CA2102267A1 - Use of charged phospholipids to reduce nanoparticle aggregation - Google Patents
Use of charged phospholipids to reduce nanoparticle aggregationInfo
- Publication number
- CA2102267A1 CA2102267A1 CA002102267A CA2102267A CA2102267A1 CA 2102267 A1 CA2102267 A1 CA 2102267A1 CA 002102267 A CA002102267 A CA 002102267A CA 2102267 A CA2102267 A CA 2102267A CA 2102267 A1 CA2102267 A1 CA 2102267A1
- Authority
- CA
- Canada
- Prior art keywords
- composition
- cloud point
- nanoparticles
- modifier
- surface modifier
- 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.)
- Abandoned
Links
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
- A61K49/0476—Particles, beads, capsules, spheres
- A61K49/0485—Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
- A61K49/049—Surface-modified nanoparticles, e.g. immune-nanoparticles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6927—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
- A61K47/6929—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/70—Nanostructure
- Y10S977/734—Fullerenes, i.e. graphene-based structures, such as nanohorns, nanococoons, nanoscrolls or fullerene-like structures, e.g. WS2 or MoS2 chalcogenide nanotubes, planar C3N4, etc.
- Y10S977/742—Carbon nanotubes, CNTs
- Y10S977/745—Carbon nanotubes, CNTs having a modified surface
- Y10S977/746—Modified with biological, organic, or hydrocarbon material
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/70—Nanostructure
- Y10S977/773—Nanoparticle, i.e. structure having three dimensions of 100 nm or less
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/70—Nanostructure
- Y10S977/788—Of specified organic or carbon-based composition
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/84—Manufacture, treatment, or detection of nanostructure
- Y10S977/842—Manufacture, treatment, or detection of nanostructure for carbon nanotubes or fullerenes
- Y10S977/847—Surface modifications, e.g. functionalization, coating
Abstract
ABSTRACT
This invention discloses a composition comprised of nanoparticles having a non-ionic surfactant as a surface modifier adsorbed on the surface thereof and a charged phospholipid as a cloud point modifier associated therewith, which cloud point modifier is present in an amount sufficient to increase the cloud point of the surface modifier. A preferred non-ionic surfactant surface modifier is a poloxamine or tyloxapol, and preferred charged phospholipid cloud point modifiers include dimyristoyl phosphatidyl glycerol. This invention further discloses a method of making nanoparticles having a non-ionic surfactant as a surface modifier adsorbed on the surface and a charged phospholipid as a cloud point modifier associated therewith, comprised of contacting said nanoparticles with the cloud point modifier for a time and under conditions sufficient to increase the cloud point of the surface modifier.
This invention discloses a composition comprised of nanoparticles having a non-ionic surfactant as a surface modifier adsorbed on the surface thereof and a charged phospholipid as a cloud point modifier associated therewith, which cloud point modifier is present in an amount sufficient to increase the cloud point of the surface modifier. A preferred non-ionic surfactant surface modifier is a poloxamine or tyloxapol, and preferred charged phospholipid cloud point modifiers include dimyristoyl phosphatidyl glycerol. This invention further discloses a method of making nanoparticles having a non-ionic surfactant as a surface modifier adsorbed on the surface and a charged phospholipid as a cloud point modifier associated therewith, comprised of contacting said nanoparticles with the cloud point modifier for a time and under conditions sufficient to increase the cloud point of the surface modifier.
Description
2 ~ ~
USE OF CHARGED PHOSPHOLIPIDS TO
REDUCE NANOPARTICLE AGGREGATION
FIELD OF THE INVENTION
This invention relates to therapeutic and diagnostic compositions with a modified cloud point, and to a method for the preparation thereof.
BACKGROUND OF THE INVENTION
Nanoparticles, described in U.S. Patent No.
5,145,684, are particles consisting of a poorly soluble therapeutic or diagnostic agent onto which are adsorbed a non-crosslinked surface modifier, and which have a mean particle size of less than about 400 nanometers (nm).
As a result of their small size, sterilization of therapeutic and diagnostic agents in nanoparticulate form stabilized by a surface modifier (surfactant) is difficult. Filtration using a filter of 0.22 ~m mesh size is sufficient to remove most bacteria and viruses, but the nanoparticles, due to their sizes, cannot be sterile filtered. Conventional autoclaving (steam heat) at 121C
will result in substantial aggregation and/or growth of particle size, rendering the resulting particles unusable.
The aggregation of nanoparticles upon heating is directly related to the precipitation of the surface modifier (surfactant) at temperatures above the cloud point of the surfactant where the bound surfactant molecules are likely to dissociate from the nanoparticles and precipitate, l~aving the nanoparticles unprotected. The unprotected nanoparticles can then aggregate into clusters of particles. Upon cooling, the surfactant redissolves into the solution, which then coats the aggregated particles and prevent them from dissociating into smaller ones. See Figure 1.
This in~ention is directed to novel compositions that allow autoclaving of nanoparticles with reduced or no particle size growth. These compositions provide for a modification of the cloud point of the surface modifier in - 2 - 21 ~22~7 , the composition such that the nanoparticles do not agglomerate during autoclaving. This invention is also directed to a method of making such compositions.
BRIEF SUMMARY OF THE INVENTION
This invention is directed to a composition comprised of nanoparticles having a non-ionic surfactant as a surface modifier adsorbed on the surface thereof and a charged phospholipid as a cloud point modifier associated therewith, which cloud point modifier is present in an amount sufficient to increase the cloud point of the surface modifier.
This invention is further directed to a method of making nanoparticles having a non-ionic surfactant as a surface modifier adsorbed on the surface thereof and a charged phospholipid as a cloud point modifier associated therewith, said method comprising contacting said nanoparticles with the cloud point modifier for a time and under conditions sufficient to increase the cloud point of the non-ionic surfactant.
DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to a composition comprised of nanoparticles having a non-ionic surfactant as 25 a surface modifier adsorbed on the surface thereof and a ~
phospholipid as a cloud point modifier associated ~ ~-therewith, which cloud point modifier is present in an ~ -amount sufficient to increase the cloud point of the -surface modifier. In a preferred embodiment, the cloud ~ ~
30 point of the non-ionic surfactant is increased above the ~ ~-temperature for autoclaving of the nanoparticles to prevent -agglomeration.
