CA2406536C - Preparation of injectable suspensions having improved injectability - Google Patents
Preparation of injectable suspensions having improved injectability Download PDFInfo
- Publication number
- CA2406536C CA2406536C CA002406536A CA2406536A CA2406536C CA 2406536 C CA2406536 C CA 2406536C CA 002406536 A CA002406536 A CA 002406536A CA 2406536 A CA2406536 A CA 2406536A CA 2406536 C CA2406536 C CA 2406536C
- Authority
- CA
- Canada
- Prior art keywords
- suspension
- viscosity
- composition
- microparticles
- injection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
Injectable compositions having improved injectability. The injectable compositions include microparticles in an aqueous injection vehicle having a viscosity of at least 20 cp at 20.degree. C. The increased viscosity of the injection vehicle that constitutes the fluid phase of the suspension significantly reduces in vivo injectabilit y failures. The injectable compositions can be made by mixing dry microparticles with an aqueous injection vehicle to form a suspension, and then mixing the suspension with a viscosity enhancing agent to increase the viscosity of the fluid phase of the suspensi on to the desired level for improved injectability.
Description
Preparation of Injectable Suspensions Having Improved Inj ectability Background of the Invention Field of the Invention The present invention relates to preparation of injectable compositions. More particularly, the present invention relates to injectable suspensions having improved injectability, and to methods for the preparation of such injectable suspensions.
Related Art Injectable suspensions are heterogeneous systems that typically consist of a solid phase dispersed in a liquid phase, the liquid phase being aqueous or nonaqueous. To be effective and pharmaceutically acceptable, injectable suspensions should preferably be:
sterile; stable; resuspendable; syringeable; injectable; isotonic; and nonirritating. The foregoing characteristics result in manufacturing, storage, and usage requirements that make injectable suspensions one of the most difficult dosage forms to develop.
Injectable suspensions are parenteral compositions in that they are introduced into an organism or host by means other than through the gastrointestinal tract.
Particularly, injectable suspensions are introduced into a host by subcutaneous (SC) or intramuscular (IM) injection. Injectable suspensions may be formulated as a ready-to-use injection or require a reconstitution step prior to use. Injectable suspensions typically contain between 0.5% and 5.0% solids, with a particle size of less than 5 m for IM or SC
administration.
Parenteral suspensions are frequently administered through needles about one-half to two inches long, 19 to 22 gauge, with an internal diameter in the range of 700 to 400 microns, respectively.
To develop an effective and pharmaceutically acceptable injectable suspension, a number of characteristics must be evaluated. These characteristics include syringeability, injectability, clogging, resuspendability, and viscosity. As will be readily apparent to one skilled in the art, other characteristics and factors should be considered in developing an injectable suspension (see, for example, Floyd, A.G. and Jain, S., Injectable Emulsions and Suspensions, Chapter 7 in Pharmaceutical Dosage Forms: Disperse Systems Vol.
Related Art Injectable suspensions are heterogeneous systems that typically consist of a solid phase dispersed in a liquid phase, the liquid phase being aqueous or nonaqueous. To be effective and pharmaceutically acceptable, injectable suspensions should preferably be:
sterile; stable; resuspendable; syringeable; injectable; isotonic; and nonirritating. The foregoing characteristics result in manufacturing, storage, and usage requirements that make injectable suspensions one of the most difficult dosage forms to develop.
Injectable suspensions are parenteral compositions in that they are introduced into an organism or host by means other than through the gastrointestinal tract.
Particularly, injectable suspensions are introduced into a host by subcutaneous (SC) or intramuscular (IM) injection. Injectable suspensions may be formulated as a ready-to-use injection or require a reconstitution step prior to use. Injectable suspensions typically contain between 0.5% and 5.0% solids, with a particle size of less than 5 m for IM or SC
administration.
Parenteral suspensions are frequently administered through needles about one-half to two inches long, 19 to 22 gauge, with an internal diameter in the range of 700 to 400 microns, respectively.
To develop an effective and pharmaceutically acceptable injectable suspension, a number of characteristics must be evaluated. These characteristics include syringeability, injectability, clogging, resuspendability, and viscosity. As will be readily apparent to one skilled in the art, other characteristics and factors should be considered in developing an injectable suspension (see, for example, Floyd, A.G. and Jain, S., Injectable Emulsions and Suspensions, Chapter 7 in Pharmaceutical Dosage Forms: Disperse Systems Vol.
2. Edited by Lieberman, H.A., Rieger, M.M., and Banker, G.S., Marcel Dekker, New York (1996), referred to herein as "the Floyd et al, Chapter").
Syringeability describes the ability of an injectable suspension to pass easily through a hypodermic needle on transfer from a vial prior to inj ection. It includes characteristics such as ease of withdrawal, clogging and foaming tendencies, and accuracy of dose measurements. As descnbed in the Floyd et al. Chapter, increase in the viscosity, density, particle size, and concentration of solids in suspension hinders the syringeability of suspensions.
Injectability refers to the performance of the suspension dLuing injection.
Injectability includes factors such as pressure or force required for injection, evenness of flow, aspiration qualities, and freedom from clogging.
Clogging refers to the blockage of syringe needles while administering a suspension. It may occur because of a single large particle, or an aggregate that blocks the lumen of the needle due to a bridging effect of the particles. Clogging at or near the needle end may be caused by restrictions to flow from the suspension. This may involve a number of factors, such as the injection vehicle, wetting of particles, particle size and distribution, particle shape, viscosity, and flow characteristics of the suspension.
Resuspendability descnbes the ability of the suspension to uniformly disperse with m inimal shaking after it has stood for some time. Resuspendability can be a problem for suspensions that undergo "caking" upon standing due to settling of the deflocculated particles. "Caking" refers to a process by which the particles undergo growth and fusion to form a nondispersible mass of material.
Viscosity describes the resistance that a liquid system offers to flow when it is subjected to an applied shear stress. A more viscous system requires greater force or stress to make it flow at the same rate as a less viscous system. A liquid system will exhibit either Newtonian or non-Newtonian flow based on a linear or a non-linear increase, respectively, in the rate of shear with the shearing stress. Structured vehicles used in suspensions exhibit non-Newtonian flow and are typically plastic, pseudoplastic, or shear-thinning with some thixotropy (exhibiting a decrease in viscosity with an increase in the rate of shear).
In design of injection vehicles, viscosity enhancers are added in order to retard settling of the particles in the vial and syringe. However, viscosity is typically kept low, in order to facilitate mixing, resuspension of the particles with the vehicle, and to make the suspension easier to inject (i.e., low force on the syringe plunger). For example, Lupron Depot I from TAP Pharmaceuticals (inean particle size of approximately 8 Ftm) utilizes an injection vehicle with a viscosity of approximately 5.4 cp. The fluid phase of a suspension of Decapeptyl from DebioPharm (mean particle size of approximately 40 m), when prepared as directed, has a viscosity of approximately 19.7 cp. Conventional parenteral suspensions are dilute, with limitations for viscosity because of syringeability and injectability constraints. See, for example, the Floyd, et al. Chapter noted above.
Injectable compositions containing microparticle preparations are particularly susceptible to injectability problems. Microparticle suspensions may contain 10-15%
solids, as compared with 0.5-5% solids in other types of injectable suspensions.
Microparticles, particularly controlled release microparticles containing an active agent or other type of substance to be released, range in size up to about 250 m, as compared with a particle size of less than 5 m recommended for IM or SC administration. The higher concentration of solids, as well as the larger solid particle size, make it more difficult to successftllly inject microparticle suspensions. This is particularly true since it is also desired to inject the microparticle suspensions using as small a needle as possible to minimize patient discomfort.
Thus, there is a need in the art for an injectable composition with improved injectability. There is a particular need in the art for an injectable composition that solves the injectability problems associated with microparticle suspensions. The present invention, the description of which is fully set forth below, solves the need in the art for such injectable compositions.
Summary of the Invention The present invention relates to injectable compositions having improved injectability, and to methods for the preparation of such injectable compositions. In one aspect of the invention, a composition suitable for injection through a needle into a u, T is provided. The composition comprises microparticles having a polymeric binder, wit-,- a mass median diameter of at least about 10 m. The composition also includes an aqueous injection vehicle (the injection vehicle not being the aqueous injection vehicle that consists of 3% by volume sodium carboxymethyl cellulose, 1% by volume polysorbate 20,0.9% by volume sodium chloride, and a remaining percentage by volume of water). The microparticles are suspended in the injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, the fluid phase of the suspension having a viscosity of at least 20 cp at 20 C. In other embodiments, the fluid phase of the suspension has a viscosity at 20 C of at least about 30 cp, 40 cp, 50 cp, and 60 cp. The composition may also comprise a viscosity enhancing agent, a density enhancing agent, a tonicity enhancing agent, and/or a wetting agent. The composition can be administered to a host by injection.
Syringeability describes the ability of an injectable suspension to pass easily through a hypodermic needle on transfer from a vial prior to inj ection. It includes characteristics such as ease of withdrawal, clogging and foaming tendencies, and accuracy of dose measurements. As descnbed in the Floyd et al. Chapter, increase in the viscosity, density, particle size, and concentration of solids in suspension hinders the syringeability of suspensions.
Injectability refers to the performance of the suspension dLuing injection.
Injectability includes factors such as pressure or force required for injection, evenness of flow, aspiration qualities, and freedom from clogging.
Clogging refers to the blockage of syringe needles while administering a suspension. It may occur because of a single large particle, or an aggregate that blocks the lumen of the needle due to a bridging effect of the particles. Clogging at or near the needle end may be caused by restrictions to flow from the suspension. This may involve a number of factors, such as the injection vehicle, wetting of particles, particle size and distribution, particle shape, viscosity, and flow characteristics of the suspension.
Resuspendability descnbes the ability of the suspension to uniformly disperse with m inimal shaking after it has stood for some time. Resuspendability can be a problem for suspensions that undergo "caking" upon standing due to settling of the deflocculated particles. "Caking" refers to a process by which the particles undergo growth and fusion to form a nondispersible mass of material.
Viscosity describes the resistance that a liquid system offers to flow when it is subjected to an applied shear stress. A more viscous system requires greater force or stress to make it flow at the same rate as a less viscous system. A liquid system will exhibit either Newtonian or non-Newtonian flow based on a linear or a non-linear increase, respectively, in the rate of shear with the shearing stress. Structured vehicles used in suspensions exhibit non-Newtonian flow and are typically plastic, pseudoplastic, or shear-thinning with some thixotropy (exhibiting a decrease in viscosity with an increase in the rate of shear).
In design of injection vehicles, viscosity enhancers are added in order to retard settling of the particles in the vial and syringe. However, viscosity is typically kept low, in order to facilitate mixing, resuspension of the particles with the vehicle, and to make the suspension easier to inject (i.e., low force on the syringe plunger). For example, Lupron Depot I from TAP Pharmaceuticals (inean particle size of approximately 8 Ftm) utilizes an injection vehicle with a viscosity of approximately 5.4 cp. The fluid phase of a suspension of Decapeptyl from DebioPharm (mean particle size of approximately 40 m), when prepared as directed, has a viscosity of approximately 19.7 cp. Conventional parenteral suspensions are dilute, with limitations for viscosity because of syringeability and injectability constraints. See, for example, the Floyd, et al. Chapter noted above.
Injectable compositions containing microparticle preparations are particularly susceptible to injectability problems. Microparticle suspensions may contain 10-15%
solids, as compared with 0.5-5% solids in other types of injectable suspensions.
Microparticles, particularly controlled release microparticles containing an active agent or other type of substance to be released, range in size up to about 250 m, as compared with a particle size of less than 5 m recommended for IM or SC administration. The higher concentration of solids, as well as the larger solid particle size, make it more difficult to successftllly inject microparticle suspensions. This is particularly true since it is also desired to inject the microparticle suspensions using as small a needle as possible to minimize patient discomfort.
Thus, there is a need in the art for an injectable composition with improved injectability. There is a particular need in the art for an injectable composition that solves the injectability problems associated with microparticle suspensions. The present invention, the description of which is fully set forth below, solves the need in the art for such injectable compositions.
Summary of the Invention The present invention relates to injectable compositions having improved injectability, and to methods for the preparation of such injectable compositions. In one aspect of the invention, a composition suitable for injection through a needle into a u, T is provided. The composition comprises microparticles having a polymeric binder, wit-,- a mass median diameter of at least about 10 m. The composition also includes an aqueous injection vehicle (the injection vehicle not being the aqueous injection vehicle that consists of 3% by volume sodium carboxymethyl cellulose, 1% by volume polysorbate 20,0.9% by volume sodium chloride, and a remaining percentage by volume of water). The microparticles are suspended in the injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, the fluid phase of the suspension having a viscosity of at least 20 cp at 20 C. In other embodiments, the fluid phase of the suspension has a viscosity at 20 C of at least about 30 cp, 40 cp, 50 cp, and 60 cp. The composition may also comprise a viscosity enhancing agent, a density enhancing agent, a tonicity enhancing agent, and/or a wetting agent. The composition can be administered to a host by injection.
Thus, according to one aspect of the present invention, there is provided a composition suitable for injection through a needle into a host, comprising:
microparticles comprising a polymeric binder; and an injection vehicle comprising a viscosity enhancing agent, wherein said microparticles are suspended in said injection vehicle at a concentration of greater than about 30 mgJml to form a suspension, wherein a fluid phase of said suspension has a viscosity greater than about 20 cp and less than about 600 cp at 20 C, wherein the viscosity of said fluid phase of said suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
In another aspect of the present invention, there is provided a method of making a composition suitable for injection through a needle into a host, comprising: (a) providing microparticles comprising a polymeric binder, said microparticles having a mass median diameter of at least about 10 m; (b) providing an aqueous injection vehicle comprising a viscosity enhancing agent and having a viscosity of at least 20 cp at 20 C; and (c) suspending the microparticles in the aqueous injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein the viscosity of a fluid phase of the suspension is in the range of from about 20 cp to about 600 cp at 20 C, wherein the viscosity of the fluid phase of the suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
In a further aspect of the present invention, another method for preparing a composition suitable for injection through a needle into a host is provided. In such a method, dry microparticles comprising a polymeric binder are mixed with an aqueous injection vehicle to form a first Thus, according to one aspect of the present invention, there is provided a composition suitable for injection through a needle into a host, comprising:
microparticles comprising a polymeric binder; and an injection vehicle, wherein said microparticles are suspended in said injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein a fluid phase of said suspension has a viscosity greater than about 20 cp and less than about 600 cp at 20 C, wherein the viscosity of said fluid phase of said suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
In another aspect of the present invention, there is provided a method of making a composition suitable for injection through a needle into a host, comprising: (a) providing microparticles comprising a polymeric binder, said microparticles having a mass median diameter of at least about 10 m; (b) providing an aqueous injection vehicle having a viscosity of at least 20 cp at 20 C; and (c) suspending the microparticles in the aqueous injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein the viscosity of a fluid phase of the suspension is in the range of from about 20 cp to about 600 cp at 20 C, wherein the viscosity of the fluid phase of the suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
In a further aspect of the present invention, another method for preparing a composition suitable for injection through a needle into a host is provided. In such a method, dry microparticles are mixed with an aqueous injection vehicle to form a first suspension. The first suspension is mixed with a viscosity enhancing agent to form suspension. The first suspension is mixed with a viscosity enhancing agent to form a second suspension. The viscosity enhancing agent increases the viscosity of the fluid phase of the second suspension. The first suspension may be withdrawn into a first syringe, prior to mixing with the viscosity enhancing agent. The first suspension may be mixed with the viscosity enhancing agent by coupling the first syringe containing the first suspension to a second syringe that contains the viscosity enhancing agent. The first suspension and the viscosity enhancing agent are then repeatedly passed between the first and second syringes.
According to another aspect of the present invention, there is provided a method for preparing a composition suitable for injection through a needle into a host, comprising: (a) mixing dry microparticles comprising a polymeric binder with an aqueous injection vehicle to form a first suspension wherein the concentration of microparticles in the first suspension is greater than about 30 mg/ml; and (b) mixing the first suspension with a viscosity enhancing agent to form a second suspension, wherein the viscosity enhancing agent increases viscosity of a fluid phase of the second suspension to be in the range of from about 20 cp to about 600 cp at 20 C, wherein the viscosity of the fluid phase of the second suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
According to still another aspect of the present invention, there is provided a use of a composition for injection into a host through syringe having a needle ranging in diameter from 18-22 gauge, said composition comprising a second suspension prepared from: (a) dry microparticles comprising a polymeric binder, mixed with an aqueous injection vehicle to form a first suspension, wherein the concentration of microparticles in the first suspension is greater than about 30 mg/ml; and (b) the first suspension mixed with a viscosity enhancing agent to form the second suspension, wherein the viscosity enhancing agent increases viscosity of a fluid phase of the second suspension in a range of from about 20 cp to about 600 cp at 20 C.
According to yet another aspect of the present invention, there is provided a use of a composition for injection into a host through syringe having a needle ranging in diameter from 18-22 gauge, said composition prepared from: (a) dry microparticles comprising a polymeric binder, mixed with an aqueous injection vehicle to form a suspension wherein the concentration of microparticles in the suspension is greater than about 30 mg/ml, wherein the aqueous injection vehicle prior to mixing has a viscosity at 20 C of less than about 60 cp;
(b) the viscosity of a fluid phase of the suspension is changed to a range of from about 20 cp to about 600 cp at 20 C.; and (c) the suspension is withdrawn into the syringe.
