WO2005046671A1 - Method for preparing submicron particles of paclitaxel - Google Patents
Method for preparing submicron particles of paclitaxel Download PDFInfo
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- WO2005046671A1 WO2005046671A1 PCT/US2004/036604 US2004036604W WO2005046671A1 WO 2005046671 A1 WO2005046671 A1 WO 2005046671A1 US 2004036604 W US2004036604 W US 2004036604W WO 2005046671 A1 WO2005046671 A1 WO 2005046671A1
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- Prior art keywords
- solvent
- particles
- suspension
- water
- solution
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
Definitions
- the present invention is concerned with the formation of submicron particles of an antineoplastic agent, particularly paclitaxel or its derivative compounds, by precipitating the antineoplastic agent in an aqueous medium to form a pre-suspension followed by homogenization.
- Surfactants with phospholipids conjugated with a water soluble or hydrophilic polymer, such as polyethylene glycol (PEG), are used as coating for the particles.
- the articles produced generally have an average particle size of less than about 1000 nm and are not rapidly soluble.
- the small size of the particles improves the dissolution rate of the drag, and hence improving its bioavailability and potentially its toxicity profiles.
- particle size for example, for oral administration, it is desirable to have a particle size of less than about 7 ⁇ m.
- the particles are preferably less than about 10 ⁇ m in size.
- the present invention provides methods for preparing and compositions of submicron particles of an antineoplastic agent, particularly paclitaxel or its derivative compounds.
- the solubility of the antineoplastic agent is greater in a water-miscible first solvent than in a second solvent, which is aqueous.
- the methods include (i) mixing into the water-miscible first solvent or the second solvent or both the water- miscible first solvent and the second solvent a first surface modifier comprising a phospholipid conjugated with a water-soluble or hydrophilic polymer; (ii) dissolving the antineoplastic agent in the water-miscible first solvent to form a solution; (iii) mixing the solution with the second solvent to define a pre-suspension of particles; and (iv) homogenizing the pre-suspension to form a suspension of particles having an average effective particle size of less than about 1 ⁇ m.
- the particles have an average effective particle size of less than about 400 nm, more preferably less than 200 nm, and most preferably, less than about 150 nm.
- the water-soluble or hydrophilic polymer conjugating to the phospholipid is polyethylene glycol (PEG).
- a second surface modifier can be mixed into the water-miscible first solvent or the second solvent or both the water-miscible first solvent and the second solvent.
- a preferred second surface modifier is poloxamer.
- the homo enization is carried out at about 30°C or greater.
- the methods can further include removing the water-miscible first solvent or the entire liquid phase from the suspension.
- the water- miscible first solvent is removed simultaneously with homogenization
- the method can also further include sterilizing the composition.
- the particles are not soluble.
- the particles do not aggregate under stressed conditions or upon storage.
- FIG. 1 shows a diagrammatic representation of one method of the present invention
- FIG. 2 shows a diagrammatic representation of another method of the present invention
- FIG. 3 shows amorphous particles prior to homogenization
- FIG. 4 shows particles after annealing by homogenization
- FIG. 5 is an X-Ray diffractogram of microprecipitated itraconazole with polyethylene glycol-660 12-hydroxystearate before and after homogenization
- FIG. 6 shows Carbamazepirie crystals before homogenization
- FIG. 7 shows Carbamazepine microparticulate after homogenization (Avestin
- FIG. 8 is a diagram illustrating the Microprecipitation Process for Prednisolone
- FIG. 9 is a photomicrograph of prednisolone suspension before homogenization
- FIG. 10 is a photomicrograph of prednisolone suspension after homogenization
- FIG. 11 illustrates a comparison of size distributions of nanosuspensions (this invention) and a commercial fat emulsion
- FIG. 12 shows the X-ray powder diffraction patterns for raw material itraconazole (top) and SMP-2-PRE (bottom). The raw material pattern has been shifted upward for clarity
- FIG. 13a shows the DSC trace for raw material itraconazole
- FIG. 13b shows the DSC trace for SMP-2-PRE
- FIG. 13a shows the DSC trace for raw material itraconazole
- FIG. 13b shows the DSC trace for SMP-2-PRE
- FIG. 13a shows the DSC trace for raw material itraconazole
- FIG. 13b shows the DSC
- FIG. 14 illustrates the DSC trace for SMP-2-PRE showing the melt of the less stable polymorph upon heating to 160°C, a recrystallization event upon cooling, and the subsequent melting of the more stable polymorph upon reheating to 180°C;
- FIG. 15 illustrates a comparison of SMP-2-PRE samples after homogenization.
- Solid line sample seeded with raw material itraconazole.
- Dashed line unseeded sample. The solid line has been shifted by 1 W/g for clarity;
- FIG. 16 illustrates the effect of seeding during precipitation.
- the unseeded trace (dashed line) has been shifted upward by 1.5 W/g for clarity; and
- FIG. 17 illustrates the effect of seeding the drug concentrate through aging.
- Top x-ray diffraction pattern is for crystals prepared from fresh drug concentrate, and is consistent with the stable polymorph (see FIG. 12, top).
- Bottom pattern is for crystals prepared from aged (seeded) drug concentrate, and is consistent with the metastable polymorph (see FIG. 12, bottom).
- the top pattern has been shifted upward for clarity.
- FIG. 18 shows that the dissolution of two formulations of submicron paclitaxel particles;
- FIG. 19 shows the effect of various stressed conditions on the particle size of submicron particles of paclitaxel;
- FIG. 20 shows the effect of storage on the particle size of submicron particles ofpaclitaxel.
- the present invention is susceptible of embodiments in many different forms. Preferred embodiments of the invention are disclosed with the understanding that the present disclosure is to be considered as exemplifications of the principles of the invention and are not intended to limit the broad aspects of the invention to the embodiments illustrated.
- the present invention provides compositions and methods for forrning small particles of an organic compound.
- An organic compound for use in the process of this invention is any organic chemical entity whose solubility decreases from one solvent to another.
- This organic compound might be a pharmaceutically active compound, which can be selected from therapeutic agents, diagnostic agents, cosmetics, nutritional supplements, and pesticides.
- the therapeutic agents can be selected from a variety of known pharmaceuticals such as, but are not limited to: analgesics, anesthetics, analeptics, adrenergic agents, adrenergic blocking agents, adrenolytics, adrenocorticoids, adrenomimetics, anticholinergic agents, anticholinesterases, anticonvulsants, alkylating agents, alkaloids, allosteric inhibitors, anabolic steroids, anorexiants, antacids, antidiarrheals, antidotes, antifolics, antipyretics, antirheumatic agents, psychotherapeutic agents, neural blocking agents, anti-inflammatory agents, antihelmintics, anti-arrhythmic agents, antibiotics, anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antifungals, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antimalarials,
- Antineoplastic, or anticancer agents include but are not limited to paclitaxel and derivative compounds, and other antineoplastics selected from the group consisting of alkaloids, antimetabolites, enzyme inhibitors, alkylating agents and antibiotics.
- the therapeutic agent can also be a biologic, which includes but is not limited to proteins, polypeptides, carbohydrates, polynucleotides, and nucleic acids.
- the protein can be an antibody, which can be polyclonal or monoclonal. Diagnostic agents include the x-ray imaging agents and contrast media.