The nanoparticles useful in the practice of this invention include a non-ionic surface modifier. Surface modifiers useful herein physically adhere to the surface of the therapeutic or diagnostic agent but do not chemically ~ -react with the agent or itself. Individually adsorbed molecules of the surface modifier are essentially free of intermolecular crosslinkages. Preferred surface modifiers . . .~ :
~ ~ , - ~ : :
:,, . ~ : -2 ~ 7 , can be selected from known non-ionic surfactants, including the poloxamines such as Tetronic~ 908 (also known as Poloxamine 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, available from BASF, or Tetronic 1508 (T-1508), or a polymer of the alkyl aryl polyether alcohol type, such as tyloxapol.
The surface modifiers are commercially available and/or can be prepared by techniques known in the art. Two or more surface modifiers can be used in combination.
The nanoparticles useful in the practice of this invention can be prepared according to the methods disclosed in U.S. Patent No. 5,145,684, whose disclosure is incorporated herein by reference. Briefly, nanoparticles are prepared by dispersing a poorly soluble therapeutic or diagnostic agent in a liquid dispersion medium and wet-grinding the agent in the presence of grinding media to reduce the particle size of the contrast agent to an effective average paxticle size of less than about 400 nm.
The particles can be reduced in size in the presence of a surface modifier.
A general procedure for preparing the particles useful in the practice of this invention follows. The therapeutic or diagnostic agent selected is obtained commercially and/or prepared by techniques known in the art as described above, in a conventional coarse form. It is preferred, but not essential, that the particle size of the coarse therapeutic or diagnostic substance selected be less than about 100 ~m as determined by sieve analysis. If the coarse particle size of that agent is greater than about 100 ~m, then it is preferred that the coarse particles of the therapeutic or diagnostic agent be reduced in size to less than 100 ~m using a conventional milling method such as airjet or fragmentation milling.
The coarse therapeutic or diagnostic agent selected can then be added to a liquid medium in which it is essentially insoluble to form a premix. The concentration of the therapeutic or diagnostic agent in the liquid medium can vary from about 0.1-60%, and preferably , " ' ~ . , '"'' , _ 4 ~ 22~7 is from 5-30% (w/w). It is preferred, but not essential, that the surface modifier be present in the premix. The concentration of the surface modifier can vary from about 0.1 to 90%, and preferably is 1-75%, more preferably 10-60%
and most preferably 10-30% by weight based on the total combined weight of the drug substance and surface modifier.
The apparent viscosity of the premix suspension is preferably less than about 1000 centipoise.
The premix can be used directly by wet grinding to reduce the average particle size in the dispersion to less than 400 nm. It is preferred that the premix be used directly when a ball mill is used for attrition.
Alternatively, the therapeutic or diagnostic agent and, optionally, the surface modifier, can be dispersed in the liquid medium using suitable agitation, e.g., a roller mill or a Cowles type mixer, until a homogeneous dispersion is observed in which there are no large agglomerates visible to the naked eye. It is preferred that the premix be ~-subjected to such a premilling dispersion step when a recirculating media mill is used for attrition.
Wet grinding can take place in any suitable - ;~
dispersion mill, including, for example, a ball mill, an attritor mill, a vibratory mill, and media mills such as a sand mill and a bead mill. A media mill is preferred due to the relatively shorter milling time required to provide the intended result, i.e., the desired reduction in particle size. For media milling, the apparent viscosity of the premix preferably is from about 100 to about 1000 -~
centipoise. For ball milling, the apparent viscosity of the premix preferably is from about 1 up to about 100 centipoise. Such ranges tend to afford an optimal balance between efficient particle fragmentation and media erosion.
The grinding media for the particle size reduction step can be selected from rigid media preferably spherical or particulate in form having an average size less than about 3 mm and, more preferably, less than about 1 mm. Such media desirably can provide the particles of the invention with shorter processing times and impart less -~
wear to the milling equipment. The selection of material - 5 - ?~ 22~7 "
for the grinding media is not believed to be critical.
However, preferred media have a density greater than about
USE OF CHARGED PHOSPHOLIPIDS TO
REDUCE NANOPARTICLE AGGREGATION
FIELD OF THE INVENTION
This invention relates to therapeutic and diagnostic compositions with a modified cloud point, and to a method for the preparation thereof.
BACKGROUND OF THE INVENTION
Nanoparticles, described in U.S. Patent No.
5,145,684, are particles consisting of a poorly soluble therapeutic or diagnostic agent onto which are adsorbed a non-crosslinked surface modifier, and which have a mean particle size of less than about 400 nanometers (nm).
As a result of their small size, sterilization of therapeutic and diagnostic agents in nanoparticulate form stabilized by a surface modifier (surfactant) is difficult. Filtration using a filter of 0.22 ~m mesh size is sufficient to remove most bacteria and viruses, but the nanoparticles, due to their sizes, cannot be sterile filtered. Conventional autoclaving (steam heat) at 121C
will result in substantial aggregation and/or growth of particle size, rendering the resulting particles unusable.
The aggregation of nanoparticles upon heating is directly related to the precipitation of the surface modifier (surfactant) at temperatures above the cloud point of the surfactant where the bound surfactant molecules are likely to dissociate from the nanoparticles and precipitate, l~aving the nanoparticles unprotected. The unprotected nanoparticles can then aggregate into clusters of particles. Upon cooling, the surfactant redissolves into the solution, which then coats the aggregated particles and prevent them from dissociating into smaller ones. See Figure 1.
This in~ention is directed to novel compositions that allow autoclaving of nanoparticles with reduced or no particle size growth. These compositions provide for a modification of the cloud point of the surface modifier in - 2 - 21 ~22~7 , the composition such that the nanoparticles do not agglomerate during autoclaving. This invention is also directed to a method of making such compositions.
BRIEF SUMMARY OF THE INVENTION
This invention is directed to a composition comprised of nanoparticles having a non-ionic surfactant as a surface modifier adsorbed on the surface thereof and a charged phospholipid as a cloud point modifier associated therewith, which cloud point modifier is present in an amount sufficient to increase the cloud point of the surface modifier.
This invention is further directed to a method of making nanoparticles having a non-ionic surfactant as a surface modifier adsorbed on the surface thereof and a charged phospholipid as a cloud point modifier associated therewith, said method comprising contacting said nanoparticles with the cloud point modifier for a time and under conditions sufficient to increase the cloud point of the non-ionic surfactant.
DETAILED DESCRIPTION OF THE INVENTION
This invention is directed to a composition comprised of nanoparticles having a non-ionic surfactant as 25 a surface modifier adsorbed on the surface thereof and a ~
phospholipid as a cloud point modifier associated ~ ~-therewith, which cloud point modifier is present in an ~ -amount sufficient to increase the cloud point of the -surface modifier. In a preferred embodiment, the cloud ~ ~
30 point of the non-ionic surfactant is increased above the ~ ~-temperature for autoclaving of the nanoparticles to prevent -agglomeration.