In still a further aspect of the invention, a method for preparing a composition suitable for injection through a needle into a host is provided. The method comprises:
(a) mixing dry microparticles with an aqueous injection vehicle that comprises a viscosity enhancing agent to form a suspension;
(b) removing water from the suspension; and -6a-(c) reconstituting the suspension with a quantity of sterile water for injection to form an injectable suspension, wherein the quantity of sterile water for injection is sufficient to achieve a viscosity of a fluid phase of the injectable suspension that provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
Features and Advantages A feature of the present invention is that the injectable compositions can be used to inject varying types of microparticles, and varying types of active agents or other substances, into a host.
A further feature of the present invention is that it allows microparticles to be wetted to achieve a homogeneous suspension, while improving injectability into a host and reducing in vivo injectability failures.
The present invention advantageously provides medically acceptable injectability rates for high concentration suspensions, and for suspensions having large particle size.
The present invention also advantageously provides an efficient method of improving in vivo injectability without introducing microbial contamination or compromising aseptic conditions.
-6b-Detailed Description of the Preferred Embodiments Overview The present invention relates to injectable compositions having improved injectability, and to methods for the preparation of such injectable compositions. The injectable compositions of the present invention overcome injectability problems, particularly injectability failures that occur upon injection into muscle or subcutaneous tissue. Such injectability failures will be referred to herein as "in vivo injectability failures." In vivo injectability failures often manifest themselves in the form of a plug at the tip of the needle, and occur immediately or shortly after injection has been initiated. In vivo injectability failures are typically not predicted by laboratory or other in vitro testing.
The inventors have unexpectedly discovered that injectability is improved, and in vivo injectability failures significantly and unexpectedly reduced, by increasing the viscosity of the fluid phase of an injectable suspension. This is in contrast to conventional teachings that an increase in the viscosity hinders injectability and syringeability.
Viscous vehicles, however, are not optimal for preparing homogeneous suspensions of microparticles because of the relative inability of viscous vehicles to penetrate and wet out a mass of dry particles. Suspensions prepared with viscous vehicles are prone to clump irreversibly. Consequently, such suspensions are not injectable via needles of medically acceptable size. A furtller disadvantage of viscous suspensions is the lack of ease of transferring such suspensions from the vial or container used to prepare the suspension to the syringe used for injection.
The present invention also solves the additional problems that arise from use of a viscous injection vehicle. In accordance with the present invention, microparticles are suspended in an injection vehicle having suitable wetting characteristics. The viscosity of the fluid phase of the injectable suspension is increased prior to injecting the suspension in order to improve injectability, and to reduce in vivo injectability failures.
To ensure clarity of the description that follows, the following definitions are provided. By "microparticles" or "microspheres" is meant particles that contain an active agent or other substance dispersed or dissolved within a polymer that serves as a matrix or binder of the particle. The polymer is preferably biodegradable and biocompatible. By "biodegradable" is meant a material that should degrade by bodily processes to products readily disposable by the body and should not accumulate in the body. The products of the biodegradation should also be biocompatible with the body. By "biocompatible"
is meant not toxic to the body, is pharmaceutically acceptable, is not carcinogenic, and does not significantly induce inflammation in body tissues. As used herein, "body"
preferably refers to the human body, but it should be understood that body can also refer to a non-human animal body. By "weight %" or "% by weight" is meant parts by weight per hundred parts total weight of microparticle. For example, 10 wt.% active agent would mean 10 parts active agent by weight and 90 parts polymer by weight. Unless otherwise indicated to the contrary, percentages (%) reported herein are by voluine. By "controlled release microparticle" or "sustained release microparticle" is meant a microparticle from which an active agent or otlier type of substance is released as a function of time. By "mass median diameter" is meant the diameter at which half of the distribution (volume percent) has a larger diameter and half has a smaller diameter.
Method and Examples The following examples are provided to explain the invention, and to describe the materials and methods used in carrying out the invention. The examples are not intended to limit the invention in any manner.
Example 1- In vitro Sieve Test Stacdy To evaluate in vivo injectability failures, an in vitro sieve test study was conducted to assess and predict in vivo injectability, and to determine the key factors affecting injectability. The following factors were investigated during the in vitro sieve test study:
injection vehicle formulation; microparticle morphology; needle diameter;
suspension concentration; and particle size as exhibited by sieve screen size used to screen the microparticles during the manufacturing process.
Three batches of risperidone microparticles were manufactured at a 125 gm scale using a process substantially the same as that disclosed in U.S. Patent No.
5,792,477, the entirety of which is incorporated herein by reference (see, for example, Example 1 in U.S.
Patent No. 5,792,477). Three batches of risperidone microparticles were manufactured at a 1 Kg scale using the process described below in Example 7. All batches had similar particle sizes (ranging from a Mass Median Diaineter of 91 m to 121 m) based on Hyac-Royco analysis of representative bulk material sieved through a 180 m sieve screen. A
160 mg or 320 mg quantity of the microparticles (equivalent to a 50 or 100 mg dose of the risperidone active agent) was transferred, using a manual Perry powder filler with a 5/16 inch ID barrel, into a 5cc glass vial, and capped with a Teflon lined septum.
microparticles comprising a polymeric binder; and an injection vehicle comprising a viscosity enhancing agent, wherein said microparticles are suspended in said injection vehicle at a concentration of greater than about 30 mgJml to form a suspension, wherein a fluid phase of said suspension has a viscosity greater than about 20 cp and less than about 600 cp at 20 C, wherein the viscosity of said fluid phase of said suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
In another aspect of the present invention, there is provided a method of making a composition suitable for injection through a needle into a host, comprising: (a) providing microparticles comprising a polymeric binder, said microparticles having a mass median diameter of at least about 10 m; (b) providing an aqueous injection vehicle comprising a viscosity enhancing agent and having a viscosity of at least 20 cp at 20 C; and (c) suspending the microparticles in the aqueous injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein the viscosity of a fluid phase of the suspension is in the range of from about 20 cp to about 600 cp at 20 C, wherein the viscosity of the fluid phase of the suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
In a further aspect of the present invention, another method for preparing a composition suitable for injection through a needle into a host is provided. In such a method, dry microparticles comprising a polymeric binder are mixed with an aqueous injection vehicle to form a first Thus, according to one aspect of the present invention, there is provided a composition suitable for injection through a needle into a host, comprising:
microparticles comprising a polymeric binder; and an injection vehicle, wherein said microparticles are suspended in said injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein a fluid phase of said suspension has a viscosity greater than about 20 cp and less than about 600 cp at 20 C, wherein the viscosity of said fluid phase of said suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
In another aspect of the present invention, there is provided a method of making a composition suitable for injection through a needle into a host, comprising: (a) providing microparticles comprising a polymeric binder, said microparticles having a mass median diameter of at least about 10 m; (b) providing an aqueous injection vehicle having a viscosity of at least 20 cp at 20 C; and (c) suspending the microparticles in the aqueous injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein the viscosity of a fluid phase of the suspension is in the range of from about 20 cp to about 600 cp at 20 C, wherein the viscosity of the fluid phase of the suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
In a further aspect of the present invention, another method for preparing a composition suitable for injection through a needle into a host is provided. In such a method, dry microparticles are mixed with an aqueous injection vehicle to form a first suspension. The first suspension is mixed with a viscosity enhancing agent to form suspension. The first suspension is mixed with a viscosity enhancing agent to form a second suspension. The viscosity enhancing agent increases the viscosity of the fluid phase of the second suspension. The first suspension may be withdrawn into a first syringe, prior to mixing with the viscosity enhancing agent. The first suspension may be mixed with the viscosity enhancing agent by coupling the first syringe containing the first suspension to a second syringe that contains the viscosity enhancing agent. The first suspension and the viscosity enhancing agent are then repeatedly passed between the first and second syringes.
According to another aspect of the present invention, there is provided a method for preparing a composition suitable for injection through a needle into a host, comprising: (a) mixing dry microparticles comprising a polymeric binder with an aqueous injection vehicle to form a first suspension wherein the concentration of microparticles in the first suspension is greater than about 30 mg/ml; and (b) mixing the first suspension with a viscosity enhancing agent to form a second suspension, wherein the viscosity enhancing agent increases viscosity of a fluid phase of the second suspension to be in the range of from about 20 cp to about 600 cp at 20 C, wherein the viscosity of the fluid phase of the second suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
According to still another aspect of the present invention, there is provided a use of a composition for injection into a host through syringe having a needle ranging in diameter from 18-22 gauge, said composition comprising a second suspension prepared from: (a) dry microparticles comprising a polymeric binder, mixed with an aqueous injection vehicle to form a first suspension, wherein the concentration of microparticles in the first suspension is greater than about 30 mg/ml; and (b) the first suspension mixed with a viscosity enhancing agent to form the second suspension, wherein the viscosity enhancing agent increases viscosity of a fluid phase of the second suspension in a range of from about 20 cp to about 600 cp at 20 C.
According to yet another aspect of the present invention, there is provided a use of a composition for injection into a host through syringe having a needle ranging in diameter from 18-22 gauge, said composition prepared from: (a) dry microparticles comprising a polymeric binder, mixed with an aqueous injection vehicle to form a suspension wherein the concentration of microparticles in the suspension is greater than about 30 mg/ml, wherein the aqueous injection vehicle prior to mixing has a viscosity at 20 C of less than about 60 cp;
(b) the viscosity of a fluid phase of the suspension is changed to a range of from about 20 cp to about 600 cp at 20 C.; and (c) the suspension is withdrawn into the syringe.
In still a further aspect of the invention, a method for preparing a composition suitable for injection through a needle into a host is provided. The method comprises:
(a) mixing dry microparticles with an aqueous injection vehicle that comprises a viscosity enhancing agent to form a suspension;
(b) removing water from the suspension; and -6a-(c) reconstituting the suspension with a quantity of sterile water for injection to form an injectable suspension, wherein the quantity of sterile water for injection is sufficient to achieve a viscosity of a fluid phase of the injectable suspension that provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
Features and Advantages A feature of the present invention is that the injectable compositions can be used to inject varying types of microparticles, and varying types of active agents or other substances, into a host.
A further feature of the present invention is that it allows microparticles to be wetted to achieve a homogeneous suspension, while improving injectability into a host and reducing in vivo injectability failures.
The present invention advantageously provides medically acceptable injectability rates for high concentration suspensions, and for suspensions having large particle size.
The present invention also advantageously provides an efficient method of improving in vivo injectability without introducing microbial contamination or compromising aseptic conditions.
-6b-Detailed Description of the Preferred Embodiments Overview The present invention relates to injectable compositions having improved injectability, and to methods for the preparation of such injectable compositions. The injectable compositions of the present invention overcome injectability problems, particularly injectability failures that occur upon injection into muscle or subcutaneous tissue. Such injectability failures will be referred to herein as "in vivo injectability failures." In vivo injectability failures often manifest themselves in the form of a plug at the tip of the needle, and occur immediately or shortly after injection has been initiated. In vivo injectability failures are typically not predicted by laboratory or other in vitro testing.
The inventors have unexpectedly discovered that injectability is improved, and in vivo injectability failures significantly and unexpectedly reduced, by increasing the viscosity of the fluid phase of an injectable suspension. This is in contrast to conventional teachings that an increase in the viscosity hinders injectability and syringeability.
Viscous vehicles, however, are not optimal for preparing homogeneous suspensions of microparticles because of the relative inability of viscous vehicles to penetrate and wet out a mass of dry particles. Suspensions prepared with viscous vehicles are prone to clump irreversibly. Consequently, such suspensions are not injectable via needles of medically acceptable size. A furtller disadvantage of viscous suspensions is the lack of ease of transferring such suspensions from the vial or container used to prepare the suspension to the syringe used for injection.
The present invention also solves the additional problems that arise from use of a viscous injection vehicle. In accordance with the present invention, microparticles are suspended in an injection vehicle having suitable wetting characteristics. The viscosity of the fluid phase of the injectable suspension is increased prior to injecting the suspension in order to improve injectability, and to reduce in vivo injectability failures.
To ensure clarity of the description that follows, the following definitions are provided. By "microparticles" or "microspheres" is meant particles that contain an active agent or other substance dispersed or dissolved within a polymer that serves as a matrix or binder of the particle. The polymer is preferably biodegradable and biocompatible. By "biodegradable" is meant a material that should degrade by bodily processes to products readily disposable by the body and should not accumulate in the body. The products of the biodegradation should also be biocompatible with the body. By "biocompatible"
is meant not toxic to the body, is pharmaceutically acceptable, is not carcinogenic, and does not significantly induce inflammation in body tissues. As used herein, "body"
preferably refers to the human body, but it should be understood that body can also refer to a non-human animal body. By "weight %" or "% by weight" is meant parts by weight per hundred parts total weight of microparticle. For example, 10 wt.% active agent would mean 10 parts active agent by weight and 90 parts polymer by weight. Unless otherwise indicated to the contrary, percentages (%) reported herein are by voluine. By "controlled release microparticle" or "sustained release microparticle" is meant a microparticle from which an active agent or otlier type of substance is released as a function of time. By "mass median diameter" is meant the diameter at which half of the distribution (volume percent) has a larger diameter and half has a smaller diameter.
Method and Examples The following examples are provided to explain the invention, and to describe the materials and methods used in carrying out the invention. The examples are not intended to limit the invention in any manner.
Example 1- In vitro Sieve Test Stacdy To evaluate in vivo injectability failures, an in vitro sieve test study was conducted to assess and predict in vivo injectability, and to determine the key factors affecting injectability. The following factors were investigated during the in vitro sieve test study:
injection vehicle formulation; microparticle morphology; needle diameter;
suspension concentration; and particle size as exhibited by sieve screen size used to screen the microparticles during the manufacturing process.
Three batches of risperidone microparticles were manufactured at a 125 gm scale using a process substantially the same as that disclosed in U.S. Patent No.
5,792,477, the entirety of which is incorporated herein by reference (see, for example, Example 1 in U.S.
Patent No. 5,792,477). Three batches of risperidone microparticles were manufactured at a 1 Kg scale using the process described below in Example 7. All batches had similar particle sizes (ranging from a Mass Median Diaineter of 91 m to 121 m) based on Hyac-Royco analysis of representative bulk material sieved through a 180 m sieve screen. A
160 mg or 320 mg quantity of the microparticles (equivalent to a 50 or 100 mg dose of the risperidone active agent) was transferred, using a manual Perry powder filler with a 5/16 inch ID barrel, into a 5cc glass vial, and capped with a Teflon lined septum.
Two injection vehicles were used in the in vitro sieve test study. The first injection vehicle ("Formula 1") was an aqueous vehicle consisting of 1.5% by volume carboxymethyl cellulose (CMC), 30% by voluine sorbitol, and 0.2% by volume Tween 20 (polysorbate 20). The viscosity of the first injection vehicle was approximately 27 cp at 20 C. The second injection vehicle ("Formula 2") was an aqueous vehicle consisting of 0.75% by volume CMC, 15% by volume sorbitol, and 0.2% by volume Tween 20 (polysorbate 20). The viscosity of the second injection vehicle was approximately 7 cp at 20 C.
The microparticle suspension was prepared as follows. The injection vehicle was aspirated into a 5cc syringe through a needle. The vehicle was then injected into the glass vial containing the microparticles, and the needle was removed. The glass vial was then rolled between the palms until the microparticles were completely suspended, approximately one minute. The needle was reinserted into the vial so that the bevel of the needle was just through the septum with the opening facing toward the vial bottom. The vial was inverted and the suspension was withdrawn. The syringe was rotated 180 around its axis, and the remaining suspension was aspirated into the syringe.
Sieve screens with mesh opening sizes of 180, 212, 250, 300, 355, and 425 m were used. The bevel of the syringe needle was placed on the mesh of the sieve screen so that the bevel was in full contact with the mesh. The needle was oriented so the opening of the needle was flush against the mesh of the screen. This prevented the mesh from entering the bevel, while maintaining the required restrictive area. The suspension was tried on the smallest sieve mesh first (highest screen resistance). If the suspension fouled the needle on this sieve mesh, the needle was unclogged by retracting the plunger of the syringe, depressing the plunger while the syringe was in the upward position, and passing an aliquot of suspension through the needle. The injection process was tried again using the next greater mesh size, and repeated until the suspension was successfully injected. All preparations were done in triplicate.
A three-factor Box-Behnlcen statistical designed experiment was constructed to evaluate the following independent variables: manufacturing bulk sieve size (125, 150, and 180 m); needle ID(19 TW, 20 RW, and 22 RW gauge - ID of 19 TW (thin wall) equivalent to 18 RW (regular wall)); and suspension concentration (0.074, 0.096, and 0.138 w/w - corresponds to approximately 300 mg microparticle dose diluted with 4, 3, and 2cc, respectively, of injection vehicle).
The microparticle suspension was prepared as follows. The injection vehicle was aspirated into a 5cc syringe through a needle. The vehicle was then injected into the glass vial containing the microparticles, and the needle was removed. The glass vial was then rolled between the palms until the microparticles were completely suspended, approximately one minute. The needle was reinserted into the vial so that the bevel of the needle was just through the septum with the opening facing toward the vial bottom. The vial was inverted and the suspension was withdrawn. The syringe was rotated 180 around its axis, and the remaining suspension was aspirated into the syringe.
