition, the polymer non-solvent can be used to predissolve the active agent;
the resulting solution can then be added to the polymer solution such that a transient continuous phase results. The transient continuous phase can be further processed prior to precipitation of the active agent or polymer.
A specific example of this method is the manufacture of a device comprising D,L-PLA (100% D,L-Poly(lactic acid), 5K MW) and ovalbumin at a 1% (w/w) load.
1) A 5% (w/v) D,L-PLA solution was prepared by dissolving D,L-PLA in DMSO at 50 mg D,L-PLA per ml of DMSO.
2) The active agent ovalbumin was dissolved in deionized water at a concentration of 100 mg/ml. 20 microliters of the aqueous solution was added to 39.6 ml of the polymer solution in a dropwise manner, with mixing.
3) The solution from step 2 was atomized by an air atomization. The atomized droplets are collected in a-70 C cure phase (ethanol), resulting in formation of the polymer matrix, with drug distributed throughout.
4) The microparticles were separated from the cure phase by filtration and freeze-dried.

5) The dry product was sieved through a 180 m mesh sieve.

'EXAMPLE 3: POLYMER SOLVENT/POLYMER NON-SOLVENT
The general procedure for the formation of microparticles using a mixture of a polymer solvent and a polymer non-solvent, is similar to the Polymer Solvent Method, described in detail above, with the exception that the continuous phase is comprised of a polymer solvent and a polymer non-solvent, for example, DMSO
and ethanol. It is understood that the polymer non-solvent in this example is also an active agent non-solvent.

A specific example of this method is the manufacture of a sustained release device comprising PLGA and azaline B acetate at a 60% (w/w) load.
1) A 10% (w/v) solution of PLGA copolymer (10K MW, hydrophilic end groups) in a mixture of DMSO/ethanol (75:25 v/v) was prepared.
2) Azaline B acetate, in dry powder form was dissolved in the polymer solution at approximately room temperature to give a final concentration of 0.233g of azaline B acetate per ml of polymer solution.
3) The solution from step 2 was atomized by an ultrasonic atomizing probe (Sonics & Materials #630-0507) at a constant flow rate of 0.3 mi/minute.
4) The atomized droplets were frozen upon passage through a cold nitrogen gas phase and then into liquid nitrogen. The liquid nitrogen layer was placed over a frozen non-solvent phase (100% ethanol).
5) The liquid nitrogen layer containing the frozen droplets was allowed to evaporate at -80 C. The frozen non-solvent phase was allowed to melt at -80 C and the polymer solvent/active agent non-solvent (DMSO/ethanol) was extracted from the frozen droplets over an 18 hour incubation time at -80 C
employing ethanol as the cure phase.
6) The microparticles were separated from the cure phase by filtration and freeze-dried.
7) The dry product was sieved through a 180 m mesh sieve.

Microparticles containing a 54% and a 68% load of azaline B (depicted in Figure 2) were also prepared employing this process.

EXAMPLE 4: POLYMER SOLVENT/ACTIVE AGENT NON-SOLVENT
(OLIVE OIL CURE PHASE) The general procedure for the formation of microparticles using a mixture of polymer solvent/active agent non-solvent, is similar to the Polymer Solvent Method, described in detail above, with the exception that the continuous phase comprises a polymer solvent/active agent non-solvent.
A specific example of this method, is the preparation of a sustained release device comprising PLGA and azaline B at a load 70% (w/w) active agent.
1) A 10% (w/v) solution of PLGA copolymer (10K MW, hydrophilic end groups) in a mixture of DMSO/acetone (80:20 v/v) was prepared.
2) Azaline B acetate, in dry powder form was dissolved in the polymer solution at room temperature to give a final concentration of 0.233 g of azaline B per ml of polymer solution.
3) The solution resulting from step 2 was atomized by an ultrasonic atomizing probe (Sonics & Materials #630-0507) at a constant flow rate of 0.3 ml/minute.
4) The atomized droplets were frozen upon contact with cold (4 C) olive oil.
5) The polymer solvent/active agent non-solvent (DMSO/acetone) was extracted from the frozen droplets over a 7 day incubation time at 4 C, with mixing.

6) The microparticles were separated from the oil by the formation of an emulsion in which the oil phase containing the microspheres was rapidly mixed with a 4X volume of a heptane/ethanol mixture (75:25 v/v). The microparticles were separated from the emulsion phase by filtration. The emulsion/filtration procedure was repeated 3 times.
7) The microparticles were separated from the final emulsion phase by filtration and freeze-dried.
8) The dry product was sieved through a 180 m mesh sieve.

EXAMPLE 4.1: POLYMER SOLVENT/ACTIVE AGENT NON-SOLVENT-65% (w/w) LOAD (HEPTANE/ETHANOL 75:25 CURE
PHASE) 1) A 10% (w/v) PLGA copolymer solution was prepared by dissolving PLGA
copolymer (10K MW, hydrophilic end groups) in a mixture of DMSO/acetone (80:20 v/v).
2) Azaline B acetate, in dry powder form was dissolved in the polymer solution at room temperature to give a final concentration of 0.233 g of azaline B per ml of polymer solution.
3) The solution resulting from step 2 was atomized by an ultrasonic atomizing probe (Sonics & Materials #630-0507) at a constant flow rate of 0.3 mUminute.
4) The atomized droplets were frozen upon passage through a cold nitrogen gas phase and then into liquid nitrogen. The liquid nitrogen layer was placed over a frozen non-solvent phase (75:25% v/v heptane:ethanol).
5) The liquid nitrogen layer containing the frozen droplets was allowed to evaporate at -80 C. The frozen non-solvent phase was allowed to melt at -80 C and the polymer solvent/active agent non-solvent (DMSO/acetone) was extracted from the frozen droplets over an 18 hour incubation time at -80 C employing a mixture of heptane/ethanol (75:25) as the cure phase.
6) The microparticles were separated from the non-solvent phase by filtration and freeze-dried.
7) The dry product was sieved through a 180 m mesh sieve.

EXAMPLE 4.2: POLYMER SOLVENT/ACTIVE AGENT NON-SOLVENT-68% (w/w) LOAD (ETHANOL CURE PHASE) 1) A 10% (w/v) PLGA copolymer solution was prepared by dissolving PLGA
copolymer (10K MW, hydrophilic end groups) in a mixture of DMSO/acetone (80:20 v/v).
2) Azaline B acetate, in dry powder form was dissolved in the polymer solution at room temperature to give a final concentration of 0.233 g of azaline B per ml of polymer solution.

3) The solution resulting from step 2 was atomized by an ultrasonic atomizing probe (Sonics & Materials #630-0507) at a constant flow rate of 0.3 ml/minute.
4) The atomized droplets were frozen upon passage through a cold nitrogen gas phase and then into liquid nitrogen. The liquid nitrogen layer was placed over a frozen non-solvent phase (ethanol).
5) The liquid nitrogen layer containing the frozen droplets was allowed to evaporate at -80 C. The frozen non-solvent phase was allowed to melt at -80 C and the polymer solvent/active agent non-solvent (DMSO/acetone) was extracted from the frozen droplets over an 18 hour incubation time at -80 C
employing ethanol as the cure phase.
6) The microparticles were separated from the non-solvent phase by filtration and freeze-dried.
7) The dry product was broken up by a gentle, manual grinding and passed through a 180 m mesh sieve.

EXAMPLE 5: MANUFACTURE OF STERILE PRODUCT USING THE
"MICROPARTICULATE METHOD"-POLYMER
SOLVENT/ACTIVE AGENT NON-SOLVENT
The method can be used to produce sterile product by enabling the sterile filtration (0.2 m) of the polymer/active agent solution, prior to further processing.
For example, the manufacture of a sterile 15% (w/w) loaded azaline B
acetate/PLGA formulation was performed as follows:
1) A 20% (w/v) solution of PLGA copolymer (10K MW, hydrophilic end groups) in dichloromethane was prepared by dissolving 0.2 g of PLGA per ml of dichloromethane. The polymer solution (639 ml) was introduced into a sterile vessel, equipped with a rotor-stator homogenizer, using 0.22 m filtration. The polymer solution was chilled to approximately -77 C.
2) Azaline B was dissolved in DMSO at a concentration of 12.5% (w/w) by dissolving 0.125 g of azaline B per gram of DMSO.

3) 135 g of the azaline B solution was introduced slowly into the sterile tank containing the polymer solution via 0.22 m filtration. The rotor-stator homogenizer was run immersed in the polymer solution and the temperature was maintained at approximately -77 C during the addition of the azaline B/DMSO solution.
4) The DMSO/azaline B solution freezes upon introduction to the cold polymer solution and is dispersed throughout the dichloromethane polymer solution by action of the rotor-stator homogenizer. As the DMSO and dichloromethane mix, peptide precipitates as a microsuspension.
5) The resulting microsuspension was atomized by air atomization and the droplets frozen by contact with liquid nitrogen.
6) The frozen droplets were mixed with an excess volume of ethanol upon which the DMSO and the dichloromethane were extracted to produce a polymer matrix with the active agent dispersed throughout.

The following Table summarizes the PLGA microparticles, prepared according to Examples 1 through 5. %Load and Encapsulation Efficiency were determined by analysis of the nitrogen content of the microparticles using a Elemental Analyzer available from Exeter Analytical, Inc., Lowell, MA.

Example Polynier/Active Process Freeze Phase Cure Phase Product Load Encapsulation %D
Phase (%w/w) Efficiency % Tar et 1.1 DMSO Atomization Liquid Nitrogen -80 C Etlianol Microparticles 63 90 1.2 DMSO Atomization Liquid Nitrogen -80 C Microparticles 63 90 Heptane/Ethanol y 75:25 2 DMSO/Water Atomization Ethanol (<0 C) -80 C Ethanol Microparticles 1 67 3 DMSO/F,tlianol Atomization Liquid Nitrogen -80 C Ethanol Microparticles 60 85 w o ~ o 4 DMSO/Acetone Atomization Liquid Nitrogen 4 C Olive Oil Microparticles 70 100 4.1 DMSO/Acetone Atomization Liquid Nitrogen -80 C Microparticles 65 93 Heptane/Ethanol 75:25 4.2 DMSO/Acetone Atomization Liquid Nitrogen -80 C Ethanol Microparticles 68 Methylene Atomization Liquid Nitrogen -80 C Ethanol Microparticles 15 (Sterile) 100 Cliloride/DMSO "Micro-particulate"

WO 99/15154 1'C3Y[]S98/39603 In Yivo Data EXAMPLE 6; RAT ESTROUS MODEL
The Rat Estrous Cyclicity Model is described in detail in Hahn er al., Biological Assays Utilized to Characte,rize LHRH and its Analogs. in: LERH and its Analogs, Contraception and T'herapeutia Applications (Eds. Vickery BH, Nestor rJ, and Hafez ESE), pp. 49-60. MTP Press Ltd, Lancaster, England,1984.
The model is used to assess the pharmacodynamic effect which an effective serum level of azaline B (at least 2.0 ng/ml), provided by the administration ofa sustained release devicc of the invention, has on the estrous cycle of the rat. When the minimum effective concentration of azaline B is present in serum, tlie estrus phase of the estrous cycle of the rat is suppressed and the rat remains in the diestrus phase of the estrous cycle.
Microparticles containing an effective amount of azaline B were prepared according to the "Particulate Method," described above, and the methods of 15 Examples 1 and 3. The presettce of azalirte B activity was measured as the percent of a test group which remained in the diestrus phase of the estrous cycle.
iAnimala were subcutaneously injected with equal amounts of azaline B either encapsulated in a tnicroparticle or unencapsulated. The injections employed a vehicle of 3%
carboxymethyI cellulose (low viseosity) and 1% Tween-20 in saline. The results are depicted in Figures I and 2 which show a plot of the percent of animals per treatment group in diestrnls for each formulation evaluated versus time.
Figure 1 show that rats treated with the particulate formulations, were observed to begin cycling after 8-10 days. The rats treated with the niicroparticles prepared according to the method of the invention, specifically Examples 1 and 3, as shown in Figure 2 had a ftirther delay in the onset of cycling, indicating the presence of an effective serum coneentration for a longer period of time.