The nanoparticles useful in the practice of this invention include a non-ionic surface modifier. Surface modifiers useful herein physically adhere to the surface of the therapeutic or diagnostic agent but do not chemically ~ -react with the agent or itself. Individually adsorbed molecules of the surface modifier are essentially free of intermolecular crosslinkages. Preferred surface modifiers . . .~ :
~ ~ , - ~ : :
:,, . ~ : -2 ~ 7 , can be selected from known non-ionic surfactants, including the poloxamines such as Tetronic~ 908 (also known as Poloxamine 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, available from BASF, or Tetronic 1508 (T-1508), or a polymer of the alkyl aryl polyether alcohol type, such as tyloxapol.
The surface modifiers are commercially available and/or can be prepared by techniques known in the art. Two or more surface modifiers can be used in combination.
The nanoparticles useful in the practice of this invention can be prepared according to the methods disclosed in U.S. Patent No. 5,145,684, whose disclosure is incorporated herein by reference. Briefly, nanoparticles are prepared by dispersing a poorly soluble therapeutic or diagnostic agent in a liquid dispersion medium and wet-grinding the agent in the presence of grinding media to reduce the particle size of the contrast agent to an effective average paxticle size of less than about 400 nm.
The particles can be reduced in size in the presence of a surface modifier.
A general procedure for preparing the particles useful in the practice of this invention follows. The therapeutic or diagnostic agent selected is obtained commercially and/or prepared by techniques known in the art as described above, in a conventional coarse form. It is preferred, but not essential, that the particle size of the coarse therapeutic or diagnostic substance selected be less than about 100 ~m as determined by sieve analysis. If the coarse particle size of that agent is greater than about 100 ~m, then it is preferred that the coarse particles of the therapeutic or diagnostic agent be reduced in size to less than 100 ~m using a conventional milling method such as airjet or fragmentation milling.
The coarse therapeutic or diagnostic agent selected can then be added to a liquid medium in which it is essentially insoluble to form a premix. The concentration of the therapeutic or diagnostic agent in the liquid medium can vary from about 0.1-60%, and preferably , " ' ~ . , '"'' , _ 4 ~ 22~7 is from 5-30% (w/w). It is preferred, but not essential, that the surface modifier be present in the premix. The concentration of the surface modifier can vary from about 0.1 to 90%, and preferably is 1-75%, more preferably 10-60%
and most preferably 10-30% by weight based on the total combined weight of the drug substance and surface modifier.
The apparent viscosity of the premix suspension is preferably less than about 1000 centipoise.
The premix can be used directly by wet grinding to reduce the average particle size in the dispersion to less than 400 nm. It is preferred that the premix be used directly when a ball mill is used for attrition.
Alternatively, the therapeutic or diagnostic agent and, optionally, the surface modifier, can be dispersed in the liquid medium using suitable agitation, e.g., a roller mill or a Cowles type mixer, until a homogeneous dispersion is observed in which there are no large agglomerates visible to the naked eye. It is preferred that the premix be ~-subjected to such a premilling dispersion step when a recirculating media mill is used for attrition.
Wet grinding can take place in any suitable - ;~
dispersion mill, including, for example, a ball mill, an attritor mill, a vibratory mill, and media mills such as a sand mill and a bead mill. A media mill is preferred due to the relatively shorter milling time required to provide the intended result, i.e., the desired reduction in particle size. For media milling, the apparent viscosity of the premix preferably is from about 100 to about 1000 -~
centipoise. For ball milling, the apparent viscosity of the premix preferably is from about 1 up to about 100 centipoise. Such ranges tend to afford an optimal balance between efficient particle fragmentation and media erosion.
The grinding media for the particle size reduction step can be selected from rigid media preferably spherical or particulate in form having an average size less than about 3 mm and, more preferably, less than about 1 mm. Such media desirably can provide the particles of the invention with shorter processing times and impart less -~
wear to the milling equipment. The selection of material - 5 - ?~ 22~7 "
for the grinding media is not believed to be critical.
However, preferred media have a density greater than about
3 g/cm3. Zirconium oxide, such as 95% ZrO stabilized with magnesia, zirconium silicate, and glass grinding media provide particles having levels of contamination which are believed to be acceptable for the preparation of therapeutic or diagnostic compositions. However, other media, such as stainless steel, titania, alumina, and 95%
ZrO stabilized with yttrium, are believed to be useful.
The attrition time can vary widely and depends primarily upon the particular wet grinding mill selected.
For ball mills, processing times of up to five days or longer may be required. On the other hand, processing times of less than 1 day (residence times of about one minute up to several hours) have provided the desired results using a high shear media mill.
The particles must be reduced in size at a temperature which does not significantly degrade the therapeutic or diagnostic agent. Processing temperatures of less than about 30-40C are ordinarily preferred. If desired, the processing equipment can be cooled with conventional cooling equipment. The method is conveniently carried out under conditions of ambient temperature and at processing pressures which are safe and effective for the milling process. For example, ambient processing pressures are typical of ball mills, attritor mills and vibratory mills. Processing pressures up to about 20 psi (1.4 kg/cm2) are typical of media milling.
The surface modifier, if not present in the premix, must be added to the dispersion after attrition in an amount as described for the premix. Thereafter, the dispersion can be mixed, e.g., by shaking vigorously.~
Optionally, the dispersion can be subjected to a sonication step, e.g., using an ultrasonic power supply. For example, the dispersion can be subjected to ultrasonic energy having a frequency of 20-80 kHz for a time of about 1 to 120 seconds.
The relative amount of therapeutic or diagnostic agent and surface modifier can vary widely and the optimal - 6 - 7,~ ~22~7 amount of the surface modifier can depend, for example, upon the particular therapeutic or diagnostic agent and surface modifier selected, the critical micelle concentration of the surface modifier if it forms micelles, the hydrophilic lipophilic balance (HLB) of the stabilizer, the melting point of the stabilizer, its water solubility, the surface tension of water solutions of the stabilizer, etc. The surface modifier preferably is present in an amount of about 0.1-10 mg per square meter surface area of the therapeutic or diagnostic agent. The surface modifier can be present in an amount of 0.1-90%, preferably 1-75%, more preferably 10-60%, and most preferably 10-30% by weight based on the total weight of the dry particle.