Sieve screens with mesh opening sizes of 180, 212, 250, 300, 355, and 425 m were used. The bevel of the syringe needle was placed on the mesh of the sieve screen so that the bevel was in full contact with the mesh. The needle was oriented so the opening of the needle was flush against the mesh of the screen. This prevented the mesh from entering the bevel, while maintaining the required restrictive area. The suspension was tried on the smallest sieve mesh first (highest screen resistance). If the suspension fouled the needle on this sieve mesh, the needle was unclogged by retracting the plunger of the syringe, depressing the plunger while the syringe was in the upward position, and passing an aliquot of suspension through the needle. The injection process was tried again using the next greater mesh size, and repeated until the suspension was successfully injected. All preparations were done in triplicate.
A three-factor Box-Behnlcen statistical designed experiment was constructed to evaluate the following independent variables: manufacturing bulk sieve size (125, 150, and 180 m); needle ID(19 TW, 20 RW, and 22 RW gauge - ID of 19 TW (thin wall) equivalent to 18 RW (regular wall)); and suspension concentration (0.074, 0.096, and 0.138 w/w - corresponds to approximately 300 mg microparticle dose diluted with 4, 3, and 2cc, respectively, of injection vehicle).
The following scoring system was used:
Score Result 0 Needle Bloclc 1 Passes through a 425 m screen 2 Passes through a 355 m screen 3 Passes through a 300 m screen 4 Passes through a 250 m screen 5 Passes through a 212 m screen Table 1 below shows the score obtained for screen resistance tests using this scoring system for the 1 Kg and the 125 gm batches for each of the injection vehicles tested.
Mean Score Mfg Bulk Sieve Size n Formula 2 7cp Formula 1 27cp 1Kg Batches <180 9 2.3 2.3 <125 9 3.4 3.7 125Gm Batches <180 6 1.5 2.0 <150 6 3.0 2.8 <125 6 3.0 2.5 As shown in Table 1, the screen resistance tests showed no significant difference between the two injection vehicles tested. Variations in suspension concentration and injection vehicle viscosity showed little to no effect. For the 1Kg Batches, the mean scores were identical for the <180 manufacturing bulk sieve size, even though-the viscosity of the Formula 1 injection vehicle was approximately 27 cp, and the viscosity of the Formula 2 injection vehicle was significantly less, approximately 7 cp. The scores for the other 1 Kg Batch and for the 125 Gm Batches varied modestly (0.2 to 0.5) between the two injection vehicles, thereby indicating that the injection vehicle viscosity had little effect. The tests conducted during the in vitro sieve test study show that in vitro injectability is strongly controlled by microparticle morphology and size. Needle gauge had a more modest effect.
Score Result 0 Needle Bloclc 1 Passes through a 425 m screen 2 Passes through a 355 m screen 3 Passes through a 300 m screen 4 Passes through a 250 m screen 5 Passes through a 212 m screen Table 1 below shows the score obtained for screen resistance tests using this scoring system for the 1 Kg and the 125 gm batches for each of the injection vehicles tested.
Mean Score Mfg Bulk Sieve Size n Formula 2 7cp Formula 1 27cp 1Kg Batches <180 9 2.3 2.3 <125 9 3.4 3.7 125Gm Batches <180 6 1.5 2.0 <150 6 3.0 2.8 <125 6 3.0 2.5 As shown in Table 1, the screen resistance tests showed no significant difference between the two injection vehicles tested. Variations in suspension concentration and injection vehicle viscosity showed little to no effect. For the 1Kg Batches, the mean scores were identical for the <180 manufacturing bulk sieve size, even though-the viscosity of the Formula 1 injection vehicle was approximately 27 cp, and the viscosity of the Formula 2 injection vehicle was significantly less, approximately 7 cp. The scores for the other 1 Kg Batch and for the 125 Gm Batches varied modestly (0.2 to 0.5) between the two injection vehicles, thereby indicating that the injection vehicle viscosity had little effect. The tests conducted during the in vitro sieve test study show that in vitro injectability is strongly controlled by microparticle morphology and size. Needle gauge had a more modest effect.
As will be discussed in more detail below, in vivo data supported the responses of microparticle morphology, size, and suspension concentration, but contradicted the effect of injection vehicle viscosity. Particularly, the in vivo studies showed a dramatic improvement in injectability with increased injection vehicle viscosity.
In vivo Injectability Exatrzple 2 - Pig Study The injectability of risperidone microparticles was evaluated in Yorkshire weanling pigs. The study revealed that the IM injectability of risperidone microparticles is dependent upon injection vehicle viscosity and microparticle size. Reducing the injection vehicle viscosity led to a higher rate of injection failures due to needle clogging.
Risperidone microparticles were manufactured at the 125 gm scale in the same manner noted above for the in vitro sieve test study. The microparticles were sized to < 125 m and < 150 m using USA Standard Testing Sieves Nos. 120 and 100, respectively. The same two injection vehicles (Formula 1 and Formula 2) described above for the in vitro sieve test study were used in the pig study. 19 gauge TW x 1.5 inch hypodermic needles (Becton-Dickinson Precisionglide catalog nuinber 305187) and 3 cc hypodermic syringes (Becton-Dickinson catalog number 309585) were used.
The injection experiments were conducted in male and female Yorlcshire weanling pigs approximately 6 weeks in age (10-15 kg). The animals were anesthetized with low doses of Telazole and Xylazine and with halothane if needed. Injection sites were shaved and cleansed with betadine swabs prior to microparticle administration.
Injections to the hind quarters were administered to the biceps femoris in the upper hind limb. Injection sites in the legs were to the superficial digital flexor muscles in the forelimb, and to the cranial tibial muscle in the hindlimb.
Microparticles and injection vehicles were equilibrated to ambient temperature for at least 30 minutes. Using a 3 ml syringe equipped with a 1.5 inch 19 gauge thin wall needle, the prescribed volume of injection vehicle was withdrawn into the syringe, and injected into the vial containing the microparticles. The microparticles were suspended in the injection vehicle by orienting the vial horizontally and rolling it between the palms of the operator's hands. This was done without removing the needle/syringe from the septum. The time required to fully suspend the microparticles was approximately one minute.
The suspended microparticles were then withdrawn into the same needle/syringe and injected. Following insertion of the needle and prior to injection of the suspension, the syringe plunger was withdrawn slightly to confirm that the needle was located in the extravascular space. The time interval between aspiration of the suspension and injection was usually less than one minute. Injection regions were evaluated to pinpoint the site of microparticle deposition and to assess the distribution of microparticles in the tissue.
Table 2 below shows the effect on injectability as a function of injection vehicle viscosity, injection site, and microparticle concentration. A vehicle viscosity of "high"
refers to the injection vehicle of Formula 1 described above, having a viscosity of approximately 27 cp at 20 C. Similarly, a vehicle viscosity of "low" refers to the injection vehicle of Formula 2 described above, having a viscosity of approximately 7 cp at 20 C.
The size of the microparticles for the results shown in Table 2 is 180 m.
Vehicle Microparticle Viscosity Dose Volume Site Failure rate High 160 mg 1 mL Hind 0/10 quarter High 160 mg 1 mL Leg 1/8 Low 160 mg 1mL Hind 4/7 quarter High 320 mg 1 mL Hind 0/4 quarter As can be seen from Table 2, increased failure rates were observed with the lower viscosity injection vehicle (4 failures with 7 injections), and when the injection site was in the leg (1 failure per 8 injections). The increased failure rate due to reduced viscosity was statistically significant at the 1% level (Fisher Exact Test).
Table 3 below summarizes injectability data for microparticles fractionated by size.
Similar trends were observed when the system was stressed by decreasing the vehicle viscosity, witll failure rates being higher with the <180 m fraction. The <125 m fraction and the <150 .m fraction were indistinguishable in terms of failure rate. The low viscosity data show statistically significant differences between <180 m fraction and <150 m fraction, and between <180 m fraction and <125gm fraction at 1% and 3%
confidence levels, respectively (Fisher Exact Test).
Avg. %
Max. delivered particle size Vehicle Volume Failure (failed (gm) Viscosity (mL) Site rate injections)' 180 High 2.0 Leg 0/5 n/a 150 High 2.0 Leg 0/5 n/a 125 High 2.0 Leg 0/5 n/a 180 High 1.0 Leg 2/4 0 150 High 1.0 Leg 0/4 n/a 125 High 1.0 Leg 0/4 n/a 180 Low 2.0 Hind quarter 8/10 33 150 Low 2.0 Hind quarter 2/10 18 125 Low 2.0 Hind quarter 3/10 80 'Average fraction of dose delivered prior to needle clog (failed injections only) The in vivo pig study demonstrates a lower inj ectability failure rate with a higher viscosity injection vehicle, over a range of particle sizes. The in vitro sieve test study did not predict the viscosity dependence observed in the pig study.
Exanaple 3 - Sheep Study A two-part sheep study was conducted to investigate in vivo injectability as a fi.inction of injection vehicle composition and viscosity, and suspension concentration. In Part I, risperidone microparticles were prepared at the 1 Kg scale using the process described below in Example 7. A batch of placebo microparticles was prepared using the process shown and described in U.S. Patent No. 5,922,253, the entirety of which is incorporated herein by reference. The two types of microparticles were studied at two suspension concentrations of 150 and 300 mg/inl. Animal injectability tests were conducted using 3 cc syringes and 22 gauge TW x 1.5 inch needles (Becton-Diclcinson).
In vivo Injectability Exatrzple 2 - Pig Study The injectability of risperidone microparticles was evaluated in Yorkshire weanling pigs. The study revealed that the IM injectability of risperidone microparticles is dependent upon injection vehicle viscosity and microparticle size. Reducing the injection vehicle viscosity led to a higher rate of injection failures due to needle clogging.
Risperidone microparticles were manufactured at the 125 gm scale in the same manner noted above for the in vitro sieve test study. The microparticles were sized to < 125 m and < 150 m using USA Standard Testing Sieves Nos. 120 and 100, respectively. The same two injection vehicles (Formula 1 and Formula 2) described above for the in vitro sieve test study were used in the pig study. 19 gauge TW x 1.5 inch hypodermic needles (Becton-Dickinson Precisionglide catalog nuinber 305187) and 3 cc hypodermic syringes (Becton-Dickinson catalog number 309585) were used.
The injection experiments were conducted in male and female Yorlcshire weanling pigs approximately 6 weeks in age (10-15 kg). The animals were anesthetized with low doses of Telazole and Xylazine and with halothane if needed. Injection sites were shaved and cleansed with betadine swabs prior to microparticle administration.
Injections to the hind quarters were administered to the biceps femoris in the upper hind limb. Injection sites in the legs were to the superficial digital flexor muscles in the forelimb, and to the cranial tibial muscle in the hindlimb.
Microparticles and injection vehicles were equilibrated to ambient temperature for at least 30 minutes. Using a 3 ml syringe equipped with a 1.5 inch 19 gauge thin wall needle, the prescribed volume of injection vehicle was withdrawn into the syringe, and injected into the vial containing the microparticles. The microparticles were suspended in the injection vehicle by orienting the vial horizontally and rolling it between the palms of the operator's hands. This was done without removing the needle/syringe from the septum. The time required to fully suspend the microparticles was approximately one minute.
The suspended microparticles were then withdrawn into the same needle/syringe and injected. Following insertion of the needle and prior to injection of the suspension, the syringe plunger was withdrawn slightly to confirm that the needle was located in the extravascular space. The time interval between aspiration of the suspension and injection was usually less than one minute. Injection regions were evaluated to pinpoint the site of microparticle deposition and to assess the distribution of microparticles in the tissue.
Table 2 below shows the effect on injectability as a function of injection vehicle viscosity, injection site, and microparticle concentration. A vehicle viscosity of "high"
refers to the injection vehicle of Formula 1 described above, having a viscosity of approximately 27 cp at 20 C. Similarly, a vehicle viscosity of "low" refers to the injection vehicle of Formula 2 described above, having a viscosity of approximately 7 cp at 20 C.
The size of the microparticles for the results shown in Table 2 is 180 m.
Vehicle Microparticle Viscosity Dose Volume Site Failure rate High 160 mg 1 mL Hind 0/10 quarter High 160 mg 1 mL Leg 1/8 Low 160 mg 1mL Hind 4/7 quarter High 320 mg 1 mL Hind 0/4 quarter As can be seen from Table 2, increased failure rates were observed with the lower viscosity injection vehicle (4 failures with 7 injections), and when the injection site was in the leg (1 failure per 8 injections). The increased failure rate due to reduced viscosity was statistically significant at the 1% level (Fisher Exact Test).
Table 3 below summarizes injectability data for microparticles fractionated by size.
Similar trends were observed when the system was stressed by decreasing the vehicle viscosity, witll failure rates being higher with the <180 m fraction. The <125 m fraction and the <150 .m fraction were indistinguishable in terms of failure rate. The low viscosity data show statistically significant differences between <180 m fraction and <150 m fraction, and between <180 m fraction and <125gm fraction at 1% and 3%
confidence levels, respectively (Fisher Exact Test).
Avg. %
Max. delivered particle size Vehicle Volume Failure (failed (gm) Viscosity (mL) Site rate injections)' 180 High 2.0 Leg 0/5 n/a 150 High 2.0 Leg 0/5 n/a 125 High 2.0 Leg 0/5 n/a 180 High 1.0 Leg 2/4 0 150 High 1.0 Leg 0/4 n/a 125 High 1.0 Leg 0/4 n/a 180 Low 2.0 Hind quarter 8/10 33 150 Low 2.0 Hind quarter 2/10 18 125 Low 2.0 Hind quarter 3/10 80 'Average fraction of dose delivered prior to needle clog (failed injections only) The in vivo pig study demonstrates a lower inj ectability failure rate with a higher viscosity injection vehicle, over a range of particle sizes. The in vitro sieve test study did not predict the viscosity dependence observed in the pig study.
Exanaple 3 - Sheep Study A two-part sheep study was conducted to investigate in vivo injectability as a fi.inction of injection vehicle composition and viscosity, and suspension concentration. In Part I, risperidone microparticles were prepared at the 1 Kg scale using the process described below in Example 7. A batch of placebo microparticles was prepared using the process shown and described in U.S. Patent No. 5,922,253, the entirety of which is incorporated herein by reference. The two types of microparticles were studied at two suspension concentrations of 150 and 300 mg/inl. Animal injectability tests were conducted using 3 cc syringes and 22 gauge TW x 1.5 inch needles (Becton-Diclcinson).
Five injection vehicles were used in Part I. The five injection vehicles were made using one or more of the three injection vehicle formulations shown below:
Vehicle A 0.9% Saline; 0.1% Tween 20 Vehicle B 1.5% CMC; 30% Sorbitol; 0.2% Tween 20 Vehicle C 3% CMC; 0.1% Tween 20; 0.9% Saline Animal studies were conducted using domestic sheep weighing approximately 100-150 pounds. The animals were anesthetized with Telazole/Xylazine/Atropine intramuscularly and further suppleinented with isofluorane gas (approximately 1-2%) during the injection procedure. Prior to injection, the animal's dorsal, gluteal, and upper leg regions were shaved and cleaned with alcohol. Injection sites were visualized prior to and during dosing using ultrasound (El Medical).
The microparticles and injection vehicles were equilibrated to ambient temperature prior to dose suspension. Using a 3 cc syringe and 22 gauge thin-walled needle, the vehicle was aspirated and injected into the microparticle vial. The risperidone microparticles were suspended in 1 ml of vehicle at approximate concentrations of 150 or 300 mg/ml. Placebo microparticles were suspended in 2 or 1 ml of vehicle at approximate concentrations of 150 or 300 mg/ml. The vial was then agitated by hand for approximately 1 minute until the microparticles were suspended. The suspension was then aspirated back into the syringe using the same needle. Care was taken to recover the maximum a.mount of suspension from the vial. Preparation of dose suspensions was conducted randomly by three individuals.
All doses were injected by a single individual into the animal almost immediately after preparation. The rate of injection was maintained constant at approximately 5-10 seconds.
The results from Part I are shown in Table 4 below. Viscosities were determined by Brookfield Model LVT viscometer fitted witli a UL adapter. Densities were measured for Vehicles A, B, and C. Densities for the combination vehicles made up of Vehicles A, B, and C were determined by interpolation based upon the ratio of Vehicles A, B, and C in the combination vehicle.
Vehicle A 0.9% Saline; 0.1% Tween 20 Vehicle B 1.5% CMC; 30% Sorbitol; 0.2% Tween 20 Vehicle C 3% CMC; 0.1% Tween 20; 0.9% Saline Animal studies were conducted using domestic sheep weighing approximately 100-150 pounds. The animals were anesthetized with Telazole/Xylazine/Atropine intramuscularly and further suppleinented with isofluorane gas (approximately 1-2%) during the injection procedure. Prior to injection, the animal's dorsal, gluteal, and upper leg regions were shaved and cleaned with alcohol. Injection sites were visualized prior to and during dosing using ultrasound (El Medical).
The microparticles and injection vehicles were equilibrated to ambient temperature prior to dose suspension. Using a 3 cc syringe and 22 gauge thin-walled needle, the vehicle was aspirated and injected into the microparticle vial. The risperidone microparticles were suspended in 1 ml of vehicle at approximate concentrations of 150 or 300 mg/ml. Placebo microparticles were suspended in 2 or 1 ml of vehicle at approximate concentrations of 150 or 300 mg/ml. The vial was then agitated by hand for approximately 1 minute until the microparticles were suspended. The suspension was then aspirated back into the syringe using the same needle. Care was taken to recover the maximum a.mount of suspension from the vial. Preparation of dose suspensions was conducted randomly by three individuals.
All doses were injected by a single individual into the animal almost immediately after preparation. The rate of injection was maintained constant at approximately 5-10 seconds.