EXAMPLE 7: EVALTJ1kTION OF AZALINE B SERUM LEVELS
Microparticles were processed using the "Particulate Method" described above and the methods of Examples 1 and 3. Animals were subcutaneously injected with equal amounts of araline B either encapsulated in a microparticle or unencapsulated. The injections employed a vehicle of 3% carboxymethyl cellulose (low viscosity) and 1% Tween-20 in saline. Serum levels (ng/ml) were determined at various times over a 28 day period and the results are show in Figure 3 as a plot of 'the concentration of azaline B (ng/ml), versus time. Serum levels were determined using an electrochemiluminescent immunoassay method. In this method quantitation is performed using an antibody that is specific for azaline B, and concentration is determined by comparison to a standard curve.
Briefly, the animals were anesthetized with halothane and blood samples were collected via a lateral tail vein. The blood was clotted at room temperature, centrifuged at approximately 6000xg for about five minutes and stored at -70 C until analysis could be performed.
Figure 3 is a graph of the serum levels of azaline B versus time. The Figure demonstrates that the release profile of high load microparticles prepared according the methods of Examples 1 and 3 was improved over that seen with microparticles prepared according to the "Particulate Method."
While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims (28)

What is claimed is:
1. A method of forming a polymer-based sustained release device comprising the steps of (a) forming a polymer/biologically active agent solution by mixing a polymer, a continuous phase comprising one or more polymer solvents and a biologically active agent wherein the polymer and biologically active agent are present in relative concentrations such that the device contains about 50% by weight or more of active agent;
(b) forming droplets of the polymer/biologically active agent solution;
(c) freezing the droplets of the polymer/biologically active agent solution;
and (d) removing the continuous phase of step (a) thereby forming a solid polymer/biologically active agent matrix.
2. The method of Claim 1 wherein the continuous phase further comprises a polymer non-solvent, wherein the amount of non-solvent achieves solubilization of the active agent and does not cause substantial precipitation of the polymer.
3. The method of Claim 2 wherein the non-solvent is ethanol.
4. The method of Claim 1 wherein the continuous phase further comprises an active agent non-solvent, wherein the amount of non-solvent achieves solubilization of the active agent and does not cause substantial precipitation of the polymer.
5. The method of Claim 1 wherein the continuous phase further comprises an active agent non-solvent, wherein the non-solvent achieves the active agent as a microparticulate in the continuous phase and does not cause substantial precipitation of the polymer.
6. The method of any one of Claims 1-5 wherein the continuous phase is removed by evaporation.
7. The method of Claim 6 wherein the continuous phase is removed by extraction.
8. The method of Claim 7 wherein the extraction solvent employed in the extraction step is an oil.
9. The method of any one of Claims 1-5 wherein the droplets are microdroplets.
10. The method of any one of Claims 1-5 wherein the continuous phase comprises DMSO.
11. The method of any one of Claims 1-5 wherein the biologically active agent is a peptide, an antigen or a small molecule drug.
12. The method of any one of Claims 1-5 wherein the biologically active agent is an LHRH analog.
13. The method of Claim 12 wherein the LHRH analog is azaline B.
14. The method of any one of Claims 1-5 wherein the polymer is selected from the group consisting of: poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, blends, and copolymers thereof.
15. A polymer-based sustained release device produced by a method comprising the steps of:

a) forming a polymer/biologically active agent solution by mixing a polymer, a continuous phase comprising one or more polymer solvents and a biologically active agent wherein the polymer and active agent are present in relative concentrations such that the device contains about 50% by weight or more of active agent;

b) forming droplets of the polymer/biologically active agent solution;