Therapeutic and diagnostic agents useful in the composition of the present invention include those disclosed in U.S. Patent No. 5,145,684, and EP-A 498,482, whose disclosures are incorporated herein by reference. A
preferred diagnostic agent is the x-ray imaging agent WIN-8883 (ethyl 3,5-diacetoamido-2,4,6-triiodobenzoate), the 20 ethyl ester of diatrazoic acid. ~-As used herein, particle size refers to a mean particle size as measured by conventional particle size measuring techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation. By "an effective average particle size of less than about 900 nm"
it is meant that at least 90% of the particles have a particle size of less than about 400 nm when measured by the above-noted techniques. In preferred embodiments of the invention, the effective average particle size is less than about 300 nm, and more preferably less than about 250 nm. In some embodiments of the invention, an effective mean particle size of less than about 200 nm has been achieved. With reference to the effective mean particle size, it is preferred that at least 95% and, more preferably, at least 99% of the particles have a particle size less than the effective average, e.g., 400 nm. In - particularly preferred embodiments, essentially all of the particles have a size less than 400 nm. In some - 7 - 21~22~7 , embodiments, essentially all of the particles have a size less than 250 nm.
A method for the preparation of a nanoparticle composition according to this invention includes the steps of introducing a therapeutic or diagnostic agent, a liquid medium, grinding media, and optionally, a surface modifier into a grinding vessel; wet grinding to reduce the particle size of the therapeutic or diagnostic agent to less than about 400 nm; and separating the particles and optionally the liquid medium from the grinding vessel and grinding media, for example, by suction, filtration or evaporation.
If the surface modifier is not present during wet grinding, it can be admixed with the particles thereafter. The liquid medium, most often water, can serve as the pharmaceutically acceptable carrier. The method preferably is carried out under aseptic conditions. Therea~ter, the nanoparticle composition preferably is subjected to a sterilization process.
As noted elsewhere herein, sterile filtration will not provide adequate sterilization for nanoparticles.
Therefore, other methods of sterilization are required.
For example, steam or moist heat sterilization at temperatures of about 121C for a time period of about 15 minutes can be used. At altitudes near sea level, such conditions are attained by using steam at a pressure of 15 pounds per square inch (psi) in excess of atmospheric pressure.
Dry heat sterilization may also be performed, although the temperatures used for dry heat sterilization are typically 160C for time periods of 1 to 2 hours.
Sterilization takes place in the presence of cloud point modifiers such as charged phospholipids.
The cloud point is the temperature at which the surface modifier (surfactant) precipitates out of solution as described above. By the phrase "cloud point modifier"
is meant a compound which influences the cloud point of surface modifiers. In particular, the cloud point modifiers useful in the present invention raise the cloud point of the surface modifiers in the compositions. In - 8 ~ ~ 2~7 this way, the surface modifiers do not dissociate from the surface of the nanoparticles at temperatures used in autoclaving. Therefore, nanoparticles thus modified do not agglomerate during the sterilization process, and thus ~-~
retain their effective average particle sizes of less than about 400 nm after sterilization.
Examples of cloud point modifiers include charged phospholipids. Charged phospholipids include any lipid having a net charge, i.e., any ionic phospholipid with a net positive or negative charge. Examples include such phospholipids as the synthetic phospholipid dimyristoyl phosphatidyl glycerol (DMPG), 1-palmitoyl-2-oleoyl phosphatidyl-serine, DL-alpha-phosphatidyl-L-serine-dipalmitoyl, and cardiolipin (diphosphatidyl glycerol).
Synthetic phospholipids are typically available in high purity and are relatively stable and physiologically tolerable. A preferred phospholipid is a negatively charged phospholipid. A preferred negatively charged phospholipid is dimyristoyl phosphatidyl glycerol.
The charged phospholipid can be present in an amount of 0.005-20%, preferably 0.01-15~, more preferably -;
0.05-10%, by weight based on the total weight of the nanoparticle suspension.
Isotonicity refers to the osmotic pressure of a solution. A solution which will be administered into the blood stream of an individual is typically prepared such that the osmotic pressure of that solution is the same as the osmotic pressure of blood. Such a solution is said to be isotonic.
An isotonicity maintaining compound is a compound which provides for the maintenance or alteration of a solution so as to make that solution isotonic. Such an isotonicity maintaining compound will adjust the osmotic pressure of a solution containing the compositions of the present invention so as to provide, or maintain~ an isotonic solution.
Exemplary isotonicity maintaining compounds include mannitol, dextrose, sodium chloride, potassium ` - 9 - 2~022~7 ,~
chloride, and Ringer's lactate. Preferred isotonicity maintaining compounds include mannitol and dextrose.
The pH value of a solution to be delivered into the body of a subject is also an important factor.
Typically, pH values should not be either too acidic or too basic. To maintain the appropriate pH value of a solution, it is preferable to provide pH value maintaining compounds.
These compounds provide a buffering capacity to the solution, to prevent extremes of p~ values of the solution upon storage or upon subsequent manipulation.
Exemplary pH value maintaining compounds include the well known buffers such as Tris base, HEPES, carbonate, phosphate, citrate and acetate salts. A preferred buffer is sodium phosphate (either mono- or di-basic, or both).
The composition of the present invention can be further provided with a non-ionic surfactant after sterilization (such as by autoclaving). The purpose of this additional non-ionic surfactant is to help mask the charges on the surface of the nanoparticles containing phospholipids according to the present invention. Masking these charges imparts longer circulation time for the nanoparticles used in intravenous applications.
This invention further discloses a method of making nanoparticles having a non-ionic surface modifier adsorbed on the surface and a charged phospholipid cloud point modifier associated therewith, comprised of contacting said nanoparticles with the cloud point modifier for a time and under conditions sufficient to increase the cloud point of the surface modifier.
This method involves the preparation of therapeutic or diagnostic nanoparticles, as discussed elsewhere herein, and contacting those nanoparticles with a cloud point modifier. Contacting may be by admixing a suspension of nanoparticles with a solution of cloud point modifier, followed by sterilization at a temperature and for a time sufficient to effect sterilization of the nanoparticle suspension.
lO ~022~7 The following examples further illustrate the invention and are not to be construed as limiting of the specification and claims in any way.
S Ex~mPle 1. Effect of ~hospholipids on the ~articL Q
size of WIN 8883/Tyloxapol n~nQR~ticl~S~
Samples were prepared according to the following general protocol. 0.001 grams (g) each of the tested phospholipids was weighed into individual 2 ml vial. Then, 0.5 ml of WIN 8883/Tyloxapol nanoparticle suspension comprised of the diagnostic agent WIN 8883 (the ethyl ester of diatrazoic acid) plus the surfactant tyloxapol was then added to each vial. The samples were then sonicated for 15 minutes. Unless otherwise stated, each sample was next autoclaved at 121C for 20 minutes. After the samples were cooled, 10 ~l of each sample was diluted to 15 ml in Malvern buffer and tested for particle size and zeta potential.