- Examples of x-ray imaging agents include WDSf-8883 (ethyl 3,5-diacetamido-2,4,6- triiodobenzoate) also known as the ethyl ester of diatrazoic.acid (EEDA), WIN 67722, i.e., (6-ethoxy-6-oxohexyl-3,5-bis(acetamido)-2,4,6-triiodobenzoate; ethyl-2-(3,5- bis(acetamido)-2,4,6-triiodo-benzoyloxy) butyrate (WIN 16318); ethyl diatrizoxyacetate (WIN 12901); ethyl 2-(3,5-bis(acetarnido)-2,4,6- triiodobenzoyloxy)propionate (WIN 16923); N-ethyl 2-(3,5-bis(acetamido)-2,4,6- triiodobenz
- Preferred contrast agents include those that are expected to disintegrate relatively rapidly under physiological conditions, thus minimizing any particle associated inflammatory response. Disintegration may result from enzymatic hydrolysis, solubilization of carboxylic acids at physiological pH, or other mechanisms. Thus, poorly soluble iodinated carboxylic acids such as iodipamide, diatrizoic acid, and metrizoic acid, along with hydrolytically labile iodinated species such as WIN 67721, WIN 12901, WIN 68165, and WIN 68209 or others may be preferred.
- Other contrast media include, but are not limited to, particulate preparations of magnetic resonance imaging aids such as gadolinium chelates, or other paramagnetic contrast agents.
- gadopentetate dimeglumine Magnevist®
- gadoteridol Prohance®
- a description of these classes of therapeutic agents and diagnostic agents and a listing of species within each class can be found in Martindale, The Extra Pharmacopoeia, Twenty-ninth Edition, The Pharmaceutical Press, London, 1989 which is incorporated herein by reference and made a part hereof.
- the therapeutic agents and diagnostic agents are commercially available and/or can be prepared by techniques known in the art.
- a cosmetic agent is any active ingredient capable of having a cosmetic activity.
- Examples of these active ingredients can be, inter alia, emollients, humectants, free radical-inhibiting agents, anti-inflarnmatories, vitamins, depigmenting agents, anti- acne agents, antiseborrhoeics, keratolytics, slimmmg agents, skin coloring agents and sunscreen agents, and in particular linoleic acid, retinol, retinoic acid, ascorbic acid alkyl esters, polyunsaturated fatty acids, nicotinic esters, tocopherol nicotinate, unsaponifiables of rice, soybean or shea, ceramides, hydroxy acids such as glycolic acid, selenium derivatives, antioxidants, beta-carotene, gamma-orizanol and stearyl glycerate.
- the cosmetics are commercially available and/or can be prepared by techniques known in the art.
- nutritional supplements contemplated for use in the practice of the present invention include, but are not limited to, proteins, carbohydrates, water-soluble vitamins (e.g., vitamin C, B-complex vitamins, and the like), fat-soluble vitamins (e.g., vitamins A, D, E, K, and the like), and herbal extracts.
- the nutritional supplements are commercially available and/or can be prepared by techniques known in the art.
- pesticide is understood to encompass herbicides, insecticides, acaricides, nematicides, ectoparasiticides and fungicides.
- Examples of compound classes to which the pesticide in the present invention may belong include ureas, xriazines, triazoles, carbamates, phosphoric acid esters, dinitroanilines, morpholines, acylalanines, pyrethroids, benzilic acid esters, diphenylethers and polycyclic halogenated hydrocarbons.
- Specific examples of pesticides in each of these classes are listed in Pesticide Manual, 9th Edition, British Crop Protection Council.
- the pesticides are commercially available and/or can be prepared by techniques known in the art.
- the organic compound or the pharmaceutically active compound is poorly water-soluble.
- water-soluble is a solubility of the compound in water of less than about 10 mg/mL, and preferably less than 1 mg/mL. These poorly water-soluble agents are most suitable for aqueous suspension preparations since there are limited alternatives of formulating these agents in an aqueous medium.
- the present invention can also be practiced with water-soluble pharmaceutically active compounds, by entrapping these compounds in a solid carrier matrix (for example, polylactaide-polyglycolide copolymer, albumin, starch), or by encapsulating these compounds in a surrounding vesicle that is impermeable to the pharmaceutical compound. This encapsulating vesicle can be a polymeric coating such as polyacrylate.
- the small particles prepared from these water soluble pharmaceutical agents can be modified to improve chemical stability and control the pharmacokinetic properties of the agents by controlling the release of the agents from the particles.
- water-soluble pharmaceutical agents include, but are not limited to, simple organic compounds, proteins, peptides, nucleotides, oligonucleotides, and carbohydrates.
- the particles of the present invention have an average effective particle size of generally less than about 100 ⁇ m as measured by dynamic light scattering methods, e.g., photocorrelation spectroscopy, laser diff action, low-angle laser light scattering (LALLS), medium-angle laser light scattering (MALLS), light obscuration methods (Coulter method, for example), rheology, or microscopy (light or electron).
- dynamic light scattering methods e.g., photocorrelation spectroscopy, laser diff action, low-angle laser light scattering (LALLS), medium-angle laser light scattering (MALLS), light obscuration methods (Coulter method, for example), rhe
- the particles can be prepared in a wide range of sizes, such as from about 20 ⁇ m to about 10 nm, from about 10 ⁇ m to about 10 nm, from about 2 ⁇ m to about 10 nm, from about 1 ⁇ m to about 10 nm, from about 400 nm to about 50 nm, from about 200 nm to about 50 nm or any range or combination of ranges therein.
- the preferred average effective particle size depends on factors such as the intended route of administration, formulation, solubility, toxicity and bioavailability of the compound.
- the particles preferably have an average effective particle size of less than about 7 ⁇ m, and more preferably less than about 2 ⁇ m or any range or combination of ranges therein.
- Parenteral administration includes intravenous, intra-arterial, intrathecal, intraperitoneal, intraocular, intra- articular, intradural, intraventricular, intrapericardial, intramuscular, intraderrnal or subcutaneous injection.
- Particles sizes for oral dosage forms can be in excess of 2 ⁇ m. The particles can range in size up to about 100 ⁇ m, provided that the particles have sufficient bioavailability and other characteristics of an oral dosage form.
- Oral dosage forms include tablets, capsules, caplets, soft and hard gel capsules, or other delivery vehicle for delivering a drug by oral administration.
- the present invention is further suitable for providing particles of the organic compound in a form suitable for pulmonary administration.
- Particles sizes for pulmonary dosage forms can be in excess of 500 nm and typically less than about 10 ⁇ m.
- the particles in the suspension can be aerosolized and administered by a nebulizer for pulmonary administration.
- the particles can be administered as dry powder by a dry powder inhaler after removing the liquid phase from the suspension, or the dry powder can be resuspended in a non-aqueous propellant for administration by a metered dose inhaler.
- a suitable propellant is a hydrofluorocarbon (HFC) such as HFC- 134a (1,1,1,2-tetrafluoroethane) and HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane).
- HFC hydrofluorocarbon
- HFC's Unlike chlorofluorcarbons (CFC's), HFC's exhibit little or no ozone depletion potential. Dosage forms for other routes of delivery, such as nasal, topical, ophthalmic, nasal, buccal, rectal, vaginal, transdermal and the like can also be formulated from the particles made from the present invention. The processes for preparing the particles can be separated into four general categories.
- Each of the categories of processes share the steps of: (1) dissolving an organic compound in a water miscible first solvent to create a first solution, (2) mixing the first solution with a second solvent of water to precipitate the organic compound to create a pre-suspension, and (3) adding energy to the presuspension in the form of high-shear mixing or heat, or a combination of both, to provide a stable form of the organic compound having the desired size ranges defined above.
- the mixing steps and the adding energy step can be carried out in consecutive steps or simultaneously.