c) freezing the droplets of the polymer/biologically active agent solution;
and d) removing the continuous phase of step (a) thereby forming a solid polymer/biologically active agent matrix.
16. The polymer-based sustained release device of Claim 15 wherein the continuous phase further comprises a polymer non-solvent, wherein the amount of non-solvent achieves solubilization of the active agent and does not cause substantial precipitation of the polymer.
17. The polymer-based sustained release device of Claim 15 wherein the continuous phase further comprises an active agent non-solvent, wherein the amount of non-solvent achieves solubilization of the active agent and does not cause substantial precipitation of the polymer.
18. The polymer-based sustained release device of Claim 15 wherein the continuous phase further comprises an active agent non-solvent, wherein the amount of non-solvent achieves the active agent as a microparticulate in the continuous phase and does not cause substantial precipitation of the polymer.
19. The polymer-based sustained release device of any one of Claims 15-18, wherein the device is in the form of microparticles.
20. The polymer-based sustained release device of any one of Claims 15-18 wherein the continuous phase comprises DMSO.
21. The polymer-based sustained release device of any one of Claims 15-18 wherein the continuous phase is removed by extraction.
22. The polymer-based sustained release device of Claim 21 wherein the extraction solvent employed in the extraction step is an oil.
23. The polymer-based sustained release device of any one of-Claims 15-18 wherein the continuous phase is removed by evaporation.
24. The polymer-based sustained release device of any one of Claims 15-18, wherein the polymer is selected from the group consisting of poly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s, poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, blends, and copolymers thereof.
25. The polymer-based sustained release device of any one of Claims 15-18 wherein the active agent is a peptide, an antigen or a small molecule drug.
26. The polymer-based sustained release device of any one of Claims 15-18 wherein the active agent is an LHRH analog.
27. The polymer-based sustained release device of Claim 26 wherein the LHRH
analog is azaline B.
28. A use of the polymer-based sustained release device of any one of claims 15 to 27 for providing a dose of a therapeutically effective level of an active agent in a subject for a sustained period.
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Families Citing this family (411)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5922253A (en) * 1995-05-18 1999-07-13 Alkermes Controlled Therapeutics, Inc. Production scale method of forming microparticles
US5989463A (en) * 1997-09-24 1999-11-23 Alkermes Controlled Therapeutics, Inc. Methods for fabricating polymer-based controlled release devices
US6723517B1 (en) * 1998-06-02 2004-04-20 Minerva Biotechnologies Corporation Use of self-assembled monolayers to probe the structure of a target molecule
US6387410B1 (en) 1998-09-10 2002-05-14 Norton Healthcare Ltd Anti-inflammatory pharmaceutical formulations
US6514525B2 (en) 1998-09-10 2003-02-04 Norton Healthcare Ltd Anti-inflammatory pharmaceutical formulations
EP1074248A1 (en) * 1999-07-08 2001-02-07 Arnold Hilgers Delivery system for biological material
US6458387B1 (en) * 1999-10-18 2002-10-01 Epic Therapeutics, Inc. Sustained release microspheres
JP4992068B2 (en) 2000-01-27 2012-08-08 メディミューン,エルエルシー Ultra high affinity neutralizing antibody
US7229619B1 (en) 2000-11-28 2007-06-12 Medimmune, Inc. Methods of administering/dosing anti-RSV antibodies for prophylaxis and treatment
CA2401652A1 (en) * 2000-03-01 2001-09-07 Medimmune, Inc. High potency recombinant antibodies and method for producing them
US7074803B2 (en) * 2001-03-02 2006-07-11 Durect Corporation Opioid formulations
ATE449596T1 (en) * 2000-08-15 2009-12-15 Univ Illinois METHOD FOR PRODUCING MICROPARTICLES
US6824822B2 (en) * 2001-08-31 2004-11-30 Alkermes Controlled Therapeutics Inc. Ii Residual solvent extraction method and microparticles produced thereby
US7666445B2 (en) 2000-10-20 2010-02-23 The Trustees Of The University Of Pennsylvania Polymer-based surgically implantable haloperidol delivery systems and methods for their production and use
DE60138641D1 (en) 2000-10-27 2009-06-18 Baxter Healthcare Sa PREPARATION OF MICRO BEADS
TWI327600B (en) 2000-11-28 2010-07-21 Medimmune Llc Methods of administering/dosing anti-rsv antibodies for prophylaxis and treatment
US7179900B2 (en) * 2000-11-28 2007-02-20 Medimmune, Inc. Methods of administering/dosing anti-RSV antibodies for prophylaxis and treatment
US6818216B2 (en) * 2000-11-28 2004-11-16 Medimmune, Inc. Anti-RSV antibodies
US6855493B2 (en) * 2000-11-28 2005-02-15 Medimmune, Inc. Methods of administering/dosing anti-RSV antibodies for prophylaxis and treatment
EP2357187A1 (en) 2000-12-12 2011-08-17 MedImmune, LLC Molecules with extended half-lives, compositions and uses thereof
EP1355666B1 (en) 2000-12-22 2012-06-13 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Use of repulsive guidance molecule (RGM) and its modulators
US20040096451A1 (en) * 2002-07-25 2004-05-20 Young James F. Methods of treating and preventing RSV, hMPV, and PIV using anti-RSV, anti-hMPV, and anti-PIV antibodies
US20030044406A1 (en) * 2001-03-02 2003-03-06 Christine Dingivan Methods of preventing or treating inflammatory or autoimmune disorders by administering CD2 antagonists in combination with other prophylactic or therapeutic agents
US6730772B2 (en) 2001-06-22 2004-05-04 Venkatram P. Shastri Degradable polymers from derivatized ring-opened epoxides
DE60226613D1 (en) * 2001-08-16 2008-06-26 Baxter Int PHARMACEUTICAL FORMS CONTAINING MICROPARTICLES AND GAS
US6818613B2 (en) 2001-11-07 2004-11-16 Ortho-Mcneil Pharmaceutical, Inc. Aqueous sustained-release formulations of proteins
US8133501B2 (en) 2002-02-08 2012-03-13 Boston Scientific Scimed, Inc. Implantable or insertable medical devices for controlled drug delivery
US8685427B2 (en) 2002-07-31 2014-04-01 Boston Scientific Scimed, Inc. Controlled drug delivery
US7132100B2 (en) 2002-06-14 2006-11-07 Medimmune, Inc. Stabilized liquid anti-RSV antibody formulations
US7425618B2 (en) * 2002-06-14 2008-09-16 Medimmune, Inc. Stabilized anti-respiratory syncytial virus (RSV) antibody formulations
US8920826B2 (en) 2002-07-31 2014-12-30 Boston Scientific Scimed, Inc. Medical imaging reference devices
PT1534335E (en) 2002-08-14 2012-02-28 Macrogenics Inc Fcgammariib-specific antibodies and methods of use thereof
PT2301965E (en) 2002-10-16 2015-05-20 Purdue Pharma Lp Antibodies that bind cell-associated ca 125/o722p and methods of use thereof
US6800663B2 (en) * 2002-10-18 2004-10-05 Alkermes Controlled Therapeutics Inc. Ii, Crosslinked hydrogel copolymers
KR100709015B1 (en) * 2002-11-13 2007-04-18 (주)아모레퍼시픽 Polymeric microparticulates for sustained release of drug and their preparation methods
JP4838706B2 (en) 2003-01-06 2011-12-14 コリクサ コーポレイション Certain aminoalkyl glucosaminidophosphate compounds and their use
US7960522B2 (en) 2003-01-06 2011-06-14 Corixa Corporation Certain aminoalkyl glucosaminide phosphate compounds and their use
CA2512729C (en) 2003-01-09 2014-09-16 Macrogenics, Inc. Identification and engineering of antibodies with variant fc regions and methods of using same
BRPI0406724A (en) 2003-01-13 2005-12-20 Macrogenics Inc Dimeric fusion protein, methods of treating, preventing or ameliorating one or more symptoms of an autoimmune disorder and one or more symptoms of idiopathic thrombocytopenic purpura, pharmaceutical composition, nucleic acid, vector, host cell, method of recombinantly producing polypeptide, isolated polypeptide , fragment of either polypeptide, and, isolated nucleic acid molecule
US7658998B2 (en) * 2003-01-22 2010-02-09 Alkermes Controlled Therapeutics, Inc. Method of preparing sustained release microparticles
DE10303974A1 (en) 2003-01-31 2004-08-05 Abbott Gmbh & Co. Kg Amyloid β (1-42) oligomers, process for their preparation and their use
EP2656854B1 (en) 2003-02-04 2015-05-20 Cornell Research Foundation, Inc. Uses of aromatic-cationic peptide
US7736391B2 (en) 2003-02-06 2010-06-15 Tonaba Healthscience Ii, Llc Cosmetic and reconstructive prostheses with a microencapsulated biologically compatible rupture indicator for sustained release and methods of detecting compromise of a prosthesis
AU2004224530A1 (en) * 2003-03-26 2004-10-07 Ltt Bio-Pharma Co., Ltd. Intravenous nanoparticles for targenting drug delivery and sustained drug release
KR20110094361A (en) 2003-04-11 2011-08-23 메디뮨 엘엘씨 Recombinant il-9 antibodies and uses thereof
DK1625149T3 (en) 2003-05-01 2016-05-30 Cornell Res Foundation Inc METHOD AND carrying complexes for delivery of molecules to cells
US7326571B2 (en) * 2003-07-17 2008-02-05 Boston Scientific Scimed, Inc. Decellularized bone marrow extracellular matrix
RU2426590C2 (en) * 2003-07-18 2011-08-20 Бакстер Интернэшнл Инк. Method of production, use and composition of minor spherical particles produced in controlled phase separation
US20070092452A1 (en) * 2003-07-18 2007-04-26 Julia Rashba-Step Methods for fabrication, uses, compositions of inhalable spherical particles
US20050142205A1 (en) * 2003-07-18 2005-06-30 Julia Rashba-Step Methods for encapsulating small spherical particles prepared by controlled phase separation
EP1646354A4 (en) * 2003-07-22 2010-03-17 Baxter Int Small spherical particles of low molecular weight organic molecules and methods of preparation and use thereof
JP4934426B2 (en) 2003-08-18 2012-05-16 メディミューン,エルエルシー Antibody humanization
EP2441474B1 (en) 2003-10-17 2015-08-05 Joslin Diabetes Center, Inc. Methods and compositions for modulating adipocyte function
US7309500B2 (en) * 2003-12-04 2007-12-18 The Board Of Trustees Of The University Of Illinois Microparticles
US20060053516A1 (en) * 2003-12-05 2006-03-09 The University Of Hong Kong Genetically modified plants comprising SARS-CoV viral nucleotide sequences and methods of use thereof for immunization against SARS
US7371381B2 (en) 2003-12-12 2008-05-13 Amgen Inc. Anti-galanin antibodies and uses thereof
US8329203B2 (en) 2004-01-12 2012-12-11 The Trustees Of The University Of Pennsylvania Drug-containing implants and methods of use thereof
US8221778B2 (en) 2005-01-12 2012-07-17 The Trustees Of The University Of Pennsylvania Drug-containing implants and methods of use thereof
US20050220887A1 (en) * 2004-01-20 2005-10-06 Alkermes Controlled Therapeutics, Inc. Method for milling frozen microparticles
RU2376028C2 (en) 2004-01-23 2009-12-20 Корнелл Рисеч Фаундейшн, Инк. Method for reduction of oxidising injury (versions)
KR101040415B1 (en) * 2004-04-15 2011-06-09 알케르메스,인코포레이티드 Polymer-based sustained release device
CN103393601A (en) 2004-05-12 2013-11-20 巴克斯特国际公司 Microspheres comprising protein and showing injectability at high concentration of protein