The following phospholipids were tested:
~a) POPS: l-Palmitoyl-2-oleoyl-phosphatidylserine (b) DPPS: Dilpalmitoylphosphatidylserine (c) DPPE:
Dipalmitoylphosphatidylmonomethylethanolamine (d) DMPG: Dimyristoylphosphatidylglycerol (e) Cardiolipin : ::
The data are presented in Table l.
'- ` ' :.-,' , ' ' ` - 11 2~02267 Table 1: Effect of Phospholipids on the Nanoparticul~ Suspe~sion Upon Autoclayina Samples in the following study contained 15% WIN 8883 and 3% Tyloxapol Addltiye Mean Particle Size Zeta Potential (nmL ___. (mVL
None 159 -6 (not autoclaved) 0.35% Cardiolipin 162 -28 0.2% POPS 164 -22 15 0.5% POPS 175 -34 0.2% DPPS 281 -18 0.5% DPPS 266 -20 0.2% DPPE 469 -8 20 None 202 -6 (not autoclaved) 0.2% DMPG 235 -20 0.2% Cardiolipin 326 -15 :
0.2% DPPS 309 -14 Samples in the following study contained 15% WIN 8883 and 3.5% Tetronic 908.
Addi~'ve Mean Particle Size Zeta Potential !nm) (mV~ :
None 173 -o.g (not autoclaved) 0.2% Cardiolipin 367 -4 ~-35 0.5% DMPG 490 -26 : :
Example 2. Effect of phospholipids on the particle :
size of WIN 8883 nanoparticles with other surface modifiers. :~ :
,. . : : : -: ~ ~ : .
'~1022~7 The procedure described in Example 1 was used to examine the effects of the phospholipid DMPG on nanoparticles prepared with surfactants such as T908, DM970 (Rhone-Poulenc), RE960 (Rhone-Poulenc) and CO990 (Rhone-Poulenc). DM970 and C0990 are alkyl phenol ethoxylates.
RE960 is an anionic surfactant, i.e., polyethoxylated nonylphenol phosphate. The results of these experiments are shown in Tables 2 and 3.
Table 2.
All samples contain 15% WIN 8883, 0.2% DMPG and 3% of a surfactant specified in the first column.
Su~factant Mean Particle Zeta Polydispersity Size (nm) Potential (mV) Before Autoclaving at 121C/20 min None 201 0.16 T-908 174 0.13 Autoclaved at 121C/20 min None 284 -58 0.20 T-908 502 -39 0.22 DM970 731 -33 0.31 CO990 654 -48 0.2g Before Autoclaving at 121C/20 min None 238 -52 0.17 T-908 192 -12 0.15 35 DM970 191 -16 0.16 CO990 190 -38 0.17 Added 0.25% extra DMPG and Autoclaved at 121C/20 min (Total 0.45% DMPG1 `~ - 13 - ~ ~ 22 ~ 7 None 234-60 0.13 T-908 477-37 0.246 DM970 583-37 0.295 CO990 628-48 0.248 Table 3. All samples contained 15% WIN 8883 ~x~ieients Autoclave Mean Size Poly-Sterilization !nm) __ dispersity (121C/20 min) 10 0.2% DMPG no 196 0.14 0.2% DOSS no 205 0.15 3% DM970, 10% PEG-400 no 183 0.21 3% DM970, 0.2% DMPG no 193 0.18 15 0.2% DMPG yes 709 0.24 0.5% DMPG yes 279 0.26 0.2% DOSS yes 640 0.27 0.5% DOSS yes 278 0.24 10% PEG-400 yes 592 0.30 0.2% RE960 yes 747 0.29 ~ ~
' :-Exa~ple 3. Effect of various phospholipids on par~icle size distrib~iQ
The procedure described in Example 1 was used to -~
examine the effects of various phospholipids on -~
nanoparticles. The results of these experiments are shown in Tables 4 and 5.
- 14 _ 2~ ~22~7 Table 4 All samples contained 15% WIN 8883. Unless otherwise stated, all samples were autoclaved at 121C for 20 minutes.
rD~P~l Mean Particle SizePolyd~persity ~nm) 0.2% (not 196 0.174 autoclaved) 0.2% 242 0.134 0.2% 224 0.194 0.4~ 239 0.199 0.7% 239 0.187 15 1.2% 251 0.193 Table 5 PhosphQ~ AutoclaveMean Size Poly~ispe~sity (121C/~0 min) lnmL
None no 159 0.143 0.5% POPS yes 174 0.157 0.2% POPS yes 164 0.137 0.5% DPPS yes 266 0.137 25 0.2% DPPS yes 281 0.141 0.2% DPPE yes 469 0.135 0.35% yes 162 0.141 Cardiolipin 30 Example 4. Effects of various phQ~holipids on the - `
cloud point of tyloxapol.
Most phospholipids with negative charge raise the cloud point of tyloxapol and stabilize the particle size after 121C for 20 minutes. Lipids were weighed directly into a 2 ml vial which 1 ml filled and bath sonicated to dissolve. The cloud point of 1% tyloxapol with various lipids is shown in Table 6.
- 15 - ~ L~ 2~7 .
Table 6 PhospholipidCloud Point (C) none 96 :
0.1% POPS >130 O.S% POPS >130 0.1% DPPS 117 0.1% DPPE 96 0.5% Cardiolipin 120 0.1% Cardiolipin >130 The foregoing specification, including the :
specific e~bodiments and examples is intended to be illustrative of the present invention and is not to be 15 taken as limiting. Numerous other variations and ~ :
modifications can be effected without departing from the true spirit and scope of the present invention. :
ZrO stabilized with yttrium, are believed to be useful.
The attrition time can vary widely and depends primarily upon the particular wet grinding mill selected.
For ball mills, processing times of up to five days or longer may be required. On the other hand, processing times of less than 1 day (residence times of about one minute up to several hours) have provided the desired results using a high shear media mill.
The particles must be reduced in size at a temperature which does not significantly degrade the therapeutic or diagnostic agent. Processing temperatures of less than about 30-40C are ordinarily preferred. If desired, the processing equipment can be cooled with conventional cooling equipment. The method is conveniently carried out under conditions of ambient temperature and at processing pressures which are safe and effective for the milling process. For example, ambient processing pressures are typical of ball mills, attritor mills and vibratory mills. Processing pressures up to about 20 psi (1.4 kg/cm2) are typical of media milling.
The surface modifier, if not present in the premix, must be added to the dispersion after attrition in an amount as described for the premix. Thereafter, the dispersion can be mixed, e.g., by shaking vigorously.~
Optionally, the dispersion can be subjected to a sonication step, e.g., using an ultrasonic power supply. For example, the dispersion can be subjected to ultrasonic energy having a frequency of 20-80 kHz for a time of about 1 to 120 seconds.