The results from Part I are shown in Table 4 below. Viscosities were determined by Brookfield Model LVT viscometer fitted witli a UL adapter. Densities were measured for Vehicles A, B, and C. Densities for the combination vehicles made up of Vehicles A, B, and C were determined by interpolation based upon the ratio of Vehicles A, B, and C in the combination vehicle.
Viscosity Density Conc Vehicle (cp) (mg/ml) (mg/ml)Z Failures Vehicle A 1.0 1.01 150 8/10 Vehicle B 24.0 1.11 150 1/10 24.0 1.11 300 0/10 Vehicle C 56.0 1.04 150 0/10 56.0 1.04 150 1/10' 56.0 1.04 300 0/10 3 Parts Vehicle B: l Part 11.1 1.08 300 0/5 Vehicle A
1 Part Vehicle B: 3 Parts 2.3 1.03 300 7/10 Vehicle A
1Placebo Microparticles. All other results are risperidone microparticles.
2 mg microparticles/ml diluent In order to isolate the effect of injection vehicle viscosity on injectability, additional sheep injectability tests (Part II) were conducted. The injectability results are shown below in Table 5. Viscosities were detennined by Brookfield Model LVT
viscometer fitted with a UL adapter. In Part II, the suspension concentration was fixed at 300 mg/ml. The tests in Part II were carried out using risperidone microparticles prepared in the same manner as in Part I, using the same injection protocol. The injection vehicles included Vehicle C and Vehicle A as described above, as well as injection vehicles prepared by diluting Vehicle C with Vehicle A. For example, the injection vehicle fonnulation having a viscosity of 22.9 cp is fonnulated by combining Vehicle C
and Vehicle A in a 1:1 ratio, thereby forming Diluent 1.
1 Part Vehicle B: 3 Parts 2.3 1.03 300 7/10 Vehicle A
1Placebo Microparticles. All other results are risperidone microparticles.
2 mg microparticles/ml diluent In order to isolate the effect of injection vehicle viscosity on injectability, additional sheep injectability tests (Part II) were conducted. The injectability results are shown below in Table 5. Viscosities were detennined by Brookfield Model LVT
viscometer fitted with a UL adapter. In Part II, the suspension concentration was fixed at 300 mg/ml. The tests in Part II were carried out using risperidone microparticles prepared in the same manner as in Part I, using the same injection protocol. The injection vehicles included Vehicle C and Vehicle A as described above, as well as injection vehicles prepared by diluting Vehicle C with Vehicle A. For example, the injection vehicle fonnulation having a viscosity of 22.9 cp is fonnulated by combining Vehicle C
and Vehicle A in a 1:1 ratio, thereby forming Diluent 1.
Density Conc Vehicle Viscosity (cp) (mg/mI) (mg/ml) Failures Vehicle C 63.8 1.04 300 2/10 1:1 Vehicle C: Diluent 1 37.6* 1.03 300 2/10 1:1 Vehicle C: Vehicle A 22.9 1.03 300 1/10 (Diluent 1) 1:1 Diluent 1: Vehicle A 11.3 1.02 300 5/10 (Diluent 2) 1:1 Diluent 2: Vehicle A 1.4 1.01 300 7/10 Vehicle A 1 1.01 300 10/10 *estimate, insufficient sample The data for Parts I and II shown in Tables 4 and 5 clearly show that the injection vehicle viscosity has an effect on injectability. Viscosities of at least about 20 cp are necessary for successful and medically acceptable injectability rates. At viscosities of less than or equal to about 11 cp, in vivo injectability failures increase significantly.
The effect of a density enhancing agent can be seen by comparing the injectability failures using the vehicle in Table 4 having a viscosity of 11.1 cp with the vehicle in Table 5 having a viscosity of 11.3 cp. The viscosity of these two vehicles is nearly the same.
However, the Table 4 vehicle had 0/5 failures while the Table 5 vehicle had 5/10 failures.
The Table 4 vehicle has a higher density (1.08 mg/ml) compared to the Table 5 vehicle (1.02 mg/inl). The Table 4 vehicle includes a density enliancing agent, sorbitol, while the Table 5 vehicle contains no sorbitol or other density enhancing agent.
Example 4- Ex Vivo Injectability Tests Injectability tests were conducted with several injection vehicles prepared at viscosities exceeding -50 cp. Injection vehicles having viscosities in excess of 50 cp were mixed, using a syringe-syringe mixing method described in more detail in Example 5 below, in which the viscosity enhancing agent was introduced after suspending the microparticles in the 50 cp vehicle.
The effect of a density enhancing agent can be seen by comparing the injectability failures using the vehicle in Table 4 having a viscosity of 11.1 cp with the vehicle in Table 5 having a viscosity of 11.3 cp. The viscosity of these two vehicles is nearly the same.
However, the Table 4 vehicle had 0/5 failures while the Table 5 vehicle had 5/10 failures.
The Table 4 vehicle has a higher density (1.08 mg/ml) compared to the Table 5 vehicle (1.02 mg/inl). The Table 4 vehicle includes a density enliancing agent, sorbitol, while the Table 5 vehicle contains no sorbitol or other density enhancing agent.
Example 4- Ex Vivo Injectability Tests Injectability tests were conducted with several injection vehicles prepared at viscosities exceeding -50 cp. Injection vehicles having viscosities in excess of 50 cp were mixed, using a syringe-syringe mixing method described in more detail in Example 5 below, in which the viscosity enhancing agent was introduced after suspending the microparticles in the 50 cp vehicle.
Subcutaneous injections of blank (placebo) PLGA (poly(d,l-lactic-co-glycolic acid)) microparticles, having an approximate mass median diameter of 50 m, were made into previously harvested pig skin using four injection vehicles having viscosities at -25 C
of approximately 53.1 to >1000 cp at the time of formulation. The vehicles were subsequently autoclaved before use, and the final viscosity (viscosity of the fluid phase of the injectable suspension) varied between approximately 5-60% from the nominal starting viscosity value. The most viscous injection vehicle was approximately 13 times the viscosity of the 50 cp formulation. In this ex vivo model, increasing the viscosity of the fluid phase of the injectable suspension decreased injection failure rate, even when microparticle concentration was raised from 175 to 250 mg/ml, at a needle size of 22 G.
Maximal improvement in inj ectability, within this range of concentration and needle size, was achieved with injection vehicles having a viscosity of approximately 250 cp.
In another study, four injection vehicles having measured viscosities of 53 to 251cp were evaluated for subcutaneous injectability in anesthetized pigs.
Microparticle concentrations were 150 and 190 mg/ml. Injection failure was directly related to microparticle concentration, and inversely related to viscosity level. At 53 cp, approximately 50% of injections failed, while at higher viscosities, failures diminished. At the highest viscosity (251cp), zero failures were recorded at both microparticle concentrations.
Exanaple 5- Metlaods for Preparing Injectable Compositions Methods for preparing injectable compositions in accordance with the present invention will now be described. In accordance with the present invention, microparticles are first mixed with an injection vehicle having suitable viscosity and wetting characteristics to achieve a homogeneous mono-particulate suspension. The viscosity of the fluid phase of the suspension.is then changed, preferably increased, to achieve a viscosity that inhibits suspension separation and clogging under conditions of normal clinical use. In accordance with one method of the present invention, dry microparticles are mixed with an aqueous injection vehicle to form a first suspension. The first suspension is mixed with a viscosity enhancing agent to form a second suspension. The viscosity enhancing agent increases the viscosity of the fluid phase of the second suspension. The second suspension is then injected into a host.
of approximately 53.1 to >1000 cp at the time of formulation. The vehicles were subsequently autoclaved before use, and the final viscosity (viscosity of the fluid phase of the injectable suspension) varied between approximately 5-60% from the nominal starting viscosity value. The most viscous injection vehicle was approximately 13 times the viscosity of the 50 cp formulation. In this ex vivo model, increasing the viscosity of the fluid phase of the injectable suspension decreased injection failure rate, even when microparticle concentration was raised from 175 to 250 mg/ml, at a needle size of 22 G.
Maximal improvement in inj ectability, within this range of concentration and needle size, was achieved with injection vehicles having a viscosity of approximately 250 cp.
In another study, four injection vehicles having measured viscosities of 53 to 251cp were evaluated for subcutaneous injectability in anesthetized pigs.
Microparticle concentrations were 150 and 190 mg/ml. Injection failure was directly related to microparticle concentration, and inversely related to viscosity level. At 53 cp, approximately 50% of injections failed, while at higher viscosities, failures diminished. At the highest viscosity (251cp), zero failures were recorded at both microparticle concentrations.
Exanaple 5- Metlaods for Preparing Injectable Compositions Methods for preparing injectable compositions in accordance with the present invention will now be described. In accordance with the present invention, microparticles are first mixed with an injection vehicle having suitable viscosity and wetting characteristics to achieve a homogeneous mono-particulate suspension. The viscosity of the fluid phase of the suspension.is then changed, preferably increased, to achieve a viscosity that inhibits suspension separation and clogging under conditions of normal clinical use. In accordance with one method of the present invention, dry microparticles are mixed with an aqueous injection vehicle to form a first suspension. The first suspension is mixed with a viscosity enhancing agent to form a second suspension. The viscosity enhancing agent increases the viscosity of the fluid phase of the second suspension. The second suspension is then injected into a host.
One embodiment for carrying out such a method will now be described. Vialed dry microparticles are mixed with an aqueous injection vehicle having a viscosity less than about 60 cp at 20 C, preferably about 20 - 50 centipoise. The concentration of microparticles in the mixture is greater than about 30 mg/ml, preferably about 100-400 mg microparticles/ml. The mixture is agitated until a homogeneous suspension is formed. The homogeneous suspension is withdrawn into a first hypodermic syringe. The first syringe is connected to a second syringe containing a viscosity enhancing agent. A
viscosity enhancing agent suitable for use with the present invention is sodium carboxymethyl cellulose (CMC), preferably having a viscosity of from about 1000 to about 2000 cp at 20 C. It should be understood that the present invention is not limited to the use of CMC
as the viscosity enhancing agent, and other suitable viscosity enhancing agents may be used. The added volume of the viscosity enhancing agent is approximately 10-25% of the volume of the microparticle suspension.
The microparticle suspension and the viscosity enhancing agent are mixed to form the injectable composition by repeatedly passing the microparticle suspension and the viscosity enhancing agent between the first and second syringes. Such a syringe-syringe mixing method was used in the injectability tests described in Example 4 above. After mixing with the viscosity enhancing agent, the viscosity of the fluid phase of the inicroparticle suspension is from about 200 cp to about 600 cp at 20 C. A
hypodermic needle is attached to the syringe containing the injectable composition, and the injectable composition is injected into a host in a manner well=lcnown to one of skill in the art.
An alternate embodiment for carrying out the method of the present invention will now be described. Dry microparticles are mixed with an aqueous injection vehicle having a viscosity of less than about 60 cp at 20 C to form a suspension. The viscosity of the fluid phase of the suspension is changed in a manner that will be described in more detail below. The suspension that constitutes the injectable composition is withdrawn into a syringe, and the injectable composition is injected from the syringe into the host.
Preferably, the viscosity of the fluid phase of the suspension is changed after the suspension has been withdrawn into the syringe.
In one aspect of this alternate embodiment, the viscosity is changed by changing the temperature of the fluid phase of the injectable suspension. The methods and techniques for changing the viscosity of a liquid by changing the temperature of the liquid are readily apparent to one skilled in the art. The temperature of the fluid phase of the suspension is changed until the desired viscosity of the fluid phase has been reached. The suspension now has the desired fluid phase viscosity for injection into a host, and constitutes the injectable composition. At this point, the.suspension is withdrawn into the syringe and injected into the host. Alternatively, the suspension can be withdrawn into the syringe prior to changing the temperature of the fluid phase of the suspension to acllieve the desired fluid phase viscosity. For example, an injection vehicle that comprises a polymer solution can be used as the viscosity of polymer solutions is temperature-dependent. A polymer solution can be used to suspend the microparticles under low-viscosity conditions suitable for wetting and suspension formation. Once the microparticles are suspended, the suspension is drawn up into a syringe. The temperature is then changed to induce higher viscosity in the injection vehicle constituting the fluid phase of the suspension, and the suspension having increased viscosity is injected into a host.
In another aspect of this alternate embodiment, the viscosity is changed by adding a viscosity enhancing agent to the suspension. The suspension is withdrawn into the syringe, and then the viscosity enhancing agent is added to the suspension in the syringe, thereby increasing the viscosity of the aqueous injection vehicle constituting the fluid phase of the suspension. The suspension now has the desired fluid phase viscosity for injection into a host, and constitutes the injectable composition. The suspension is then injected into the host. Preferably, the viscosity enhancing agent is added to the suspension iinmediately prior to injection into the host. Suitable viscosity enhancing agents include sodium carboxymethyl cellulose, polyvinylpyrrolidone (PVP), such as PLASDONE, available from GAF Chemicals Corp., Wayne, NJ, and hydroxypropylmethylcellulose (HPMC), such as Methocel, available from Dow Chemical Co., Midland, MI. However, other viscosity enhancing agents may be used, as would be readily apparent to one of skill in the art.
In another embodiment of the invention, the injectable compositions of the present invention are prepared by providing microparticles that comprise a polymeric binder and that have a mass median diameter of at least about 10 m. The mass median diameter of the microparticles is preferably less than about 250 m, and more preferably, in the range of from about 20 gm to about 150 m. Such microparticles can be made in the manner disclosed and described herein, or in any other manner lcnown to one skilled in the art. An aqueous injection vehicle is provided. Such an aqueous injection vehicle can be made in the manner disclosed and described herein, or in any other manner known to one skilled in the art. The microparticles are suspended in the aqueous injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, the fluid phase of the suspension having a viscosity of at least 20 cp at 20 C.
In yet a further einbodiment of the present invention, dry microparticles are mixed with an aqueous injection vehicle containing a viscosity enhancing agent to form a suspension. Suitable viscosity enhancing agents include sodium carboxymethyl cellulose, polyvinylpyrrolidone (PVP), such as PLASDONE, available from GAF Chemicals Corp., Wayne, NJ, and hydroxypropylmethylcellulose (HPMC), such as Methocel, available from Dow Chemical Co., Midland, MI. However, otller viscosity enhancing agents may be used, as would be readily apparent to one of skill in the art. The suspension is then dispensed into vials. The vials are lyophilized (or vacuum dried) to remove the water.
Prior to injection, the vial contents are reconstituted with sterile water for inj ection in a quantity sufficient to achieve the desired viscosity for the fluid phase of the reconstituted injectable suspension. Preferably, the vial contents are reconstituted with a quantity of sterile water for injection sufficient to achieve a viscosity of a fluid phase of the injectable suspension that provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
Exatiiple 6 - Injectable Conzpositions The injectable compositions of the present invention will now be described.
The injectable compositions of the present invention are suitable for injection through a needle into a host. In one einbodiment, the injectable compositions comprise inicroparticles suspended in an aqueous injection vehicle. The microparticles preferably have a mass median diameter of at least about 10 m to about 250 m, preferably in the range of from about 20 m to about 150 m. However, it should be understood that the invention is not limited to microparticles in this size range, and that smaller or larger microparticles may also be used.
The microparticles preferably comprise a polymeric binder. Suitable polymeric binder materials include poly(glycolic acid), poly-d,l-lactic acid, poly-l-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, polyphosphazines, albumin, casein, and waxes. Poly (d,l-lactic-co-glycolic acid) 'is commercially available from Allcermes, Inc. (Blue Ash, OH). A suitable product commercially available from Alkermes, Inc. is a 50:50 poly(d,l-lactic-co-glycolic acid) known as MEDISORBOO 5050 DL. This product has a mole percent coinposition of 50%
lactide and 50% glycolide. Other suitable commercially available products are MEDISORBO 6535 DL, 7525 DL, 8515 DL and poly(d,l-lactic acid) (100 DL).
Poly(lactide-co-glycolides) are also commercially available from Boehringer Ingelheim (Germany) under its Resomer0 mark, e.g., PLGA 50:50 (Resomer(I RG 502), PLGA
75:25 (Resomer(D RG 752) and d,l-PLA (Resomer0 RG 206), and from Birmingham Polymers (Birmingham, Alabama). These copolymers are available in a wide range of molecular weights and ratios of lactic acid to glycolic acid.
One type of microparticle suitable for use with the present invention is a sustained-release microparticle that is biodegradable. However, it should be understood by one skilled in the art that the present invention is not limited to biodegradable or other types of sustained-release microparticles. As would be apparent to one skilled in the art, the molecular weight of the polymeric binder material for biodegradable microparticles is of some importance. The molecular weight should be high enough to permit the formation of satisfactory polymer coatings, i.e., the polyiner should be a good film former. Usually, a satisfactory molecular weight is in the range of 5,000 to 500,000 daltons, preferably about 150,000 daltons. However, since the properties of the film are also partially dependent on the particular polymeric binder material being used, it is very difficult to specify an appropriate molecular weight range for all polymers. The molecular weight of the polymer is also important from the point of view of its influence upon the biodegradation rate of the polymer. For a diffusional mechanism of drug release, the polymer should remain intact until all of the drug is released from the microparticles and then degrade.
The drug can also be released from the microparticles as the polymeric binder bioerodes. By an appropriate selection of polymeric materials a microparticle formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties. This is useful in according multiphasic release patterns.
