CA2108192C - Use of tyloxapol as a nanoparticle stabilizer and dispersant - Google Patents
Use of tyloxapol as a nanoparticle stabilizer and dispersant Download PDFInfo
- Publication number
- CA2108192C CA2108192C CA002108192A CA2108192A CA2108192C CA 2108192 C CA2108192 C CA 2108192C CA 002108192 A CA002108192 A CA 002108192A CA 2108192 A CA2108192 A CA 2108192A CA 2108192 C CA2108192 C CA 2108192C
- Authority
- CA
- Canada
- Prior art keywords
- tyloxapol
- retinoic acid
- composition
- particle size
- nanoparticles
- 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 - Fee Related
Links
Classifications
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- 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
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61K9/08—Solutions
-
- 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
-
- 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
Abstract
The present invention is directed to a composition comprised of nanoparticles having tyloxapol adsorbed on the surface thereof. In a preferred embodiment, said nanoparticle contains a diagnostic or therapeutic agent therein. In a further preferred embodiment, the nanoparticles contain a further surface modifier associated therewith. This invention further discloses a method of making nanoparticles having tyloxapol adsorbed on the surface, said method comprising contacting said nanoparticles with tyloxapol for a time and under conditions sufficient to provide a nanoparticle-tyloxapol composition. The present invention is also directed to a method of diagnosis comprising administering to a mammal a contrast effective amount of particles of nanoparticles having tyloxapol adsorbed on the surface thereof, and generating a diagnostic image of said mammal.
Description
~108 19 2 THE USE OF TYLOXAPOL AS A NANOPARTICLE
STABILIZER AND DISPERSANT
FIELD OF THE INVENTION
The present invention is directed to nanoparticles containing a diagnostic or therapeutic agent and tyloxapol associated therewith.
BACKGROUND OF THE INVENTION
Nanoparticles, described in U.S. Patent No. 5,145,684, are particles consisting of a poorly soluble therapeutic or diagnostic aqent orito which are adsorbed a non-crosslinked surface modifier, and which have an average particle size of less than about 400 nanometers (nm).
Tyloxapol (4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde) is a nonionic liquid polymer of the alkyl aryl polyether alcohol type.
Tyloxapol, also known as "Superinone", is disclosed as useful as a nonionic surface active agent in a lung surfactant composition in U.S. Patent No. 4,826,821 and as a stabilizincl agent. for 2-dimethylaminoethyl 4-n-butylaminoberizoate in U.S. Patent No. 3,272,700.
The present irivention is directed to the use of tyloxapol in nanoparticle formulations. Tyloxapol may act as a stabilizer and/or a dispersant. Tyloxapol also functions as a surface modifier. Tyloxapol serves as an excellent wetting agent and affords enhanced blood pool residence via. reduced macrophage uptake.
SIJMMARY OF THE INVENTION
The present irivention is directed to a composition comprised of nanoparticles having tyloxapol adsorbed on the surface thereof. In a preferred embodiment, the nanoparticles are comprised of a diagnostic or therapeutic agent. In a further preferred embodiment, the nanoparticles comprise a further auxiliary surface modifier _ - 2 -associated therewith which can function to reduce particle agglomeration during sterilization.
This invention further discloses a method of making nanoparticles having tyloxapol adsorbed on the surface thereof, said method comprising contacting said nanoparticles, comprising an insoluble diagnostic or therapeutic substance, with tyloxapol for a time and under conditions sufficient to provide a corresponding nanoparticle-tyloxapol composition.
The present invention is also directed to a method of diagnosis comprising administering to a mammal a contrast effective amount of particles of nanoparticles having tyloxapol adsorbed on the surface thereof, and generating a diagnostic iinage of said mammal.
The present invention is further directed to a method of treatment comprising administering to a mammal a therapeutically effective amount of nanoparticles comprising a therapeutic agent having tyloxapol adsorbed on the surface thereof.
DETAILEI) DESCRIPTION OF THE INVENTION
This invention is described hereinafter primarily in conjunction with tyloxapol as a surface modifier for nanoparticles. However, it is believed that the invention can be practiced with other nonionic liquid polymers of the alkyl aryl polyether alcohol type.
The present invention is directed to a composition comprised of nanoparticles having tyloxapol adsorbed on the surface thereof.
In a preferred embodiment, the nanoparticles comprise a further sui-face modifier associated therewith. Surface modifiers useful herein physically adhere to the surface of the nanoparticle but do not chemically react with the nanoparticle or itself. Individually adsorbed molecules of the surface modifier are essentially free of intermolecular crosslinkages. Suitable surface modifiers can be selected from known organic and inorganic pharmaceutical excipients such as various polymers, low-molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
Representative examples of surface modifiers include gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available TweensTM, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethy:Lcellu:Lose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropy:Lcellu:Lose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, tr:iethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Most of these surface modifiers are knowri pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986.
Particularly preferred surface modifiers include polyvinylpyrrolidone, poloxamers such as Pluronic' F68 and F108, which Eire block copolymers of ethylene oxide and propylene ox_Lde, and poloxamines such as TetronicT"' 908 (also known as Poloxamine 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide ancl ethylene oxide to ethylenediamine, available from BASF', dextran, lecithin, dialkylesters of sodium sulfosuccinic acid, such as Aerosol OTT"', which is a dioctyl ester of sodium sulfosuccinic acid, available from American Cyariamid, DuponolT"' P, which is a sodium lauryl sulfate, available from DuPont, TritonTM X-200, which is an alkyl aryl polyether sulfonate, available from Rohm and Haas, Tween 80, which is a polyoxyethylene sorbitan fatty acid ester, available from ICI Specialty Chemicals, and CarbowaxTM 3350 and 934, which are polyethylene glycols available from Union Carbide. Surface modifiers which have been found to be particularly useful include Tetronic 908, the TweensTM, Pluronic F-68 and polyvinylpyrrolidone. Other useful surface modifiers include:
decanoyl-N-m.ethylglucamide;
n-decyl B-D-glucopyranoside;
n-decyl B-D-maltopyranoside;
n-dodecyl B-D-glucopyranoside;
n-dodecyl l3-D-maltoside;
heptanoyl-N-methylglucamide n-heptyl B-D-glucopyranoside;
n-heptyl I3-D-thioglucoside;
n-hexyl B-D-glucopyranoside;
nonanoyl-N-methylglucamide;
n-nonyl B-D-glucopyranoside;
octanoyl-N-methylglucamide;
n-octyl B-D-glucopyranoside;
octyl B-D-thioglucopyranoside;
and the like.
Particularly preferred auxiliary surface modifiers are those which impart resistance to particle aggregation during sterilization and include dioctylsulfosuccinate (DOSS), polyethylene glycol, glycerol, sodium dodecyl sulfate, dodecyl t:rimethyl ammonium bromide and a charged phospholipid such ,3s dimyristoyl phophatidyl glycerol. 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 tyloxapol that is associated with the nanoparticles may function as a surface modifier, as a stabilizer, isnd/or as a dispersant. Alternatively, the tyloxapol may serve other purposes. In one embodiment of the present invention, tyloxapol serves all three functions. In another embodiment, the tyloxapol may serve as a stabilizer and/or a dispersant, whereas another compound acts as a surface modifier, as discussed elsewhere herein.
_ 5 _ The nanoparticles of the present invention contain a diagnostic or therapeutic agent. 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.
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 particle 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 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 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 *Trade-mark media, such as staiLnless 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 mil:ls, 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 usinci a hicjh shear media mill.
The particles must be reduced in size at a temperature which does not sigriificantly degrade the therapeutic or diagnostic aqent. Processing temperatures of less than about 30-40 C are ordinarily preferred. If desired, the processing equipmerit can be cooled with conventional cooling equipment. The method is conveniently carried out under condit:_ons of ambient temperature and at processing pressures whJ_ch are safe and effective for the milling process. Foi- 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 addeci to the dispersion after attrition in an amount as described for the premix. Thereafter, the dispersion can be nlixed, 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 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 bEilance (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 United States Patent No. 5,145,684, and EP-A 498,482. In addition, those diagnostic agents disclosed in copending Canadian Patent Application Ser. No. 2,106,413 may also be used. Preferred diagnostic agents include ethyl 3,5-diacetoamido-2,4,6-triiodobenzoate (WIN 8883), ethyl 2-[3,5-bis(acetamido)-2,4,6-triiodobenzoyloxy]butyrate (WIN 16318), diethyl 2-[3,5-bis(acetamido)-2,4,6-triiodobenzoyloxy]malonate (WIN 67721), and 6-ethoxy-6-oxohexyl 3,5-bis(acetamido)-2,4,6-triiodobenzoate (WIN 67722 disclosed in the above-mentioned Canadian Patent Application). A particularly preferred diagnostic agent is the x-ray imaging agent WIN 8883. A particular preferred therapeutic agent is retinoic acid.
As used herein, particle size refers to a number average particle size as measured by conventional particle size measuring techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photo correlation spectroscopy, or disk centrifugation. By "an effective average particle size of less than about 400 nm"
it is meant that at least 90% of the particles have a weight average particle size of less than about 400 nm when measured by the above-noted techniques. In preferred embodiments of the invention, the effective average 3a 26299-73 particle size is less than about 300 nm, and more preferably less than about 250 nm, In some embodiments of the invention, an effective average particle size of less than about 200 nm has been achieved. With reference to the effective average 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 embodiments, assentially all of the particles have a size less than 250 nm. The lower limit is riot critical, but practically it is in general about 1 nm.
The present invention includes the nanoparticle composition with tyloxapol associated on the surface thereof, as described elsewhere herein, formulated into compositions together with one or more non-toxic physiologica:Lly acceptable carriers, adjuvants or vehicles which are collectively referred to herein as carriers, for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration, or the like.
The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenous, intramusculai- or subcutaneous), intracisternally, intravaginal:Ly, intraperitoneally, locally (powders, ointments or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutioris, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaque:ous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneqlycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wettincl, emulsifying, and dispensing agents.
Prevention of' the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It: may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like.
Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, f'or example, aluminum monostearate and gelatin.
~
-Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as 5 sodium citrate or ciicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, maniiitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, 10 as for examp:Le, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic ac:Ld, certain complex silicates and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcoho:L and qlycerol monostearate, (h) adsorbents, as for example, kaoliri and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as :=illers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes.
The active coinpounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, t:he liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetatia, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,,3-butyleneglycol, dimethylformamide, oils, in par=:icular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, aqar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the preserit invention with suitable non-irritating excipients oi- carriers such as cocoa butter, polyethyleneqlycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this inverition include ointments, powders, sprays and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers or propellants as may be required. Ophthalmic formulations, eye ointments, powders _ 12 _ and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the compositions of the present invention may be varied so as to obtain an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, on the route of administration, on the desired duration of treatment and other factors.
The total daily dose of the compounds of this invention administered to a host in single of divided dose may be in amounts, for example, of from about 1 nanomol to about 5 micromoles per kilogram of body weight. Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated.