- the categories of processes are distinguished based upon the physical properties of the organic compound as determined through x-ray diffraction studies, differential scanning calorimetry (DSC) studies, or other suitable study conducted prior to the energy-addition step and after the energy-addition step.
- the organic compound in the presuspension takes an amorphous form, a semi-crystalline form or a supercooled liquid form and has an average effective particle size.
- the organic compound is in a crystalline form having an average effective particle size essentially the same or less than that of the presuspension.
- the organic compound is in a crystalline form and has an average effective particle size.
- the organic compound After the energy-addition step the organic compound is in a crystalline form having essentially the same average effective particle size as prior to the energy-addition step but the crystals after the energy-addition step are less likely to aggregate. The lower tendency of the organic compound to aggregate is observed by laser dynamic light scattering and light microscopy.
- the organic compound prior to the energy-addition step the organic compound is in a crystalline form that is friable and has an average effective particle size. What is meant by the term "friable" is that the particles are fragile and are more easily broken down into smaller particles.
- the organic compound After the energy- addition step the organic compound is in a crystalline form having an average effective particle size smaller than the crystals of the pre-suspension.
- the subsequent energy-addition step can be carried out more quickly and efficiently when compared to an organic compound in a less friable crystalline mo ⁇ hology.
- the first solution and second solvent are simultaneously subjected to the energy-addition step.
- the energy-addition step can be carried out in any fashion wherein the presuspension or the first solution and second solvent are exposed to cavitation, shearing or impact forces.
- the energy-addition step is an annealing step.
- Annealing is defined in this invention as the process of converting matter that is thermodynamically unstable into a more stable form by single or repeated application of energy (direct heat or mechanical stress), followed by thermal relaxation. This lowering of energy may be achieved by conversion of the solid form from a less ordered to a more ordered lattice structure. Alternatively, this stabilization may occur by a reordering of the surfactant molecules at the solid-liquid interface.
- the first process category as well as the second, third, and fourth process categories, can be further divided into two subcategories, Method A and B, shown diagrammatically in FIGS. 1 and 2.
- the first solvent according to the present invention is a solvent or mixture of solvents in which the organic compound of interest is relatively soluble and which is miscible with the second solvent.
- solvents include, but are not limited to water- miscible protic compounds, in which a hydrogen atom in the molecule is bound to an electronegative atom such as oxygen, nitrogen, or other Group VA, VIA and VII A in the Periodic Table of elements.
- solvents examples include, but are not limited to, alcohols, amines (primary or secondary), oximes, hydroxamic acids, carboxylic acids, sulfonic acids, phosphonic acids, phosphoric acids, amides and ureas.
- Other examples of the first solvent also include aprotic organic solvents. Some of these aprotic solvents can form hydrogen bonds with water, but can only act as proton acceptors because they lack effective proton donating groups.
- One class of aprotic solvents is a dipolar aprotic solvent, as defined by the International Union of Pure and Applied Chemistry (IUPAC Compendium of Chemical Terminology, 2nd Ed., 1997): A solvent with a comparatively high relative permittivity (or dielectric constant), greater than ca.
- Dipolar aprotic solvents can be selected from the group consisting of: amides
- ureas (fully substituted, with no hydrogen atoms attached to nitrogen), ethers, cyclic ethers, nitriles, ketones, sulfones, sulfoxides, fully substituted phosphates, phosphonate esters, phosphoramides, nitro compounds, and the like.
- DMSO Dimethylsulfoxide
- NMP N- methyl-2-pyrrolidinone
- 2-pyrrolidinone 1,3-dimethylimidazohdinone
- DMA dimethylacetamide
- DMF dimethylformamide
- DHF dioxane
- acetone tetrahydrofuran
- THF tetramethylenesulfone
- HMPA hexamethylphosphoramide
- Solvents may also be chosen that are generally water-immiscible, but have sufficient water solubility at low volumes (less than 10%) to act as a water-miscible first solvent at these reduced volumes.
- Aromatics include, but are not limited to, benzene (substituted or unsubstituted), and monocyclic or polycyclic arenes.
- substituted benzenes include, but are not limited to, xylenes (ortho, meta, or para), and toluene.
- alkanes include but are not limited to hexane, neopentane, heptane, isooctane, and cyclohexane.
- halogenated aromatics include, but are not restricted to, chlorobenzene, bromobenzene, and chlorotoluene.
- halogenated alkanes and alkenes include, but are not restricted to, trichloroethane, methylene chloride, ethylenedichloride (EDC), and the like.
- N-methyl-2-pyrrolidinone also called N-methyl-2-pyrrolidone
- 2-pyrrolidinone also called 2-pyrrolidone
- l,3-dimethyl-2-imidazolidinone DI
- dimethylsulfoxide dimethylacetamide
- acetic acid lactic acid
- methanol ethanol
- isopropanol 3-pentanol
- n-propanol benzyl alcohol
- glycerol butylene glycol (butanediol)
- ethylene glycol, propylene glycol, mono- and diacylated monoglycerides such as glyceryl caprylate
- dimethyl isosorbide acetone, dimethylsulfone, dimethylformamide, 1,4-dioxane, tetramethylenesulfone (sulfolane), acetonitrile, nitromethane, tetra
- a preferred first solvent is N-methyl-2-pyrrolidinone.
- Another preferred first solvent is lactic acid.
- the second solvent is an aqueous solvent. This aqueous solvent may be water by itself. This solvent may also contain buffers, salts, surfactant(s), water-soluble polymers, and combinations of these excipients.
- Method A the organic compound (“drug") is first dissolved in the first solvent to create a first solution.
- the organic compound can be added from about 0.1% (w/v) to about 50% (w/v) depending on the solubility of the organic compound in the first solvent. Heating of the concentrate from about 30°C to about 100°C may be necessary to ensure total dissolution of the compound in the first solvent.
- a second aqueous solvent is provided with one or more optional surface modifiers such as an anionic surfactant, a cationic surfactant, a nonionic surfactant or a biologically surface active molecule added thereto.
- Suitable anionic surfactants include but are not limited to alkyl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, triethanolamine stearate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, sodium alginate, dioctyl sodium sulfosuccinate, phosphatidyl choline, phosphatidyl glycerol, phosphatidyl inosine, phosphatidylserine, phosphatidic acid and their salts, glyceryl esters, sodium carboxymethylcellulose, cholic acid and other bile acids (e.g., cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid) and salts thereof (e.g., sodium deoxycholate, etc.).
- Suitable cationic surfactants include but are not limited to quaternary ammonium compounds, such as benzalkonium chloride, cetyltrimethylammonium bromide, chitosans, lauryldirnemylbenzylammonium chloride, acyl camitine hydrochlorides, or alkyl pyridinium halides.
- anionic surfactants phospholipids may be used.
- Suitable phospholipids include, for example phosphatidylcholine, phosphatidylethanolamine, diacyl-glycero-phosphoethanolamine (such as dimyristoyl-glycero-phosphoethanolamine (DMPE), dipalmitoyl-glycero- phosphoethanolarnine (DPPE), distearoyl-glycero-phosphoethanolamine (DSPE), and dioleolyl-glycero-phosphoethanolamine (DOPE)), phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, lysophospholipids, egg or soybean phospholipid or a combination thereof.
- DMPE dimyristoyl-glycero-phosphoethanolamine
- DPPE dipalmitoyl-glycero- phosphoethanolarnine
- DSPE distearoyl-glycero-phosphoethanolamine
- DOPE dioleolyl-g
- the phospholipid may be salted or desalted, hydrogenated or partially hydrogenated or natural semisynthetic or synthetic.
- the phospholipid may also be conjugated with a water-soluble or hydrophilic polymer.