The microparticles may include an active agent or other type of substance that is released from the microparticles into the host. Such active agents can include 1,2-benzazoles, more particularly, 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles. The most preferred active agents of this kind are 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one ("risperidone") and 3-[2-[4-(6-fluro-1,2-benzisoxazol-3-yl)-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one ("9-hydroxyrisperidone") and the pharmaceutically acceptable salts thereof.
Risperidone (which term, as used herein, is intended to include its pharmaceutically acceptable salts) is most preferred. Risperidone can be prepared in accordance with the teachings of U.S. Patent No. 4,804,663. 9-hydroxyrisperidone can be prepared in accordance with the teachings of U.S. Patent No. 5,158,952.
Other biologically active agents include non-steroidal antifertility agents;
parasympathomimetic agents; psychotherapeutic agents; tranquilizers;
decongestants;
sedative hypnotics; steroids; sulfonamides; sympathomimetic agents; vaccines;
vitamins;
antimalarials; anti-migraine agents; anti-Parkinson agents such as Lrdopa;
anti-spasmodics;
anticholinergic agents (e.g. oxybutynin); antitussives; bronchodilators;
cardiovascular agents such as coronary vasodilators and nitroglycerin; alkaloids; analgesics;
narcotics such as codeine, dihydrocodienone, meperidine, morphine and the like; non-narcotics such as salicylates, aspirin, acetaminophen, d-propoxyphene and the like; opioid receptor antagonists, such as naltrexone and naloxone; antibiotics such as gentamycin, tetracycline and penicillins; anti-cancer agents; anti-convulsants; anti-emetics;
antihistamines; anti-inflammatory agents such as hormonal agents, hydrocortisone, prednisolone, prednisone, non-hormonal agents, allopurinol, indomethacin, phenylbutazone and the like;
prostaglandins and cytotoxic drugs.
Still other suitable active agents include estrogens, antibacterials;
antifungals;
antivirals; anticoagulants; anticonvulsants; antidepressants; antihistamines;
and immunological agents.
Other examples of suitable biologically active agents include peptides and proteins, analogs, muteins, and active fragments thereof, such as immunoglobulins, antibodies, cytokines (e.g. lympholdnes, monokines, chemoldnes), blood clottin^ 'actors, hemopoietic factors, interleukins (IL-2, IL-3, IL-4, IL-6), interferons (B-IFN.. ..-IFN
and y-IFN), erythropoietin, nucleases, tumor necrosis factor, colony stimulating --a.ctors (e.g., GCSF, GM-CSF, MCSF), insulin, enzymes (e.g., superoxide dismutase, tissue plasminogen activator), tumor suppressors, blood proteins, hormones and hormone analogs (e.g., growth hormone, adrenocorticotropic hormone and luteinizing hormone releasing hormone (LHRH)), vaccines (e.g., tumoral, bacterial and viral antigens); somatostatin;
antigens;
blood coagulation factors; growth factors (e.g., nerve growth factor, insulin-like growth factor); 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, carboplatin, methotrexate and adriainycin; antipyretic and analgesic 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 heparin; hemostatic agents such as thrombin, menadione sodium bisulfite and acetomenaphthone; antituberculous agents such as isoniazide and ethanbutol;
hormones such as prednisolone sodium phosphate and methimazole.
The microparticles can be mixed by size or by type. However, it should be understood that the present invention is not limited to the use of biodegradable or other types of microparticles that contain an active agent. In one embodiment, the microparticles are mixed in a manner that provides for the delivery of active agent to the patient in a multiphasic manner and/or in a manner that provides different active agents to the patient at different times, or a mixture of active agents at the same time. For example, secondary antibiotics, vaccines, or any desired active agent, either in microparticle form or in conventional, unencapsulated form can be blended with a primary active agent and provided to the patient.
The microparticles are preferably suspended in the injection vehicle at a concentration of greater than about 30 mg/ml. In one embodiment, the microparticles are suspended at a concentration of from about 150 mg/ml to about 300 mg/ml. In another embodiment, the microparticles. are suspended at a concentration of from about 100 mg/ml to about 400 mg/ml. However, it should be understood that the invention is not limited to a particular concentration.
viscosity enhancing agent suitable for use with the present invention is sodium carboxymethyl cellulose (CMC), preferably having a viscosity of from about 1000 to about 2000 cp at 20 C. It should be understood that the present invention is not limited to the use of CMC
as the viscosity enhancing agent, and other suitable viscosity enhancing agents may be used. The added volume of the viscosity enhancing agent is approximately 10-25% of the volume of the microparticle suspension.
The microparticle suspension and the viscosity enhancing agent are mixed to form the injectable composition by repeatedly passing the microparticle suspension and the viscosity enhancing agent between the first and second syringes. Such a syringe-syringe mixing method was used in the injectability tests described in Example 4 above. After mixing with the viscosity enhancing agent, the viscosity of the fluid phase of the inicroparticle suspension is from about 200 cp to about 600 cp at 20 C. A
hypodermic needle is attached to the syringe containing the injectable composition, and the injectable composition is injected into a host in a manner well=lcnown to one of skill in the art.
An alternate embodiment for carrying out the method of the present invention will now be described. Dry microparticles are mixed with an aqueous injection vehicle having a viscosity of less than about 60 cp at 20 C to form a suspension. The viscosity of the fluid phase of the suspension is changed in a manner that will be described in more detail below. The suspension that constitutes the injectable composition is withdrawn into a syringe, and the injectable composition is injected from the syringe into the host.
Preferably, the viscosity of the fluid phase of the suspension is changed after the suspension has been withdrawn into the syringe.
In one aspect of this alternate embodiment, the viscosity is changed by changing the temperature of the fluid phase of the injectable suspension. The methods and techniques for changing the viscosity of a liquid by changing the temperature of the liquid are readily apparent to one skilled in the art. The temperature of the fluid phase of the suspension is changed until the desired viscosity of the fluid phase has been reached. The suspension now has the desired fluid phase viscosity for injection into a host, and constitutes the injectable composition. At this point, the.suspension is withdrawn into the syringe and injected into the host. Alternatively, the suspension can be withdrawn into the syringe prior to changing the temperature of the fluid phase of the suspension to acllieve the desired fluid phase viscosity. For example, an injection vehicle that comprises a polymer solution can be used as the viscosity of polymer solutions is temperature-dependent. A polymer solution can be used to suspend the microparticles under low-viscosity conditions suitable for wetting and suspension formation. Once the microparticles are suspended, the suspension is drawn up into a syringe. The temperature is then changed to induce higher viscosity in the injection vehicle constituting the fluid phase of the suspension, and the suspension having increased viscosity is injected into a host.
In another aspect of this alternate embodiment, the viscosity is changed by adding a viscosity enhancing agent to the suspension. The suspension is withdrawn into the syringe, and then the viscosity enhancing agent is added to the suspension in the syringe, thereby increasing the viscosity of the aqueous injection vehicle constituting the fluid phase of the suspension. The suspension now has the desired fluid phase viscosity for injection into a host, and constitutes the injectable composition. The suspension is then injected into the host. Preferably, the viscosity enhancing agent is added to the suspension iinmediately prior to injection into the host. Suitable viscosity enhancing agents include sodium carboxymethyl cellulose, polyvinylpyrrolidone (PVP), such as PLASDONE, available from GAF Chemicals Corp., Wayne, NJ, and hydroxypropylmethylcellulose (HPMC), such as Methocel, available from Dow Chemical Co., Midland, MI. However, other viscosity enhancing agents may be used, as would be readily apparent to one of skill in the art.
In another embodiment of the invention, the injectable compositions of the present invention are prepared by providing microparticles that comprise a polymeric binder and that have a mass median diameter of at least about 10 m. The mass median diameter of the microparticles is preferably less than about 250 m, and more preferably, in the range of from about 20 gm to about 150 m. Such microparticles can be made in the manner disclosed and described herein, or in any other manner lcnown to one skilled in the art. An aqueous injection vehicle is provided. Such an aqueous injection vehicle can be made in the manner disclosed and described herein, or in any other manner known to one skilled in the art. The microparticles are suspended in the aqueous injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, the fluid phase of the suspension having a viscosity of at least 20 cp at 20 C.
In yet a further einbodiment of the present invention, dry microparticles are mixed with an aqueous injection vehicle containing a viscosity enhancing agent to form a suspension. Suitable viscosity enhancing agents include sodium carboxymethyl cellulose, polyvinylpyrrolidone (PVP), such as PLASDONE, available from GAF Chemicals Corp., Wayne, NJ, and hydroxypropylmethylcellulose (HPMC), such as Methocel, available from Dow Chemical Co., Midland, MI. However, otller viscosity enhancing agents may be used, as would be readily apparent to one of skill in the art. The suspension is then dispensed into vials. The vials are lyophilized (or vacuum dried) to remove the water.
Prior to injection, the vial contents are reconstituted with sterile water for inj ection in a quantity sufficient to achieve the desired viscosity for the fluid phase of the reconstituted injectable suspension. Preferably, the vial contents are reconstituted with a quantity of sterile water for injection sufficient to achieve a viscosity of a fluid phase of the injectable suspension that provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
Exatiiple 6 - Injectable Conzpositions The injectable compositions of the present invention will now be described.
The injectable compositions of the present invention are suitable for injection through a needle into a host. In one einbodiment, the injectable compositions comprise inicroparticles suspended in an aqueous injection vehicle. The microparticles preferably have a mass median diameter of at least about 10 m to about 250 m, preferably in the range of from about 20 m to about 150 m. However, it should be understood that the invention is not limited to microparticles in this size range, and that smaller or larger microparticles may also be used.
The microparticles preferably comprise a polymeric binder. Suitable polymeric binder materials include poly(glycolic acid), poly-d,l-lactic acid, poly-l-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, polyphosphazines, albumin, casein, and waxes. Poly (d,l-lactic-co-glycolic acid) 'is commercially available from Allcermes, Inc. (Blue Ash, OH). A suitable product commercially available from Alkermes, Inc. is a 50:50 poly(d,l-lactic-co-glycolic acid) known as MEDISORBOO 5050 DL. This product has a mole percent coinposition of 50%
lactide and 50% glycolide. Other suitable commercially available products are MEDISORBO 6535 DL, 7525 DL, 8515 DL and poly(d,l-lactic acid) (100 DL).
Poly(lactide-co-glycolides) are also commercially available from Boehringer Ingelheim (Germany) under its Resomer0 mark, e.g., PLGA 50:50 (Resomer(I RG 502), PLGA
75:25 (Resomer(D RG 752) and d,l-PLA (Resomer0 RG 206), and from Birmingham Polymers (Birmingham, Alabama). These copolymers are available in a wide range of molecular weights and ratios of lactic acid to glycolic acid.
One type of microparticle suitable for use with the present invention is a sustained-release microparticle that is biodegradable. However, it should be understood by one skilled in the art that the present invention is not limited to biodegradable or other types of sustained-release microparticles. As would be apparent to one skilled in the art, the molecular weight of the polymeric binder material for biodegradable microparticles is of some importance. The molecular weight should be high enough to permit the formation of satisfactory polymer coatings, i.e., the polyiner should be a good film former. Usually, a satisfactory molecular weight is in the range of 5,000 to 500,000 daltons, preferably about 150,000 daltons. However, since the properties of the film are also partially dependent on the particular polymeric binder material being used, it is very difficult to specify an appropriate molecular weight range for all polymers. The molecular weight of the polymer is also important from the point of view of its influence upon the biodegradation rate of the polymer. For a diffusional mechanism of drug release, the polymer should remain intact until all of the drug is released from the microparticles and then degrade.
The drug can also be released from the microparticles as the polymeric binder bioerodes. By an appropriate selection of polymeric materials a microparticle formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties. This is useful in according multiphasic release patterns.
The microparticles may include an active agent or other type of substance that is released from the microparticles into the host. Such active agents can include 1,2-benzazoles, more particularly, 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles. The most preferred active agents of this kind are 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one ("risperidone") and 3-[2-[4-(6-fluro-1,2-benzisoxazol-3-yl)-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one ("9-hydroxyrisperidone") and the pharmaceutically acceptable salts thereof.
Risperidone (which term, as used herein, is intended to include its pharmaceutically acceptable salts) is most preferred. Risperidone can be prepared in accordance with the teachings of U.S. Patent No. 4,804,663. 9-hydroxyrisperidone can be prepared in accordance with the teachings of U.S. Patent No. 5,158,952.
Other biologically active agents include non-steroidal antifertility agents;
parasympathomimetic agents; psychotherapeutic agents; tranquilizers;
decongestants;
sedative hypnotics; steroids; sulfonamides; sympathomimetic agents; vaccines;
vitamins;
antimalarials; anti-migraine agents; anti-Parkinson agents such as Lrdopa;
anti-spasmodics;
anticholinergic agents (e.g. oxybutynin); antitussives; bronchodilators;
cardiovascular agents such as coronary vasodilators and nitroglycerin; alkaloids; analgesics;
narcotics such as codeine, dihydrocodienone, meperidine, morphine and the like; non-narcotics such as salicylates, aspirin, acetaminophen, d-propoxyphene and the like; opioid receptor antagonists, such as naltrexone and naloxone; antibiotics such as gentamycin, tetracycline and penicillins; anti-cancer agents; anti-convulsants; anti-emetics;
antihistamines; anti-inflammatory agents such as hormonal agents, hydrocortisone, prednisolone, prednisone, non-hormonal agents, allopurinol, indomethacin, phenylbutazone and the like;
prostaglandins and cytotoxic drugs.
Still other suitable active agents include estrogens, antibacterials;
antifungals;
antivirals; anticoagulants; anticonvulsants; antidepressants; antihistamines;
and immunological agents.
Other examples of suitable biologically active agents include peptides and proteins, analogs, muteins, and active fragments thereof, such as immunoglobulins, antibodies, cytokines (e.g. lympholdnes, monokines, chemoldnes), blood clottin^ 'actors, hemopoietic factors, interleukins (IL-2, IL-3, IL-4, IL-6), interferons (B-IFN.. ..-IFN
and y-IFN), erythropoietin, nucleases, tumor necrosis factor, colony stimulating --a.ctors (e.g., GCSF, GM-CSF, MCSF), insulin, enzymes (e.g., superoxide dismutase, tissue plasminogen activator), tumor suppressors, blood proteins, hormones and hormone analogs (e.g., growth hormone, adrenocorticotropic hormone and luteinizing hormone releasing hormone (LHRH)), vaccines (e.g., tumoral, bacterial and viral antigens); somatostatin;
antigens;
blood coagulation factors; growth factors (e.g., nerve growth factor, insulin-like growth factor); 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, carboplatin, methotrexate and adriainycin; antipyretic and analgesic 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 heparin; hemostatic agents such as thrombin, menadione sodium bisulfite and acetomenaphthone; antituberculous agents such as isoniazide and ethanbutol;
hormones such as prednisolone sodium phosphate and methimazole.
The microparticles can be mixed by size or by type. However, it should be understood that the present invention is not limited to the use of biodegradable or other types of microparticles that contain an active agent. In one embodiment, the microparticles are mixed in a manner that provides for the delivery of active agent to the patient in a multiphasic manner and/or in a manner that provides different active agents to the patient at different times, or a mixture of active agents at the same time. For example, secondary antibiotics, vaccines, or any desired active agent, either in microparticle form or in conventional, unencapsulated form can be blended with a primary active agent and provided to the patient.
The microparticles are preferably suspended in the injection vehicle at a concentration of greater than about 30 mg/ml. In one embodiment, the microparticles are suspended at a concentration of from about 150 mg/ml to about 300 mg/ml. In another embodiment, the microparticles. are suspended at a concentration of from about 100 mg/ml to about 400 mg/ml. However, it should be understood that the invention is not limited to a particular concentration.
The aqueous injection vehicle preferably has a viscosity of at least 20 cp at 20 C.
In one embodiment, the injection vehicle has a viscosity greater than 50 cp and less than 60 cp at 20 C. The viscosity of the injection vehicle preferably provides injectability of the composition through a needle ranging in diameter from 18-22 gauge. As known to one skilled in the art, an 18 gauge regular wall (RW) needle has a nominal inner diameter (ID) of 0.033 in., and a 22 gauge regular wall needle has a nominal inner diameter of 0.016 in.
The injection vehicle may comprise a viscosity enhancing agent. A preferred viscosity enhancing agent is sodium carboxymethyl cellulose, although other suitable viscosity enhancing agents may also be used. The injection vehicle may also comprise a density enhancing agent that increases the density of the injection vehicle. A
preferred density enhancing agent is sorbitol, although other suitable density enhancing agents may also be used. The injection vehicle may also comprise a tonicity adjusting agent to adjust the tonicity to preclude toxicity problems and improve biocompatibility. A
preferred tonicity adjusting agent is sodium chloride, although other suitable tonicity adjusting agents may also be used.
The injection vehicle may also comprise a wetting agent to ensure complete wetting of the microparticles by the injection vehicle. Preferred wetting agents include polysorbate (Tween 20), polysorbate 40 (Tween 40), and polysorbate 80 (Tween 80).
One preferred injection vehicle is an aqueous injection vehicle that comprises 1.5%
20 sodium carboxymethyl cellulose, 30% sorbitol, and 0.2% polysorbate 20.
Another preferred injection vehicle is an aqueous injection vehicle that comprises 3%
sodium carboxymethyl cellulose, 0.9% saline, and 0.1% polysorbate 20.
Exanzple 7 -1 Kg Process A process for preparing microparticles containing risperidone as the active agent will now be described. The following 1 Kg process (400 grams of active agent and 600 grams of polymer) is for a theoretical drug loading of the microparticles of 40%. The actual drug loading that is achieved by the process described below ranges from about 35%
to about 39%.