A method for the preparation of a nanoparticle composition according to this invention includes the steps of introducing a t]nerapeutic 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 therapo=_utic or diagnostic agent to less than about 400 nm; and separating the particles and optionally the liquid miedium 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 iaith the particles thereafter. The liquid mediuin, most often water, can serve as the pharmaceutically acceptable carrier. The method preferably is carried out under aseptic conditions. Thereafter, the nanoparticle composition preferably is subjected to a sterilization process.
This invention further discloses a method of making nanoparticles having tyloxapol adsorbed on the surface thereof, said method comprising contacting said nanoparticles with tyloxapol for a time and under conditions sufficient to provide a nanoparticle-tyloxapol composition.
This method involves the preparation of therapeutic or diagnostic nanoparticles, as discussed elsewhere herein, and contacting those nanoparticles with tyloxapol.
Contacting may be by admixing a suspension of nanoparticles with a solut.ion of tyloxapol for a time period and under conditions suitable for the formation of a nanoparticle-tyloxapol composition.
The concentration of tyloxapol 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 tyloxapol. The time of contacting may be from 60 seconds to about 48 hours.
In a preferred embodiment, the method comprises the further addition of other surface modifiers associated with the nanopart.icles. The method is practiced according to the techniques described elsewhere herein.
The present invention is also directed to a method of diagnosis cornprisirig administering to a mammal a contrast effective amount of particles of nanoparticles having tyloxapol adsorbed on the surface thereof, and generating a diagnostic ir:iage of' said mammal. In a preferred embodiment, t:he narioparticles comprise a further surface modifier associated therewith.
A method for ciiagnostic imaging for use in medical procedures iri accordance with this invention comprises administerinq to the body of a test subject in need of a diagnostic inlage ari effective contrast producing amount of the above-described diagnostic image contrast composition.
In addition to human patients, the test subject can include mammalian species such as rabbits, dogs, cats, monkeys, sheep, pigs, horses, bovine animals and the like.
Thereafter, at least a portion of the body containing the -administered. contrast agent is exposed to x-rays or a magnetic field to produce an x-ray or magnetic resonance image pattern corresponding to the presence of the contrast agent. The image pattern can then be visualized.
In x-ray imaging, transmitted radiation is used to produce a radiograph based upon overall tissue attenuation characteristics. X-rays pass through various tissues and are attenuated by scattering, i.e., reflection or refraction or energy absorption. However, certain body organs, vessels and anatomical sites exhibit so little absorption of x-ray radiation that radiographs of these body portions are difficult to obtain. To overcome this problem, radiologists routinely introduce an x-ray absorbing medium containing a contrast agent into such body organs, vessels and anatomical sites.
Any x-ray visualization technique, preferably, a high contrast technique such as computed tomography, can be applied in a conventional manner. Alternatively, the image pattern can :be observed directly on an x-ray sensitive phosphor screen-silver halide photographic film combination.
Visualization with a magnetic resonance imaging system can be accomolished with commercially available magnetic imaging systems such as a General Electric 1.5 T Sigma imaging system [1H resonant frequency 63.9 megahertz (MHz)]. Commercia:Lly available magnetic resonance imaging systems are typically characterized by the magnetic field strength used, with a field strength of 2.0 Tesla as the current maxiinum anci 0.2 Tesla as the current minimum. For a given field strength, each detected nucleus has a characteristic frequency. For example, at a field strength of 1.0 Tesla, the resonance frequency for hydrogen is 42.57 MHz; for phosphorus-31 it is 17.24 MHz; and for sodium-23 it is 11.26 MHz.
A contrast effective amount of the compositions of the present invention is that amount necessary to provide tissue visua:Lization with, for example, magnetic resonance imaging or x--ray irnaging. Means for determining a contrast effective amount in a particular subject will depend, as is well known in the art, on the nature of the magnetically reactive material used, the mass of the subject being imaged, the sensitivity of the magnetic resonance or x-ray imaging system and the like.
After administration of the compositions of the present invention, the subject mammal is maintained for a time period sufficient for the administered compositions to be distributed throughout the subject and enter the tissues of the mamma.l. Typically, a sufficient time period is from about 20 minutes to about 90 minutes and, preferably from about 20 minutes to about 60 minutes.
The following examples further illustrate the invention and are not to be construed as limiting of the specification and claims in any way. Specific embodiments of the invention are illustrated in the following examples:
Example 1. Imaqing studies with Tyloxapol and ethyl 3,-5-diacetoamido-2 4f6-triiodobenzoate (WIN
$$$3).
A formulation of WIN 8883 was prepared using Tyloxapol as the stabi:lizer in the amounts of 20 grams (gm) of WIN
8883 per 100 ml of suspension and 3 gm of tyloxapol per 100 ml of suspension in phosphate buff'ered saline (PBS). The suspension was milled for 7 days after which the average particle size was determined by light scattering to be 185 nm. Stability testing in fresh rat plasma and simulated gastric fluici did riot show any aggregation. The formulation was serit for computer-aided tomography X-ray imaging studies at both the Center for Imaging and Pharmaceutical Research (CIPR) at the Massachusetts General Hospital and at Stanford University Medical School, Department of Radiology.
At CIPR, the 'Pyloxapol suspension provided excellent images of ax_Lllary and subscapular lymph nodes upon injection in the forepaws of male, white New Zealand rabbits (approximate weight = 2.5 k g) at times of 12 and 36 hours post: injection of 0.5 ml as a single bolus injection. At Stariford, the injection of 3 ml/kg afforded excellent imaging of the vasculature followed by -16- ~108192 opacification of both the liver and spleen at long times post injection (i.e., > 30 min.).
Example 2. Imaging studies with Tyloxapol and WIN
LUI..$L
A formulation of WIN 16318 was prepared as in Example 1 only using 10 gm of WIN 16318 per 100 ml formulation and 3.4 gm of Ty:Loxapol per 100 ml of formulation and milling for 14 days. At the end of this process, the particle size was determined by light scattering to be 289 nm. The formulation was sent to Stanford for imaging studies where IV injection resultted in prolonged blood pool opacification followed by concentration within the liver and spleen.
Example 3. Irnaging studies with Tyloxapol and WIN
$$$.
A formulation was prepared as in Example 1 using 10 gm of WIN 8883 per 100 ml formulation and 3 gm of Tyloxapol per 100 ml formulation. After milling for 7 days, the particle size was <ietermined to be 170 nm by light scattering. Imaging at CIPR demonstrated excellent imaging of axillary and subscapular lymph nodes at 12 hours post injection.
Example 4. Imaainq studies with Tyloxapol and WIN
772,1.
A formulation was prepared as in Example 1 only using 15 gm of WIN 67721 per 100 formulation and 4.0 gm of Tyloxapol per 100 rnl of formulation. After milling for 3 days, the particle size was determined to be 207 nm by light scattering. Imaging at CIPR demonstrated excellent axillary and subscapular lymph node opacification after injection of 0.5 m:L subcutaneously in the forepaw of the rabbits at 12 hours post injection.
Example 5. Imaging studies with Tyloxapol and WIN
772,2.
A formulation was prepared as in Example 4 only using WIN 67722. 'rhe suspension was milled for 3 days and achieved a particle size of 186 nm as determined by light scattering. Imaging at CIPR demonstrated excellent axillary and subscapular lymph node opacification after injection of 0.5 ml subcutaneously in the forepaw of the rabbit at times of 12 hr post injection.
Example 6.
During extensive screening studies involving over 40 poorly soluble compounds, it was found that tyloxapol stabilized a much ]higher percentage (about 80%) of compounds in the form of nanoparticles than all other surface modifiers itested.
Example 7. Tyloxapol Stabilized Retinoic Acid Nanoparticles Tyloxapol was shown to be a good stabilizer for the therapeutic compound retinoic acid. A nanoparticle formulation (7% retinoic acid, 3% tyloxapol) wet-milled according to the technique described in U.S. Patent 5,145,684 to a mean particle size of 130 nm exhibited a mean particle size of 145 nm seven months later.
The foregoing specification, including the specific embodiments and examples is intended to be illustrative of the present :invent_Lon and is not to be taken as limiting.
Numerous other variations and modifications can be effected without depa::ting from the true spirit and scope of the present invention.
STABILIZER AND DISPERSANT
FIELD OF THE INVENTION
The present invention is directed to nanoparticles containing a diagnostic or therapeutic agent and tyloxapol associated therewith.
BACKGROUND OF THE INVENTION
Nanoparticles, described in U.S. Patent No. 5,145,684, are particles consisting of a poorly soluble therapeutic or diagnostic aqent orito which are adsorbed a non-crosslinked surface modifier, and which have an average particle size of less than about 400 nanometers (nm).
Tyloxapol (4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde) is a nonionic liquid polymer of the alkyl aryl polyether alcohol type.
Tyloxapol, also known as "Superinone", is disclosed as useful as a nonionic surface active agent in a lung surfactant composition in U.S. Patent No. 4,826,821 and as a stabilizincl agent. for 2-dimethylaminoethyl 4-n-butylaminoberizoate in U.S. Patent No. 3,272,700.
The present irivention is directed to the use of tyloxapol in nanoparticle formulations. Tyloxapol may act as a stabilizer and/or a dispersant. Tyloxapol also functions as a surface modifier. Tyloxapol serves as an excellent wetting agent and affords enhanced blood pool residence via. reduced macrophage uptake.
SIJMMARY OF THE INVENTION
The present irivention is directed to a composition comprised of nanoparticles having tyloxapol adsorbed on the surface thereof. In a preferred embodiment, the nanoparticles are comprised of a diagnostic or therapeutic agent. In a further preferred embodiment, the nanoparticles comprise a further auxiliary surface modifier _ - 2 -associated therewith which can function to reduce particle agglomeration during sterilization.
This invention further discloses a method of making nanoparticles having tyloxapol adsorbed on the surface thereof, said method comprising contacting said nanoparticles, comprising an insoluble diagnostic or therapeutic substance, with tyloxapol for a time and under conditions sufficient to provide a corresponding nanoparticle-tyloxapol composition.
The present invention is also directed to a method of diagnosis comprising administering to a mammal a contrast effective amount of particles of nanoparticles having tyloxapol adsorbed on the surface thereof, and generating a diagnostic iinage of said mammal.
The present invention is further directed to a method of treatment comprising administering to a mammal a therapeutically effective amount of nanoparticles comprising a therapeutic agent having tyloxapol adsorbed on the surface thereof.
DETAILEI) DESCRIPTION OF THE INVENTION
This invention is described hereinafter primarily in conjunction with tyloxapol as a surface modifier for nanoparticles. However, it is believed that the invention can be practiced with other nonionic liquid polymers of the alkyl aryl polyether alcohol type.
The present invention is directed to a composition comprised of nanoparticles having tyloxapol adsorbed on the surface thereof.