- a preferred polymer is polyethylene glycol (PEG), which is also known as the monomethoxy polyethyleneglycol (mPEG).
- PEG polyethylene glycol
- mPEG monomethoxy polyethyleneglycol
- the molecule weights of the PEG can vary, for example, from 200 to 50,000.
- Some commonly used PEG's that are commercially available include PEG 350, PEG 550, PEG 750, PEG 1000, PEG 2000, PEG 3000, and PEG 5000.
- the phospholipid or the PEG-phospholipid conjugate may also incorporate a functional group which can covalently attach to a ligand including but not limited to proteins, peptides, carbohydrates, glycoproteins, antibodies, or pharmaceutically active agents. These functional groups may conjugate with the ligands through, for example, amide bond formation, disulfide or thioether formation, or biotin/streptavidin binding.
- ligand-binding functional groups include but are not limited to hexanoylamine, dodecanylamine, 1,12- dodecanedicarboxylate, thioethanol, 4-(p-maleimidophenyl)butyramide (MPB), 4-(p- maleimidomethyl)cyclohexane-carboxamide (MCC), 3-(2-pyridyldithio)propionate (PDP), succinate, glutarate, dodecanoate, and biotin.
- MPB 4-(p-maleimidophenyl)butyramide
- MCC 4-(p-maleimidomethyl)cyclohexane-carboxamide
- PDP 3-(2-pyridyldithio)propionate
- Suitable nonionic surfactants include: polyoxyethylene fatty alcohol ethers (Macrogol and Brij), polyoxyethylene sorbitan fatty acid esters (Polysorbates), polyoxyethylene fatty acid esters (Myrj), sorbitan esters (Span), glycerol monostearate, polyethylene glycols, polypropylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers (poloxamers), poloxamines, methylcellulose, h droxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, noncrystalline cellulose, polysaccharides including starch and starch derivatives such as hydroxyethylstarch (HES), polyvinyl alcohol, and polyvinylpyrrohdone.
- HES hydroxyethylstarch
- the nonionic surfactant is a polyoxyethylene and polyoxypropylene copolymer and preferably a block copolymer of propylene glycol and ethylene glycol.
- polymers are sold under the tradename POLOXAMER also sometimes referred to as PLURONIC®, and sold by several suppliers including Spectrum Chemical and Ruger.
- polyoxyethylene fatty acid esters is included those having short alkyl chains.
- SOLUTOL® HS 15 polyethylene-660- hydroxystearate, manufactured by BASF Aktiengesellschaft.
- Surface-active biological molecules include such molecules as albumin, casein, hirudin or other appropriate proteins.
- Polysaccharide biologies are also included, and consist of but not limited to, starches, heparin and chitosans. It may also be desirable to add a pH adjusting agent to the second solvent such as sodium hydroxide, hydrochloric acid, tris buffer or citrate, acetate, lactate, meglumine, or the like.
- the second solvent should have a pH within the range of from about 3 to about 11.
- excipients for oral dosage forms one or more of the following excipients may be utilized: 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, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,
- the method for preparing small particles of an organic compound includes the steps of adding the first solution to the second solvent.
- the addition rate is dependent on the batch size, and precipitation kinetics for the organic compound. Typically, for a small-scale laboratory process (preparation of 1 liter), the addition rate is from about 0.05 cc per minute to about 10 cc per minute. During the addition, the solutions should be under constant agitation.
- the method further includes the step of subjecting the pre-suspension to an energy-addition step to convert the amo ⁇ hous particles, supercooled liquid or semicrystalline solid to a more stable, crystalline solid state.
- the resulting particles will have an average effective particles size as measured by dynamic light scattering methods (e.g., photocorrelation spectroscopy, laser diffraction, low-angle laser light scattering (LALLS), medium- angle laser light scattering (MALLS), light obscuration methods (Coulter method, for example), rheology, or microscopy (light or electron) within the ranges set forth above).
- dynamic light scattering methods e.g., photocorrelation spectroscopy, laser diffraction, low-angle laser light scattering (LALLS), medium- angle laser light scattering (MALLS), light obscuration methods (Coulter method, for example), rheology, or microscopy (light or electron) within the ranges set forth above.
- process category four the first solution and the second solvent are combined while simultaneously conducting the energy-addition step.
- the energy-addition step involves adding energy through sonication, homogenization, countercurrent flow homogenization, microfluidization, or other methods of providing impact
- the energy-addition step is effected by a piston gap homogenizer such as the one sold by Avestin Inc. under the product designation EmulsiFlex-C160.
- the energy-addition step may be accomplished by ultrasonication using an ultrasonic processor such as the Vibra-Cell Ultrasonic Processor (600W), manufactured by Sonics and Materials, Inc.
- the energy-addition step may be accomplished by use of an emulsification apparatus as described in U.S. Patent No. 5,720,551 which is inco ⁇ orated herein by reference and made a part hereof.
- the temperature of the processed sample may be desirable to within the range of from approximately -30°C to 30°C.
- Method B differs from Method A in the following respects.
- the first difference is a surfactant or combination of surfactants is added to the first solution.
- the surfactants may be selected from the groups of anionic, nonionic, cationic surfactants, and surface-active biological modifiers set forth above.
- Comparative Example of Method A and Method B and USPN 5.780.062 United States Patent No. 5,780,062 discloses a process for preparing small particles of an organic compound by first dissolving the compound in a suitable water- miscible first solvent. A second solution is prepared by dissolving a polymer and an amphiphile in aqueous solvent. The first solution is then added to the second solution to form a precipitate that consists of the organic compound and a polymer-amphiphile complex.
- the '062 Patent does not disclose utilizing the energy-addition step of this invention in Methods A and B. Lack of stability is typically evidenced by rapid aggregation and particle growth. In some instances, amo ⁇ hous particles recrystallize as large crystals.
- Methods A and B are further distinguished from the process of the '062 patent by the absence of a step of forming a polymer-amphiphile complex prior to precipitation.
- a polymer-amphiphile complex cannot be formed as no polymer is added to the diluent (aqueous) phase.
- the surfactant which may also act as an amphiphile, or polymer, is dissolved with the organic compound in the first solvent. This precludes the formation of any amphiphile-polymer complexes prior to precipitation.
- each of the formulations has two solutions, a concentrate and an aqueous diluent, which are mixed together and then sonicated.
- the concentrate in each formulation has an organic compound (itraconazole), a water miscible solvent (N-methyl-2-pyrrolidinone or NMP) and possibly a polymer (poloxamer 188).
- the aqueous diluent has water, a tris buffer and possibly a polymer (poloxamer 188) and/or a surfactant (sodium deoxycholate). The average particle diameter of the organic particle is measured prior to sonication and after sonication.
- the first formulation A has as the concentrate itraconazole and NMP.
- the aqueous diluent includes water, poloxamer 188, tris buffer and sodium deoxycholate.
- the aqueous diluent includes a polymer (poloxamer 188), and an amphiphile (sodium deoxycholate), which may form a polymer/amphiphile complex, and, therefore, is in accordance with the disclosure of the '062 Patent. (However, again the '062 Patent does not disclose an energy addition step.)
- the second formulation B has as the concentrate itraconazole, NMP and poloxamer 188.
- the aqueous diluent includes water, tris buffer and sodium deoxycholate. This formulation is made in accordance with the present invention.
- aqueous diluent does not contain a combination of a polymer (poloxamer) and an amphiphile (sodium deoxycholate), a polymer/amphiphile complex cannot form prior to the mixing step.