A drug solution is prepared by dissolving 400 grams of risperidone (Janssen Pharmaceutica, Beerse, Belgium) in 1267 grams of benzyl alcohol to form a 24 wt.% drug solution. A polymer solution is formed by dissolving 600 grams of MEDISO.RB
DL polymer (Alkermes, Inc., Blue Ash, Ohio) in 3000 grams of ethyl acetate to form a 16.7 wt.% polymer solution. The drug solution and the polymer solution are combined to form a first, discontinuous phase.
The second, continuous phase is prepared by preparing a 30 liter solution of 1%
PVA, the PVA acting as an emulsifier. To this is added 2086 grains of ethyl acetate to fonn a 6.5 wt.% solution of ethyl acetate.
The two phases are combined using a static mixer, such as a 1/2" Kenics static mixer available from Chemineer, Inc., North Andover, MA. A total flow rate of 3 L/min generally provides microparticle size distributions with a mass median diaineter (MMD) in the range of about 80-90 . The ratio of continuous phase to discontinuous phase is 5:1 (v/v). The length of the static mixer can vary from about 9 inches to about 88 inches.
Lengths greater than about 48 inches results in the greatest percent yield in a microparticle size range of 25-150 .
The quench liquid is 2.5% solution of ethyl acetate and water-for-injection (WFI) at 5-10 C. The volume of the quench liquid is 0.25L per gram of batch size. The quench step is carried out for a time period greater t11an about 4 hours, with stirring of the microparticles in the quench tanlc.
After completion of the quench step, the microparticles are transferred to a collecting, de-watering, and drying device. The microparticles are rinsed using a chilled (approximately 5 C) 17 liter 25% ethanol solution. The microparticles are dried, and then re-slurried in a re-slurry tanlc using a 25% ethanol solution (extraction medium) maintained at a temperature lower than the Tg (glass transition temperature) of the microparticles. The microparticles are then transferred back to the quench tank for washing for a time period of at least 6 hours with another extraction medium (25%
ethanol solution) that is maintained at a temperature higher than the Tg of the microparticles.
The Tg of the microparticles is about 18 C (about room temperature), and the temperature of the extraction medium in the quench tank is greater than about 18 C, preferably 25 1 C.
The microparticles are transferred back to the collecting, de-watering, and drying device for de-watering and final drying. Drying continues for a time period greater than about 16 hours.
Coizclusiorz While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of example only, and not limitation. The present invention is not limited to controlled release microparticle injectable suspensions, nor is it limited to a particular active agent, polymer or solvent, nor is the present invention limited to a particular scale or batch size. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.
In one embodiment, the injection vehicle has a viscosity greater than 50 cp and less than 60 cp at 20 C. The viscosity of the injection vehicle preferably provides injectability of the composition through a needle ranging in diameter from 18-22 gauge. As known to one skilled in the art, an 18 gauge regular wall (RW) needle has a nominal inner diameter (ID) of 0.033 in., and a 22 gauge regular wall needle has a nominal inner diameter of 0.016 in.
The injection vehicle may comprise a viscosity enhancing agent. A preferred viscosity enhancing agent is sodium carboxymethyl cellulose, although other suitable viscosity enhancing agents may also be used. The injection vehicle may also comprise a density enhancing agent that increases the density of the injection vehicle. A
preferred density enhancing agent is sorbitol, although other suitable density enhancing agents may also be used. The injection vehicle may also comprise a tonicity adjusting agent to adjust the tonicity to preclude toxicity problems and improve biocompatibility. A
preferred tonicity adjusting agent is sodium chloride, although other suitable tonicity adjusting agents may also be used.
The injection vehicle may also comprise a wetting agent to ensure complete wetting of the microparticles by the injection vehicle. Preferred wetting agents include polysorbate (Tween 20), polysorbate 40 (Tween 40), and polysorbate 80 (Tween 80).
One preferred injection vehicle is an aqueous injection vehicle that comprises 1.5%
20 sodium carboxymethyl cellulose, 30% sorbitol, and 0.2% polysorbate 20.
Another preferred injection vehicle is an aqueous injection vehicle that comprises 3%
sodium carboxymethyl cellulose, 0.9% saline, and 0.1% polysorbate 20.
Exanzple 7 -1 Kg Process A process for preparing microparticles containing risperidone as the active agent will now be described. The following 1 Kg process (400 grams of active agent and 600 grams of polymer) is for a theoretical drug loading of the microparticles of 40%. The actual drug loading that is achieved by the process described below ranges from about 35%
to about 39%.
A drug solution is prepared by dissolving 400 grams of risperidone (Janssen Pharmaceutica, Beerse, Belgium) in 1267 grams of benzyl alcohol to form a 24 wt.% drug solution. A polymer solution is formed by dissolving 600 grams of MEDISO.RB
DL polymer (Alkermes, Inc., Blue Ash, Ohio) in 3000 grams of ethyl acetate to form a 16.7 wt.% polymer solution. The drug solution and the polymer solution are combined to form a first, discontinuous phase.
The second, continuous phase is prepared by preparing a 30 liter solution of 1%
PVA, the PVA acting as an emulsifier. To this is added 2086 grains of ethyl acetate to fonn a 6.5 wt.% solution of ethyl acetate.
The two phases are combined using a static mixer, such as a 1/2" Kenics static mixer available from Chemineer, Inc., North Andover, MA. A total flow rate of 3 L/min generally provides microparticle size distributions with a mass median diaineter (MMD) in the range of about 80-90 . The ratio of continuous phase to discontinuous phase is 5:1 (v/v). The length of the static mixer can vary from about 9 inches to about 88 inches.
Lengths greater than about 48 inches results in the greatest percent yield in a microparticle size range of 25-150 .
The quench liquid is 2.5% solution of ethyl acetate and water-for-injection (WFI) at 5-10 C. The volume of the quench liquid is 0.25L per gram of batch size. The quench step is carried out for a time period greater t11an about 4 hours, with stirring of the microparticles in the quench tanlc.
After completion of the quench step, the microparticles are transferred to a collecting, de-watering, and drying device. The microparticles are rinsed using a chilled (approximately 5 C) 17 liter 25% ethanol solution. The microparticles are dried, and then re-slurried in a re-slurry tanlc using a 25% ethanol solution (extraction medium) maintained at a temperature lower than the Tg (glass transition temperature) of the microparticles. The microparticles are then transferred back to the quench tank for washing for a time period of at least 6 hours with another extraction medium (25%
ethanol solution) that is maintained at a temperature higher than the Tg of the microparticles.
The Tg of the microparticles is about 18 C (about room temperature), and the temperature of the extraction medium in the quench tank is greater than about 18 C, preferably 25 1 C.
The microparticles are transferred back to the collecting, de-watering, and drying device for de-watering and final drying. Drying continues for a time period greater than about 16 hours.
Coizclusiorz While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of example only, and not limitation. The present invention is not limited to controlled release microparticle injectable suspensions, nor is it limited to a particular active agent, polymer or solvent, nor is the present invention limited to a particular scale or batch size. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.
Claims (50)
1. A composition suitable for injection through a needle into a host, comprising:
microparticles comprising a polymeric binder; and an injection vehicle comprising a viscosity enhancing agent, wherein said microparticles are suspended in said injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein a fluid phase of said suspension has a viscosity greater than about 20 cp and less than about 600 cp at 20°C, wherein the viscosity of said fluid phase of said suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
microparticles comprising a polymeric binder; and an injection vehicle comprising a viscosity enhancing agent, wherein said microparticles are suspended in said injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein a fluid phase of said suspension has a viscosity greater than about 20 cp and less than about 600 cp at 20°C, wherein the viscosity of said fluid phase of said suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
2. The composition of claim 1, wherein said viscosity enhancing agent comprises sodium carboxymethyl cellulose.
3. The composition of claim 1, wherein said injection vehicle comprises a density enhancing agent.
4. The composition of claim 3, wherein said density enhancing agent comprises sorbitol.
5. The composition of claim 1, wherein said injection vehicle comprises a tonicity adjusting agent.
6. The composition of claim 5, wherein said tonicity adjusting agent comprises sodium chloride.
7. The composition of any one of claims 1 to 6, wherein said injection vehicle further comprises a wetting agent.
8. The composition of claim 7, wherein said wetting agent is selected from the group consisting of polysorbate 20, polysorbate 40, and polysorbate 80.
9. The composition of claim 1, wherein the viscosity of said fluid phase of said suspension is greater than 40 cp and less than 60 cp at 20°C.
10. The composition of claim 9, wherein said injection vehicle comprises 1.5% sodium carboxymethyl cellulose, 30%
sorbitol, and 0.2% polysorbate 20.
sorbitol, and 0.2% polysorbate 20.
11. The composition of claim 9, wherein said injection vehicle comprises 3% sodium carboxymethyl cellulose, 0.9%
saline, and 0.1% polysorbate 20.
saline, and 0.1% polysorbate 20.
12. The composition of claim 1, wherein said microparticles further comprise an active agent encapsulated within said polymeric binder.
13. The composition of claim 12, wherein said polymeric binder is selected from the group consisting of poly(glycolic acid), poly-d,l-lactic acid, poly-l-lactic acid, copolymers of the foregoing, poly(aliphatic carboxylic acids), copolyoxalates, polycaprolactone, polydioxanone, poly(ortho carbonates), poly(acetals), poly(lactic acid-caprolactone), polyorthoesters, poly(glycolic acid-caprolactone), polyanhydrides, polyphosphazines, albumin, casein, and waxes.
14. The composition of claim 12, wherein said polymeric binder is poly(d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 85:15 to about 50:50.
15. The composition of claim 12 or 14, wherein said active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.
16. The composition of claim 1, wherein the mass median diameter of said microparticles is less than about 250 µm.
17. The composition of claim 1, wherein the mass median diameter of said microparticles is in the range of from about 20 µm to about 150 µm.
18. A method for preparing a composition suitable for injection through a needle into a host, comprising:
(a) mixing dry microparticles comprising a polymeric binder with an aqueous injection vehicle to form a first suspension wherein the concentration of microparticles in the first suspension is greater than about 30 mg/ml; and (b) mixing the first suspension with a viscosity enhancing agent to form a second suspension, wherein the viscosity enhancing agent increases viscosity of a fluid phase of the second suspension to be in the range of from about 20 cp to about 600 cp at 20°C, wherein the viscosity of the fluid phase of the second suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
(a) mixing dry microparticles comprising a polymeric binder with an aqueous injection vehicle to form a first suspension wherein the concentration of microparticles in the first suspension is greater than about 30 mg/ml; and (b) mixing the first suspension with a viscosity enhancing agent to form a second suspension, wherein the viscosity enhancing agent increases viscosity of a fluid phase of the second suspension to be in the range of from about 20 cp to about 600 cp at 20°C, wherein the viscosity of the fluid phase of the second suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
19. The method of claim 18, wherein the viscosity of the fluid phase of the second suspension after step (b) is from about 200 cp to about 600 cp at 20°C.
20. The method of claim 18, wherein the viscosity of the aqueous injection vehicle prior to step (b) is less than about 60 cp at 20°C.
21. The method of claim 18, wherein a viscosity of the viscosity enhancing agent is from about 1000 to about 2000 cp at 20°C.
22. The method of claim 18, wherein the viscosity enhancing agent comprises sodium carboxymethyl cellulose.
23. The method of claim 18, wherein a volume of the viscosity enhancing agent mixed with the first suspension is approximately 10-25% of the volume of the first suspension.
24. The method of claim 18, further comprising before step (b) :
(c) withdrawing the first suspension into a first syringe.
(c) withdrawing the first suspension into a first syringe.
25. The method of claim 24, wherein step (b) comprises:
(i) providing a second syringe containing the viscosity enhancing agent;
(ii) coupling the first syringe to the second syringe so that fluid can pass between the first and second syringes; and (iii) repeatedly passing the first suspension and the viscosity enhancing agent between the first and second syringes.
(i) providing a second syringe containing the viscosity enhancing agent;
(ii) coupling the first syringe to the second syringe so that fluid can pass between the first and second syringes; and (iii) repeatedly passing the first suspension and the viscosity enhancing agent between the first and second syringes.
26. The method of claim 18, wherein the microparticles comprise a polymeric binder.
27. The method of claim 18, wherein the microparticles comprise a polymeric binder.
28. A composition suitable for injection through a needle into a host prepared by the method of claim 18.
29. The composition of claim 28, wherein the viscosity of the fluid phase of the second suspension is greater than about 50 cp and less than about 60 cp at 20°C.
30. The composition of claim 28, wherein the microparticles comprise an active agent and a polymeric binder.
31. The composition of claim 30, wherein the polymeric binder is poly (d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 85:15 to about 50:50.
32. The composition of claim 30, wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.
33. A use of the composition of any one of claims 28 to 32 for injection into a host through a needle ranging in diameter from 18-22 gauge.
34. A use of a composition for injection into a host through syringe having a needle ranging in diameter from 18-22 gauge, said composition comprising a second suspension prepared from: (a) dry microparticles comprising a polymeric binder mixed with an aqueous injection vehicle to form a first suspension, wherein the concentration of microparticles in the first suspension is greater than about 30 mg/ml; and (b) the first suspension mixed with a viscosity enhancing agent to form the second suspension, wherein the viscosity enhancing agent increases viscosity of a fluid phase of the second suspension in a range of from about 20 cp to about 600 cp at 20°C.
35. The use of claim 34, wherein the microparticles comprise a polymeric binder.
36. A use of a composition for injection into a host through syringe having a needle ranging in diameter from 18-22 gauge, said composition prepared from:
(a) dry microparticles comprising a polymeric binder, mixed with an aqueous injection vehicle to form a suspension wherein the concentration of microparticles in the suspension is greater than about 30 mg/ml, wherein the aqueous injection vehicle prior to mixing has a viscosity at 20 C of less than about 60 cp;
(b) the viscosity of a fluid phase of the suspension is changed to a range of from about 20 cp to about 600 cp at 20°C; and (c) the suspension is withdrawn into the syringe.
(a) dry microparticles comprising a polymeric binder, mixed with an aqueous injection vehicle to form a suspension wherein the concentration of microparticles in the suspension is greater than about 30 mg/ml, wherein the aqueous injection vehicle prior to mixing has a viscosity at 20 C of less than about 60 cp;
(b) the viscosity of a fluid phase of the suspension is changed to a range of from about 20 cp to about 600 cp at 20°C; and (c) the suspension is withdrawn into the syringe.
37. The use of claim 36, wherein the temperature of the fluid phase of the suspension is changed in step (b).
38. The use of claim 36, wherein step (c) is performed prior to step (b), and a viscosity enhancing agent is added to the suspension in the syringe in step (b) to thereby increase the viscosity of the fluid phase of the suspension.
39. The use of claim 38, wherein the viscosity enhancing agent comprises sodium carboxymethyl cellulose.
40. The use of claim 36, wherein step (c) is performed prior to step (b).
41. A method of making a composition suitable for injection through a needle into a host, comprising:
(a) providing microparticles comprising a polymeric binder, said microparticles having a mass median diameter of at least about 10 µm;
(b) providing an aqueous injection vehicle comprising a viscosity enhancing agent and having a viscosity of at least 20 cp at 20°C; and (c) suspending the microparticles in the aqueous injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein the viscosity of a fluid phase of the suspension is in the range of from about 20 cp to about 600 cp at 20°C, wherein the viscosity of the fluid phase of the suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
(a) providing microparticles comprising a polymeric binder, said microparticles having a mass median diameter of at least about 10 µm;
(b) providing an aqueous injection vehicle comprising a viscosity enhancing agent and having a viscosity of at least 20 cp at 20°C; and (c) suspending the microparticles in the aqueous injection vehicle at a concentration of greater than about 30 mg/ml to form a suspension, wherein the viscosity of a fluid phase of the suspension is in the range of from about 20 cp to about 600 cp at 20°C, wherein the viscosity of the fluid phase of the suspension provides injectability of the composition through a needle ranging in diameter from 18-22 gauge.
42. A composition suitable for injection through a needle into a host prepared by the method of claim 41.
43. The composition of claim 42, wherein the microparticles further comprise an active agent.
44. The composition of claim 42, wherein the polymeric binder is poly (d,l-lactide-co-glycolide) having a molar ratio of lactide to glycolide in the range of from about 100:0 to about 50:50.
45. The composition of claim 43, wherein the active agent is selected from the group consisting of risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable salts thereof.
46. A method for preparing a composition suitable for injection through a needle into a host, comprising:
(a) mixing dry microparticles comprising a polymeric binder with an aqueous injection vehicle that comprises a viscosity enhancing agent to form a suspension, wherein the concentration of microparticles in the suspension is greater than about 30 mg/ml;
(b) removing water from the suspension; and (c) reconstituting the suspension with a quantity of sterile water for injection to form an injectable suspension, wherein the quantity of sterile water for injection is sufficient to achieve a viscosity of a fluid phase of the injectable suspension in the range of from about 20 cp to about 600 cp at 20°C to provide injectability of the injectable suspension through a needle ranging in diameter from 18-22 gauge.
(a) mixing dry microparticles comprising a polymeric binder with an aqueous injection vehicle that comprises a viscosity enhancing agent to form a suspension, wherein the concentration of microparticles in the suspension is greater than about 30 mg/ml;
(b) removing water from the suspension; and (c) reconstituting the suspension with a quantity of sterile water for injection to form an injectable suspension, wherein the quantity of sterile water for injection is sufficient to achieve a viscosity of a fluid phase of the injectable suspension in the range of from about 20 cp to about 600 cp at 20°C to provide injectability of the injectable suspension through a needle ranging in diameter from 18-22 gauge.