In a preferred embodiment, the nanoparticles comprise a further sui-face modifier associated therewith. Surface modifiers useful herein physically adhere to the surface of the nanoparticle but do not chemically react with the nanoparticle or itself. Individually adsorbed molecules of the surface modifier are essentially free of intermolecular crosslinkages. Suitable surface modifiers can be selected from known organic and inorganic pharmaceutical excipients such as various polymers, low-molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
Representative examples of surface modifiers include gelatin, casein, lecithin (phosphatides), gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, e.g., macrogol ethers such as cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, e.g., the commercially available TweensTM, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethy:Lcellu:Lose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropy:Lcellu:Lose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, tr:iethanolamine, polyvinyl alcohol, and polyvinylpyrrolidone (PVP). Most of these surface modifiers are knowri pharmaceutical excipients and are described in detail in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and The Pharmaceutical Society of Great Britain, the Pharmaceutical Press, 1986.
Particularly preferred surface modifiers include polyvinylpyrrolidone, poloxamers such as Pluronic' F68 and F108, which Eire block copolymers of ethylene oxide and propylene ox_Lde, and poloxamines such as TetronicT"' 908 (also known as Poloxamine 908), which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide ancl ethylene oxide to ethylenediamine, available from BASF', dextran, lecithin, dialkylesters of sodium sulfosuccinic acid, such as Aerosol OTT"', which is a dioctyl ester of sodium sulfosuccinic acid, available from American Cyariamid, DuponolT"' P, which is a sodium lauryl sulfate, available from DuPont, TritonTM X-200, which is an alkyl aryl polyether sulfonate, available from Rohm and Haas, Tween 80, which is a polyoxyethylene sorbitan fatty acid ester, available from ICI Specialty Chemicals, and CarbowaxTM 3350 and 934, which are polyethylene glycols available from Union Carbide. Surface modifiers which have been found to be particularly useful include Tetronic 908, the TweensTM, Pluronic F-68 and polyvinylpyrrolidone. Other useful surface modifiers include:
decanoyl-N-m.ethylglucamide;
n-decyl B-D-glucopyranoside;
n-decyl B-D-maltopyranoside;
n-dodecyl B-D-glucopyranoside;
n-dodecyl l3-D-maltoside;
heptanoyl-N-methylglucamide n-heptyl B-D-glucopyranoside;
n-heptyl I3-D-thioglucoside;
n-hexyl B-D-glucopyranoside;
nonanoyl-N-methylglucamide;
n-nonyl B-D-glucopyranoside;
octanoyl-N-methylglucamide;
n-octyl B-D-glucopyranoside;
octyl B-D-thioglucopyranoside;
and the like.
Particularly preferred auxiliary surface modifiers are those which impart resistance to particle aggregation during sterilization and include dioctylsulfosuccinate (DOSS), polyethylene glycol, glycerol, sodium dodecyl sulfate, dodecyl t:rimethyl ammonium bromide and a charged phospholipid such ,3s dimyristoyl phophatidyl glycerol. 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 tyloxapol that is associated with the nanoparticles may function as a surface modifier, as a stabilizer, isnd/or as a dispersant. Alternatively, the tyloxapol may serve other purposes. In one embodiment of the present invention, tyloxapol serves all three functions. In another embodiment, the tyloxapol may serve as a stabilizer and/or a dispersant, whereas another compound acts as a surface modifier, as discussed elsewhere herein.
_ 5 _ The nanoparticles of the present invention contain a diagnostic or therapeutic agent. 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.
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 particle 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 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 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 *Trade-mark media, such as staiLnless 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 mil:ls, 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 usinci a hicjh shear media mill.
The particles must be reduced in size at a temperature which does not sigriificantly degrade the therapeutic or diagnostic aqent. Processing temperatures of less than about 30-40 C are ordinarily preferred. If desired, the processing equipmerit can be cooled with conventional cooling equipment. The method is conveniently carried out under condit:_ons of ambient temperature and at processing pressures whJ_ch are safe and effective for the milling process. Foi- 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 addeci to the dispersion after attrition in an amount as described for the premix. Thereafter, the dispersion can be nlixed, 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 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 bEilance (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 United States Patent No. 5,145,684, and EP-A 498,482. In addition, those diagnostic agents disclosed in copending Canadian Patent Application Ser. No. 2,106,413 may also be used. Preferred diagnostic agents include ethyl 3,5-diacetoamido-2,4,6-triiodobenzoate (WIN 8883), ethyl 2-[3,5-bis(acetamido)-2,4,6-triiodobenzoyloxy]butyrate (WIN 16318), diethyl 2-[3,5-bis(acetamido)-2,4,6-triiodobenzoyloxy]malonate (WIN 67721), and 6-ethoxy-6-oxohexyl 3,5-bis(acetamido)-2,4,6-triiodobenzoate (WIN 67722 disclosed in the above-mentioned Canadian Patent Application). A particularly preferred diagnostic agent is the x-ray imaging agent WIN 8883. A particular preferred therapeutic agent is retinoic acid.
As used herein, particle size refers to a number average particle size as measured by conventional particle size measuring techniques well known to those skilled in the art, such as sedimentation field flow fractionation, photo correlation spectroscopy, or disk centrifugation. By "an effective average particle size of less than about 400 nm"
it is meant that at least 90% of the particles have a weight average particle size of less than about 400 nm when measured by the above-noted techniques. In preferred embodiments of the invention, the effective average 3a 26299-73 particle size is less than about 300 nm, and more preferably less than about 250 nm, In some embodiments of the invention, an effective average particle size of less than about 200 nm has been achieved. With reference to the effective average 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 embodiments, assentially all of the particles have a size less than 250 nm. The lower limit is riot critical, but practically it is in general about 1 nm.
The present invention includes the nanoparticle composition with tyloxapol associated on the surface thereof, as described elsewhere herein, formulated into compositions together with one or more non-toxic physiologica:Lly acceptable carriers, adjuvants or vehicles which are collectively referred to herein as carriers, for parenteral injection, for oral administration in solid or liquid form, for rectal or topical administration, or the like.
The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenous, intramusculai- or subcutaneous), intracisternally, intravaginal:Ly, intraperitoneally, locally (powders, ointments or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutioris, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaque:ous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneqlycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wettincl, emulsifying, and dispensing agents.
Prevention of' the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It: may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like.
Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, f'or example, aluminum monostearate and gelatin.
~
-Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as 5 sodium citrate or ciicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, maniiitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, 10 as for examp:Le, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic ac:Ld, certain complex silicates and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcoho:L and qlycerol monostearate, (h) adsorbents, as for example, kaoliri and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as :=illers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes.
The active coinpounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, t:he liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetatia, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,,3-butyleneglycol, dimethylformamide, oils, in par=:icular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, aqar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the preserit invention with suitable non-irritating excipients oi- carriers such as cocoa butter, polyethyleneqlycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this inverition include ointments, powders, sprays and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers or propellants as may be required. Ophthalmic formulations, eye ointments, powders _ 12 _ and solutions are also contemplated as being within the scope of this invention.
Actual dosage levels of active ingredients in the compositions of the present invention may be varied so as to obtain an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dosage level therefore depends upon the desired therapeutic effect, on the route of administration, on the desired duration of treatment and other factors.
The total daily dose of the compounds of this invention administered to a host in single of divided dose may be in amounts, for example, of from about 1 nanomol to about 5 micromoles per kilogram of body weight. Dosage unit compositions may contain such amounts of such submultiples thereof as may be used to make up the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination with other drugs and the severity of the particular disease being treated.
A method for the preparation of a nanoparticle composition according to this invention includes the steps of introducing a t]nerapeutic 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 therapo=_utic or diagnostic agent to less than about 400 nm; and separating the particles and optionally the liquid miedium 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 iaith the particles thereafter. The liquid mediuin, most often water, can serve as the pharmaceutically acceptable carrier. The method preferably is carried out under aseptic conditions. Thereafter, the nanoparticle composition preferably is subjected to a sterilization process.
This invention further discloses a method of making nanoparticles having tyloxapol adsorbed on the surface thereof, said method comprising contacting said nanoparticles with tyloxapol for a time and under conditions sufficient to provide a nanoparticle-tyloxapol composition.
This method involves the preparation of therapeutic or diagnostic nanoparticles, as discussed elsewhere herein, and contacting those nanoparticles with tyloxapol.
Contacting may be by admixing a suspension of nanoparticles with a solut.ion of tyloxapol for a time period and under conditions suitable for the formation of a nanoparticle-tyloxapol composition.
The concentration of tyloxapol 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 tyloxapol. The time of contacting may be from 60 seconds to about 48 hours.
In a preferred embodiment, the method comprises the further addition of other surface modifiers associated with the nanopart.icles. The method is practiced according to the techniques described elsewhere herein.
The present invention is also directed to a method of diagnosis cornprisirig administering to a mammal a contrast effective amount of particles of nanoparticles having tyloxapol adsorbed on the surface thereof, and generating a diagnostic ir:iage of' said mammal. In a preferred embodiment, t:he narioparticles comprise a further surface modifier associated therewith.
A method for ciiagnostic imaging for use in medical procedures iri accordance with this invention comprises administerinq to the body of a test subject in need of a diagnostic inlage ari effective contrast producing amount of the above-described diagnostic image contrast composition.
In addition to human patients, the test subject can include mammalian species such as rabbits, dogs, cats, monkeys, sheep, pigs, horses, bovine animals and the like.
Thereafter, at least a portion of the body containing the -administered. contrast agent is exposed to x-rays or a magnetic field to produce an x-ray or magnetic resonance image pattern corresponding to the presence of the contrast agent. The image pattern can then be visualized.
In x-ray imaging, transmitted radiation is used to produce a radiograph based upon overall tissue attenuation characteristics. X-rays pass through various tissues and are attenuated by scattering, i.e., reflection or refraction or energy absorption. However, certain body organs, vessels and anatomical sites exhibit so little absorption of x-ray radiation that radiographs of these body portions are difficult to obtain. To overcome this problem, radiologists routinely introduce an x-ray absorbing medium containing a contrast agent into such body organs, vessels and anatomical sites.
Any x-ray visualization technique, preferably, a high contrast technique such as computed tomography, can be applied in a conventional manner. Alternatively, the image pattern can :be observed directly on an x-ray sensitive phosphor screen-silver halide photographic film combination.
Visualization with a magnetic resonance imaging system can be accomolished with commercially available magnetic imaging systems such as a General Electric 1.5 T Sigma imaging system [1H resonant frequency 63.9 megahertz (MHz)]. Commercia:Lly available magnetic resonance imaging systems are typically characterized by the magnetic field strength used, with a field strength of 2.0 Tesla as the current maxiinum anci 0.2 Tesla as the current minimum. For a given field strength, each detected nucleus has a characteristic frequency. For example, at a field strength of 1.0 Tesla, the resonance frequency for hydrogen is 42.57 MHz; for phosphorus-31 it is 17.24 MHz; and for sodium-23 it is 11.26 MHz.