US8728525B2 (en) 2004-05-12 2014-05-20 Baxter International Inc. Protein microspheres retaining pharmacokinetic and pharmacodynamic properties
PT1758558E (en) * 2004-05-12 2013-12-05 Baxter Healthcare Sa Oligonucleotide-containing microspheres, their use for the manufacture of a medicament for treating diabetes type 1
WO2005112894A1 (en) 2004-05-12 2005-12-01 Baxter International Inc. Nucleic acid microspheres, production and delivery thereof
JP2008507540A (en) 2004-07-21 2008-03-13 チューレン ユニバーシティ ヘルス サイエンス センター Treatment of renal dysfunction and multiple myeloma using PACAP compounds
JP2008513540A (en) 2004-09-21 2008-05-01 メディミューン,インコーポレーテッド Antibody to respiratory syncytial virus and method for producing vaccine for the virus
JP2008518023A (en) 2004-10-27 2008-05-29 メディミューン,インコーポレーテッド Regulation of antibody specificity by altering affinity for cognate antigens
US20060115485A1 (en) * 2004-10-29 2006-06-01 Medimmune, Inc. Methods of preventing and treating RSV infections and related conditions
US7748343B2 (en) 2004-11-22 2010-07-06 The Board Of Trustees Of The University Of Illinois Electrohydrodynamic spraying system
WO2006060779A2 (en) * 2004-12-03 2006-06-08 Case Western Reserve University Novel methods, compositions and devices for inducing neovascularization
WO2006078841A1 (en) * 2005-01-21 2006-07-27 President And Fellows Of Harvard College Systems and methods for forming fluidic droplets encapsulated in particles such as colloidal particles
US11246913B2 (en) 2005-02-03 2022-02-15 Intarcia Therapeutics, Inc. Suspension formulation comprising an insulinotropic peptide
AU2006227377B2 (en) 2005-03-18 2013-01-31 Medimmune, Llc Framework-shuffling of antibodies
AU2006236439B2 (en) 2005-04-15 2012-05-03 Macrogenics, Inc. Covalent diabodies and uses thereof
WO2012018687A1 (en) 2010-08-02 2012-02-09 Macrogenics, Inc. Covalent diabodies and uses thereof
MX2007013213A (en) * 2005-04-25 2007-12-12 Amgen Inc Biodegradable peptide sustained release compositions containing porogens.
US8017152B2 (en) 2005-05-27 2011-09-13 Stratosphere Pharma Ab Cores and microcapsules suitable for parenteral administration as well as process for their manufacture
KR20080025174A (en) 2005-06-23 2008-03-19 메디뮨 인코포레이티드 Antibody formulations having optimized aggregation and fragmentation profiles
BRPI0611714A2 (en) 2005-06-30 2009-01-13 Abbott Lab il-12 / p40 binding proteins
CA2618681C (en) 2005-08-10 2015-10-27 Macrogenics, Inc. Identification and engineering of antibodies with variant fc regions and methods of using same
EP2500354A3 (en) 2005-08-19 2012-10-24 Abbott Laboratories Dual variable domain immunoglobulin and uses thereof
US20090215992A1 (en) * 2005-08-19 2009-08-27 Chengbin Wu Dual variable domain immunoglobulin and uses thereof
JP5364870B2 (en) 2005-08-19 2013-12-11 アッヴィ・インコーポレイテッド Dual variable domain immunoglobulins and uses thereof
US7612181B2 (en) * 2005-08-19 2009-11-03 Abbott Laboratories Dual variable domain immunoglobulin and uses thereof
CN103784937B (en) 2005-09-16 2017-04-26 科内尔研究基金会 Methods for reducing CD36 expression
JP2009510002A (en) 2005-09-30 2009-03-12 アボット ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト Binding domains of proteins of the repulsion-inducing molecule (RGM) protein family, and functional fragments thereof, and uses thereof
WO2007064972A2 (en) 2005-11-30 2007-06-07 Abbott Laboratories Monoclonal antibodies against amyloid beta protein and uses thereof
PL1954718T3 (en) 2005-11-30 2015-04-30 Abbvie Inc Anti-a globulomer antibodies, antigen-binding moieties thereof, corresponding hybridomas, nucleic acids, vectors, host cells, methods of producing said antibodies, compositions comprising said antibodies, uses of said antibodies and methods of using said antibodies
JP5131971B2 (en) * 2005-12-26 2013-01-30 株式会社Lttバイオファーマ Water-soluble non-peptide low molecular weight drug-containing nanoparticles
WO2007100895A2 (en) 2006-02-27 2007-09-07 The Johns Hopkins University Cancer treatment with gamma-secretase inhibitors
US8747870B2 (en) 2006-04-20 2014-06-10 University Of Utah Research Foundation Polymeric compositions and methods of making and using thereof
CA2649915A1 (en) * 2006-04-20 2007-11-01 University Of Utah Research Foundation Polymeric compositions and methods of making and using thereof
US20070281031A1 (en) * 2006-06-01 2007-12-06 Guohan Yang Microparticles and methods for production thereof
SG10201504662WA (en) 2006-06-14 2015-07-30 Macrogenics Inc Methods For The Treatment Of Autoimmune Disorders Using Immunosuppressive Monoclonal Antibodies With Reduced Toxicity
EP2505209A1 (en) 2006-06-26 2012-10-03 MacroGenics, Inc. Fcgamma-RIIB-specific antibodies and methods of the use thereof
US20080075777A1 (en) * 2006-07-31 2008-03-27 Kennedy Michael T Apparatus and methods for preparing solid particles
CN105168146A (en) 2006-08-04 2015-12-23 巴克斯特国际公司 Microsphere-based composition for preventing and/or reversing new-onset autoimmune diabetes
WO2008021133A2 (en) 2006-08-09 2008-02-21 Intarcia Therapeutics, Inc. Osmotic delivery systems and piston assemblies
MY162024A (en) 2006-08-28 2017-05-31 La Jolla Inst Allergy & Immunology Antagonistic human light-specific human monoclonal antibodies
CA3053981C (en) 2006-09-07 2022-07-12 Scott & White Memorial Hospital Methods and compositions based on diphtheria toxin-interleukin-3 conjugates
KR101625961B1 (en) 2006-09-08 2016-05-31 애브비 바하마스 리미티드 Interleukin-13 binding proteins
US20100143254A1 (en) 2006-10-16 2010-06-10 Medimmune, Llc Molecules with reduced half-lives, compositions and uses thereof
US20080121733A1 (en) * 2006-11-29 2008-05-29 Donald Ackley Droplet generating device and method
US8455626B2 (en) 2006-11-30 2013-06-04 Abbott Laboratories Aβ conformer selective anti-aβ globulomer monoclonal antibodies
BRPI0720582B1 (en) 2006-12-18 2021-08-24 Takeda Pharmaceutical Company Limited PROLONGED RELEASE COMPOSITION, PROCESS FOR THE PREPARATION OF THE SAME, PHARMACEUTICAL COMPOSITION, PROPHYLATIC OR THERAPEUTIC AGENT, AND, USE OF A PHYSIOLOGICALLY ACTIVE SUBSTANCE
WO2008101116A1 (en) * 2007-02-14 2008-08-21 Brigham And Women's Hospital, Inc. Crosslinked polymers and methods of making the same
EP2124952A2 (en) 2007-02-27 2009-12-02 Abbott GmbH & Co. KG Method for the treatment of amyloidoses
NZ580447A (en) 2007-04-23 2011-06-30 Intarcia Therapeutics Inc Suspension formulations of insulinotropic peptides and uses thereof
WO2008134807A1 (en) * 2007-05-04 2008-11-13 The University Of Sydney Method for manufacturing a porous polymer matrix
CN101678113B (en) * 2007-05-14 2012-05-30 日本株式会社Ltt生物医药 Low-molecule drug-containing nanoparticle having sustained release negatively charged group
US20090232801A1 (en) * 2007-05-30 2009-09-17 Abbot Laboratories Humanized Antibodies Which Bind To AB (1-42) Globulomer And Uses Thereof
PE20090329A1 (en) * 2007-05-30 2009-03-27 Abbott Lab HUMANIZED ANTIBODIES AGAINST GLOBULOMER AB (20-42) AND ITS USES
EP1997830A1 (en) 2007-06-01 2008-12-03 AIMM Therapeutics B.V. RSV specific binding molecules and means for producing them
KR101799337B1 (en) 2007-06-21 2017-12-20 마크로제닉스, 인크. Covalent diabodies and uses thereof
EP2626371A1 (en) 2007-07-31 2013-08-14 MedImmune, LLC Multispecific epitope binding proteins and uses thereof
US8728528B2 (en) 2007-12-20 2014-05-20 Evonik Corporation Process for preparing microparticles having a low residual solvent volume
BRPI0907046A2 (en) 2008-01-18 2015-07-28 Medimmune Llc Engineered cysteine antibody, isolated nucleic acid, vector, host cell, antibody conjugate, pharmaceutical composition, methods of detecting cancer, autoimmune, inflammatory or infectious disorders in an individual and inhibiting proliferation of a target cell
US8420088B2 (en) 2008-01-28 2013-04-16 Novartis Ag Methods and compositions using FGF23 fusion polypeptides
TW200936156A (en) 2008-01-28 2009-09-01 Novartis Ag Methods and compositions using Klotho-FGF fusion polypeptides
CN101939019B (en) 2008-02-07 2014-07-16 康奈尔大学 Methods for preventing or treating insulin resistance
US8343140B2 (en) 2008-02-13 2013-01-01 Intarcia Therapeutics, Inc. Devices, formulations, and methods for delivery of multiple beneficial agents
CN104056248A (en) 2008-02-26 2014-09-24 康奈尔大学 Methods For Prevention And Treatment Of Acute Renal Injury
US8962803B2 (en) 2008-02-29 2015-02-24 AbbVie Deutschland GmbH & Co. KG Antibodies against the RGM A protein and uses thereof
AU2009218436A1 (en) * 2008-02-29 2009-09-03 Coloplast A/S Compositions and methods for augmentation and regeneration of living tissue in a subject
KR20110014607A (en) 2008-04-29 2011-02-11 아보트 러보러터리즈 Dual variable domain immunoglobulins and uses thereof
CN102083969A (en) 2008-05-06 2011-06-01 乔斯林糖尿病中心股份有限公司 Methods and compositions for inducing brown adipogenesis
CA2723219A1 (en) 2008-05-09 2009-11-12 Abbott Gmbh & Co. Kg Antibodies to receptor of advanced glycation end products (rage) and uses thereof
US9109026B2 (en) 2008-06-03 2015-08-18 Abbvie, Inc. Dual variable domain immunoglobulins and uses thereof
EP3002299A1 (en) 2008-06-03 2016-04-06 AbbVie Inc. Dual variable domain immunoglobulins and uses thereof
US9216152B2 (en) * 2008-06-27 2015-12-22 Tepha, Inc. Injectable delivery of microparticles and compositions therefore
EP2810654A1 (en) 2008-07-08 2014-12-10 AbbVie Inc. Prostaglandin E2 binding proteins and uses thereof
CA2729949A1 (en) 2008-07-08 2010-01-14 Abbott Laboratories Prostaglandin e2 dual variable domain immunoglobulins and uses thereof
US8323615B2 (en) 2008-08-20 2012-12-04 Baxter International Inc. Methods of processing multi-phasic dispersions
US8323685B2 (en) 2008-08-20 2012-12-04 Baxter International Inc. Methods of processing compositions containing microparticles
US8367427B2 (en) 2008-08-20 2013-02-05 Baxter International Inc. Methods of processing compositions containing microparticles
JP6049260B2 (en) 2008-10-10 2016-12-21 ダナ ファーバー キャンサー インスティテュート インコーポレイテッド Chemical modulators of pro-apoptotic BAX and BCL-2 polypeptides
CN102143996A (en) * 2008-10-30 2011-08-03 大卫·刘 Micro-spherical porous biocompatible scaffolds and methods and apparatus for fabricating same
EP3549951A3 (en) 2008-12-09 2019-11-20 Dana Farber Cancer Institute, Inc. Methods and compositions for specific modulation of mcl-1
MX2011006416A (en) 2008-12-19 2011-07-12 Macrogenics Inc Covalent diabodies and uses thereof.
JP2012515790A (en) * 2009-01-23 2012-07-12 サーモディクス ファーマシューティカルズ, インコーポレイテッド Continuous double emulsion process for fine particle production
RU2011135768A (en) * 2009-01-29 2013-03-10 Эбботт Лэборетриз PROTEINS BINDING IL-1
US20110165063A1 (en) * 2009-01-29 2011-07-07 Abbott Laboratories Il-1 binding proteins
WO2010087927A2 (en) 2009-02-02 2010-08-05 Medimmune, Llc Antibodies against and methods for producing vaccines for respiratory syncytial virus
US8030026B2 (en) * 2009-02-24 2011-10-04 Abbott Laboratories Antibodies to troponin I and methods of use thereof