47. The method of claim 46, wherein the viscosity of the fluid phase of the injectable suspension after step (c) is from about 200 cp to about 600 cp at 20°C.
48. The method of claim 46, wherein a viscosity of the viscosity enhancing agent is from about 1000 cp to about 2000 cp at 20°C.
49. The method of claim 46, wherein the viscosity enhancing agent comprises sodium carboxymethyl cellulose.
50. The method of claim 46, wherein step (b) is carried out by vacuum drying.
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PCT/US2001/012652 WO2001091720A2 (en) | 2000-05-25 | 2001-04-19 | Preparation of injectable suspensions having improved injectability |
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Families Citing this family (147)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
UA72189C2 (en) | 1997-11-17 | 2005-02-15 | Янссен Фармацевтика Н.В. | Aqueous suspensions of 9-hydroxy-risperidone fatty acid esters provided in submicron form |
US6770478B2 (en) * | 2000-02-10 | 2004-08-03 | The Regents Of The University Of California | Erythrocytic cells and method for preserving cells |
US6495164B1 (en) * | 2000-05-25 | 2002-12-17 | Alkermes Controlled Therapeutics, Inc. I | Preparation of injectable suspensions having improved injectability |
US6824822B2 (en) | 2001-08-31 | 2004-11-30 | Alkermes Controlled Therapeutics Inc. Ii | Residual solvent extraction method and microparticles produced thereby |
US7758890B2 (en) * | 2001-06-23 | 2010-07-20 | Lyotropic Therapeutics, Inc. | Treatment using dantrolene |
KR100525189B1 (en) * | 2002-10-10 | 2005-10-31 | 메디칸(주) | Injectable solid material for human soft tissue volume replacement |
US7731947B2 (en) | 2003-11-17 | 2010-06-08 | Intarcia Therapeutics, Inc. | Composition and dosage form comprising an interferon particle formulation and suspending vehicle |
EP2526996B1 (en) * | 2002-12-20 | 2019-09-11 | Xeris Pharmaceuticals, Inc. | Formulation for intracutaneous injection |
WO2004064752A2 (en) * | 2003-01-22 | 2004-08-05 | Alkermes Controlled Therapeutics, Inc. | Method of preparing sustained release microparticles |
ES2862337T3 (en) * | 2003-03-04 | 2021-10-07 | Lyotropic Therapeutics Inc | Dantrolene compositions |
US20040247672A1 (en) * | 2003-05-16 | 2004-12-09 | Alkermes Controlled Therapeutics, Inc. | Injectable sustained release compositions |
US20050032811A1 (en) | 2003-08-06 | 2005-02-10 | Josiah Brown | Methods for administering aripiprazole |
KR101285137B1 (en) | 2003-09-03 | 2013-07-11 | 미스콘 트레이딩 에스.에이. | Methods for the treatment of endometriosis |
US8092527B2 (en) * | 2003-09-03 | 2012-01-10 | Brennan William A | System and method for breast augmentation |
US7169180B2 (en) * | 2003-09-03 | 2007-01-30 | Brennan William A | System and method for breast augmentation |
US7906125B2 (en) * | 2003-09-18 | 2011-03-15 | Boston Scientific Scimed, Inc. | Solid or semi-solid therapeutic formulations |
US20050064045A1 (en) * | 2003-09-18 | 2005-03-24 | Sheng-Ping Zhong | Injectable therapeutic formulations |
SI1675573T2 (en) | 2003-10-23 | 2012-08-31 | Otsuka Pharma Co Ltd | Controlled release sterile injectable aripiprazole formulation and method |
WO2005042026A1 (en) * | 2003-10-31 | 2005-05-12 | Wakamoto Pharmaceutical Co., Ltd. | Water-based composition undergoing reversible thermogelation |
ATE531374T1 (en) | 2004-04-15 | 2011-11-15 | Alkermes Inc | DELAYED RELEASE POLYMER BASED DEVICE |
US20060110423A1 (en) * | 2004-04-15 | 2006-05-25 | Wright Steven G | Polymer-based sustained release device |
US7456254B2 (en) * | 2004-04-15 | 2008-11-25 | Alkermes, Inc. | Polymer-based sustained release device |
US20050260272A1 (en) * | 2004-05-05 | 2005-11-24 | Alkermes Controlled Therapeutics, Inc. | Method of forming microparticles that include a bisphosphonate and a polymer |
CA2569513C (en) * | 2004-06-04 | 2013-08-06 | Camurus Ab | Preformulation for liquid crystalline phase structure |
ITMI20041245A1 (en) * | 2004-06-22 | 2004-09-22 | Ibsa Inst Biochimique Sa | INJECTABLE PHARMACEUTICAL COMPOSITIONS INCLUDING DICLOFENAC SODIUM AND B-CYCLODESTRINE |
EP1679065A1 (en) * | 2005-01-07 | 2006-07-12 | OctoPlus Sciences B.V. | Controlled release compositions for interferon based on PEGT/PBT block copolymers |
WO2006083761A2 (en) | 2005-02-03 | 2006-08-10 | Alza Corporation | Solvent/polymer solutions as suspension vehicles |
US11246913B2 (en) | 2005-02-03 | 2022-02-15 | Intarcia Therapeutics, Inc. | Suspension formulation comprising an insulinotropic peptide |
US8318210B2 (en) * | 2005-02-28 | 2012-11-27 | Neos Therapeutics, Lp | Compositions and methods of making sustained release liquid formulations |
US7862552B2 (en) | 2005-05-09 | 2011-01-04 | Boston Scientific Scimed, Inc. | Medical devices for treating urological and uterine conditions |
US8263109B2 (en) * | 2005-05-09 | 2012-09-11 | Boston Scientific Scimed, Inc. | Injectable bulking compositions |
US20060251581A1 (en) * | 2005-05-09 | 2006-11-09 | Mcintyre Jon T | Method for treatment of uterine fibroid tumors |
NZ566763A (en) | 2005-08-19 | 2011-06-30 | Amylin Pharmaceuticals Inc | Exendin-4 for treating diabetes, obesity and reducing body weight |
US8852638B2 (en) | 2005-09-30 | 2014-10-07 | Durect Corporation | Sustained release small molecule drug formulation |
EP3058972A1 (en) | 2005-11-17 | 2016-08-24 | Zogenix, Inc. | Delivery of viscous formulations by needle-free injection |
US20090038701A1 (en) | 2006-01-17 | 2009-02-12 | Baxter International Inc. | Device, system and method for mixing |
AU2007266475B2 (en) | 2006-05-30 | 2009-12-03 | Intarcia Therapeutics, Inc. | Two-piece, internal-channel osmotic delivery system flow modulator |
DK2049081T3 (en) | 2006-08-09 | 2013-02-25 | Intarcia Therapeutics Inc | Osmotic delivery systems and piston arrangements |
JP4941977B2 (en) * | 2007-04-11 | 2012-05-30 | 大蔵製薬株式会社 | Oral jelly-like pharmaceutical composition of benzisoxazole derivative |
HRP20130259T1 (en) | 2007-04-23 | 2013-04-30 | Intarcia Therapeutics, Inc. | SUSPENSION FORMULATIONS OF INSULINOTROPIC PEPTIDES AND THEIR USE |
MX337286B (en) | 2007-05-25 | 2016-02-22 | Indivior Uk Ltd | Sustained delivery formulations of risperidone compounds. |
US10092524B2 (en) | 2008-06-11 | 2018-10-09 | Edge Therapeutics, Inc. | Compositions and their use to treat complications of aneurysmal subarachnoid hemorrhage |
ES2443537T3 (en) | 2007-07-26 | 2014-02-19 | Aqtis Ip Bv | Microparticles comprising PCL and uses thereof |
ES2661037T3 (en) * | 2007-07-31 | 2018-03-27 | Otsuka Pharmaceutical Co., Ltd. | Procedures for producing a suspension of aripiprazole and a lyophilized formulation |
WO2009056990A2 (en) * | 2007-08-21 | 2009-05-07 | Actavis Group Ptc Ehf | Paliperidone polymorphs |
US9987221B2 (en) * | 2007-08-23 | 2018-06-05 | Boston Scientific Scimed, Inc. | Injectable hydrogel compositions |
KR20100067684A (en) * | 2007-11-05 | 2010-06-21 | 보오슈 앤드 롬 인코포레이팃드 | Water-immiscible materials as vehicles for drug delivery |
WO2009102467A2 (en) | 2008-02-13 | 2009-08-20 | Intarcia Therapeutics, Inc. | Devices, formulations, and methods for delivery of multiple beneficial agents |
ES2527448T3 (en) | 2008-04-28 | 2015-01-23 | Zogenix, Inc. | New formulations for the treatment of migraine |
WO2009143285A2 (en) | 2008-05-21 | 2009-11-26 | Amylin Pharmaceuticals, Inc. | Exendins to lower cholestrol and triglycerides |
US8613951B2 (en) | 2008-06-16 | 2013-12-24 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticles with mTor inhibitors and methods of making and using same |
PL2774608T3 (en) * | 2008-06-16 | 2020-05-18 | Pfizer Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8318211B2 (en) | 2008-06-16 | 2012-11-27 | Bind Biosciences, Inc. | Therapeutic polymeric nanoparticles comprising vinca alkaloids and methods of making and using same |
EP2306991B1 (en) * | 2008-06-27 | 2019-12-25 | Tepha, Inc. | Injectable delivery of microparticles and compositions therefore |
LT2341905T (en) | 2008-09-04 | 2020-09-25 | Amylin Pharmaceuticals, Llc | Sustained release formulations using non-aqueous carriers |
US20100063879A1 (en) * | 2008-09-05 | 2010-03-11 | Yellowpages.Com Llc | Systems and Methods to Selectively Provide Information Based on User Interest |
US8563041B2 (en) * | 2008-12-12 | 2013-10-22 | Bind Therapeutics, Inc. | Therapeutic particles suitable for parenteral administration and methods of making and using same |
EA201100765A1 (en) | 2008-12-15 | 2012-04-30 | Бинд Биосаиэнсис | Long-term circulation nanoparticles |
ES2650667T3 (en) | 2009-09-28 | 2018-01-19 | Intarcia Therapeutics, Inc | Rapid establishment and / or termination of substantial steady state drug administration |
EA036522B1 (en) | 2009-12-11 | 2020-11-19 | Пфайзер Инк. | Pharmaceutical composition suitable for lyophilization comprising a plurality of therapeutic particles |
JP5965844B2 (en) | 2009-12-15 | 2016-08-10 | バインド セラピューティックス インコーポレイテッド | Therapeutic polymer nanoparticle compositions having high glass transition temperature or high molecular weight copolymers |
US8889193B2 (en) | 2010-02-25 | 2014-11-18 | The Johns Hopkins University | Sustained delivery of therapeutic agents to an eye compartment |
WO2012012460A1 (en) | 2010-07-19 | 2012-01-26 | Xeris Pharmaceuticals, Inc. | Stable glucagon formulations for the treatment of hypoglycemia |
WO2012039979A2 (en) | 2010-09-10 | 2012-03-29 | The Johns Hopkins University | Rapid diffusion of large polymeric nanoparticles in the mammalian brain |
JP5893616B2 (en) | 2010-10-18 | 2016-03-23 | 大日本住友製薬株式会社 | Sustained release formulation for injection |
WO2012109363A2 (en) | 2011-02-08 | 2012-08-16 | The Johns Hopkins University | Mucus penetrating gene carriers |
US20120208755A1 (en) | 2011-02-16 | 2012-08-16 | Intarcia Therapeutics, Inc. | Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers |
WO2012122535A2 (en) | 2011-03-10 | 2012-09-13 | Xeris Pharmaceuticals, Inc. | Stable formulations for parenteral injection of peptide drugs |
CA2853942C (en) | 2011-10-31 | 2020-08-25 | Xeris Pharmaceuticals, Inc. | Formulations for the treatment of diabetes |
EP2804632B1 (en) | 2012-01-19 | 2019-09-18 | The Johns Hopkins University | Nanoparticle formulations with enhanced mucosal penetration |
WO2013138343A1 (en) | 2012-03-16 | 2013-09-19 | The Johns Hopkins University | Controlled release formulations for the delivery of hif-1 inhibitors |
CN104394891B (en) | 2012-03-16 | 2019-04-16 | 约翰霍普金斯大学 | For delivering non-linear segmented copolymer-drug conjugates of activating agent |
JOP20200109A1 (en) | 2012-04-23 | 2017-06-16 | Otsuka Pharma Co Ltd | Injectable preparation |
JP6360040B2 (en) | 2012-05-03 | 2018-07-18 | カラ ファーマシューティカルズ インコーポレイテッド | Mucus-permeable coated particles, compositions, pharmaceutical compositions, pharmaceutical formulations, and methods for forming them |
US11596599B2 (en) | 2012-05-03 | 2023-03-07 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
KR102140989B1 (en) | 2012-05-03 | 2020-08-04 | 칼라 파마슈티컬스, 인크. | Pharmaceutical nanoparticles showing improved mucosal transport |
US9827191B2 (en) | 2012-05-03 | 2017-11-28 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US9889208B2 (en) | 2012-05-04 | 2018-02-13 | The Johns Hopkins University | Lipid-based drug carriers for rapid penetration through mucus linings |
US9125805B2 (en) | 2012-06-27 | 2015-09-08 | Xeris Pharmaceuticals, Inc. | Stable formulations for parenteral injection of small molecule drugs |
SG11201500554XA (en) | 2012-07-26 | 2015-02-27 | Camurus Ab | Opioid formulations |
WO2014016428A1 (en) | 2012-07-26 | 2014-01-30 | Camurus Ab | Opioid formulations |
SI2895156T1 (en) | 2012-09-17 | 2019-08-30 | Pfizer Inc. | Process for preparing therapeutic nanoparticles |
WO2014124006A1 (en) | 2013-02-05 | 2014-08-14 | The Johns Hopkins University | Nanoparticles for magnetic resonance imaging tracking and methods of making and using thereof |
US9018162B2 (en) | 2013-02-06 | 2015-04-28 | Xeris Pharmaceuticals, Inc. | Methods for rapidly treating severe hypoglycemia |
CA2939562C (en) * | 2014-02-11 | 2023-02-14 | Dr. Reddy's Laboratories Ltd. | Parenteral compositions of celecoxib |
WO2015127389A1 (en) | 2014-02-23 | 2015-08-27 | The Johns Hopkins University | Hypotonic enema formulations and methods of use |
BR112016021130A2 (en) | 2014-03-14 | 2017-08-15 | Pfizer | THERAPEUTIC NANOPARTICLES, PHARMACEUTICAL COMPOSITION INCLUDING THE SAID NANOPARTICLES, PROCESS FOR THE PREPARATION AND USE THEREOF |
CA2957399C (en) | 2014-08-06 | 2023-09-26 | Xeris Pharmaceuticals, Inc. | Syringes, kits, and methods for intracutaneous and/or subcutaneous injection of pastes |
US11504322B2 (en) | 2014-08-28 | 2022-11-22 | The General Hospital Corporation | Injectable slurries and methods of manufacturing the same |
AU2015308790B2 (en) | 2014-08-28 | 2020-12-03 | The General Hospital Corporation | Compositions and methods for treatment of neurological disorders |
US11471401B2 (en) | 2014-08-28 | 2022-10-18 | The General Hospital Corporation | Injectable slurries and methods of manufacturing the same |
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 |
EP4445952A3 (en) | 2014-12-15 | 2025-01-15 | The Johns Hopkins University | Sunitinib formulations and methods for use thereof in treatment of glaucoma |
CA2974715C (en) | 2015-01-27 | 2020-05-05 | The Johns Hopkins University | Hypotonic hydrogel formulations for enhanced transport of active agents at mucosal surfaces |
US20160303281A1 (en) | 2015-04-17 | 2016-10-20 | Rochal Industries, Llc | Composition and kits for pseudoplastic microgel matrices |
AU2016267052B2 (en) | 2015-05-22 | 2022-01-20 | The Bot Of The Leland Stanford Junior University | Treatment of post-bariatric hypoglycemia with GLP-1 antagonists |
AU2016271132A1 (en) | 2015-05-29 | 2017-12-07 | Launchpad Medical, Llc | Compositions and methods for adhesion to surfaces |
KR20240042548A (en) | 2015-06-03 | 2024-04-02 | 인타르시아 세라퓨틱스 인코포레이티드 | Implant placement and removal systems |
US9649364B2 (en) | 2015-09-25 | 2017-05-16 | Xeris Pharmaceuticals, Inc. | Methods for producing stable therapeutic formulations in aprotic polar solvents |
US10322169B2 (en) | 2015-06-10 | 2019-06-18 | Evonik Roehm Gmbh | Process for preparing a powder comprising a human coagulation factor protein and a lactic acid polymer |
AR106018A1 (en) | 2015-08-26 | 2017-12-06 | Achillion Pharmaceuticals Inc | ARYL, HETEROARYL AND HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF MEDICAL DISORDERS |
ES2908479T3 (en) | 2015-08-26 | 2022-04-29 | Achillion Pharmaceuticals Inc | Compounds for the treatment of immune and inflammatory disorders |
EA201890788A1 (en) | 2015-09-21 | 2018-09-28 | Тева Фармасьютикалз Интернэшнл Гмбх | PREPARATIONS OF OLANZAPIN WITH DELAYED DELIVERY |
US11590205B2 (en) | 2015-09-25 | 2023-02-28 | Xeris Pharmaceuticals, Inc. | Methods for producing stable therapeutic glucagon formulations in aprotic polar solvents |