A contrast effective amount of the compositions of the present invention is that amount necessary to provide tissue visua:Lization with, for example, magnetic resonance imaging or x--ray irnaging. Means for determining a contrast effective amount in a particular subject will depend, as is well known in the art, on the nature of the magnetically reactive material used, the mass of the subject being imaged, the sensitivity of the magnetic resonance or x-ray imaging system and the like.
After administration of the compositions of the present invention, the subject mammal is maintained for a time period sufficient for the administered compositions to be distributed throughout the subject and enter the tissues of the mamma.l. Typically, a sufficient time period is from about 20 minutes to about 90 minutes and, preferably from about 20 minutes to about 60 minutes.
The following examples further illustrate the invention and are not to be construed as limiting of the specification and claims in any way. Specific embodiments of the invention are illustrated in the following examples:
Example 1. Imaqing studies with Tyloxapol and ethyl 3,-5-diacetoamido-2 4f6-triiodobenzoate (WIN
$$$3).
A formulation of WIN 8883 was prepared using Tyloxapol as the stabi:lizer in the amounts of 20 grams (gm) of WIN
8883 per 100 ml of suspension and 3 gm of tyloxapol per 100 ml of suspension in phosphate buff'ered saline (PBS). The suspension was milled for 7 days after which the average particle size was determined by light scattering to be 185 nm. Stability testing in fresh rat plasma and simulated gastric fluici did riot show any aggregation. The formulation was serit for computer-aided tomography X-ray imaging studies at both the Center for Imaging and Pharmaceutical Research (CIPR) at the Massachusetts General Hospital and at Stanford University Medical School, Department of Radiology.
At CIPR, the 'Pyloxapol suspension provided excellent images of ax_Lllary and subscapular lymph nodes upon injection in the forepaws of male, white New Zealand rabbits (approximate weight = 2.5 k g) at times of 12 and 36 hours post: injection of 0.5 ml as a single bolus injection. At Stariford, the injection of 3 ml/kg afforded excellent imaging of the vasculature followed by -16- ~108192 opacification of both the liver and spleen at long times post injection (i.e., > 30 min.).
Example 2. Imaging studies with Tyloxapol and WIN
LUI..$L
A formulation of WIN 16318 was prepared as in Example 1 only using 10 gm of WIN 16318 per 100 ml formulation and 3.4 gm of Ty:Loxapol per 100 ml of formulation and milling for 14 days. At the end of this process, the particle size was determined by light scattering to be 289 nm. The formulation was sent to Stanford for imaging studies where IV injection resultted in prolonged blood pool opacification followed by concentration within the liver and spleen.
Example 3. Irnaging studies with Tyloxapol and WIN
$$$.
A formulation was prepared as in Example 1 using 10 gm of WIN 8883 per 100 ml formulation and 3 gm of Tyloxapol per 100 ml formulation. After milling for 7 days, the particle size was <ietermined to be 170 nm by light scattering. Imaging at CIPR demonstrated excellent imaging of axillary and subscapular lymph nodes at 12 hours post injection.
Example 4. Imaainq studies with Tyloxapol and WIN
772,1.
A formulation was prepared as in Example 1 only using 15 gm of WIN 67721 per 100 formulation and 4.0 gm of Tyloxapol per 100 rnl of formulation. After milling for 3 days, the particle size was determined to be 207 nm by light scattering. Imaging at CIPR demonstrated excellent axillary and subscapular lymph node opacification after injection of 0.5 m:L subcutaneously in the forepaw of the rabbits at 12 hours post injection.
Example 5. Imaging studies with Tyloxapol and WIN
772,2.
A formulation was prepared as in Example 4 only using WIN 67722. 'rhe suspension was milled for 3 days and achieved a particle size of 186 nm as determined by light scattering. Imaging at CIPR demonstrated excellent axillary and subscapular lymph node opacification after injection of 0.5 ml subcutaneously in the forepaw of the rabbit at times of 12 hr post injection.
Example 6.
During extensive screening studies involving over 40 poorly soluble compounds, it was found that tyloxapol stabilized a much ]higher percentage (about 80%) of compounds in the form of nanoparticles than all other surface modifiers itested.
Example 7. Tyloxapol Stabilized Retinoic Acid Nanoparticles Tyloxapol was shown to be a good stabilizer for the therapeutic compound retinoic acid. A nanoparticle formulation (7% retinoic acid, 3% tyloxapol) wet-milled according to the technique described in U.S. Patent 5,145,684 to a mean particle size of 130 nm exhibited a mean particle size of 145 nm seven months later.
The foregoing specification, including the specific embodiments and examples is intended to be illustrative of the present :invent_Lon and is not to be taken as limiting.
Numerous other variations and modifications can be effected without depa::ting from the true spirit and scope of the present invention.
Claims (37)
1. A nanoparticle composition for ocular administration, comprising:
(a) nanoparticles of retinoic acid; and (b) tyloxapol as a surface modifier for the retinoic acid, wherein tyloxapol is present at about 0.1% to about 90%, by weight, based on the total combined weight of retinoic acid and tyloxapol, wherein the nanoparticles of retinoic acid have an effective average particle size of less than about 400 nm.
(a) nanoparticles of retinoic acid; and (b) tyloxapol as a surface modifier for the retinoic acid, wherein tyloxapol is present at about 0.1% to about 90%, by weight, based on the total combined weight of retinoic acid and tyloxapol, wherein the nanoparticles of retinoic acid have an effective average particle size of less than about 400 nm.
2. The composition of claim 1, wherein the effective average particle size of the retinoic acid nanoparticles is less than about 300 nm.
3. The composition of claim 1, wherein the effective average particle size of the retinoic acid nanoparticles is less than about 250 nm.
4. The composition of claim 1, wherein the effective average particle size of the retinoic acid nanoparticles is less than about 200 nm.
5. The composition of any one of claims 1-4, wherein at least 90% of the retinoic acid nanoparticles have a particle size which is less than the effective average particle size.
6. The composition of any one of claims 1-4, wherein at least 95% of the retinoic acid nanoparticles have a particle size which is less than the effective average particle size.
7. The composition of any one of claims 1-4, wherein at least 99% of the retinoic acid nanoparticles have a particle size which is less than the effective average particle size.
8. The composition of any one of claims 1-7, wherein tyloxapol is present at about 1.0% to about 75%, by weight, based on the total combined weight of retinoic acid and tyloxapol.
9. The composition of any one of claims 1-8, wherein tyloxapol is present at about 10% to about 60%, by weight, based on the total weight of retinoic acid and tyloxapol.
10. The composition of any one of claims 1-9, wherein tyloxapol is present at about 10% to about 30%, by weight, based on the total weight of retinoic acid and tyloxapol.
11. The composition of any one of claims 1-7, wherein retinoic acid is present at about 0.1 to about 60%, by weight, based on the total weight of retinoic acid and tyloxapol.
12. The composition of any one of claims 1-7 or 11, wherein retinoic acid is present at about 5 to about 30%, by weight, based on the total weight of retinoic acid and tyloxapol.
13. The composition of any one of claims 1-12, further comprising at least one additional surface modifier which is not tyloxapol.
14. The composition of claim 13, wherein the additional surface modifier is selected from the group consisting of nonionic and anionic surfactants.
15. The composition of claim 13, wherein the additional surface modifier is selected from the group consisting of gelatin, casein, lecithin, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone (PVP), poloxamers, poloxamines, dextran, sodium lauryl sulfate, glycerol, dioctylsulfosuccinate (DOSS), charged phospholipids, dodecyl trimethyl ammonium bromide, dialkylesters of sodium sulfosuccinic acid, an alkyl aryl polyether sulfonate, decanoyl-N-methylglucamide, n-decyl .beta.-D-glucopyranoside, n-decyl .beta.-D-maltopyranoside, n-dodecyl .beta.-D-glucopyranoside, n-dodecyl .beta.-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl .beta.-D-glucopyranoside, n-heptyl .beta.-D-thioglucoside, n-hexyl .beta.-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl .beta.-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl .beta.-D-glucopyranoside, and octyl .beta.-D-thioglucopyranoside.
16. The composition of claim 15, wherein the additional surface modifier is selected from the group consisting of block copolymers of ethylene oxide and propylene oxide, tetrafunctional block copolymers derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, dimyristoyl phosphatidyl glycerol.
17. The composition of any one of claims 1-16, which comprises at least one additional surface modifier selected from the group consisting of dioctylsulfosuccinate (DOSS), polyethylene glycol, glycerol, sodium dodecyl sulfate, dodecyl trimethyl ammonium bromide, and dimyristoyl phosphatidyl glycerol.
18. The composition of any one of claims 1 to 17, which is an eye ointment, eye powder, or eye solution.
19. A method of making a nanoparticulate composition for ocular administration, wherein the nanoparticulate composition comprises:
(a) nanoparticles of retinoic acid; and (b) tyloxapol as a surface modifier for the retinoic acid, wherein tyloxapol is present at about 0.1% to about 90%, by weight, based on the total combined weight of retinoic acid and tyloxapol;
wherein the nanoparticles of retinoic acid have an effective average particle size of less than about 400 nm, and wherein the method comprises:
contacting the retinoic acid with tyloxapol to provide a nanoparticulate retinoic acid-tyloxapol composition.
(a) nanoparticles of retinoic acid; and (b) tyloxapol as a surface modifier for the retinoic acid, wherein tyloxapol is present at about 0.1% to about 90%, by weight, based on the total combined weight of retinoic acid and tyloxapol;
wherein the nanoparticles of retinoic acid have an effective average particle size of less than about 400 nm, and wherein the method comprises:
contacting the retinoic acid with tyloxapol to provide a nanoparticulate retinoic acid-tyloxapol composition.
20. The method of claim 19, wherein the effective average particle size of the retinoic acid nanoparticles is less than about 300 nm.
21. The method of claim 19, wherein the effective average particle size of the retinoic acid nanoparticles is less than about 250 nm.
22. The method of claim 19, wherein the effective average particle size of the retinoic acid nanoparticles is less than about 200 nm.
23. The method of any one of claims 19-22, wherein at least 90% of the retinoic acid particles have a particle size which is less than the effective average particle size.
24. The method of any one of claims 19-22, wherein at least 95% of the retinoic acid particles have a particle size which is less than the effective average particle size.
25. The method of any one of claims 19-22, wherein at least 99% of the retinoic acid particles have a particle size which is less than the effective average particle size.
26. The method of any one of claims 19-25, wherein tyloxapol is present at about 1.0% to about 75%, by weight, based on the total combined weight of retinoic acid and tyloxapol.
27. The method of any one of claims 19-25, wherein tyloxapol is present at about 10% to about 60%, by weight, based on the total weight of retinoic acid and tyloxapol.
28. The method of any one of claims 19-25, wherein tyloxapol is present at about 10% to about 30%, by weight, based on the total weight of retinoic acid and tyloxapol.