- Table 1 shows the average particle diameters measured by laser diffraction on three replicate suspension preparations. An initial size determination was made, after which the sample was sonicated for 1 minute. The size determination was then repeated. The large size reduction upon sonication of Method A was indicative of particle aggregation.
- a drug suspension resulting from application of the processes described in this invention may be administered directly as an injectable solution, provided Water for Injection is used in formulation and an appropriate means for solution sterilization is applied. Sterilization may be accomplished by methods well known in the art such as steam or heat sterilization, gamma irradiation and the like. Other sterilization methods, especially for particles in which greater than 99% of the particles are less than 200 nm, would also include pre-filtration first through a 3.0 micron filter followed by filtration through a 0.45-micron particle filter, followed by steam or heat sterilization or sterile filtration through two redundant 0.2-micron membrane filters.
- Yet another means of sterilization is sterile filtration of the concentrate prepared from the first solvent containing drag and optional surfactant or surfactants and sterile filtration of the aqueous diluent. These are then combined in a sterile mixing container, preferably in an isolated, sterile environment. Mixing, homogenization, and further processing of the suspension are then carried out under aseptic conditions. Yet another procedure for sterilization would consist of heat sterilization or autoclaving within the homogenizer itself, before, during, or subsequent to the homogenization step. Processing after this heat treatment would be carried out under aseptic conditions.
- a solvent-free suspension may be produced by solvent removal after precipitation.
- the solvent-free particles can be formulated into various dosage forms as desired for a variety of administrative routes, such as oral, pulmonary, nasal, topical, intramuscular, and the like.
- any undesired excipients such as surfactants maybe replaced by a more desirable excipient by use of the separation methods described in the above paragraph.
- the solvent and first excipient may be discarded with the supernatant after centrifugation or filtration. A fresh volume of the suspension vehicle without the solvent and without the first excipient may then be added. Alternatively, a new surfactant may be added.
- a suspension consisting of drug, N-methyl-2- pyrrolidinone (solvent), poloxamer 188 (first excipient), sodium deoxycholate, glycerol and water may be replaced with phospholipids (new surfactant), glycerol and water after centrifugation and removal of the supernatant.
- the methods of the first process category generally include the step of dissolving the organic compound in a water miscible first solvent followed by the step of mixing this solution with an aqueous solvent to form a presuspension wherein the organic compound is in an amo ⁇ hous form, a semicrystalline form or in a supercooled liquid form as determined by x-ray diffraction studies, DSC, light microscopy or other analytical techniques and has an average effective particle size within one of the effective particle size ranges set forth above.
- the mixing step is followed by an energy-addition step.
- Second Process Category The methods of the second processes category include essentially the same steps as in the steps of the first processes category but differ in the following respect.
- An x-ray diffraction, DSC or other suitable analytical techniques of the presuspension shows the organic compound in a crystalline form and having an average effective particle size.
- the organic compound after the energy-addition step has essentially the same average effective particle size as prior to the energy-addition step but has less of a tendency to aggregate into larger particles when compared to that of the particles of the presuspension. Without being bound to a theory, it is believed the differences in the particle stability may be due to a reordering of the surfactant molecules at the solid-liquid interface.
- Friable particles can be formed by selecting suitable solvents, surfactants or combination of surfactants, the temperature of the individual solutions, the rate of mixing and rate of precipitation and the like. Friability may also be enhanced by the introduction of lattice defects (e.g., cleavage planes) during the steps of mixing the first solution with the aqueous solvent. This would arise by rapid crystallization such as that afforded in the precipitation step.
- lattice defects e.g., cleavage planes
- these friable crystals are converted to crystals that are kinetically stabilized and having an average effective particle size smaller than those of the presuspension.
- Kinetically stabilized means particles have a reduced tendency to aggregate when compared to particles that are not kinetically stabilized.
- the energy- addition step results in a breaking up of the friable particles.
- the methods of the fourth process category include the steps of the first process category except that the mixing step is carried out simultaneously with the energy- ddition step.
- Polvmo ⁇ h Control further provides additional steps for controlling the crystal structure of an organic compound to ultimately produce a suspension of the compound in the desired size range and a desired crystal structure.
- crystal structure is the arrangement of the atoms within the unit cell of the crystal.
- Compounds that can be crystallized into different crystal structures are said to be polymo ⁇ hic. Identification of polymo ⁇ hs is important step in drug formulation since different polymo ⁇ hs of the same drug can show differences in solubility, therapeutic activity, bioavailability, and suspension stability. Accordingly, it is important to control the polymo ⁇ hic form of the compound for ensuring product purity and batch-to-batch reproducibility.
- the steps to control the polymo ⁇ hic form of the compound includes seeding the first solution, the second solvent or the pre-suspension to ensure the formation of the desired polymo ⁇ h. Seeding includes using a seed compound or adding energy.
- the seed compound is a pharmaceutically-active compound in the desired polymo ⁇ hic form.
- the seed compound can also be an inert impurity, a compound unrelated in structure to the desired polymo ⁇ h but with features that may lead to templating of a crystal nucleus, or an organic compound with a structure similar to that of the desired polymo ⁇ h.
- the seed compound can be precipitated from the first solution.
- This method includes the steps of adding the organic compound in sufficient quantity to exceed the solubility of the organic compound in the first solvent to create a supersaturated solution.
- the supersaturated solution is treated to precipitate the organic compound in the desired polymo ⁇ hic form.
- Treating the supersaturated solution includes aging the solution for a time period until the formation of a crystal or crystals is observed to create a seeding mixture.
- energy can be added in a variety of ways including the energy addition steps described above. Further energy can be added by heating, or by exposing the pre-suspension to electromagnetic energy, particle beam or electron beam sources.
- the electromagnetic energy includes light energy (ultraviolet, visible, or infrared) or coherent radiation such as that provided by a laser, microwave energy such as that provided by a maser (microwave amplification by stimulated emission of radiation), dynamic electromagnetic energy, or other radiation sources. It is further contemplated utilizing ultrasound, a static electric field, or a static magnetic field, or combinations of these, as the energy-addition source.
- the method for producing seed crystals from an aged supersaturated solution includes the steps of: (i) adding a quantity of an organic compound to the first organic solvent to create a supersaturated solution, (ii) aging the supersaturated solution to form detectable crystals to create a seeding mixture; and (iii) mixing the seeding mixture with the second solvent to precipitate the organic compound to create a pre-suspension.
- the presuspension can then be further processed as described in detail above to provide an aqueous suspension of the organic compound in the desired polymo ⁇ h and in the desired size range.
- Seeding can also be accomplished by adding energy to the first solution, the second solvent or the pre-suspension provided that the exposed liquid or liquids contain the organic compound or a seed material.
- the energy can be added in the same fashion as described above for the supersaturated solution.
- the present invention provides a composition of matter of an organic compound in a desired polymo ⁇ hic form essentially free of the unspecified polymo ⁇ h or polymo ⁇ hs.
- the organic compound is a pharmaceutically active substance.
- One such example is set forth in example 16 below where seeding during microprecipitation provides a polymo ⁇ h of itraconazole essentially free of the polymo ⁇ h of the raw material. It is contemplated the methods of this invention can be used to selectively produce a desired polymo ⁇ h for numerous pharmaceutically active compounds.
- Submicron suspensions of antineoplastic agents The methods described previously in this application can be used to prepare formulations containing suspensions of submicron particles of water-insoluble antineoplastic agents, particularly paclitaxel or its derivative compounds, including, but are limited to, docetaxel and other paclitaxel analogs. These formulations generally permit high drug loading containing 1-20% w/v drag. Higher than 20% w/v drag loading can also be accomplished with these formulations.