PE20121094A1 (en) 2009-03-05 2012-09-13 Abbvie Inc IL-17 BINDING PROTEINS
US8283162B2 (en) 2009-03-10 2012-10-09 Abbott Laboratories Antibodies relating to PIVKAII and uses thereof
EP3563862B1 (en) 2009-03-20 2021-05-05 The General Hospital Corporation d/b/a Massachusetts General Hospital D-arg-2'6'-dimethyltyrosine-lys-phe-nh2 for use in the prevention of secondary complications of burn injuries
WO2010141329A1 (en) 2009-06-01 2010-12-09 Medimmune, Llc Molecules with extended half-lives and uses thereof
AU2010270979B2 (en) 2009-06-22 2015-04-23 Medimmune, Llc Engineered Fc regions for site-specific conjugation
WO2011020079A1 (en) * 2009-08-13 2011-02-17 Calmune Corporation Antibodies against human respiratory syncytial virus (rsv) and methods of use
EP3292868A1 (en) 2009-08-24 2018-03-14 Stealth Peptides International, Inc. Methods and compositions for preventing or treating opthalmic conditions
MX2012002605A (en) 2009-08-29 2012-04-02 Abbott Lab Therapeutic dll4 binding proteins.
IN2012DN02737A (en) * 2009-09-01 2015-09-11 Abbott Lab
WO2011035205A2 (en) 2009-09-18 2011-03-24 Calmune Corporation Antibodies against candida, collections thereof and methods of use
NZ624569A (en) 2009-09-28 2016-01-29 Intarcia Therapeutics Inc Rapid establishment and/or termination of substantial steady-state drug delivery
CA2776581C (en) 2009-10-05 2020-12-15 Cornell University Methods for the prevention or treatment of heart failure
US8568726B2 (en) 2009-10-06 2013-10-29 Medimmune Limited RSV specific binding molecule
PL2486141T3 (en) 2009-10-07 2018-07-31 Macrogenics, Inc. Fc region-containing polypeptides that exhibit improved effector function due to alterations of the extent of fucosylation, and methods for their use
CA2775959A1 (en) 2009-10-15 2011-04-21 Abbott Laboratories Dual variable domain immunoglobulins and uses thereof
UY32979A (en) 2009-10-28 2011-02-28 Abbott Lab IMMUNOGLOBULINS WITH DUAL VARIABLE DOMAIN AND USES OF THE SAME
US8420083B2 (en) * 2009-10-31 2013-04-16 Abbvie Inc. Antibodies to receptor for advanced glycation end products (RAGE) and uses thereof
JP5908406B2 (en) 2009-11-02 2016-04-26 ジ アドミニストレーターズ オブ ザ トゥレーン エデュケーショナル ファンド Pituitary adenylate cyclase activating polypeptide (PACAP) analogs and methods of use thereof
CA2780069C (en) 2009-12-08 2018-07-17 Abbott Gmbh & Co. Kg Monoclonal antibodies against the rgm a protein for use in the treatment of retinal nerve fiber layer degeneration
WO2011082328A1 (en) 2009-12-31 2011-07-07 Stealth Peptides International, Inc. Methods for performing a coronary artery bypass graft procedure
AU2010339410A1 (en) 2009-12-31 2012-07-19 Stealth Peptides International, Inc. Methods for the prevention or treatment of vessel occlusion injury
AU2011207432A1 (en) 2010-01-25 2012-08-02 Cornell University Aromatic-cationic peptides and uses of same
EP3167896A1 (en) 2010-02-26 2017-05-17 University of Florida Research Foundation, Inc. Mitochondrial-targeted antioxidants protect against mechanical ventilation-induced diaphragm dysfunction and skeletal muscle atrophy
SG10201501562VA (en) 2010-03-02 2015-04-29 Abbvie Inc Therapeutic dll4 binding proteins
EP3040080A1 (en) 2010-03-15 2016-07-06 Stealth Peptides International, Inc. Combination therapies using cyclosporine and aromatic cationic peptides
WO2011130377A2 (en) 2010-04-15 2011-10-20 Abbott Laboratories Amyloid-beta binding proteins
JP2013532124A (en) 2010-05-03 2013-08-15 ステルス ペプチドズ インターナショナル インコーポレイテッド Aromatic cationic peptides and uses thereof
NZ603829A (en) 2010-05-06 2015-03-27 Novartis Ag Compositions and methods of use for therapeutic low density lipoprotein -related protein 6 (lrp6) antibodies
SG185415A1 (en) 2010-05-06 2012-12-28 Novartis Ag Compositions and methods of use for therapeutic low density lipoprotein - related protein 6 (lrp6) multivalent antibodies
WO2011143562A2 (en) 2010-05-14 2011-11-17 Abbott Laboratories Il-1 binding proteins
US20120009196A1 (en) 2010-07-08 2012-01-12 Abbott Laboratories Monoclonal antibodies against hepatitis c virus core protein
CN107569675A (en) 2010-07-09 2018-01-12 康德生物医疗技术公司 The method of fluoride-free flux after prevention or treatment ischemia/reperfusion injury
NZ603488A (en) 2010-07-09 2015-02-27 Crucell Holland Bv Anti-human respiratory syncytial virus (rsv) antibodies and methods of use
UY33492A (en) 2010-07-09 2012-01-31 Abbott Lab IMMUNOGLOBULINS WITH DUAL VARIABLE DOMAIN AND USES OF THE SAME
US9120862B2 (en) 2010-07-26 2015-09-01 Abbott Laboratories Antibodies relating to PIVKA-II and uses thereof
SG188190A1 (en) 2010-08-03 2013-04-30 Abbott Lab Dual variable domain immunoglobulins and uses thereof
JP6147665B2 (en) 2010-08-14 2017-06-14 アッヴィ・インコーポレイテッド Amyloid beta-binding protein
EP3333188B1 (en) 2010-08-19 2022-02-09 Zoetis Belgium S.A. Anti-ngf antibodies and their use
SI2606070T1 (en) 2010-08-20 2017-04-26 Novartis Ag Antibodies for epidermal growth factor receptor 3 (her3)
CN103260639A (en) 2010-08-26 2013-08-21 Abbvie公司 Dual variable domain immunoglobulins and uses thereof
WO2012050673A1 (en) 2010-10-14 2012-04-19 Wisconsin Alumni Research Foundation Methods for the treatment of x-linked hypophosphatemia and related disorders
US20130245233A1 (en) 2010-11-24 2013-09-19 Ming Lei Multispecific Molecules
US20120275996A1 (en) 2010-12-21 2012-11-01 Abbott Laboratories IL-1 Binding Proteins
MY163368A (en) 2010-12-21 2017-09-15 Abbvie Inc Il-1-alpha and -beta bispecific dual variable domain immunoglobulins and their use
US20120208755A1 (en) 2011-02-16 2012-08-16 Intarcia Therapeutics, Inc. Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers
CN103796665B (en) 2011-03-24 2018-10-30 康奈尔大学 Aromatic-cationic peptides and application thereof
EP2699264B1 (en) 2011-04-20 2018-03-14 Medlmmune, LLC Antibodies and other molecules that bind b7-h1 and pd-1
NZ618016A (en) 2011-05-21 2015-05-29 Macrogenics Inc Deimmunized serum-binding domains and their use for extending serum half-life
EP3574919A1 (en) 2011-07-13 2019-12-04 AbbVie Inc. Methods and compositions for treating asthma using anti-il-13 antibodies
CA2845536A1 (en) 2011-08-15 2013-02-21 Amplimmune, Inc. Anti-b7-h4 antibodies and their uses
WO2013027191A1 (en) 2011-08-25 2013-02-28 Novartis Ag Methods and compositions using fgf23 fusion polypeptides
AU2012310328A1 (en) 2011-09-23 2014-04-10 Technophage, Investigação E Desenvolvimento Em Biotecnologia, S.A. Anti-Tumor Necrosis Factor-alpha agents and uses thereof
JP6157481B2 (en) 2011-09-29 2017-07-05 メイヨ ファンデーション フォア メディカル エディケイション アンド リサーチ Aromatic cationic peptides and methods of use thereof
JP6346092B2 (en) 2011-10-17 2018-06-20 コーネル ユニヴァーシティー Aromatic cationic peptides and uses thereof
SG11201401791WA (en) 2011-10-24 2014-08-28 Abbvie Inc Immunobinders directed against sclerostin
TW201328707A (en) 2011-12-05 2013-07-16 Novartis Ag Antibodies for epidermal growth factor receptor 3 (HER3) directed to domain II of HER3
ES2758433T3 (en) 2011-12-05 2020-05-05 Novartis Ag Antibodies to epidermal growth factor receptor 3 (HER3)
CA2858550A1 (en) 2011-12-09 2013-06-13 Stealth Peptides International, Inc. Aromatic-cationic peptides and uses of same
JP6336397B2 (en) 2011-12-14 2018-06-06 アッヴィ・ドイチュラント・ゲー・エム・ベー・ハー・ウント・コー・カー・ゲー Compositions and methods for diagnosing and treating iron-related disorders
EP3800200A1 (en) 2011-12-14 2021-04-07 AbbVie Deutschland GmbH & Co. KG Composition and method for the diagnosis and treatment of iron-related disorders
EP3539982A3 (en) 2011-12-23 2020-01-15 Pfizer Inc Engineered antibody constant regions for site-specific conjugation and methods and uses therefor
CA2861610A1 (en) 2011-12-30 2013-07-04 Abbvie Inc. Dual specific binding proteins directed against il-13 and/or il-17
MX352772B (en) 2012-01-27 2017-12-07 Abbvie Deutschland Composition and method for diagnosis and treatment of diseases associated with neurite degeneration.
CN105343869A (en) 2012-02-22 2016-02-24 康德生物医疗技术公司 Methods and compositions for preventing or treating ophthalmic conditions
WO2013126775A1 (en) 2012-02-23 2013-08-29 Cornell University Aromatic-cationic peptides and uses of same
NZ630020A (en) 2012-03-08 2016-08-26 Halozyme Inc Conditionally active anti-epidermal growth factor receptor antibodies and methods of use thereof
US9585970B2 (en) 2012-06-04 2017-03-07 Novartis Ag Site-specific labeling methods and molecules produced thereby
US9617334B2 (en) 2012-06-06 2017-04-11 Zoetis Services Llc Caninized anti-NGF antibodies and methods thereof
US9670276B2 (en) 2012-07-12 2017-06-06 Abbvie Inc. IL-1 binding proteins
EP2879688A4 (en) 2012-08-02 2015-12-16 Stealth Peptides Int Inc Methods for treatment of atherosclerosis
CN110193077A (en) 2012-10-22 2019-09-03 康德生物医疗技术公司 The method for reducing relevant to heart failure risk and relative factor
BR112015009961B1 (en) 2012-11-01 2020-10-20 Abbvie Inc. binding protein capable of binding to dll4 and vegf, as well as a composition comprising it as a composition comprising it
RU2015115956A (en) 2012-11-09 2017-01-10 Пфайзер Инк. ANTIBODIES SPECIFIC TO THE THROMBOCYTE B GROWTH FACTOR, AND THEIR COMPOSITION AND APPLICATION
EP3287172A1 (en) 2012-12-06 2018-02-28 Stealth Peptides International, Inc. Combinations of peptide therapeutics and methods for using same
WO2014100483A1 (en) 2012-12-19 2014-06-26 Amplimmune, Inc. Anti-human b7-h4 antibodies and their uses
RU2691428C2 (en) 2012-12-21 2019-06-13 МЕДИММЬЮН, ЭлЭлСи Antibodies to h7cr
DK2953976T3 (en) 2013-02-08 2021-06-21 Novartis Ag SPECIFIC MODIFICATION PLACES IN ANTIBODIES FOR THE PRODUCTION OF IMMUNE CONJUGATES
WO2014124258A2 (en) 2013-02-08 2014-08-14 Irm Llc Specific sites for modifying antibodies to make immunoconjugates
HUE046924T2 (en) 2013-03-01 2020-03-30 Stealth Biotherapeutics Corp Methods and compositions for the prevention or treatment of barth syndrome
HUE046596T2 (en) 2013-03-01 2020-03-30 Stealth Biotherapeutics Corp Methods for the treatment of mitochondrial disease
US9498532B2 (en) 2013-03-13 2016-11-22 Novartis Ag Antibody drug conjugates
US9790478B2 (en) 2013-03-14 2017-10-17 Abbott Laboratories HCV NS3 recombinant antigens and mutants thereof for improved antibody detection
US9194873B2 (en) 2013-03-14 2015-11-24 Abbott Laboratories HCV antigen-antibody combination assay and methods and compositions for use therein
EP3611189A1 (en) 2013-03-14 2020-02-19 Novartis AG Antibodies against notch 3
CA2906417C (en) 2013-03-14 2022-06-21 Robert Ziemann Hcv core lipid binding domain monoclonal antibodies
CN105007950B (en) 2013-03-15 2019-01-15 诺华股份有限公司 Antibody drug conjugate
US9469686B2 (en) 2013-03-15 2016-10-18 Abbott Laboratories Anti-GP73 monoclonal antibodies and methods of obtaining the same
CN105324396A (en) 2013-03-15 2016-02-10 艾伯维公司 Dual specific binding proteins directed against il-1 beta and il-17
WO2014185952A1 (en) 2013-05-14 2014-11-20 Stealth Peptides International, Inc. Methods for the prevention or treatment of left ventricle remodeling