29. The method of any one of claims 19-25, wherein retinoic acid is present at about 0.1 to about 60%, by weight, based on the total weight of retinoic acid and tyloxapol.
30. The method of any one of claims 19-25, wherein retinoic acid is present at about 5 to about 30%, by weight, based on the total weight of retinoic acid and tyloxapol.
31. The method of any one of claims 19-30, wherein at least one additional surface modifier is employed other than tyloxapol.
32. The method of claim 31, wherein the additional surface modifier is selected from the group consisting of nonionic and anionic surfactants.
33. The method of claim 31, wherein in the additional surface modifier is selected from the group consisting of gelatin, casein, lecithin, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone (PVP), poloxamers, poloxamines, dextran, sodium lauryl sulfate, glycerol, dioctylsulfosuccinate (DOSS), charged phospholipids, dodecyl trimethyl ammonium bromide, dialkylesters of sodium sulfosuccinic acid, an alkyl aryl polyether sulfonate, decanoyl-N-methylglucamide, n-decyl .beta.-D-glucopyranoside, n-decyl .beta.-D-maltopyranoside, n-dodecyl .beta.-D-glucopyranoside, n-dodecyl .beta.-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl .beta.-D-glucopyranoside, n-heptyl .beta.-D-thioglucoside, n-hexyl .beta.-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl .beta.-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl .beta.-D-glucopyranoside, and octyl .beta.-D-thioglucopyranoside.
34. The method of claim 31, wherein the additional surface modifier is selected from the group consisting of block copolymers of ethylene oxide and propylene oxide, tetrafunctional block copolymers derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, dimyristoyl phosphatidyl glycerol.
35. The method of claim 31, wherein the additional surface modifier is selected from the group consisting of dioctylsulfosuccinate (DOSS), polyethylene glycol, glycerol, sodium dodecyl sulfate, dodecyl trimethyl ammonium bromide, and dimyristoyl phosphatidyl glycerol.
36. A therapeutic nanoparticle composition for ocular administration, which is a suspension comprising:
(a) nanoparticles of retinoic acid having an effective average particle size of 1 to 400 nm, (b) tyloxapol as a surface modifier, and (c) a non-toxic physiologically acceptable aqueous liquid medium in which the retinoic acid is poorly soluble, wherein tyloxapol is present in an amount of 10 to 60% by weight based on the total combined weight of the retinoic acid nanoparticles and tyloxapol and the retinoic acid nanoparticles are present in an amount of 0.1 to 60% by weight based on the therapeutic nanoparticle composition.
(a) nanoparticles of retinoic acid having an effective average particle size of 1 to 400 nm, (b) tyloxapol as a surface modifier, and (c) a non-toxic physiologically acceptable aqueous liquid medium in which the retinoic acid is poorly soluble, wherein tyloxapol is present in an amount of 10 to 60% by weight based on the total combined weight of the retinoic acid nanoparticles and tyloxapol and the retinoic acid nanoparticles are present in an amount of 0.1 to 60% by weight based on the therapeutic nanoparticle composition.
37. The composition of claim 36, wherein the retinoic acid nanoparticles are contained in an amount of 5 to 30% by weight based on the composition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US07/990,874 US5429824A (en) | 1992-12-15 | 1992-12-15 | Use of tyloxapole as a nanoparticle stabilizer and dispersant |
| US990,874 | 1992-12-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2108192A1 CA2108192A1 (en) | 1994-06-16 |
| CA2108192C true CA2108192C (en) | 2007-07-03 |
Family
ID=25536608
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002108192A Expired - Fee Related CA2108192C (en) | 1992-12-15 | 1993-10-12 | Use of tyloxapol as a nanoparticle stabilizer and dispersant |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US5429824A (en) |
| EP (1) | EP0602702B1 (en) |
| JP (3) | JPH06199658A (en) |
| KR (1) | KR100320390B1 (en) |
| AT (1) | ATE178788T1 (en) |
| AU (1) | AU665669B2 (en) |
| CA (1) | CA2108192C (en) |
| CZ (1) | CZ274793A3 (en) |
| DE (1) | DE69324456T2 (en) |
| DK (1) | DK0602702T3 (en) |
| ES (1) | ES2130217T3 (en) |
| FI (1) | FI935395A (en) |
| GR (1) | GR3030059T3 (en) |
| HU (1) | HU219333B (en) |
| IL (1) | IL107874A (en) |
| MX (1) | MX9306010A (en) |
| MY (1) | MY110186A (en) |
| NO (1) | NO310543B1 (en) |
| NZ (1) | NZ248726A (en) |
| PH (1) | PH29957A (en) |
| RU (1) | RU2124886C1 (en) |
| SK (1) | SK280614B6 (en) |
| TW (1) | TW440451B (en) |
| UA (1) | UA27760C2 (en) |
Families Citing this family (190)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5346702A (en) * | 1992-12-04 | 1994-09-13 | Sterling Winthrop Inc. | Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization |
| US5298262A (en) * | 1992-12-04 | 1994-03-29 | Sterling Winthrop Inc. | Use of ionic cloud point modifiers to prevent particle aggregation during sterilization |
| US5336507A (en) * | 1992-12-11 | 1994-08-09 | Sterling Winthrop Inc. | Use of charged phospholipids to reduce nanoparticle aggregation |
| US5981719A (en) | 1993-03-09 | 1999-11-09 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
| US6090925A (en) | 1993-03-09 | 2000-07-18 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
| US5503723A (en) * | 1995-02-08 | 1996-04-02 | Eastman Kodak Company | Isolation of ultra small particles |
| US5500204A (en) * | 1995-02-10 | 1996-03-19 | Eastman Kodak Company | Nanoparticulate diagnostic dimers as x-ray contrast agents for blood pool and lymphatic system imaging |
| AU4990696A (en) * | 1995-02-24 | 1996-09-11 | Nanosystems L.L.C. | Aerosols containing nanoparticle dispersions |
| US5747001A (en) * | 1995-02-24 | 1998-05-05 | Nanosystems, L.L.C. | Aerosols containing beclomethazone nanoparticle dispersions |
| US5766629A (en) | 1995-08-25 | 1998-06-16 | Sangstat Medical Corporation | Oral cyclosporin formulations |
| US5834025A (en) * | 1995-09-29 | 1998-11-10 | Nanosystems L.L.C. | Reduction of intravenously administered nanoparticulate-formulation-induced adverse physiological reactions |
| US20050267302A1 (en) * | 1995-12-11 | 2005-12-01 | G.D. Searle & Co. | Eplerenone crystalline form exhibiting enhanced dissolution rate |
| US5976573A (en) * | 1996-07-03 | 1999-11-02 | Rorer Pharmaceutical Products Inc. | Aqueous-based pharmaceutical composition |
| US6071904A (en) * | 1996-12-11 | 2000-06-06 | Alcon Laboratories, Inc. | Process for manufacturing ophthalmic suspensions |
| WO1998035666A1 (en) * | 1997-02-13 | 1998-08-20 | Nanosystems Llc | Formulations of nanoparticle naproxen tablets |
| US6045829A (en) * | 1997-02-13 | 2000-04-04 | Elan Pharma International Limited | Nanocrystalline formulations of human immunodeficiency virus (HIV) protease inhibitors using cellulosic surface stabilizers |
| US20050004049A1 (en) * | 1997-03-11 | 2005-01-06 | Elan Pharma International Limited | Novel griseofulvin compositions |
| AU7133898A (en) * | 1997-04-18 | 1998-11-13 | Vertex Pharmaceuticals Incorporated | Nanosized aspartyl protease inhibitors |
| WO1998048847A1 (en) * | 1997-04-25 | 1998-11-05 | Nycomed Imaging As | Nanoparticle composition containing iodinated x-ray contrast agent as stabilizer for thermal sterilization |
| 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 |
| US6207392B1 (en) * | 1997-11-25 | 2001-03-27 | The Regents Of The University Of California | Semiconductor nanocrystal probes for biological applications and process for making and using such probes |
| US7816403B2 (en) | 1998-09-08 | 2010-10-19 | University Of Utah Research Foundation | Method of inhibiting ATF/CREB and cancer cell growth and pharmaceutical compositions for same |
| US20040013613A1 (en) * | 2001-05-18 | 2004-01-22 | Jain Rajeev A | Rapidly disintegrating solid oral dosage form |
| US8293277B2 (en) | 1998-10-01 | 2012-10-23 | Alkermes Pharma Ireland Limited | Controlled-release nanoparticulate compositions |
| US8236352B2 (en) * | 1998-10-01 | 2012-08-07 | Alkermes Pharma Ireland Limited | Glipizide compositions |
| US20080213378A1 (en) * | 1998-10-01 | 2008-09-04 | Elan Pharma International, Ltd. | Nanoparticulate statin formulations and novel statin combinations |
| US20070160675A1 (en) * | 1998-11-02 | 2007-07-12 | Elan Corporation, Plc | Nanoparticulate and controlled release compositions comprising a cephalosporin |
| NZ511442A (en) * | 1998-11-02 | 2003-02-28 | Elan Corp Plc | Multiparticulate modified release composition for multiple dosing of ADD patients with methylphenidate HCl |
| US20090297602A1 (en) * | 1998-11-02 | 2009-12-03 | Devane John G | Modified Release Loxoprofen Compositions |
| US6428814B1 (en) * | 1999-10-08 | 2002-08-06 | Elan Pharma International Ltd. | Bioadhesive nanoparticulate compositions having cationic surface stabilizers |
| US20040141925A1 (en) * | 1998-11-12 | 2004-07-22 | Elan Pharma International Ltd. | Novel triamcinolone compositions |
| US7521068B2 (en) | 1998-11-12 | 2009-04-21 | Elan Pharma International Ltd. | Dry powder aerosols of nanoparticulate drugs |