The relative amount of therapeutic or diagnostic agent and surface modifier can vary widely and the optimal - 6 - 7,~ ~22~7 amount of the surface modifier can depend, for example, upon the particular therapeutic or diagnostic agent and surface modifier selected, the critical micelle concentration of the surface modifier if it forms micelles, the hydrophilic lipophilic balance (HLB) of the stabilizer, the melting point of the stabilizer, its water solubility, the surface tension of water solutions of the stabilizer, etc. The surface modifier preferably is present in an amount of about 0.1-10 mg per square meter surface area of the therapeutic or diagnostic agent. The surface modifier can be present in an amount of 0.1-90%, preferably 1-75%, more preferably 10-60%, and most preferably 10-30% by weight based on the total weight of the dry particle.
Therapeutic and diagnostic agents useful in the composition of the present invention include those disclosed in U.S. Patent No. 5,145,684, and EP-A 498,482, whose disclosures are incorporated herein by reference. A
preferred diagnostic agent is the x-ray imaging agent WIN-8883 (ethyl 3,5-diacetoamido-2,4,6-triiodobenzoate), the 20 ethyl ester of diatrazoic acid. ~-As used herein, particle size refers to a mean particle size as measured by conventional particle size measuring techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation. By "an effective average particle size of less than about 900 nm"
it is meant that at least 90% of the particles have a particle size of less than about 400 nm when measured by the above-noted techniques. In preferred embodiments of the invention, the effective average particle size is less than about 300 nm, and more preferably less than about 250 nm. In some embodiments of the invention, an effective mean particle size of less than about 200 nm has been achieved. With reference to the effective mean particle size, it is preferred that at least 95% and, more preferably, at least 99% of the particles have a particle size less than the effective average, e.g., 400 nm. In - particularly preferred embodiments, essentially all of the particles have a size less than 400 nm. In some - 7 - 21~22~7 , embodiments, essentially all of the particles have a size less than 250 nm.
A method for the preparation of a nanoparticle composition according to this invention includes the steps of introducing a therapeutic or diagnostic agent, a liquid medium, grinding media, and optionally, a surface modifier into a grinding vessel; wet grinding to reduce the particle size of the therapeutic or diagnostic agent to less than about 400 nm; and separating the particles and optionally the liquid medium from the grinding vessel and grinding media, for example, by suction, filtration or evaporation.
If the surface modifier is not present during wet grinding, it can be admixed with the particles thereafter. The liquid medium, most often water, can serve as the pharmaceutically acceptable carrier. The method preferably is carried out under aseptic conditions. Therea~ter, the nanoparticle composition preferably is subjected to a sterilization process.
As noted elsewhere herein, sterile filtration will not provide adequate sterilization for nanoparticles.
Therefore, other methods of sterilization are required.
For example, steam or moist heat sterilization at temperatures of about 121C for a time period of about 15 minutes can be used. At altitudes near sea level, such conditions are attained by using steam at a pressure of 15 pounds per square inch (psi) in excess of atmospheric pressure.
Dry heat sterilization may also be performed, although the temperatures used for dry heat sterilization are typically 160C for time periods of 1 to 2 hours.
Sterilization takes place in the presence of cloud point modifiers such as charged phospholipids.
The cloud point is the temperature at which the surface modifier (surfactant) precipitates out of solution as described above. By the phrase "cloud point modifier"
is meant a compound which influences the cloud point of surface modifiers. In particular, the cloud point modifiers useful in the present invention raise the cloud point of the surface modifiers in the compositions. In - 8 ~ ~ 2~7 this way, the surface modifiers do not dissociate from the surface of the nanoparticles at temperatures used in autoclaving. Therefore, nanoparticles thus modified do not agglomerate during the sterilization process, and thus ~-~
retain their effective average particle sizes of less than about 400 nm after sterilization.
Examples of cloud point modifiers include charged phospholipids. Charged phospholipids include any lipid having a net charge, i.e., any ionic phospholipid with a net positive or negative charge. Examples include such phospholipids as the synthetic phospholipid dimyristoyl phosphatidyl glycerol (DMPG), 1-palmitoyl-2-oleoyl phosphatidyl-serine, DL-alpha-phosphatidyl-L-serine-dipalmitoyl, and cardiolipin (diphosphatidyl glycerol).
Synthetic phospholipids are typically available in high purity and are relatively stable and physiologically tolerable. A preferred phospholipid is a negatively charged phospholipid. A preferred negatively charged phospholipid is dimyristoyl phosphatidyl glycerol.
The charged phospholipid can be present in an amount of 0.005-20%, preferably 0.01-15~, more preferably -;
0.05-10%, by weight based on the total weight of the nanoparticle suspension.
Isotonicity refers to the osmotic pressure of a solution. A solution which will be administered into the blood stream of an individual is typically prepared such that the osmotic pressure of that solution is the same as the osmotic pressure of blood. Such a solution is said to be isotonic.
An isotonicity maintaining compound is a compound which provides for the maintenance or alteration of a solution so as to make that solution isotonic. Such an isotonicity maintaining compound will adjust the osmotic pressure of a solution containing the compositions of the present invention so as to provide, or maintain~ an isotonic solution.
Exemplary isotonicity maintaining compounds include mannitol, dextrose, sodium chloride, potassium ` - 9 - 2~022~7 ,~
chloride, and Ringer's lactate. Preferred isotonicity maintaining compounds include mannitol and dextrose.
The pH value of a solution to be delivered into the body of a subject is also an important factor.
Typically, pH values should not be either too acidic or too basic. To maintain the appropriate pH value of a solution, it is preferable to provide pH value maintaining compounds.
These compounds provide a buffering capacity to the solution, to prevent extremes of p~ values of the solution upon storage or upon subsequent manipulation.
Exemplary pH value maintaining compounds include the well known buffers such as Tris base, HEPES, carbonate, phosphate, citrate and acetate salts. A preferred buffer is sodium phosphate (either mono- or di-basic, or both).
The composition of the present invention can be further provided with a non-ionic surfactant after sterilization (such as by autoclaving). The purpose of this additional non-ionic surfactant is to help mask the charges on the surface of the nanoparticles containing phospholipids according to the present invention. Masking these charges imparts longer circulation time for the nanoparticles used in intravenous applications.
This invention further discloses a method of making nanoparticles having a non-ionic surface modifier adsorbed on the surface and a charged phospholipid cloud point modifier associated therewith, comprised of contacting said nanoparticles with the cloud point modifier for a time and under conditions sufficient to increase the cloud point of the surface modifier.