BR112015029395A2 (en) 2013-05-24 2017-09-19 Medimmune Llc ANTI-B7-H5 ANTIBODIES AND THEIR USES
ES2891755T3 (en) 2013-06-06 2022-01-31 Pf Medicament Anti-C10orf54 antibodies and uses thereof
CA2914566A1 (en) 2013-06-07 2014-12-11 Duke University Inhibitors of complement factor h
WO2015009414A1 (en) 2013-06-26 2015-01-22 Stealth Peptides International, Inc. Methods and compositions for regulating srca2a expression levels in myocardial infarction
WO2014209905A2 (en) 2013-06-26 2014-12-31 Stealth Peptides International, Inc. Methods and compositions for detecting and diagnosing diseases and conditions
CA2916497C (en) 2013-06-26 2022-07-12 Stealth Biotherapeutics Corp Methods for the regulation of matrix metalloproteinase expression
US10293020B2 (en) 2013-06-27 2019-05-21 Stealth Biotherapeutics Corp. Peptide therapeutics and methods for using same
CA2920020C (en) 2013-08-02 2023-03-14 Stealth Biotherapeutics Corp Methods and compositions for the prevention and treatment of friedreich's ataxia
US11384149B2 (en) 2013-08-09 2022-07-12 Macrogenics, Inc. Bi-specific monovalent Fc diabodies that are capable of binding CD32B and CD79b and uses thereof
UA116479C2 (en) 2013-08-09 2018-03-26 Макродженікс, Інк. Bi-specific monovalent fc diabodies that are capable of binding cd32b and cd79b and uses thereof
EP2840091A1 (en) 2013-08-23 2015-02-25 MacroGenics, Inc. Bi-specific diabodies that are capable of binding gpA33 and CD3 and uses thereof
EP2839842A1 (en) 2013-08-23 2015-02-25 MacroGenics, Inc. Bi-specific monovalent diabodies that are capable of binding CD123 and CD3 and uses thereof
KR20160055253A (en) 2013-09-12 2016-05-17 할로자임, 아이엔씨 Modified anti-epidermal growth factor receptor antibodies and methods of use thereof
CA2923772A1 (en) 2013-09-17 2015-03-26 University Health Network (Uhn): Technology Development And Commercialization Agents directed against a cis rgma/neogenin interaction or lipid rafts and use of the same in methods of treatment
WO2015058868A1 (en) 2013-10-25 2015-04-30 Pangaea Biotech, S.L. Compositions and methods for the treatment of cancer
WO2015066480A1 (en) 2013-11-01 2015-05-07 Regents Of The University Of Minnesota Protein scaffolds and methods of use
SG10201810298VA (en) 2013-11-13 2018-12-28 Pfizer Tumor necrosis factor-like ligand 1a specific antibodies and compositions and uses thereof
WO2015084875A1 (en) 2013-12-02 2015-06-11 Stealth Peptides International, Inc. Compositions and methods for treating vitiligo
CA2931978A1 (en) 2013-12-02 2015-06-11 Abbvie Inc. Compositions and methods for treating osteoarthritis
WO2015109212A1 (en) 2014-01-17 2015-07-23 Pfizer Inc. Anti-il-2 antibodies and compositions and uses thereof
UA119863C2 (en) 2014-01-24 2019-08-27 Нгм Біофармасьютікалс, Інк. Binding proteins and methods of use thereof
WO2015123241A1 (en) 2014-02-14 2015-08-20 Chi Andrew S Improved methods for the treatment of vascularizing cancers
EP3450571B1 (en) 2014-02-24 2023-04-05 Celgene Corporation Methods of using an activator of cereblon for neural cell expansion and the treatment of central nervous system disorders
GB201403775D0 (en) 2014-03-04 2014-04-16 Kymab Ltd Antibodies, uses & methods
US20150291689A1 (en) 2014-03-09 2015-10-15 Abbvie, Inc. Compositions and Methods for Treating Rheumatoid Arthritis
US20170021033A1 (en) 2014-03-12 2017-01-26 Novartis Ag Specific sites for modifying antibodies to make immunoconjugates
US9493568B2 (en) 2014-03-21 2016-11-15 Abbvie Inc. Anti-EGFR antibodies and antibody drug conjugates
WO2015175874A2 (en) 2014-05-16 2015-11-19 Medimmune, Llc Molecules with altered neonate fc receptor binding having enhanced therapeutic and diagnostic properties
US10576124B2 (en) 2014-05-28 2020-03-03 Stealth Biotherapeutics Corp Therapeutic compositions including frataxin, lactoferrin, and mitochondrial energy generating enzymes, and uses thereof
EP3149035A4 (en) 2014-05-28 2018-05-16 Stealth BioTherapeutics Corp Therapeutic compositions including therapeutic small molecules and uses thereof
KR102364383B1 (en) 2014-05-29 2022-02-17 마크로제닉스, 인크. Tri-specific binding molecules and methods of use thereof
US10627392B2 (en) 2014-06-17 2020-04-21 Stealth Biotherapeutics Corp Methods of identifying and monitoring mitochondrial dysfunction using monocyte screening
TWI693232B (en) 2014-06-26 2020-05-11 美商宏觀基因股份有限公司 Covalently bonded diabodies having immunoreactivity with pd-1 and lag-3, and methods of use thereof
CN107257691B (en) 2014-07-16 2021-09-21 达娜-法勃肿瘤研究所公司 HER3 inhibition in low-grade serous ovarian cancer
WO2016020791A1 (en) 2014-08-05 2016-02-11 Novartis Ag Ckit antibody drug conjugates
EP3180360A1 (en) 2014-08-12 2017-06-21 Novartis AG Anti-cdh6 antibody drug conjugates
JP6641356B2 (en) 2014-08-21 2020-02-05 ステルス バイオセラピューティックス コープ Methods and compositions for the prevention and treatment of diseases
TWI706960B (en) 2014-09-26 2020-10-11 美商宏觀基因股份有限公司 Bi-specific diabodies that are capable of binding cd19 and cd3, and uses thereof
US9889085B1 (en) 2014-09-30 2018-02-13 Intarcia Therapeutics, Inc. Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c
MA40913A (en) 2014-11-14 2017-09-20 Novartis Ag ANTIBODY-DRUG CONJUGATES
JP2017537926A (en) 2014-12-04 2017-12-21 ノバルティス アーゲー Methods and compositions using KLOTHO variant polypeptides
WO2016141108A1 (en) 2015-03-02 2016-09-09 Synlogic, Inc. Bacteria engineered to treat diseases that benefit from reduced gut inflammation and/or tightened gut mucosal barrier
US9688967B2 (en) 2014-12-05 2017-06-27 Synlogic, Inc. Bacteria engineered to treat diseases associated with hyperammonemia
SG11201704543XA (en) 2014-12-05 2017-07-28 Synlogic Inc Bacteria engineered to treat diseases associated with hyperammonemia
EP3940067A1 (en) 2014-12-05 2022-01-19 Synlogic Operating Company, Inc. Bacteria engineered to treat diseases associated with hyperammonemia
ES2934940T3 (en) 2014-12-11 2023-02-28 Pf Medicament Anti-C10orf54 antibodies and uses thereof
US10093733B2 (en) 2014-12-11 2018-10-09 Abbvie Inc. LRP-8 binding dual variable domain immunoglobulin proteins
US20160206666A1 (en) 2014-12-22 2016-07-21 Synlogic, Inc. Bacteria engineered to treat diseases that benefit from reduced gut inflammation and/or tighten gut mucosal barrier
US20160244520A1 (en) 2015-01-24 2016-08-25 Abbvie Inc. Compositions and methods for treating psoriatic arthritis
RU2017129236A (en) 2015-01-26 2019-03-07 Макродженикс, Инк. MULTIValent MOLECULES CONTAINING DR5-BINDING DOMAINS
TW201632202A (en) 2015-01-30 2016-09-16 諾華公司 Treatment of breast cancer
HUE061070T2 (en) 2015-03-03 2023-05-28 Kymab Ltd Antibodies, uses & methods
EP3294757B1 (en) 2015-05-13 2023-12-27 Synlogic Operating Company, Inc. Bacteria engineered to treat a disease or disorder
EP3294760B1 (en) 2015-05-13 2021-03-24 Synlogic Operating Company, Inc. Bacteria engineered to reduce hyperphenylalaninemia
AU2016270640B2 (en) 2015-05-29 2022-03-10 Abbvie Inc. Anti-CD40 antibodies and uses thereof
MX2017015504A (en) 2015-06-03 2018-05-15 Intarcia Therapeutics Inc Implant placement and removal systems.
TWI773646B (en) 2015-06-08 2022-08-11 美商宏觀基因股份有限公司 Lag-3-binding molecules and methods of use thereof
JP6817966B2 (en) 2015-06-10 2021-01-20 シンロジック オペレーティング カンパニー インコーポレイテッド Bacteria engineered to treat diseases associated with hyperammonemia
TW201710286A (en) 2015-06-15 2017-03-16 艾伯維有限公司 Binding proteins against VEGF, PDGF, and/or their receptors
WO2016203432A1 (en) 2015-06-17 2016-12-22 Novartis Ag Antibody drug conjugates
WO2016210373A2 (en) 2015-06-24 2016-12-29 Synlogic, Inc. Recombinant bacteria engineered for biosafety, pharmaceutical compositions, and methods of use thereof
CA3025896A1 (en) 2015-07-23 2017-01-26 The Regents Of The University Of California Antibodies to coagulation factor xia and uses thereof
GEP20227438B (en) 2015-07-30 2022-11-10 Macrogenics Inc Pd-1-binding molecules and methods of use thereof
CA2996535A1 (en) 2015-07-31 2017-02-09 Synlogic, Inc. Bacteria engineered to treat disorders involving propionate catabolism
CA2938576A1 (en) * 2015-08-12 2017-02-12 Howmedica Osteonics Corp. Methods for forming scaffolds
US11331191B2 (en) 2015-08-12 2022-05-17 Howmedica Osteonics Corp. Bioactive soft tissue implant and methods of manufacture and use thereof
EP3344266A1 (en) 2015-08-31 2018-07-11 Synlogic, Inc. Bacteria engineered to treat disorders in which oxalate is detrimental
CN116059340A (en) 2015-09-11 2023-05-05 艾伯维公司 Methods for treating relapsing forms of multiple sclerosis
US9862760B2 (en) 2015-09-16 2018-01-09 Novartis Ag Polyomavirus neutralizing antibodies
US10428145B2 (en) 2015-09-29 2019-10-01 Celgene Corporation PD-1 binding proteins and methods of use thereof
US10449259B2 (en) 2015-10-02 2019-10-22 Cornell University Enzyme-responsive peptide nanofiber compositions and uses thereof
JP7030689B2 (en) 2015-10-23 2022-03-07 ファイザー インコーポレイティッド Anti-IL-2 antibody and its composition and use
WO2017075485A1 (en) 2015-10-30 2017-05-04 Synlogic, Inc. Bacteria engineered to treat disorders in which trimethylamine (tma) is detrimental
US11685925B2 (en) 2015-10-30 2023-06-27 Synlogic Operating Company, Inc. Bacteria engineered to treat diseases that benefit from reduced gut inflammation and/or tightened gut mucosal barrier
EP3368696A1 (en) 2015-10-30 2018-09-05 Synlogic Operating Company, Inc. Bacteria engineered to treat diseases that benefit from reduced gut inflammation and/or tightened gut mucosal barrier
EP3377518B1 (en) 2015-11-16 2022-04-13 Synlogic Operating Company, Inc. Bacteria engineered to reduce hyperphenylalaninemia
MX2018006613A (en) 2015-12-02 2019-01-30 Stcube & Co Inc Antibodies and molecules that immunospecifically bind to btn1a1 and the therapeutic uses thereof.
KR20180100122A (en) 2015-12-02 2018-09-07 주식회사 에스티사이언스 Antibodies specific for glycated BTLA (B- and T-lymphocyte weakening factor)
AR107781A1 (en) 2015-12-14 2018-06-06 Macrogenics Inc BISPECIFIC MOLECULES THAT HAVE IMMUNORREACTIVITY WITH PD-1 AND CTLA-4, AND METHODS OF USE OF THE SAME
WO2017120470A1 (en) 2016-01-06 2017-07-13 Wilson D Travis Methods and compositions for the prevention and treatment of duchenne muscular dystrophy
WO2017123592A1 (en) 2016-01-11 2017-07-20 Synlogic, Inc. Bacteria engineered to treat disorders associated with bile salts
WO2017123610A2 (en) 2016-01-11 2017-07-20 Synlogic, Inc. Bacteria engineered to detoxify deleterious molecules
ES2847155T3 (en) 2016-01-21 2021-08-02 Novartis Ag Multispecific molecules targeting CLL-1
CN108472414A (en) * 2016-01-25 2018-08-31 史密夫和内修有限公司 Rectificating surgery implant
EP3241571B1 (en) 2016-05-02 2020-07-22 Howmedica Osteonics Corporation Bioactive soft tissue implant and methods of manufacture and use thereof
SG11201810102SA (en) 2016-05-16 2018-12-28 Intarcia Therapeutics Inc Glucagon-receptor selective polypeptides and methods of use thereof
CA3024450A1 (en) 2016-05-19 2017-11-23 Stealth Biotherapeutics Corp Compositions and methods for the prevention and treatment of mitochondrial myopathies