| US6375986B1 (en) | 2000-09-21 | 2002-04-23 | Elan Pharma International Ltd. | Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate |
| US6969529B2 (en) | 2000-09-21 | 2005-11-29 | Elan Pharma International Ltd. | Nanoparticulate compositions comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface stabilizers |
| US20040115134A1 (en) * | 1999-06-22 | 2004-06-17 | Elan Pharma International Ltd. | Novel nifedipine compositions |
| US6656504B1 (en) | 1999-09-09 | 2003-12-02 | Elan Pharma International Ltd. | Nanoparticulate compositions comprising amorphous cyclosporine and methods of making and using such compositions |
| PT1175214E (en) * | 1999-12-08 | 2005-04-29 | Pharmacia Corp | COMPOSITIONS OF CYCLE-OXYGENASE-2 INHIBITOR WITH A QUICK START OF ITS THERAPEUTIC EFFECT |
| UA74539C2 (en) | 1999-12-08 | 2006-01-16 | Pharmacia Corp | Crystalline polymorphous forms of celecoxib (variants), a method for the preparation thereof (variants), a pharmaceutical composition (variants) |
| HUP0201457A3 (en) * | 1999-12-08 | 2003-07-28 | Pharmacia Corp Chicago | Eplerenone crystalline form, pharmaceutical compositions containing them and their preparations |
| US20030083493A1 (en) * | 1999-12-08 | 2003-05-01 | Barton Kathleen P. | Eplerenone drug substance having high phase purity |
| US6316029B1 (en) | 2000-05-18 | 2001-11-13 | Flak Pharma International, Ltd. | Rapidly disintegrating solid oral dosage form |
| US6495164B1 (en) * | 2000-05-25 | 2002-12-17 | Alkermes Controlled Therapeutics, Inc. I | Preparation of injectable suspensions having improved injectability |
| MY120279A (en) | 2000-05-26 | 2005-09-30 | Pharmacia Corp | Use of a celecoxib composition for fast pain relief |
| PE20020146A1 (en) * | 2000-07-13 | 2002-03-31 | Upjohn Co | OPHTHALMIC FORMULATION INCLUDING A CYCLOOXYGENASE-2 (COX-2) INHIBITOR |
| US7998507B2 (en) * | 2000-09-21 | 2011-08-16 | Elan Pharma International Ltd. | Nanoparticulate compositions of mitogen-activated protein (MAP) kinase inhibitors |
| US20080241070A1 (en) * | 2000-09-21 | 2008-10-02 | Elan Pharma International Ltd. | Fenofibrate dosage forms |
| US20030224058A1 (en) * | 2002-05-24 | 2003-12-04 | Elan Pharma International, Ltd. | Nanoparticulate fibrate formulations |
| US7276249B2 (en) * | 2002-05-24 | 2007-10-02 | Elan Pharma International, Ltd. | Nanoparticulate fibrate formulations |
| US7198795B2 (en) | 2000-09-21 | 2007-04-03 | Elan Pharma International Ltd. | In vitro methods for evaluating the in vivo effectiveness of dosage forms of microparticulate of nanoparticulate active agent compositions |
| WO2002045691A2 (en) * | 2000-12-06 | 2002-06-13 | Pharmacia Corporation | Laboratory scale milling process |
| UA80393C2 (en) * | 2000-12-07 | 2007-09-25 | Алтана Фарма Аг | Pharmaceutical preparation comprising an pde inhibitor dispersed on a matrix |
| US9700866B2 (en) * | 2000-12-22 | 2017-07-11 | Baxter International Inc. | Surfactant systems for delivery of organic compounds |
| US7193084B2 (en) | 2000-12-22 | 2007-03-20 | Baxter International Inc. | Polymorphic form of itraconazole |
| US20030072807A1 (en) * | 2000-12-22 | 2003-04-17 | Wong Joseph Chung-Tak | Solid particulate antifungal compositions for pharmaceutical use |
| US6884436B2 (en) * | 2000-12-22 | 2005-04-26 | Baxter International Inc. | Method for preparing submicron particle suspensions |
| US6977085B2 (en) * | 2000-12-22 | 2005-12-20 | Baxter International Inc. | Method for preparing submicron suspensions with polymorph control |
| US20050048126A1 (en) * | 2000-12-22 | 2005-03-03 | Barrett Rabinow | Formulation to render an antimicrobial drug potent against organisms normally considered to be resistant to the drug |
| US6607784B2 (en) * | 2000-12-22 | 2003-08-19 | Baxter International Inc. | Microprecipitation method for preparing submicron suspensions |
| US6951656B2 (en) * | 2000-12-22 | 2005-10-04 | Baxter International Inc. | Microprecipitation method for preparing submicron suspensions |
| US20030096013A1 (en) * | 2000-12-22 | 2003-05-22 | Jane Werling | Preparation of submicron sized particles with polymorph control |
| US20040256749A1 (en) * | 2000-12-22 | 2004-12-23 | Mahesh Chaubal | Process for production of essentially solvent-free small particles |
| US8067032B2 (en) * | 2000-12-22 | 2011-11-29 | Baxter International Inc. | Method for preparing submicron particles of antineoplastic agents |
| US20040022862A1 (en) * | 2000-12-22 | 2004-02-05 | Kipp James E. | Method for preparing small particles |
| US6976647B2 (en) * | 2001-06-05 | 2005-12-20 | Elan Pharma International, Limited | System and method for milling materials |
| US20030087308A1 (en) * | 2001-06-22 | 2003-05-08 | Elan Pharma International Limited | Method for high through put screening using a small scale mill or microfluidics |
| US7758890B2 (en) | 2001-06-23 | 2010-07-20 | Lyotropic Therapeutics, Inc. | Treatment using dantrolene |
| US20030054042A1 (en) * | 2001-09-14 | 2003-03-20 | Elaine Liversidge | Stabilization of chemical compounds using nanoparticulate formulations |
| PT1429731E (en) * | 2001-09-19 | 2007-04-30 | Elan Pharma Int Ltd | Nanoparticulate insulin formulations |
| BR0212822A (en) * | 2001-09-25 | 2005-08-30 | Pharmacia Corp | N- (2-Hydroxyacetyl) -5- (4-piperyl) -4- (4-pyrimidinyl) -3- (4-chlorophenyl) pyrazole crystalline forms and pharmaceutical compositions containing them |
| US20060003012A9 (en) * | 2001-09-26 | 2006-01-05 | Sean Brynjelsen | Preparation of submicron solid particle suspensions by sonication of multiphase systems |
| EP1429749A2 (en) | 2001-09-26 | 2004-06-23 | Baxter International Inc. | Preparation of submicron sized nanoparticles via dispersion and solvent or liquid phase removal |
| DK1443912T3 (en) * | 2001-10-12 | 2008-01-21 | Elan Pharma Int Ltd | Compositions with a combination of immediate and controlled release properties |
| US7112340B2 (en) * | 2001-10-19 | 2006-09-26 | Baxter International Inc. | Compositions of and method for preparing stable particles in a frozen aqueous matrix |
| WO2003039601A1 (en) * | 2001-11-07 | 2003-05-15 | Imcor Pharmaceutical Company | Methods for vascular imaging using nanoparticulate contrast agents |
| EA200400782A1 (en) * | 2001-12-06 | 2005-08-25 | Рэнбакси Лабораториз Лимитед | COMPOSITION OF ISOTRETINOININ WITH CRUSHING COMPONENTS UNDER THE DEGREE OF NANOPARTICLES |
| US20030129242A1 (en) * | 2002-01-04 | 2003-07-10 | Bosch H. William | Sterile filtered nanoparticulate formulations of budesonide and beclomethasone having tyloxapol as a surface stabilizer |
| US20040101566A1 (en) * | 2002-02-04 | 2004-05-27 | Elan Pharma International Limited | Novel benzoyl peroxide compositions |
| EP1471887B1 (en) * | 2002-02-04 | 2010-04-21 | Elan Pharma International Ltd. | Nanoparticulate compositions having lysozyme as a surface stabilizer |
| MY140561A (en) | 2002-02-20 | 2009-12-31 | Nycomed Gmbh | Dosage form containing pde 4 inhibitor as active ingredient |
| WO2003080023A2 (en) * | 2002-03-20 | 2003-10-02 | Elan Pharma International Limited | Fast dissolving dosage forms having reduced friability |
| DE60309300T3 (en) * | 2002-03-20 | 2011-02-24 | Elan Pharma International Ltd. | NANOPARTICLE COMPOSITIONS OF ANGIOGENIC INHIBITORS |
| AU2003224808A1 (en) * | 2002-03-28 | 2003-10-13 | Imcor Pharmaceutical Company | Compositions and methods for delivering pharmaceutically active agents using nanoparticulates |
| US9101540B2 (en) | 2002-04-12 | 2015-08-11 | Alkermes Pharma Ireland Limited | Nanoparticulate megestrol formulations |
| CA2481390C (en) | 2002-04-12 | 2012-11-27 | Elan Pharma International Ltd. | Nanoparticulate megestrol formulations |
| US20040105889A1 (en) * | 2002-12-03 | 2004-06-03 | Elan Pharma International Limited | Low viscosity liquid dosage forms |
| US7101576B2 (en) | 2002-04-12 | 2006-09-05 | Elan Pharma International Limited | Nanoparticulate megestrol formulations |
| US20100226989A1 (en) * | 2002-04-12 | 2010-09-09 | Elan Pharma International, Limited | Nanoparticulate megestrol formulations |
| ATE419835T1 (en) * | 2002-05-06 | 2009-01-15 | Elan Pharma Int Ltd | NYSTATIN NANOPARTICLE COMPOSITIONS |
| US20070264348A1 (en) * | 2002-05-24 | 2007-11-15 | Elan Pharma International, Ltd. | Nanoparticulate fibrate formulations |
| US7348298B2 (en) * | 2002-05-30 | 2008-03-25 | Ashland Licensing And Intellectual Property, Llc | Enhancing thermal conductivity of fluids with graphite nanoparticles and carbon nanotube |
| JP4533134B2 (en) * | 2002-06-10 | 2010-09-01 | エラン ファーマ インターナショナル，リミティド | Nanoparticulate policosanol formulations and novel policosanol combinations |
| JP4776229B2 (en) * | 2002-07-16 | 2011-09-21 | エラン ファーマ インターナショナル，リミティド | Stable nanoparticulate active substance liquid dosage composition |
| UY27939A1 (en) | 2002-08-21 | 2004-03-31 | Glaxo Group Ltd | COMPOUNDS |
| ATE487470T1 (en) * | 2002-09-11 | 2010-11-15 | Elan Pharma Int Ltd | GEL-STABILIZED ACTIVE COMPOSITIONS IN NANOPARTICLE SIZE |
| WO2004032980A1 (en) * | 2002-10-04 | 2004-04-22 | Elan Pharma International Limited | Gamma irradiation of solid nanoparticulate active agents |