- the same formulation can be administered by various routes, e.g., oral, parenteral, and pulmonary.
- the particles of the antineoplastic agent can be formulated both to remove cremophor as an excipient as well as to achieve a dosage form having the characteristic of long circulation time.
- Particles formulated with surface modifiers with polyethylene glycol (PEG) functionality can be used to avoid particle opsonization and consequent reticuloendothelial system (RES) uptake.
- particles having particle size of less than 200 nm, and particularly less than 150 nm can be used to aid long-circulation time as well as tumor targeting by permeation through fenestrated tumor vasculature.
- a preferred method of preparing the submicron particles of these antineoplastic agents consists of: (i) mixing into the water-miscible first solvent or the second solvent or both the water-miscible first solvent and the second solvent a first surface modifier comprising a phospholipid conjugated with a water-soluble or hydrophilic polymer; (ii) dissolving the antineoplastic agent in the water-miscible first solvent to form a solution; (iii) mixing the solution with the second solvent to define a pre-suspension of particles; and (iv) homogenizing the pre-suspension to form a suspension of particles having an average effective particle size of less than about 1 ⁇ m.
- a preferred water- miscible first solvent is N-methyl-2-pyrrolidinone.
- the particles have an average effective particle size of less than about 400 nm, more preferably less than 200 nm, and most preferably, less than about 150 nm.
- the phospholipid used can be natural or synthetic.
- suitable phohospholipds include, but are not limited to, phosphatidylcholine, phosphatidylethanolamine, diacyl-glycero-phosphoethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, lysophospholipids, egg or soybean phospholipid or a combination thereof.
- the diacyl-glycero- phosphethanolamine can be selected from: dimyristoyl-glycero-phosphoethanolamine (DMPE), dipalmitoyl-glycero-phosphoethanolamine (DPPE), distearoyl-glycero- phosphoethanolamine (DSPE), dioleolyl-glycero-phosphoethanolamine (DOPE) or the like.
- DMPE dimyristoyl-glycero-phosphoethanolamine
- DPPE dipalmitoyl-glycero-phosphoethanolamine
- DSPE distearoyl-glycero- phosphoethanolamine
- DOPE dioleolyl-glycero-phosphoethanolamine
- the water-soluble or hydrophilic polymer conjugating to the phospholipid is polyethylene glycol (PEG), such as, but are not limited to, PEG 350, PEG 550, PEG 750, PEG 1000, PEG 2000, PEG 3000, and PEG 5000.
- hydrophilic polymer conjugates can also be used, e.g., dextran, hydroxypropyl methacrylate (HPMA), polyglutamate and the like.
- a second surface modifier can be mixed into the water-miscible first solvent or the second solvent or both the water-miscible first solvent and the second solvent.
- the second surface modifier may be needed to further stabilize the particles.
- the second surface modifier can be selected from anionic surfactants, cationic surfactants, nonionic surfactants and surface active biological modifiers as described in detail previously in this application.
- a preferred second surface modifier is poloxamer, such as poloxamer 188.
- the size of the particles produced can be controlled by the temperature at which the homogenization is carried out, as shown in the examples in Example 19.
- the homogenization is carried out at about 30°C or greater, such as at about 40°C or about 70°C.
- the methods can further include removing the water-miscible first solvent from the suspension to form an aqueous suspension of the particles which is essentially solvent free.
- the water-miscible first solvent is removed simultaneously with homogenization as described in detail in a co-pending and commonly assigned U.S. Patent Application Attorney Docket Number 113957-375.
- the method can also further include removing the entire liquid phase of the suspension to form a dry powder of the particles.
- the dry powder can be administered to a subject by the pulmonary route, or it can be resuspended in an appropriate diluent, such as a diluent suitable for parenteral or oral administration.
- the particles can also be formulated for oral administration.
- Formulations for parenteral and oral administrations are well known for those skilled in the art. The same formulation is can used for administration to a subject by various routes, such as, but are not limited to, parenteral, oral, pulmonary, topical, ophthalmic, nasal, buccal, rectal, vaginal, and transdermal.
- the method can also further include sterilizing the composition as previously described in this application.
- Methods for sterilizing pharmaceutical compositions include, but are not limited to filtration, heat sterilization, and gamma irradiation.
- Heat sterilization may be effected by the heat within the homogenizer in which the homogenizer serves as a heating and pressurization source for sterilization.
- the particles are not soluble.
- the particles can be tested for their solubility by dissolution kinetics using % transmission at 400 nm as a measure for dissolution.
- the particles are not soluble if % transmission does not return to 95% or more of the initial value.
- the particles do not aggregate under stressed conditions or upon storage. Examples of stressed conditions include, but are not limited to, thermal cycling, repeated freeze-thaw cycling, agitation, and centrifugation.
- Example 1 Preparation of itraconazole suspension by use of Process Category 1.
- Method A with homogenization. To a 3-L flask add 1680 mL of Water for Injection. Heat liquid to 60-65°C, and then slowly add 44 grams of Pluronic F-68 (poloxamer 188), and 12 grams of sodium deoxycholate, stirring after each addition to dissolve the solids. After addition of solids is complete, stir for another 15 minutes at 60-65°C to ensure complete dissolution.
- Prepare a 50 mM tris (fromemamine) buffer by dissolving 6.06 grams of tris in 800 mL of Water for Injection. Titrate this solution to pH 8.0 with 0.1 M hydrochloric acid.
- Suspension A is observed by light microscopy to consist of roughly spherical amo ⁇ hous particles (under 1 micron), either bound to each other in aggregates or freely moving by Brownian motion. See FIG. 3.
- Dynamic light scattering measurements typically afford a bimodal distribution pattern signifying the presence of aggregates (10-100 microns in size) and the presence of single amo ⁇ hous particles ranging 200-700 nm in median particle diameter.
- the suspension is immediately homogenized (at 10,000 to 30,000 psi) for 10- 30 minutes. At the end of homogenization, the temperature of the suspension in the hopper does not exceed 75°C.
- the homogenized suspension is collected in 500-mL bottles, which are cooled immediately in the refrigerator (2-8°C).
- This suspension (Suspension B) is analyzed by light microscopy and is found to consist of small elongated plates with a length of 0.5 to 2 microns and a width in the 0.2-1 micron range. See FIG. 4. Dynamic light scattering measurements typically indicate a median diameter of 200-700 nm.
- Suspension A Stability of Suspension A
- Pre-suspension Example 1
- Suspension A was stored at 2-8 °C for 12 hours and examined by light microscopy. Gross visual inspection of the sample revealed severe flocculation, with some of the contents settling to the bottom of the container. Microscopic examination indicated the presence of large, elongated, platelike crystals over 10 microns in length.
- Example 2 Preparation of itraconazole suspension by use of Process Category 1.
- Method A with ultrasonication.
- To a 500-mL stainless steel vessel add 252 mL of Water for Injection. Heat liquid to 60-65°C, and then slowly add 6.6 grams of Pluronic F-68 (poloxamer 188), and 0.9 grams of sodium deoxycholate, stirring after each addition to dissolve the solids. After addition of solids is complete, stir for another 15 minutes at 60-65°C to ensure complete dissolution.
- Prepare a 50 mM tris (tromethamine) buffer by dissolving 6.06 grams of tris in 800 mL of Water for Injection. Titrate this solution to pH 8.0 with 0.1 M hydrochloric acid.