CN105310980A (en) * | 2015-10-09 | 2016-02-10 | 北京万全德众医药生物技术有限公司 | Paliperidone controlled-release suspension oral liquid and its preparation method |
SG11201803663XA (en) | 2015-11-12 | 2018-05-30 | Graybug Vision Inc | Aggregating microparticles for therapy |
EP4374861A3 (en) | 2015-11-16 | 2024-08-07 | MedinCell S.A. | A method for morselizing and/or targeting pharmaceutically active principles to synovial tissue |
WO2017147367A1 (en) | 2016-02-26 | 2017-08-31 | The General Hospital Corporation | Medical ice slurry production and delivery systems and methods |
WO2017152014A1 (en) | 2016-03-04 | 2017-09-08 | Eiger Biopharmaceuticals, Inc. | Treatment of hyperinsulinemic hypoglycemia with exendin-4 derivatives |
WO2017197051A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Amine-linked c3-glutarimide degronimers for target protein degradation |
ES2989988T3 (en) | 2016-05-10 | 2024-11-28 | C4 Therapeutics Inc | Heterocyclic degronimers for the degradation of target proteins |
WO2017197036A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Spirocyclic degronimers for target protein degradation |
EP3455218A4 (en) | 2016-05-10 | 2019-12-18 | C4 Therapeutics, Inc. | CARBON-BONDED GLUTARIMIDE-TYPE DEGRONIMERS FOR THE DEGRADATION OF TARGET PROTEINS |
KR102574993B1 (en) | 2016-05-16 | 2023-09-06 | 인타르시아 세라퓨틱스 인코포레이티드 | Glucagon-receptor selective polypeptides and methods of use thereof |
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 |
KR20190036520A (en) | 2016-06-27 | 2019-04-04 | 아칠리온 파르마세우티칼스 인코포레이티드 | Quinazoline and indole compounds for the treatment of medical disorders |
CN109789143A (en) | 2016-07-01 | 2019-05-21 | G1治疗公司 | Antiproliferative based on pyrimidine |
EP3515408A1 (en) | 2016-09-23 | 2019-07-31 | Delpor, Inc. | Stable compositions for incretin mimetic compounds |
BR112019010236A2 (en) | 2016-11-21 | 2019-08-20 | Eiger Biopharmaceuticals Inc | buffered exendin formulations (9-39) |
US10835580B2 (en) | 2017-01-03 | 2020-11-17 | Intarcia Therapeutics, Inc. | Methods comprising continuous administration of a GLP-1 receptor agonist and co-administration of a drug |
US10350200B2 (en) * | 2017-01-23 | 2019-07-16 | Southwest Research Institute | Aqueous suspensions of oximes for autoinjectors |
US20180235899A1 (en) | 2017-02-17 | 2018-08-23 | Privo Technologies, Inc. | Particle-based multi-layer therapeutic delivery device and method |
EP3589628B1 (en) | 2017-03-01 | 2025-05-07 | Achillion Pharmaceuticals, Inc. | Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for treatment of medical disorders |
AU2018238136A1 (en) | 2017-03-20 | 2019-11-07 | Teva Pharmaceuticals International Gmbh | Sustained release olanzapine formulations |
RU2019133337A (en) | 2017-03-23 | 2021-04-23 | Грейбуг Вижн, Инк. | DRUGS AND COMPOSITIONS FOR THE TREATMENT OF EYE DISORDERS |
US10478403B1 (en) | 2017-05-03 | 2019-11-19 | Privo Technologies, Inc. | Intraoperative topically-applied non-implantable rapid release patch |
CN111201040A (en) | 2017-05-10 | 2020-05-26 | 灰色视觉公司 | Sustained release microparticles and suspensions thereof for medical therapy |
EP3630061B1 (en) | 2017-06-02 | 2024-04-03 | Xeris Pharmaceuticals, Inc. | Precipitation resistant small molecule drug formulations |
US10568842B2 (en) * | 2017-08-18 | 2020-02-25 | Lance L. Gooberman | Anti-inflammatory pharmaceutical compositions and methods of administration |
CN109589304A (en) * | 2017-10-01 | 2019-04-09 | 万特制药(海南)有限公司 | Risperidone oral administration solution and preparation method thereof |
KR20210018199A (en) | 2018-03-26 | 2021-02-17 | 씨4 테라퓨틱스, 인코포레이티드 | Cerevlon binder for decomposition of Ikaros |
WO2020041301A1 (en) | 2018-08-20 | 2020-02-27 | Achillion Pharmaceuticals, Inc. | Pharmaceutical compounds for the treatment of complement factor d medical disorders |
US11814391B2 (en) | 2018-09-06 | 2023-11-14 | Achillion Pharmaceuticals, Inc. | Macrocyclic compounds for the treatment of medical disorders |
HUE065740T2 (en) * | 2018-10-15 | 2024-06-28 | Chong Kun Dang Pharmaceutical Corp | Injectable long-acting naltrexone microparticle compositions |
CN113365617A (en) | 2018-10-16 | 2021-09-07 | 乔治亚州立大学研究基金会股份有限公司 | Carbon monoxide prodrugs for the treatment of medical conditions |
EP3983021A1 (en) * | 2019-06-14 | 2022-04-20 | Advanced Accelerator Applications | Method of treating cancer by intratumoral deposition of radioactive microparticles |
US20230103552A1 (en) * | 2020-01-03 | 2023-04-06 | Privo Technologies, Inc. | Systems and pharmaceutical compositions for treatment by direct injection of a targeted population of cells |
CN115362162A (en) | 2020-02-20 | 2022-11-18 | 艾其林医药公司 | Heteroaryl compounds for use in the treatment of complement factor D mediated disorders |
WO2021178920A1 (en) | 2020-03-05 | 2021-09-10 | C4 Therapeutics, Inc. | Compounds for targeted degradation of brd9 |
JP2023528257A (en) | 2020-05-19 | 2023-07-04 | ジー1 セラピューティクス, インコーポレイテッド | Cyclin-dependent kinase inhibitory compounds for treating medical disorders |
WO2022066774A1 (en) | 2020-09-23 | 2022-03-31 | Achillion Pharmaceuticals, Inc. | Pharmaceutical compounds for the treatment of complement mediated disorders |
BE1028769B1 (en) * | 2020-11-02 | 2022-05-31 | Flanders Color Nv | WATER BASED LIQUID RINSE LACQUER |
WO2022153262A1 (en) | 2021-01-18 | 2022-07-21 | Anton Frenkel | Pharmaceutical dosage form |
US11241330B1 (en) | 2021-04-02 | 2022-02-08 | Brixton Biosciences, Inc. | Apparatus for creation of injectable slurry |
JP2024529009A (en) | 2021-07-06 | 2024-08-01 | マーク・ヘースルトン | Treatment of serotonin reuptake inhibitor withdrawal syndrome |
CN114146020B (en) * | 2022-02-10 | 2022-04-29 | 中国远大集团有限责任公司 | Injection beauty product and preparation method and application thereof |
Family Cites Families (66)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL280825A (en) | 1962-07-11 | |||
BE744162A (en) | 1969-01-16 | 1970-06-15 | Fuji Photo Film Co Ltd | ENCAPSULATION PROCESS |
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
DE2010115A1 (en) | 1970-03-04 | 1971-09-16 | Farbenfabriken Bayer Ag, 5090 Leverkusen | Process for the production of micro-granules |
US3700215A (en) * | 1970-10-21 | 1972-10-24 | Hardman Inc | Mixing and dispensing device |
JPS523342B2 (en) | 1972-01-26 | 1977-01-27 | ||
GB1413186A (en) | 1973-06-27 | 1975-11-12 | Toyo Jozo Kk | Process for encapsulation of medicaments |
US4029782A (en) * | 1975-04-28 | 1977-06-14 | Eli Lilly And Company | Cefazolin suspension for parenteral administration |
JPS523653A (en) | 1975-06-27 | 1977-01-12 | Fuji Photo Film Co Ltd | Process for producing fine polymer particles |
IL51791A0 (en) * | 1976-04-14 | 1977-05-31 | Exxon Research Engineering Co | New injectable medicinal compositions |
US4384975A (en) | 1980-06-13 | 1983-05-24 | Sandoz, Inc. | Process for preparation of microspheres |
US4389330A (en) | 1980-10-06 | 1983-06-21 | Stolle Research And Development Corporation | Microencapsulation process |
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 |
US5385738A (en) | 1983-10-14 | 1995-01-31 | Sumitomo Pharmaceuticals Company, Ltd. | Sustained-release injection |
JPS60112713A (en) * | 1983-11-21 | 1985-06-19 | Sumitomo Chem Co Ltd | Useful sustained release injections |
JPH0657658B2 (en) * | 1985-04-11 | 1994-08-03 | 住友製薬株式会社 | Sustained release formulation |
JPS60100516A (en) * | 1983-11-04 | 1985-06-04 | Takeda Chem Ind Ltd | Preparation of sustained release microcapsule |
IE58110B1 (en) | 1984-10-30 | 1993-07-14 | Elan Corp Plc | Controlled release powder and process for its preparation |
US4804663A (en) | 1985-03-27 | 1989-02-14 | Janssen Pharmaceutica N.V. | 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles |
IE59361B1 (en) | 1986-01-24 | 1994-02-09 | Akzo Nv | Pharmaceutical preparation for obtaining a highly viscous hydrogel or suspension |
US4803075A (en) * | 1986-06-25 | 1989-02-07 | Collagen Corporation | Injectable implant composition having improved intrudability |
AU2810189A (en) | 1987-10-30 | 1989-05-23 | Stolle Research & Development Corporation | Low residual solvent microspheres and microencapsulation process |
US5158952A (en) | 1988-11-07 | 1992-10-27 | Janssen Pharmaceutica N.V. | 3-[2-[4-(6-fluoro-1,2-benzisoxozol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9 tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]pyrimidin-4-one, compositions and method of use |
IL92344A0 (en) | 1989-01-04 | 1990-07-26 | Gist Brocades Nv | Microencapsulation of bioactive substances in biocompatible polymers,microcapsules obtained and pharmaceutical preparation comprising said microcapsules |
US5019400A (en) | 1989-05-01 | 1991-05-28 | Enzytech, Inc. | Very low temperature casting of controlled release microspheres |
EP0471036B2 (en) | 1989-05-04 | 2004-06-23 | Southern Research Institute | Encapsulation process |
US5478564A (en) | 1990-02-22 | 1995-12-26 | Teva Pharmaceutical Industries, Ltd. | Preparation of microparticles for controlled release of water-soluble substances |
US5271941A (en) * | 1990-11-02 | 1993-12-21 | Cho Chung Yoon S | Antisense oligonucleotides of human regulatory subunit RI.sub.α of cAMP-dependent protein kinases |
IT1243390B (en) | 1990-11-22 | 1994-06-10 | Vectorpharma Int | PHARMACEUTICAL COMPOSITIONS IN THE FORM OF PARTICLES SUITABLE FOR THE CONTROLLED RELEASE OF PHARMACOLOGICALLY ACTIVE SUBSTANCES AND PROCEDURE FOR THEIR PREPARATION. |
US5486362A (en) * | 1991-05-07 | 1996-01-23 | Dynagen, Inc. | Controlled, sustained release delivery system for treating drug dependency |
HU222501B1 (en) | 1991-06-28 | 2003-07-28 | Endorecherche Inc. | For the preparation of a sustained release pharmaceutical composition and method comprising MPA or MGA |
US20020009443A1 (en) * | 1991-12-02 | 2002-01-24 | Vanitha Ramakrishman | Inhibitory immunoglobulin polypeptides to human pdgf beta receptor |
US5658593A (en) | 1992-01-16 | 1997-08-19 | Coletica | Injectable compositions containing collagen microcapsules |
US6537574B1 (en) * | 1992-02-11 | 2003-03-25 | Bioform, Inc. | Soft tissue augmentation material |
DE69328677T2 (en) | 1992-02-28 | 2000-08-31 | Collagen Corp., Palo Alto | HIGHLY CONCENTRATED, HOMOGENIZED COLLAGEN COMPOSITIONS |
US5656297A (en) | 1992-03-12 | 1997-08-12 | Alkermes Controlled Therapeutics, Incorporated | Modulated release from biocompatible polymers |
MX9301823A (en) * | 1992-03-30 | 1994-01-31 | Alza Corp | COMPOSITION FOR THE SUPPLY OF CONTROLLED RELEASE OF A BIOLOGICALLY ACTIVE AGENT. |
GB9211268D0 (en) * | 1992-05-28 | 1992-07-15 | Ici Plc | Salts of basic peptides with carboxyterminated polyesters |
ES2077547T3 (en) | 1992-11-17 | 2000-06-16 | Yoshitomi Pharmaceutical | SUSTAINED RELEASE MICROSPHERE CONTAINING AN ANTIPSYCHOTIC AND PRODUCTION PROCEDURE. |
DK0674506T3 (en) * | 1992-12-02 | 2001-01-08 | Alkermes Inc | Controlled release growth hormone-containing microspheres |
US5429824A (en) * | 1992-12-15 | 1995-07-04 | Eastman Kodak Company | Use of tyloxapole as a nanoparticle stabilizer and dispersant |
MY113268A (en) * | 1992-12-29 | 2002-01-31 | Insite Vision Incorporated | Plasticized bioerodible controlled delivery system |
TW376319B (en) * | 1993-04-28 | 1999-12-11 | Janssen Pharmaceutica Nv | Pharmaceutical composition containing risperidone pamoate and having a long acting activity for treating psychoses induced by the release of dopamine |
HU219487B (en) | 1993-11-19 | 2001-04-28 | Janssen Pharmaceutica Nv. | Microparticles containing risperidone, a process for their preparation, their use and pharmaceutical compositions containing them and their preparation |
AU684324B2 (en) | 1993-11-19 | 1997-12-11 | Alkermes Controlled Therapeutics Inc. Ii | Preparation of biodegradable microparticles containing a biologically active agent |
US5650173A (en) | 1993-11-19 | 1997-07-22 | Alkermes Controlled Therapeutics Inc. Ii | Preparation of biodegradable microparticles containing a biologically active agent |
US5453425A (en) | 1994-07-11 | 1995-09-26 | Janssen Pharmaceutica N.V. | Risperidone oral formulation |
DE4440337A1 (en) * | 1994-11-11 | 1996-05-15 | Dds Drug Delivery Services Ges | Pharmaceutical nanosuspensions for drug application as systems with increased saturation solubility and dissolution rate |
US5922253A (en) | 1995-05-18 | 1999-07-13 | Alkermes Controlled Therapeutics, Inc. | Production scale method of forming microparticles |
US5904935A (en) | 1995-06-07 | 1999-05-18 | Alza Corporation | Peptide/protein suspending formulations |
US5747058A (en) | 1995-06-07 | 1998-05-05 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system |
FI970522L (en) * | 1995-06-09 | 1997-04-07 | Euro Celtique Sa | Compositions and methods for providing prolonged local anesthesia |
US5942253A (en) | 1995-10-12 | 1999-08-24 | Immunex Corporation | Prolonged release of GM-CSF |
SE505146C2 (en) * | 1995-10-19 | 1997-06-30 | Biogram Ab | Particles for delayed release |
JP2000506165A (en) * | 1996-03-04 | 2000-05-23 | ザ ペン ステイト リサーチ ファウンデーション | Materials and Methods for Enhancing Cell Internalization |
US5792477A (en) * | 1996-05-07 | 1998-08-11 | Alkermes Controlled Therapeutics, Inc. Ii | Preparation of extended shelf-life biodegradable, biocompatible microparticles containing a biologically active agent |
TW487572B (en) | 1996-05-20 | 2002-05-21 | Janssen Pharmaceutica Nv | Aqueous suspensions of 9-hydroxyrisperidone fatty acid esters |
BR9815499A (en) | 1997-07-02 | 2001-01-02 | Euro Celtique Sa | Prolonged anesthesia in joints and body spaces. |
GB9718986D0 (en) | 1997-09-09 | 1997-11-12 | Danbiosyst Uk | Controlled release microsphere delivery system |
UA72189C2 (en) * | 1997-11-17 | 2005-02-15 | Янссен Фармацевтика Н.В. | Aqueous suspensions of 9-hydroxy-risperidone fatty acid esters provided in submicron form |
JP2000039867A (en) * | 1998-05-18 | 2000-02-08 | Fujitsu Ltd | Plasma display device and plasma display panel driving method |
US6143314A (en) * | 1998-10-28 | 2000-11-07 | Atrix Laboratories, Inc. | Controlled release liquid delivery compositions with low initial drug burst |
US6194006B1 (en) * | 1998-12-30 | 2001-02-27 | Alkermes Controlled Therapeutics Inc. Ii | Preparation of microparticles having a selected release profile |
US6306425B1 (en) * | 1999-04-09 | 2001-10-23 | Southern Research Institute | Injectable naltrexone microsphere compositions and their use in reducing consumption of heroin and alcohol |
HUP0203613A3 (en) | 1999-08-27 | 2005-01-28 | Brookwood Pharmaceuticals Inc | Injectable buprenorphine microparticle compositions and their use |
US6495164B1 (en) | 2000-05-25 | 2002-12-17 | Alkermes Controlled Therapeutics, Inc. I | Preparation of injectable suspensions having improved injectability |
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