This method involves the preparation of therapeutic or diagnostic nanoparticles, as discussed elsewhere herein, and contacting those nanoparticles with a cloud point modifier. Contacting may be by admixing a suspension of nanoparticles with a solution of cloud point modifier, followed by sterilization at a temperature and for a time sufficient to effect sterilization of the nanoparticle suspension.
lO ~022~7 The following examples further illustrate the invention and are not to be construed as limiting of the specification and claims in any way.
S Ex~mPle 1. Effect of ~hospholipids on the ~articL Q
size of WIN 8883/Tyloxapol n~nQR~ticl~S~
Samples were prepared according to the following general protocol. 0.001 grams (g) each of the tested phospholipids was weighed into individual 2 ml vial. Then, 0.5 ml of WIN 8883/Tyloxapol nanoparticle suspension comprised of the diagnostic agent WIN 8883 (the ethyl ester of diatrazoic acid) plus the surfactant tyloxapol was then added to each vial. The samples were then sonicated for 15 minutes. Unless otherwise stated, each sample was next autoclaved at 121C for 20 minutes. After the samples were cooled, 10 ~l of each sample was diluted to 15 ml in Malvern buffer and tested for particle size and zeta potential.
The following phospholipids were tested:
~a) POPS: l-Palmitoyl-2-oleoyl-phosphatidylserine (b) DPPS: Dilpalmitoylphosphatidylserine (c) DPPE:
Dipalmitoylphosphatidylmonomethylethanolamine (d) DMPG: Dimyristoylphosphatidylglycerol (e) Cardiolipin : ::
The data are presented in Table l.
'- ` ' :.-,' , ' ' ` - 11 2~02267 Table 1: Effect of Phospholipids on the Nanoparticul~ Suspe~sion Upon Autoclayina Samples in the following study contained 15% WIN 8883 and 3% Tyloxapol Addltiye Mean Particle Size Zeta Potential (nmL ___. (mVL
None 159 -6 (not autoclaved) 0.35% Cardiolipin 162 -28 0.2% POPS 164 -22 15 0.5% POPS 175 -34 0.2% DPPS 281 -18 0.5% DPPS 266 -20 0.2% DPPE 469 -8 20 None 202 -6 (not autoclaved) 0.2% DMPG 235 -20 0.2% Cardiolipin 326 -15 :
0.2% DPPS 309 -14 Samples in the following study contained 15% WIN 8883 and 3.5% Tetronic 908.
Addi~'ve Mean Particle Size Zeta Potential !nm) (mV~ :
None 173 -o.g (not autoclaved) 0.2% Cardiolipin 367 -4 ~-35 0.5% DMPG 490 -26 : :
Example 2. Effect of phospholipids on the particle :
size of WIN 8883 nanoparticles with other surface modifiers. :~ :
,. . : : : -: ~ ~ : .
'~1022~7 The procedure described in Example 1 was used to examine the effects of the phospholipid DMPG on nanoparticles prepared with surfactants such as T908, DM970 (Rhone-Poulenc), RE960 (Rhone-Poulenc) and CO990 (Rhone-Poulenc). DM970 and C0990 are alkyl phenol ethoxylates.
RE960 is an anionic surfactant, i.e., polyethoxylated nonylphenol phosphate. The results of these experiments are shown in Tables 2 and 3.
Table 2.
All samples contain 15% WIN 8883, 0.2% DMPG and 3% of a surfactant specified in the first column.
Su~factant Mean Particle Zeta Polydispersity Size (nm) Potential (mV) Before Autoclaving at 121C/20 min None 201 0.16 T-908 174 0.13 Autoclaved at 121C/20 min None 284 -58 0.20 T-908 502 -39 0.22 DM970 731 -33 0.31 CO990 654 -48 0.2g Before Autoclaving at 121C/20 min None 238 -52 0.17 T-908 192 -12 0.15 35 DM970 191 -16 0.16 CO990 190 -38 0.17 Added 0.25% extra DMPG and Autoclaved at 121C/20 min (Total 0.45% DMPG1 `~ - 13 - ~ ~ 22 ~ 7 None 234-60 0.13 T-908 477-37 0.246 DM970 583-37 0.295 CO990 628-48 0.248 Table 3. All samples contained 15% WIN 8883 ~x~ieients Autoclave Mean Size Poly-Sterilization !nm) __ dispersity (121C/20 min) 10 0.2% DMPG no 196 0.14 0.2% DOSS no 205 0.15 3% DM970, 10% PEG-400 no 183 0.21 3% DM970, 0.2% DMPG no 193 0.18 15 0.2% DMPG yes 709 0.24 0.5% DMPG yes 279 0.26 0.2% DOSS yes 640 0.27 0.5% DOSS yes 278 0.24 10% PEG-400 yes 592 0.30 0.2% RE960 yes 747 0.29 ~ ~
' :-Exa~ple 3. Effect of various phospholipids on par~icle size distrib~iQ
The procedure described in Example 1 was used to -~
examine the effects of various phospholipids on -~
nanoparticles. The results of these experiments are shown in Tables 4 and 5.
- 14 _ 2~ ~22~7 Table 4 All samples contained 15% WIN 8883. Unless otherwise stated, all samples were autoclaved at 121C for 20 minutes.
rD~P~l Mean Particle SizePolyd~persity ~nm) 0.2% (not 196 0.174 autoclaved) 0.2% 242 0.134 0.2% 224 0.194 0.4~ 239 0.199 0.7% 239 0.187 15 1.2% 251 0.193 Table 5 PhosphQ~ AutoclaveMean Size Poly~ispe~sity (121C/~0 min) lnmL
None no 159 0.143 0.5% POPS yes 174 0.157 0.2% POPS yes 164 0.137 0.5% DPPS yes 266 0.137 25 0.2% DPPS yes 281 0.141 0.2% DPPE yes 469 0.135 0.35% yes 162 0.141 Cardiolipin 30 Example 4. Effects of various phQ~holipids on the - `
cloud point of tyloxapol.
Most phospholipids with negative charge raise the cloud point of tyloxapol and stabilize the particle size after 121C for 20 minutes. Lipids were weighed directly into a 2 ml vial which 1 ml filled and bath sonicated to dissolve. The cloud point of 1% tyloxapol with various lipids is shown in Table 6.
- 15 - ~ L~ 2~7 .