- Example 3 Preparation of itraconazole suspension by use of Process Category 1, Method B with homogenization. Prepare a 50 mM tris (tromethamine) buffer by dissolving 6.06 grams of tris in
- Example 4 Preparation of itraconazole suspension by use of Process Category 1. Method B with ultrasonication. To a 500-mL flask add 252 mL of Water for Injection. Prepare a 50 mM tris
- the resulting cooled suspension is immediately sonicated (10,000 to 25,000 Hz, at least 400 W) for 15-20 minutes, in 5- minute intervals. After the first 5-minute sonication, remove the ice bath and proceed with further sonication. At the end of ultrasonication, the temperature of the suspension in the hopper does not exceed 75°C.
- the resultant suspension is collected in a 500-mL bottle, which is cooled immediately in the refrigerator (2-8°C). Characteristics of particle mo ⁇ hology of the suspension before and after sonication were very similar to that seen in Example 1, except that in Process Category 1, Method B, the pre-sonicated material tended to form fewer and smaller aggregates which resulted in a much smaller overall particle size as measured by laser diffraction. After ultrasonication, dynamic light scattering results were typically identical to those presented in Example 1
- Example 5 Preparation of itraconazole suspension (1%) with 0.75% Solutol® HR (PEG-660 12-hvdroxystearate Process Category 2, Method B.
- Solutol (2.25 g) and itraconazole (3.0 g) were weighed into a beaker and 36 mL of filtered N-methyl-2-pyrrolidinone (NMP) was added. This mixture was stirred under low heat (up to 40°C) for approximately 15 minutes until the solution ingredients were dissolved. The solution was cooled to room temperature and was filtered through a 0.2-micron filter under vacuum. Two 60-mL syringes were filled with the filtered drug concentrate and were placed in a syringe pump.
- NMP N-methyl-2-pyrrolidinone
- the pump was set to deliver approximately 1 mL/min of concentrate to a rapidly stirred (400 ⁇ m) aqueous buffer solution.
- the buffer solution consisted of 22 g/L of glycerol in 5 mM tris buffer. Throughout concentrate addition, the buffer solution was kept in an ice bath at 2-3°C. At the end of the precipitation, after complete addition of concentrate to the buffer solution, about 100 mL of the suspension was centrifuged for 1 hour, the supernatant was discarded. The precipitate was resuspended in a 20% NMP solution in water, and again centrifuged for 1 hour. The material was dried overnight in a vacuum oven at 25°C.
- the dried material was transferred to a vial and analyzed by X- ray diffractometry using chromium radiation (see FIG. 5).
- the sonicated sample was homogenized in 3 equal aliquots each for 45 minutes (Avestin C5, 2-5°C, 15,000-20,000 psi).
- the combined fractions were centrifuged for about 3 hours, the supernatant removed, and the precipitate resuspended in 20% NMP.
- the resuspended mixture was centrifuged again (15,000 ⁇ m at 5°C).
- Example 6 Preparation of carbamazepine suspension by use of Process Category 3.
- Example 7 Preparation of 1% carbamazepine suspension with 0.125% Solutol ® by use of Process Category 3. Method B with homogenization.
- the microprecipitation step involved adding the drug concentrate to the receiving solution (distilled water) at a rate of 0.1 mL min. The receiving solution was stirred and maintained at approximately 5°C during precipitation. After precipitation, the final ingredient concentrations were 1% carbamazepine and 0.125% Solutol ® .
- the drug crystals were examined under a light microscope using positive phase contrast (400X).
- the precipitate consisted of fine needles approximately 2 microns in diameter and ranging from 50 - 150 microns in length.
- Homogenization At approximately 20,000 psi for approximately 15 minutes results in small particles, less than 1 micron in size and largely unaggregated.
- Laser diffraction analysis (Horiba) of the homogenized material showed that the particles had a mean size of 0.4 micron with 99% of the particles less than 0.8 micron.
- Low energy sonication suitable for breaking agglomerated particles, but not- with sufficient energy to cause a comminution of individual particles, of the sample before Horiba analysis had no effect on the results (numbers were the same with and without sonication).
- Example 8 Preparation of 1% carbamazepine suspension with 0.06% sodium glycodeoxycholate and 0.06% poloxamer 188 by use of Process Category 3.
- Method B with homogenization.
- a drag concentrate comprising 20% carbamazepine and 5% glycodeoxycholate in N-methyl-2- ⁇ yrrolidinone was prepared.
- the microprecipitation step involved adding the drag concentrate to the receiving solution (distilled water) at a rate of 0.1 mL/min.
- the receiving solution was stirred and maintained at approximately 5°C during precipitation.
- Equating (e ⁇ o and e ⁇ , 6PL/(Ewx 2 ) 6P 0 L/(Ew 0 xo 2 )
- the yield force, P, required to break the microprecipitated solid is one- thousandth the required force necessary to break the starting crystalline solid. If, because of rapid precipitation, lattice defects or amo ⁇ hic properties are introduced, then the modulus (E) should decrease, making the microprecipitate even easier to cleave.
- Example 9 Preparation of 1.6% (w/v) prednisolone suspension with 0.05% sodium deoxycholate and 3% N-methyl-2-pyrrolidinone Process Category 3.
- Method B A schematic of the overall manufacturing process is presented in FIG. 8. A concentrated solution of prednisolone and sodium deoxycholate was prepared. Prednisolone (32g) and sodium deoxycholate (lg) were added to a sufficient volume of 1 -methyl 2-pyrrolidinone (NMP) to produce a final volume of 60 mL. The resulting prednisolone concentration was approximately 533.3 mg/mL and the sodium deoxycholate concentration was approximately 16.67 mg/mL.
- NMP concentrate 60mL of NMP concentrate was added to 2 L of water cooled to 5°C at an addition rate of 2.5 mL/min while stirring at approximately 400 ⁇ m.
- the resulting suspension contained slender needle-shaped crystals less than 2 ⁇ m in width (FIG. 9).
- concentration contained in the precipitated suspension was 1.6% (w/v) prednisolone, 0.05% sodium deoxycholate, and 3% NMP.
- the precipitated suspension was pH adjusted to 7.5-8.5 using sodium hydroxide and hydrochloric acid then homogenized (Avestin C-50 piston-gap homogenizer) for 10 passes at 10,000 psi.
- the NMP was removed by performing 2 successive centrifugation steps replacing the supernatant each time with a fresh surfactant solution, which contained the desired concentrations of surfactants needed to stabilize the suspension (see Table 2).
- the suspension was homogenized for another 10 passes at 10,000 psi.
- the final suspension contained particles with a mean particle size of less than 1 ⁇ m, and 99% of particles less than 2 ⁇ m.
- FIG. 10 is a photomicrograph of the final prednisolone suspension after homogenization. A variety of different surfactants at varying concentrations were used in the centrifugation/surfactant replacement step (see Table 2).
- Table 2 lists combinations of surfactants that were stable with respect to particle size (mean ⁇ 1 ⁇ m, 99% ⁇ 2 ⁇ m), pH (6-8), drug concentration (less than 2% loss) and re-suspendability (resuspended in 60 seconds or less). Notably this process allows for adding the active compound to an aqueous diluent without the presence of a surfactant or other additive. This is a modification of process Method B in FIG. 2.
- Table 2 List of stable prednisolone suspensions prepared by microprecipitation process of FIG. 8 (Example 9)
- the post-precipitated dispersion was next homogenized cold (5-15 °C) for 20 passes at 10,000 psi. Following homogenization, the NMP was removed by centrifuging the suspension, removing the supernatant, and replacing the supernatant with fresh surfactant solution. This post- centrifuged suspension was then rehomogenized cold (5-15 °C) for another 20 passes at 10,000 psi.