USD840030S1 (en) 2016-06-02 2019-02-05 Intarcia Therapeutics, Inc. Implant placement guide
USD860451S1 (en) 2016-06-02 2019-09-17 Intarcia Therapeutics, Inc. Implant removal tool
JP6751165B2 (en) 2016-06-08 2020-09-02 アッヴィ・インコーポレイテッド Anti-B7-H3 antibody and antibody drug conjugate
MX2018015274A (en) 2016-06-08 2019-10-07 Abbvie Inc Anti-cd98 antibodies and antibody drug conjugates.
BR112018075653A2 (en) 2016-06-08 2019-08-27 Abbvie Inc anti-b7-h3 antibodies and drug antibody conjugates
US11567082B2 (en) 2016-07-01 2023-01-31 Dana-Farber Cancer Institute, Inc. Compositions, assays, and methods for direct modulation of fatty acid metabolism
CA3036701A1 (en) 2016-09-19 2018-03-22 Celgene Corporation Methods of treating immune disorders using pd-1 binding proteins
US10766958B2 (en) 2016-09-19 2020-09-08 Celgene Corporation Methods of treating vitiligo using PD-1 binding antibodies
WO2018083248A1 (en) 2016-11-03 2018-05-11 Kymab Limited Antibodies, combinations comprising antibodies, biomarkers, uses & methods
JP7274417B2 (en) 2016-11-23 2023-05-16 イミュノア・セラピューティクス・インコーポレイテッド 4-1BB binding protein and uses thereof
IL307966A (en) 2017-01-03 2023-12-01 Intarcia Therapeutics Inc Methods comprising continuous administration of a glp-1 receptor agonist and co-adminstration of a drug
JOP20190187A1 (en) 2017-02-03 2019-08-01 Novartis Ag Anti-ccr7 antibody drug conjugates
WO2018185618A1 (en) 2017-04-03 2018-10-11 Novartis Ag Anti-cdh6 antibody drug conjugates and anti-gitr antibody combinations and methods of treatment
US10865238B1 (en) 2017-05-05 2020-12-15 Duke University Complement factor H antibodies
EP3630835A1 (en) 2017-05-31 2020-04-08 STCube & Co., Inc. Antibodies and molecules that immunospecifically bind to btn1a1 and the therapeutic uses thereof
KR20200024158A (en) 2017-05-31 2020-03-06 주식회사 에스티큐브앤컴퍼니 How to treat cancer using antibodies and molecules that immunospecifically bind to BTN1A1
KR20200026209A (en) 2017-06-06 2020-03-10 주식회사 에스티큐브앤컴퍼니 How to treat cancer using antibodies and molecules that bind BTN1A1 or BTN1A1-ligand
AU2018290278B2 (en) 2017-06-21 2022-12-15 Synlogic Operating Company, Inc. Bacteria for the treatment of disorders
MX2020001546A (en) 2017-08-08 2020-08-03 Memorial Sloan Kettering Cancer Center Use of braf inhibitors for treating cutaneous reactions caused by treatment with a mek inhibitor.
AU2018330848A1 (en) 2017-09-08 2020-03-12 Biomx Ltd. Bacteriophage for modulating inflammatory bowel disease
CA3083363A1 (en) 2017-12-01 2019-06-06 Novartis Ag Polyomavirus neutralizing antibodies
JP7391839B2 (en) 2017-12-01 2023-12-05 ファイザー・インク Anti-CXCR5 antibodies, compositions thereof and uses thereof
US10982002B2 (en) 2018-03-12 2021-04-20 Zoetis Services Llc Anti-NGF antibodies and methods thereof
JP2021519758A (en) 2018-03-29 2021-08-12 ファイザー インコーポレイティッド LFA3 variant and its composition and usage
US10640576B2 (en) 2018-04-10 2020-05-05 Y-Biologics Inc. Cell engaging binding molecules
JP2021525071A (en) 2018-05-31 2021-09-24 ノバルティス アーゲー Hepatitis B antibody
TW202016136A (en) 2018-06-01 2020-05-01 瑞士商諾華公司 Binding molecules against bcma and uses thereof
JP2021531007A (en) 2018-07-20 2021-11-18 ピエール、ファーブル、メディカマン Receptor for VISTA
BR112021004287A2 (en) 2018-09-07 2021-08-03 Pfizer Inc. anti-avss8 antibodies and compositions and uses thereof
WO2020053742A2 (en) 2018-09-10 2020-03-19 Novartis Ag Anti-hla-hbv peptide antibodies
FI3890765T3 (en) 2018-12-06 2023-10-16 Stealth Biotherapeutics Inc D-arg-2'6'-dmt-lys-phe-nh2 for use in treating or preventing sengers syndrome
WO2020128863A1 (en) 2018-12-19 2020-06-25 Novartis Ag Anti-tnf-alpha antibodies
CU20210047A7 (en) 2018-12-21 2022-01-13 Novartis Ag ANTI-PMEL 17 ANTIBODIES AND CONJUGATES THEREOF
CN113891721A (en) 2019-03-07 2022-01-04 学校法人庆应义塾 Bacteriophage for modulating inflammatory bowel disease
CA3132959A1 (en) 2019-03-08 2020-09-17 AbTis Co., Ltd. Site-specific antibody conjugation and antibody-drug conjugate as specific embodiment thereof
TW202102526A (en) 2019-04-04 2021-01-16 美商銳進科斯生物股份有限公司 Recombinant adeno-associated viruses and uses thereof
JP2022530503A (en) 2019-04-29 2022-06-29 シンロジック オペレーティング カンパニー インコーポレイテッド Genetically engineered microorganisms
WO2020226710A1 (en) * 2019-05-07 2020-11-12 Ut-Battelle, Llc Toughened polyester composites containing polyester matrix and droplets of high boiling liquid therein
WO2020237491A1 (en) 2019-05-28 2020-12-03 Shanghaitech University Composition and methods to treat ectodermal dysplasia 2, clouston type
KR20220041118A (en) 2019-07-24 2022-03-31 스텔스 바이오테라퓨틱스 인코포레이티드 (R)-2-amino-N-((S)-L-(((S)-5-amino-L-(3-benzyl-1,2, 4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide
JP2022544004A (en) 2019-07-26 2022-10-17 リジェネックスバイオ インコーポレイテッド ENGINEERED NUCLEIC ACID REGULATORY ELEMENTS AND METHODS OF USE THEREOF
TW202126317A (en) 2019-09-24 2021-07-16 美商普拉塔生技公司 Compositions and methods for treatment of inflammatory and immune diseases
US20220411511A1 (en) 2019-09-26 2022-12-29 Stcube & Co. Antibodies specific to glycosylated ctla-4 and methods of use thereof
KR20220078644A (en) 2019-10-04 2022-06-10 스텔스 바이오테라퓨틱스 인코포레이티드 Quinone-, hydroquinone- and naphthoquinone-analogs of vatiquinone for the treatment of mitochondrial diseases
US20220356248A1 (en) 2019-10-09 2022-11-10 Stcube & Co Antibodies specific to glycosylated lag3 and methods of use thereof
WO2021188819A1 (en) 2020-03-20 2021-09-23 Synlogic Operating Company, Inc. Microorganisms engineered to reduce hyperphenylalaninemia
WO2021202463A1 (en) 2020-03-30 2021-10-07 Danisco Us Inc Anti-rsv antibodies
WO2021202473A2 (en) 2020-03-30 2021-10-07 Danisco Us Inc Engineered antibodies
AU2021246142A1 (en) 2020-04-03 2022-10-20 Stealth Biotherapeutics Inc. Compositions and methods for the prevention and/or treatment of mitochondrial disease, including Friedreich's ataxia
US20230181756A1 (en) 2020-04-30 2023-06-15 Novartis Ag Ccr7 antibody drug conjugates for treating cancer
CN116096758A (en) 2020-05-01 2023-05-09 诺华股份有限公司 Engineered immunoglobulins
US20230167193A1 (en) 2020-05-01 2023-06-01 Novartis Ag Immunoglobulin variants
WO2022076711A2 (en) 2020-10-07 2022-04-14 Regenxbio Inc. Adeno-associated viruses for ocular delivery of gene therapy
WO2022076750A2 (en) 2020-10-07 2022-04-14 Regenxbio Inc. Recombinant adeno-associated viruses for cns or muscle delivery
EP4240765A2 (en) 2020-11-06 2023-09-13 Novartis AG Antibody fc variants
US20240025993A1 (en) 2020-11-06 2024-01-25 Novartis Ag Cd19 binding molecules and uses thereof
AU2021374083A1 (en) 2020-11-06 2023-06-01 Novartis Ag Anti-cd19 agent and b cell targeting agent combination therapy for treating b cell malignancies
CN116670269A (en) 2020-12-02 2023-08-29 同生运营公司 Engineered microorganisms
JP2024502832A (en) 2020-12-31 2024-01-23 アラマー バイオサイエンシーズ, インコーポレイテッド Binding agent molecules with high affinity and/or specificity and methods for their production and use
CN116847860A (en) 2020-12-31 2023-10-03 同生运营公司 Microorganisms engineered to alleviate hyperphenylalaninemia
CA3204530A1 (en) 2021-01-12 2022-07-21 Gregory Mckenzie Synbiotic treatment regimens
UY39610A (en) 2021-01-20 2022-08-31 Abbvie Inc ANTI-EGFR ANTIBODY-DRUG CONJUGATES
AU2022259522A1 (en) 2021-04-13 2023-10-19 Synlogic Operating Company, Inc. Bacteria engineered to secrete active proteins
CA3216880A1 (en) 2021-04-16 2022-10-20 Novartis Ag Antibody drug conjugates and methods for making thereof
WO2023001894A1 (en) 2021-07-20 2023-01-26 Ags Therapeutics Sas Extracellular vesicles from microalgae, their preparation, and uses
WO2023044479A1 (en) 2021-09-17 2023-03-23 Synlogic Operating Company, Inc. Methods for reducing hyperphenylalaninemia
WO2023060272A2 (en) 2021-10-07 2023-04-13 Regenxbio Inc. Recombinant adeno-associated viruses for cns tropic delivery
WO2023060269A1 (en) 2021-10-07 2023-04-13 Regenxbio Inc. Recombinant adeno-associated viruses for targeted delivery
WO2023069255A1 (en) 2021-10-20 2023-04-27 Stealth Biotherapeutics Inc. Methods and compositions comprising peptidomimitics for treating, preventing, inhibiting, ameliorating or delaying the onset of ophthalmic conditions
WO2023077092A1 (en) 2021-10-28 2023-05-04 Regenxbio Inc. Engineered nucleic acid regulatory elements and methods and uses thereof
WO2023073599A1 (en) 2021-10-28 2023-05-04 Novartis Ag Engineered fc variants
WO2023101963A2 (en) 2021-11-30 2023-06-08 Northwestern University Compositions for inhibiting dipeptide repeat protein-ribosomal rna interaction and uses thereof
US20230227545A1 (en) 2022-01-07 2023-07-20 Johnson & Johnson Enterprise Innovation Inc. Materials and methods of il-1beta binding proteins
WO2023133321A1 (en) 2022-01-10 2023-07-13 Stealth Biotherapeutics Inc. Small molecule peptidomimetic for the treatment of tauopathies
WO2023144127A1 (en) 2022-01-31 2023-08-03 Ags Therapeutics Sas Extracellular vesicles from microalgae, their biodistribution upon administration, and uses
WO2023152633A1 (en) 2022-02-09 2023-08-17 Janssen Biotech, Inc. Methods and compositions comprising v beta 17 bispecific t cell engagers and bioengineered virus specific lymphocytes
TW202346590A (en) 2022-03-13 2023-12-01 美商銳進科斯生物股份有限公司 Modified muscle-specific promoters
WO2023201277A1 (en) 2022-04-14 2023-10-19 Regenxbio Inc. Recombinant adeno-associated viruses for cns tropic delivery
WO2023201308A1 (en) 2022-04-14 2023-10-19 Regenxbio Inc. Gene therapy for treating an ocular disease
WO2023205610A2 (en) 2022-04-18 2023-10-26 Regenxbio Inc. Hybrid aav capsids
WO2023209568A1 (en) 2022-04-26 2023-11-02 Novartis Ag Multispecific antibodies targeting il-13 and il-18
WO2023232976A1 (en) 2022-06-03 2023-12-07 Ags Therapeutics Sas Extracellular vesicles from genetically-modified microalgae containing endogenously-loaded cargo, their preparation, and uses
WO2023245171A1 (en) 2022-06-17 2023-12-21 Synlogic Operating Company, Inc. Bacteria engineered to treat diseases associated with bile acid metabolism and methods of use thereof
WO2023245168A1 (en) 2022-06-17 2023-12-21 Synlogic Operating Company, Inc. Bacteria engineered to treat diseases associated with bile acid metabolism and methods of use thereof
WO2023250478A1 (en) 2022-06-23 2023-12-28 Synlogic Operating Company, Inc. Recombinant bacteria engineered to treat diseases associated with methionine metabolism and methods of use thereof
WO2024013727A1 (en) 2022-07-15 2024-01-18 Janssen Biotech, Inc. Material and methods for improved bioengineered pairing of antigen-binding variable regions
WO2024018426A1 (en) 2022-07-22 2024-01-25 Janssen Biotech, Inc. Enhanced transfer of genetic instructions to effector immune cells
WO2024028732A1 (en) 2022-08-05 2024-02-08 Janssen Biotech, Inc. Cd98 binding constructs for treating brain tumors
WO2024028731A1 (en) 2022-08-05 2024-02-08 Janssen Biotech, Inc. Transferrin receptor binding proteins for treating brain tumors
WO2024044725A2 (en) 2022-08-24 2024-02-29 Regenxbio Inc. Recombinant adeno-associated viruses and uses thereof