| JP4776233B2 (en) * | 2002-11-12 | 2011-09-21 | エラン ファーマ インターナショナル，リミティド | Fast disintegrating solid formulation that is resistant to abrasion and contains pullulan |
| US20040173696A1 (en) * | 2002-12-17 | 2004-09-09 | Elan Pharma International Ltd. | Milling microgram quantities of nanoparticulate candidate compounds |
| CA2513064C (en) * | 2003-01-31 | 2009-11-10 | Elan Pharma International, Ltd. | Nanoparticulate topiramate formulations |
| US20040208833A1 (en) * | 2003-02-04 | 2004-10-21 | Elan Pharma International Ltd. | Novel fluticasone formulations |
| US8512727B2 (en) | 2003-03-03 | 2013-08-20 | Alkermes Pharma Ireland Limited | Nanoparticulate meloxicam formulations |
| US20100297252A1 (en) | 2003-03-03 | 2010-11-25 | Elan Pharma International Ltd. | Nanoparticulate meloxicam formulations |
| ATE406364T1 (en) | 2003-03-07 | 2008-09-15 | Schering Corp | SUBSTITUTED AZETIDINONE DERIVATIVES, THEIR PHARMACEUTICAL FORMULATIONS AND THEIR USE IN THE TREATMENT OF HYPERCHOLESTEROLEMIA |
| DE602004018617D1 (en) | 2003-03-07 | 2009-02-05 | Schering Corp | SUBSTITUTED AZETIDINONE DERIVATIVES, THEIR PHARMACEUTICAL FORMULATIONS AND THEIR USE FOR THE TREATMENT OF HYPERCHOLESTEROLMIA |
| SI1606261T1 (en) | 2003-03-10 | 2010-03-31 | Nycomed Gmbh | Novel process for the preparation of roflumilast |
| US7842232B2 (en) * | 2003-05-22 | 2010-11-30 | Elan Pharma International, Ltd. | Sterilization of dispersions of nanoparticulate active agents with gamma radiation |
| DE602004018150D1 (en) * | 2003-08-08 | 2009-01-15 | Elan Pharma Int Ltd | NEW METAXALON COMPOSITIONS |
| EP1684725A1 (en) * | 2003-10-31 | 2006-08-02 | Elan Pharma International Limited | Novel nimesulide compositions |
| ATE509618T1 (en) * | 2003-11-05 | 2011-06-15 | Elan Pharma Int Ltd | NANOPARTICLE-SHAPED COMPOSITIONS HAVING A PEPTIDE AS A SURFACE STABILIZER |
| WO2005060648A2 (en) * | 2003-12-16 | 2005-07-07 | Ashland Inc. | Lubricants with enhanced thermal conductivity containing nanomaterial |
| WO2006083326A2 (en) * | 2004-08-07 | 2006-08-10 | Cabot Corporation | Gas dispersion manufacture of nanoparticulates and nanoparticulate-containing products and processing thereof |
| US20060083694A1 (en) | 2004-08-07 | 2006-04-20 | Cabot Corporation | Multi-component particles comprising inorganic nanoparticles distributed in an organic matrix and processes for making and using same |
| US20090155331A1 (en) * | 2005-11-16 | 2009-06-18 | Elan Pharma International Limited | Injectable nanoparticulate olanzapine formulations |
| AU2005307797B2 (en) * | 2004-11-16 | 2011-06-02 | Alkermes Pharma Ireland Limited | Injectable nanoparticulate olanzapine formulations |
| UA89513C2 (en) * | 2004-12-03 | 2010-02-10 | Элан Фарма Интернешнл Лтд. | Nanoparticulate raloxifene hydrochloride composition |
| BRPI0519088A2 (en) * | 2004-12-15 | 2008-12-23 | Elan Pharma Int Ltd | nanoparticulate tacrolimus formulations |
| WO2006069098A1 (en) * | 2004-12-22 | 2006-06-29 | Elan Pharma International Ltd. | Nanoparticulate bicalutamide formulations |
| KR20070118224A (en) * | 2005-01-06 | 2007-12-14 | 엘란 파마 인터내셔널 리미티드 | Nanoparticulate candesartan formulations |
| MX2007009915A (en) | 2005-02-15 | 2007-11-06 | Elan Pharma Int Ltd | Aerosol and injectable formulations of nanoparticulate benzodiazepine. |
| CA2598288A1 (en) * | 2005-03-03 | 2006-09-14 | Elan Pharma International Limited | Nanoparticulate compositions of heterocyclic amide derivatives |
| US20060204588A1 (en) * | 2005-03-10 | 2006-09-14 | Elan Pharma International Limited | Formulations of a nanoparticulate finasteride, dutasteride or tamsulosin hydrochloride, and mixtures thereof |
| US8663694B2 (en) * | 2005-03-16 | 2014-03-04 | Takeda Gmbh | Taste masked dosage form containing roflumilast |
| CN101175480A (en) * | 2005-03-16 | 2008-05-07 | 伊兰制药国际有限公司 | Nanoparticulate leukotriene receptor antagonist/corticosteroid formulations |
| KR20070121759A (en) * | 2005-03-17 | 2007-12-27 | 엘란 파마 인터내셔널 리미티드 | Nanoparticulate bisphosphonate compositions |
| WO2006102494A2 (en) * | 2005-03-23 | 2006-09-28 | Elan Pharma International Limited | Nanoparticulate corticosteroid and antihistamine formulations |
| WO2006110809A2 (en) * | 2005-04-12 | 2006-10-19 | Elan Pharma International, Limited | Nanoparticulate lipase inhibitor formulations |
| CN101171000A (en) * | 2005-04-12 | 2008-04-30 | 依兰药物国际有限公司 | Nanoparticulate and controlled release compositions comprising cyclosporine |
| US8309133B2 (en) * | 2005-04-12 | 2012-11-13 | Alkermes Pharma Ireland Limited | Nanoparticulate quinazoline derivative formulations |
| US20090081297A1 (en) * | 2005-04-27 | 2009-03-26 | Cook Robert O | Use of surface tension reducing agents in aerosol formulations |
| US20110064803A1 (en) * | 2005-05-10 | 2011-03-17 | Elan Pharma International Limited. | Nanoparticulate and controlled release compositions comprising vitamin k2 |
| US20070003628A1 (en) * | 2005-05-10 | 2007-01-04 | Elan Pharma International Limited | Nanoparticulate clopidogrel formulations |
| US20100028439A1 (en) * | 2005-05-23 | 2010-02-04 | Elan Pharma International Limited | Nanoparticulate stabilized anti-hypertensive compositions |
| US20070042049A1 (en) * | 2005-06-03 | 2007-02-22 | Elan Pharma International, Limited | Nanoparticulate benidipine compositions |
| CA2610448A1 (en) * | 2005-06-03 | 2006-12-14 | Elan Pharma International, Limited | Nanoparticulate imatinib mesylate formulations |
| KR20080017065A (en) * | 2005-06-03 | 2008-02-25 | 엘란 파마 인터내셔널 리미티드 | Nanoparticulate acetaminophen formulations |
| JP2009517485A (en) | 2005-06-08 | 2009-04-30 | エラン・ファルマ・インターナショナル・リミテッド | Nanoparticulate and controlled release compositions containing cefditoren |
| US20070059371A1 (en) * | 2005-06-09 | 2007-03-15 | Elan Pharma International, Limited | Nanoparticulate ebastine formulations |
| AU2006259606A1 (en) * | 2005-06-13 | 2006-12-28 | Elan Pharma International, Limited | Nanoparticulate clopidogrel and aspirin combination formulations |
| JP2008543862A (en) * | 2005-06-15 | 2008-12-04 | エラン ファーマ インターナショナル リミテッド | Nanoparticulate azelnidipine formulation |
| US20070015719A1 (en) * | 2005-07-07 | 2007-01-18 | Elan Pharma International Limited | Nanoparticulate clarithromycin formulations |
| EP1937217A2 (en) * | 2005-09-13 | 2008-07-02 | Elan Pharma International Limited | Nanoparticulate tadalafil formulations |
| EP1933814A2 (en) * | 2005-09-15 | 2008-06-25 | Elan Pharma International Limited | Nanoparticulate aripiprazole formulations |
| ZA200803526B (en) * | 2005-09-26 | 2009-10-28 | Aeras Global Tb Vaccine Found | Process for stabilization of bacterial cells |
| US7829772B2 (en) * | 2005-10-27 | 2010-11-09 | Clemson University Research Foundation | Fluorescent carbon nanoparticles |
| US7858609B2 (en) * | 2005-11-28 | 2010-12-28 | Marinus Pharmaceuticals | Solid ganaxolone formulations and methods for the making and use thereof |
| US8367112B2 (en) * | 2006-02-28 | 2013-02-05 | Alkermes Pharma Ireland Limited | Nanoparticulate carverdilol formulations |
| BRPI0712130A2 (en) * | 2006-05-30 | 2012-01-17 | Elan Pharma Int Ltd | nanoparticulate posaconazole formulations |
| BRPI0713533A2 (en) * | 2006-06-26 | 2012-04-17 | Mutual Pharmaceutical Co | active agent formulations, manufacturing methods, and methods of use |
| EP2049084A2 (en) * | 2006-07-10 | 2009-04-22 | Elan Pharma International Limited | Nanoparticulate sorafenib formulations |
| CL2007002689A1 (en) | 2006-09-18 | 2008-04-18 | Vitae Pharmaceuticals Inc | COMPOUNDS DERIVED FROM PIPERIDIN-1-CARBOXAMIDA, INHIBITORS OF THE RENINE; INTERMEDIARY COMPOUNDS; PHARMACEUTICAL COMPOSITION; AND USE IN THE TREATMENT OF DISEASES SUCH AS HYPERTENSION, CARDIAC INSUFFICIENCY, CARDIAC FIBROSIS, AMONG OTHERS. |
| DE102006054013A1 (en) * | 2006-11-16 | 2008-05-21 | Clariant International Ltd. | Coating compositions containing reactive ester waxes and mixed oxide nanoparticles |
| BRPI0717721A2 (en) | 2006-11-28 | 2013-10-29 | Marinus Pharmaceuticals | "COMPLEX DRUG PARTICLES, PHARMACEUTICAL COMPOSITION, USE OF A PHARMACEUTICAL COMPOSITION, COMPLEX DRUG PARTICLES STABILIZED IN THE SIZE, METHOD FOR THE PREPARATION OF STABILIZED DRUG PARTICLES, EMOTIONAL COMPOSITION IN PHARMACEUTICAL, PHARMACEUTICAL UNDERSTANDING |
| US8426467B2 (en) | 2007-05-22 | 2013-04-23 | Baxter International Inc. | Colored esmolol concentrate |
| US8722736B2 (en) | 2007-05-22 | 2014-05-13 | Baxter International Inc. | Multi-dose concentrate esmolol with benzyl alcohol |
| US8642062B2 (en) | 2007-10-31 | 2014-02-04 | Abbott Cardiovascular Systems Inc. | Implantable device having a slow dissolving polymer |
| US20090238867A1 (en) * | 2007-12-13 | 2009-09-24 | Scott Jenkins | Nanoparticulate Anidulafungin Compositions and Methods for Making the Same |
| WO2009117401A2 (en) * | 2008-03-21 | 2009-09-24 | Elan Pharama International Limited | Compositions for site-specific delivery of imatinib and methods of use |
| US20090311335A1 (en) * | 2008-06-12 | 2009-12-17 | Scott Jenkins | Combination of a triptan and an nsaid |