Table 6 PhospholipidCloud Point (C) none 96 :
0.1% POPS >130 O.S% POPS >130 0.1% DPPS 117 0.1% DPPE 96 0.5% Cardiolipin 120 0.1% Cardiolipin >130 The foregoing specification, including the :
specific e~bodiments and examples is intended to be illustrative of the present invention and is not to be 15 taken as limiting. Numerous other variations and ~ :
modifications can be effected without departing from the true spirit and scope of the present invention. :
Claims (19)
1. A composition comprised of nanoparticles having a non-ionic surfactant as a surface modifier adsorbed on the surface thereof and a charged phospholipid as a cloud point modifier associated therewith, which cloud point modifier is present in an amount sufficient to increase the cloud point of the surface modifier.
2. The composition of claim 1 wherein said nanoparticles contain a diagnostic or therapeutic agent.
3. The composition of claim 2 wherein said diagnostic agent is the ethyl ester of diatrazoic acid.
4. The composition of claim 1 wherein said non-ionic surfactant is selected from the group consisting of a poloxamine and a polymer of the alkyl aryl polyether alcohol type.
5. The composition of claim 4 wherein said poloxamine is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine
6. The composition of claim 4 wherein said polymer of the alkyl aryl polyether alcohol type is tyloxapol.
7. The composition of claim 1 wherein said phospholipid is diacylphosphatidyl glycerol.
8. The composition of claim 1 wherein said phospholipid is dimyristoyl phosphatidyl glycerol.
9. The composition of claim 1 further comprising an isotonicity maintaining compound.
10. The composition of claim 9 wherein said isotonicity maintaining compound is selected from the group consisting of mannitol or dextrose.
11. The composition of claim 1 further comprising a pH value maintaining compound.
12. The composition of claim 11 wherein said pH
value maintaining compound is sodium phosphate.
value maintaining compound is sodium phosphate.
13. The composition of claim 1 in wherein said cloud point modifier increases the cloud point of said surface modifier above the sterilization temperature of the nanoparticles.
19. The composition of claim 13 further comprising a non-ionic surfactant added after sterilization.
15. The composition of claim 11 wherein said non-ionic surfactant is a poloxamine.
16. A method of making nanoparticles having a non-ionic surfactant as a surface modifier adsorbed on the surface and a charged phospholipid as a cloud point modifier associated therewith, comprised of contacting said nanoparticles with the cloud point modifier for a time and under conditions sufficient to increase the cloud point of the surface modifier.
17. The method of claim 16 further comprising the step of sterilizing said nanoparticle.
18. The method of claim 15 wherein said sterilizing is by steam heat autoclaving.
19. A method of making sterilized nanoparticles comprised of contacting said nanoparticles with a charged phospholipid and sterilizing said nanoparticles by steam heat sterilization.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US989,281 | 1992-12-11 | ||
| US07/989,281 US5336507A (en) | 1992-12-11 | 1992-12-11 | Use of charged phospholipids to reduce nanoparticle aggregation |
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|---|---|
| CA2102267A1 true CA2102267A1 (en) | 1994-06-12 |
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ID=25534953
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| CA002102267A Abandoned CA2102267A1 (en) | 1992-12-11 | 1993-11-02 | Use of charged phospholipids to reduce nanoparticle aggregation |
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|---|---|
| US (2) | US5336507A (en) |
| EP (1) | EP0601618A3 (en) |
| JP (1) | JPH06211646A (en) |
| KR (1) | KR940013540A (en) |
| AU (1) | AU662453B2 (en) |
| CA (1) | CA2102267A1 (en) |
| CZ (1) | CZ260293A3 (en) |
| FI (1) | FI935305A (en) |
| HU (1) | HUT65758A (en) |
| IL (1) | IL107489A0 (en) |
| NO (1) | NO934204L (en) |
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Families Citing this family (215)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9216082D0 (en) * | 1992-07-28 | 1992-09-09 | Univ Nottingham | Lymphatic delivery composition |
| US5298262A (en) * | 1992-12-04 | 1994-03-29 | Sterling Winthrop Inc. | Use of ionic cloud point modifiers to prevent particle aggregation during sterilization |
| US5346702A (en) * | 1992-12-04 | 1994-09-13 | Sterling Winthrop Inc. | Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization |
| US5429824A (en) * | 1992-12-15 | 1995-07-04 | Eastman Kodak Company | Use of tyloxapole as a nanoparticle stabilizer and dispersant |
| US5352459A (en) * | 1992-12-16 | 1994-10-04 | Sterling Winthrop Inc. | Use of purified surface modifiers to prevent particle aggregation during sterilization |
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-
1992
- 1992-12-11 US US07/989,281 patent/US5336507A/en not_active Expired - Fee Related
-
1993
- 1993-10-26 NZ NZ250062A patent/NZ250062A/en unknown
- 1993-10-30 EP EP93203045A patent/EP0601618A3/en not_active Withdrawn
- 1993-11-02 CA CA002102267A patent/CA2102267A1/en not_active Abandoned
- 1993-11-04 IL IL10748993A patent/IL107489A0/en unknown
- 1993-11-05 AU AU50468/93A patent/AU662453B2/en not_active Ceased
- 1993-11-05 KR KR1019930023382A patent/KR940013540A/en not_active Application Discontinuation
- 1993-11-15 JP JP5284616A patent/JPH06211646A/en active Pending
- 1993-11-19 NO NO934204A patent/NO934204L/en unknown
- 1993-11-29 FI FI935305A patent/FI935305A/en not_active Application Discontinuation
- 1993-12-01 CZ CZ932602A patent/CZ260293A3/en unknown
- 1993-12-09 SK SK1390-93A patent/SK139093A3/en unknown
- 1993-12-10 HU HU9303539A patent/HUT65758A/en unknown
-
1994
- 1994-05-10 US US08/240,309 patent/US5470583A/en not_active Expired - Lifetime
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|---|---|
| US5470583A (en) | 1995-11-28 |
| SK139093A3 (en) | 1994-12-07 |
| NO934204L (en) | 1994-06-13 |
| EP0601618A3 (en) | 1995-11-02 |
| FI935305A (en) | 1994-06-12 |
| JPH06211646A (en) | 1994-08-02 |
| FI935305A0 (en) | 1993-11-29 |
| EP0601618A2 (en) | 1994-06-15 |
| CZ260293A3 (en) | 1994-06-15 |
| IL107489A0 (en) | 1994-02-27 |
| AU662453B2 (en) | 1995-08-31 |
| HU9303539D0 (en) | 1994-04-28 |
| NZ250062A (en) | 1995-04-27 |
| US5336507A (en) | 1994-08-09 |
| HUT65758A (en) | 1994-07-28 |
| NO934204D0 (en) | 1993-11-19 |
| AU5046893A (en) | 1994-06-23 |
| KR940013540A (en) | 1994-07-15 |
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