Family Cites Families (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE744162A (en) * 1969-01-16 1970-06-15 Fuji Photo Film Co Ltd ENCAPSULATION PROCESS
US3887699A (en) * 1969-03-24 1975-06-03 Seymour Yolles Biodegradable polymeric article for dispensing drugs
DE2010115A1 (en) * 1970-03-04 1971-09-16 Farbenfabriken Bayer Ag, 5090 Leverkusen Process for the production of micro-granules
JPS523342B2 (en) * 1972-01-26 1977-01-27
US4166800A (en) * 1977-08-25 1979-09-04 Sandoz, Inc. Processes for preparation of microspheres
US4389330A (en) * 1980-10-06 1983-06-21 Stolle Research And Development Corporation Microencapsulation process
US4675189A (en) * 1980-11-18 1987-06-23 Syntex (U.S.A.) Inc. Microencapsulation of water soluble active polypeptides
US4542025A (en) * 1982-07-29 1985-09-17 The Stolle Research And Development Corporation Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents
US4530840A (en) * 1982-07-29 1985-07-23 The Stolle Research And Development Corporation Injectable, long-acting microparticle formulation for the delivery of anti-inflammatory agents
CH661206A5 (en) * 1983-09-23 1987-07-15 Debiopharm Sa PROCESS FOR THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF HORMONDEPENDENT DISEASES.
US4818542A (en) * 1983-11-14 1989-04-04 The University Of Kentucky Research Foundation Porous microspheres for drug delivery and methods for making same
ATE61935T1 (en) * 1985-02-07 1991-04-15 Takeda Chemical Industries Ltd PROCESS FOR PRODUCTION OF MICROCAPSULES.
JP2551756B2 (en) * 1985-05-07 1996-11-06 武田薬品工業株式会社 Polyoxycarboxylic acid ester and method for producing the same
GB2209937B (en) * 1987-09-21 1991-07-03 Depiopharm S A Water insoluble polypeptides
WO1989003678A1 (en) * 1987-10-30 1989-05-05 Stolle Research & Development Corporation Low residual solvent microspheres and microencapsulation process
WO1989005138A1 (en) * 1987-12-08 1989-06-15 Mark Chasin Method of forming bioerodible implants for improved controlled drug release
DE3744329A1 (en) 1987-12-28 1989-07-06 Schwarz Pharma Gmbh METHOD FOR THE PRODUCTION OF AT LEAST ONE ACTIVE AGENT AND A TRAITER COMPRISING PREPARATION
US4938763B1 (en) * 1988-10-03 1995-07-04 Atrix Lab Inc Biodegradable in-situ forming implants and method of producing the same
DE69005800T2 (en) * 1989-05-01 1994-05-19 Alkermes Inc METHOD FOR PRODUCING SMALL PARTICLES OF BIOLOGICALLY ACTIVE MOLECULES.
US5019400A (en) * 1989-05-01 1991-05-28 Enzytech, Inc. Very low temperature casting of controlled release microspheres
US5232707A (en) * 1989-07-10 1993-08-03 Syntex (U.S.A.) Inc. Solvent extraction process
US5478564A (en) * 1990-02-22 1995-12-26 Teva Pharmaceutical Industries, Ltd. Preparation of microparticles for controlled release of water-soluble substances
CA2040141C (en) * 1990-04-13 2002-05-14 Minoru Yamada Biodegradable high-molecular polymers, production and use therof
DE4041563A1 (en) 1990-12-22 1992-06-25 Sanol Arznei Schwarz Gmbh METHOD FOR PRODUCING ACTIVE MICROPARTICLES FROM HYDROLYTICALLY DEGRADABLE POLYMERS
AU2605592A (en) * 1991-10-15 1993-04-22 Atrix Laboratories, Inc. Polymeric compositions useful as controlled release implants
US5288502A (en) * 1991-10-16 1994-02-22 The University Of Texas System Preparation and uses of multi-phase microspheres
US5543154A (en) * 1991-12-27 1996-08-06 Merck & Co., Inc. Controlled release nifedipine delivery device
DE4201179A1 (en) * 1992-01-17 1993-07-22 Alfatec Pharma Gmbh Granulates or pellets comprising dispersion of active agent in hydrophilic macromolecules - are e.g. for treatment of depression, hypertension, rheumatism, etc.
ZA93929B (en) * 1992-02-18 1993-09-10 Akzo Nv A process for the preparation of biologically active materialcontaining polymeric microcapsules.
US5656297A (en) * 1992-03-12 1997-08-12 Alkermes Controlled Therapeutics, Incorporated Modulated release from biocompatible polymers
US5711968A (en) * 1994-07-25 1998-01-27 Alkermes Controlled Therapeutics, Inc. Composition and method for the controlled release of metal cation-stabilized interferon
US5716644A (en) * 1992-06-11 1998-02-10 Alkermes, Inc. Composition for sustained release of non-aggregated erythropoietin
US5674534A (en) * 1992-06-11 1997-10-07 Alkermes, Inc. Composition for sustained release of non-aggregated erythropoietin
JP2651320B2 (en) * 1992-07-16 1997-09-10 田辺製薬株式会社 Method for producing sustained-release microsphere preparation
FR2693905B1 (en) * 1992-07-27 1994-09-02 Rhone Merieux Process for the preparation of microspheres for the sustained release of the hormone LHRH and its analogs, microspheres and formulations obtained.
IT1255792B (en) 1992-08-05 1995-11-16 Bayer Italia Spa PHARMACEUTICAL COMPOSITIONS FOR THE ORAL ADMINISTRATION OF DIHYDROPYRIDINS IN THE FORM OF DRINK
EP1013270A3 (en) * 1992-12-02 2001-03-28 Alkermes Controlled Therapeutics, Inc. Controlled release growth hormone containing microspheres
US5307640A (en) 1993-01-25 1994-05-03 E. I. Du Pont De Nemours And Company Apparatus and method for producing frozen particles of a liquid
JPH06323712A (en) 1993-04-20 1994-11-25 E I Du Pont De Nemours & Co Method and equipment for manufacturing frozen particle by using confinement band of atomized cryogenic droplet
GB9313642D0 (en) 1993-07-01 1993-08-18 Glaxo Group Ltd Method and apparatus for the formation of particles
US5650173A (en) * 1993-11-19 1997-07-22 Alkermes Controlled Therapeutics Inc. Ii Preparation of biodegradable microparticles containing a biologically active agent
US5594091A (en) * 1994-02-21 1997-01-14 Takeda Chemical Industries, Ltd. Matrix for sustained-release preparation
GB9413202D0 (en) 1994-06-30 1994-08-24 Univ Bradford Method and apparatus for the formation of particles
US5582838A (en) * 1994-12-22 1996-12-10 Merck & Co., Inc. Controlled release drug suspension delivery device
JP2000507912A (en) * 1995-08-31 2000-06-27 アルカームズ コントロールド セラピューティックス,インコーポレイテッド Sustained release composition of active agent
US5817343A (en) * 1996-05-14 1998-10-06 Alkermes, Inc. Method for fabricating polymer-based controlled-release devices
US5989463A (en) * 1997-09-24 1999-11-23 Alkermes Controlled Therapeutics, Inc. Methods for fabricating polymer-based controlled release devices

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