| TWI580441B (en) * | 2008-09-19 | 2017-05-01 | 愛爾康研究有限公司 | Stabilized pharmaceutical sub-micron suspensions and methods of forming same |
| US20100159010A1 (en) * | 2008-12-24 | 2010-06-24 | Mutual Pharmaceutical Company, Inc. | Active Agent Formulations, Methods of Making, and Methods of Use |
| US20120065221A1 (en) | 2009-02-26 | 2012-03-15 | Theraquest Biosciences, Inc. | Extended Release Oral Pharmaceutical Compositions of 3-Hydroxy-N-Methylmorphinan and Method of Use |
| US8685458B2 (en) * | 2009-03-05 | 2014-04-01 | Bend Research, Inc. | Pharmaceutical compositions of dextran polymer derivatives |
| US7828996B1 (en) | 2009-03-27 | 2010-11-09 | Abbott Cardiovascular Systems Inc. | Method for the manufacture of stable, nano-sized particles |
| US20100291221A1 (en) * | 2009-05-15 | 2010-11-18 | Robert Owen Cook | Method of administering dose-sparing amounts of formoterol fumarate-budesonide combination particles by inhalation |
| EP2435027B1 (en) | 2009-05-27 | 2016-10-05 | Alkermes Pharma Ireland Limited | Reduction of flake-like aggregation in nanoparticulate meloxicam compositions |
| FR2945950A1 (en) | 2009-05-27 | 2010-12-03 | Elan Pharma Int Ltd | ANTICANCER NANOPARTICLE COMPOSITIONS AND METHODS FOR PREPARING THE SAME |
| JPWO2010137335A1 (en) * | 2009-05-29 | 2012-11-12 | 江崎グリコ株式会社 | Composition for promoting turnover, comprising α-lipoic acid nanoparticles |
| AR077692A1 (en) | 2009-08-06 | 2011-09-14 | Vitae Pharmaceuticals Inc | SALTS OF 2 - ((R) - (3-CHLOROPHENYL) ((R) -1 - ((S) -2- (METHYLAMINE) -3 - ((R) -TETRAHYDRO-2H-PIRAN-3-IL) PROPILCARBAMOIL ) PIPERIDIN -3-IL) METOXI) METHYL ETILCARBAMATE |
| DK2506831T3 (en) | 2009-12-03 | 2013-12-16 | Alcon Res Ltd | Carboxyvinyl polymer-containing nanoparticle suspensions |
| US9012511B2 (en) | 2010-05-19 | 2015-04-21 | Alkermes Pharma Ireland Limited | Nanoparticulate cinacalcet compositions |
| AU2012287234B2 (en) | 2011-07-22 | 2017-02-02 | Chemocentryx, Inc. | Polymorphic forms of the sodium salt of 4-tert- butyl -N-[4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl]-benzene sulfonamide |
| SI2748146T1 (en) | 2011-07-22 | 2017-10-30 | Chemocentryx, Inc. | A crystalline form of the sodium salt of 4-tert-butyl-n-(4-chloro-2-(1-oxy-pyridine-4-carbonyl)-phenyl)-benzene sulfonamide |
| MY172885A (en) | 2011-09-01 | 2019-12-13 | Glaxo Group Ltd | Novel crystal form |
| US9827191B2 (en) | 2012-05-03 | 2017-11-28 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| US11596599B2 (en) | 2012-05-03 | 2023-03-07 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| EP4008355A1 (en) | 2012-05-03 | 2022-06-08 | Kala Pharmaceuticals, Inc. | Pharmaceutical nanoparticles showing improved mucosal transport |
| EP3808339A1 (en) | 2012-05-03 | 2021-04-21 | Kala Pharmaceuticals, Inc. | Pharmaceutical nanoparticles showing improved mucosal transport |
| US10201589B2 (en) | 2013-12-11 | 2019-02-12 | University Of Massachusetts | Compositions and methods for treating disease using Salmonella T3SS effector protein (SipA) |
| PT3160958T (en) | 2014-06-25 | 2021-04-07 | Glaxosmithkline Ip Dev Ltd | Crystalline salts of (s)-6-((1-acetylpiperidin-4-yl)amino)-n-(3-(3,4-dihydroisoquinolin-2(1h)-yl)-2-hydroxypropyl)pyrimidine-4-carboxamide |
| RU2017111590A (en) | 2014-09-08 | 2018-10-10 | Глэксосмитклайн Интеллекчуал Проперти Дивелопмент Лимитед | CRYSTALLINE FORMS 2- (4- (4-ETOXY-6-OXO-1,6-DIHYDROPYRIDIN-3-IL) -2-fluorophenyl) -N- (5- (1,1,1-TRIFTOR-2-METILPROPAN- 2-yl) isoxazole-3-yl) acetamide |
| US10166197B2 (en) | 2015-02-13 | 2019-01-01 | St. John's University | Sugar ester nanoparticle stabilizers |
| MX2017013956A (en) | 2015-05-01 | 2018-09-05 | Cocrystal Pharma Inc | Nucleoside analogs for treatment of the flaviviridae family of viruses and cancer. |
| CA3001722A1 (en) | 2015-10-16 | 2017-04-20 | Marinus Pharmaceuticals, Inc. | Injectable neurosteroid formulations containing nanoparticles |
| CN109715151A (en) | 2016-08-11 | 2019-05-03 | 奥维德医疗公司 | For treating the method and composition of epilepsy sexual disorder |
| US10391105B2 (en) | 2016-09-09 | 2019-08-27 | Marinus Pharmaceuticals Inc. | Methods of treating certain depressive disorders and delirium tremens |
| WO2020118142A1 (en) | 2018-12-07 | 2020-06-11 | Marinus Pharmaceuticals, Inc. | Ganaxolone for use in prophylaxis and treatment of pospartum depression |
| EP4009982A4 (en) | 2019-08-05 | 2023-08-09 | Marinus Pharmaceuticals, Inc. | Ganaxolone for use in treatment of status epilepticus |
| CA3159382A1 (en) | 2019-11-01 | 2021-05-06 | Aquestive Therapeutics, Inc. | Prodrug compositions and methods of treatment |
| KR20220126287A (en) | 2019-11-14 | 2022-09-15 | 어퀘스티브 테라퓨틱스, 아이엔씨. | Multimodal compositions and methods of treatment |
| MX2022006014A (en) | 2019-12-06 | 2022-06-22 | Marinus Pharmaceuticals Inc | Ganaxolone for use in treating tuberous sclerosis complex. |
| CN116940351A (en) | 2021-01-15 | 2023-10-24 | 阿奎斯蒂弗医疗股份有限公司 | Prodrug compositions and methods of treatment |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB498482A (en) * | 1937-07-09 | 1939-01-09 | Walter Richardson | Improvements in and relating to mowing machines |
| GB499299A (en) * | 1937-09-09 | 1939-01-20 | Zeiss Carl | Improvements in rotating-wedge compensators |
| US4615879A (en) * | 1983-11-14 | 1986-10-07 | Vanderbilt University | Particulate NMR contrast agents for gastrointestinal application |
| GB9011588D0 (en) * | 1990-05-24 | 1990-07-11 | Wellcome Found | Prostaglandin analogues for use in medicine |
| AU642066B2 (en) * | 1991-01-25 | 1993-10-07 | Nanosystems L.L.C. | X-ray contrast compositions useful in medical imaging |
| US5145684A (en) * | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
| JP4439590B2 (en) * | 1992-06-10 | 2010-03-24 | エラン ファーマ インターナショナル，リミティド | Surface modified NSAID nanoparticles |
| US5298262A (en) * | 1992-12-04 | 1994-03-29 | Sterling Winthrop Inc. | Use of ionic cloud point modifiers to prevent particle aggregation during sterilization |
| US5302401A (en) * | 1992-12-09 | 1994-04-12 | Sterling Winthrop Inc. | Method to reduce particle size growth during lyophilization |
| US5336507A (en) * | 1992-12-11 | 1994-08-09 | Sterling Winthrop Inc. | Use of charged phospholipids to reduce nanoparticle aggregation |
-
1992
- 1992-12-15 US US07/990,874 patent/US5429824A/en not_active Expired - Lifetime
-
1993
- 1993-09-21 NZ NZ248726A patent/NZ248726A/en unknown
- 1993-09-21 AU AU47472/93A patent/AU665669B2/en not_active Ceased
- 1993-09-24 PH PH46957A patent/PH29957A/en unknown
- 1993-09-28 MX MX9306010A patent/MX9306010A/en not_active Application Discontinuation
- 1993-10-12 CA CA002108192A patent/CA2108192C/en not_active Expired - Fee Related
- 1993-10-21 TW TW082108780A patent/TW440451B/en not_active IP Right Cessation
- 1993-10-29 KR KR1019930022700A patent/KR100320390B1/en not_active IP Right Cessation
- 1993-11-10 JP JP5280799A patent/JPH06199658A/en not_active Withdrawn
- 1993-12-01 DK DK93203365T patent/DK0602702T3/en active
- 1993-12-01 AT AT93203365T patent/ATE178788T1/en not_active IP Right Cessation
- 1993-12-01 ES ES93203365T patent/ES2130217T3/en not_active Expired - Lifetime
- 1993-12-01 EP EP93203365A patent/EP0602702B1/en not_active Expired - Lifetime
- 1993-12-01 DE DE69324456T patent/DE69324456T2/en not_active Expired - Lifetime
- 1993-12-02 FI FI935395A patent/FI935395A/en unknown
- 1993-12-03 IL IL10787493A patent/IL107874A/en active IP Right Grant
- 1993-12-06 NO NO19934424A patent/NO310543B1/en not_active IP Right Cessation
- 1993-12-08 MY MYPI93002636A patent/MY110186A/en unknown
- 1993-12-10 RU RU93054941A patent/RU2124886C1/en active
- 1993-12-14 CZ CZ932747A patent/CZ274793A3/en unknown
- 1993-12-14 UA UA93003742A patent/UA27760C2/en unknown
- 1993-12-15 SK SK1424-93A patent/SK280614B6/en unknown
- 1993-12-15 HU HU9303594A patent/HU219333B/en not_active IP Right Cessation
-
1999
- 1999-04-26 GR GR990401140T patent/GR3030059T3/en unknown
-
2007
- 2007-11-29 JP JP2007309325A patent/JP2008063348A/en active Pending
-
2009
- 2009-12-25 JP JP2009294240A patent/JP2010070569A/en active Pending
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2108192C (en) | Use of tyloxapol as a nanoparticle stabilizer and dispersant | |
| EP0810855B1 (en) | Polyalkylene block copolymers as surface modifiers for nanoparticles | |
| US5326552A (en) | Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants | |
| RU2074002C1 (en) | Contrast radiographic composition, method for visualizing during tomographic experimental examinations and method for preparing said contrast radiographic composition | |
| CA2232879C (en) | Reduction of intravenously administered nanoparticulate-formulation-induced adverse physiological reactions | |
| US5534270A (en) | Method of preparing stable drug nanoparticles | |
| EP0601618A2 (en) | Use of charged phospholipids for decreasing nanoparticulate aggregation | |
| JPH10502341A (en) | Butylene oxide-ethylene oxide block copolymer surfactant as stabilizer coating for microcrystalline formulations | |
| AU673535B2 (en) | Controlled precipitation of particulate diagnostic imaging contrast agents |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20131015 |