- the particles produced by this process had a mean diameter of 0.927 ⁇ m with 99% of the particles being less than 2.36 ⁇ m.
- Example 11 Preparation of nabumetone suspension by use of Process Category 3. Method B with homogenization.
- Surfactant 2.2 g of poloxamer 188) was dissolved in 6 mL of N-methyl-2- pyrrolidinone. This solution was stirred at 45 °C for 15 minutes, after which 1.0 g of nabumetone was added. The drag dissolved rapidly.
- Diluent was prepared which consisted of 5 mM tris buffer with 2.2% glycerol, and adjusted to pH 8. A 100-mL portion of diluent was cooled in an ice bath. The drag concentrate was slowly added (approximately 0.8 mL/min) to the diluent with vigorous stirring.
- the final nanosuspension was found to be 930 nm in effective mean diameter (analyzed by laser diffraction). 99% of the particles were less than approximately 2.6 microns.
- Example 12 Preparation of nabumetone suspension by use of Process Category 3.
- Diluent was prepared, which consisted of 5 mM tris buffer with 2.2% glycerol, and which was adjusted to pH 8. The diluent was cooled in an ice bath, and the drag concentrate was slowly added (approximately 0.5 mL/min) to the diluent with vigorous stirring. This crude suspension was homogenized for 20 minutes at 15,000 psi, and for 30 minutes at 20,000 psi. The suspension was centrifuged at 15,000 ⁇ m for 15 minutes and the supernatant was removed and discarded. The remaining solid pellet was resuspended in a diluent consisting of 1.2% phospholipids. This medium was equal in volume to the amount of supernatant removed in the previous step.
- the resulting suspension was then homogenized at approximately 21,000 psi for 30 minutes.
- the final suspension was analyzed by laser diffraction and was found to contain particles with a mean diameter of 542 nm, and a 99% cumulative particle distribution sized less than 1 micron.
- Example 13 Preparation of 1 % itraconazole suspension with poloxamer with particles of a mean diameter of approximately 220 nm Itraconazole concentrate was prepared by dissolving 10.02 grams of itraconazole in 60 mL of N-methyl-2-pyrrolidinone. Heating to 70°C was required to dissolve the drag. The solution was then cooled to room temperature. A portion of 50 mM tris(hydroxymethyl)aminomethane buffer (tris buffer) was prepared and was pH adjusted to 8.0 with 5M hydrochloric acid.
- tris buffer tris(hydroxymethyl)aminomethane buffer
- An aqueous surfactant solution was prepared by combining 22 g/L poloxamer 407, 3.0 g/L egg phosphatides, 22g/L glycerol, and 3.0 g L sodium cholate dihydrate. 900 mL of the surfactant solution was mixed with 100 mL of the tris buffer to provide 1000 mL of aqueous diluent. The aqueous diluent was added to the hopper of the homogenizer (APV Gaulin Model 15MR-8TA), which was cooled by using an ice jacket. The solution was rapidly stirred (4700 ⁇ m) and the temperature was monitored.
- API Gaulin Model 15MR-8TA homogenizer
- the itraconazole concentrate was slowly added, by use of a syringe pump, at a rate of approximately 2 mL/min. Addition was complete after approximately 30 minute. The resulting suspension was stirred for another 30 minutes while the hopper was still being cooled in an ice jacket, and an aliquot was removed for analysis by light microscopy any dynamic light scatting. The remaining suspension was subsequently homogenized for 15 minutes at 10,000 psi. By the end of the homogenization the temperature had risen to 74°C. The homogenized suspension was collected in a 1-L Type I glass bottle and sealed with a rubber closure. The bottle containing suspension was stored in a refrigerator at 5°C.
- FIG. 11 shows a comparison of the size distribution of the prepared nanosuspension with that of a typical parenteral fat emulsion product (10% Intralipid®, Pharmacia).
- Example 14 Preparation of 1% itraconazole nanosuspension with hydroxyethylstarch
- Solution A Hydroxyethylstarch (1 g, Ajinomoto) was dissolved in 3 mL of N-methyl-2-pyrrolidinone (NMP). This solution was heated in a water bath to 70-80°C for 1 hour. In another container was added 1 g of itraconazole (Wyckoff). Three mL of NMP were added and the mixture heated to 70-80°C to effect dissolution (approximately 30 minutes). Phospholipid (Lipoid S-100) was added to this hot solution. Heating was continued at 70-90°C for 30 minutes until all of the phospholipid was dissolved.
- NMP N-methyl-2-pyrrolidinone
- Example 15 Prophetic example of Method A using HES
- the present invention contemplates preparing a 1% itraconazole nanosuspension with hydroxyethylstarch utilizing Method A by following the steps of Example 14 with the exception the HES would be added to the tris buffer solution instead of to the NMP solution.
- the aqueous solution may have to be heated to dissolve the HES.
- Example 16 Seeding during Homogenization to Convert a Mixture of Polvmo ⁇ hs to the More Stable Polvmo ⁇ h Sample preparation.
- An itraconazole nanosuspension was prepared by a microprecipitation-homogenization method as follows. Itraconazole (3g) and Solutol HR (2.25g) were dissolved in 36mL of N-methyl-2-pyrrolidinone (NMP) with low heat and stirring to form a drag concentrate solution. The solution was cooled to room temperature and filtered through a 0.2 ⁇ m nylon filter under vacuum to remove undissolved drag or particulate matter. The solution was viewed under polarized light to ensure that no crystalline material was present after filtering.
- NMP N-methyl-2-pyrrolidinone
- the drug concentrate solution was then added at 1.0 mL/minute to approximately 264 mL of an aqueous buffer solution (22 g/L glycerol in 5 mM tris buffer).
- the aqueous solution was kept at 2-3°C and was continuously stirred at approximately 400 ⁇ m during the drag concentrate addition.
- Approximately 100 mL of the resulting suspension was centrifuged and the solids resuspended in a pre-filtered solution of 20% NMP in water. This suspension was re-centrifuged and the solids were transferred to a vacuum oven for overnight drying at 25 °C.
- the resulting solid sample was labeled SMP 2 PRE. Sample characterization.
- the sample SMP 2 PRE and a sample of the raw material itraconazole were analyzed using powder x-ray diffractometry.
- the measurements were performed using a Rigaku MiniFlex+ instrument with copper radiation, a step size of 0.02° 22 and scan speed of 0.25° 22/minute.
- the resulting powder diffraction patterns are shown in FIG. 12.
- the patterns show that SMP-2-PRE is significantly different from the raw material, suggesting the presence of a different polymo ⁇ h or a pseudopolymo ⁇ h.
- DSC Differential scanning calorimetry
- FIGS. 13a and b Both samples were heated at 2 min to 180°C in hermetically sealed aluminum pans.
- the trace for the raw material itraconazole (FIG. 13a) shows a sha ⁇ endotherm at approximately 165°C.
- the trace for SMP 2 PRE (FIG. 13b) exhibits two endotherms at approximately
- SMP 2 PRE consists of a mixture of polymo ⁇ hs, and that the predominant form is a polymo ⁇ h that is less stable than polymo ⁇ h present in the raw material. Further evidence for this conclusion is provided by the DSC trace in FIG. 14, which shows that upon heating SMP 2 PRE through the first transition, then cooling and reheating, the less stable polymo ⁇ h melts and recrystallizes to form the more stable polymo ⁇ h. Seeding.
- a suspension was prepared by combining 0.2g of the solid SMP 2 PRE and 0.2g of raw material itraconazole with distilled water to a final volume of 20 mL (seeded sample). The suspension was stirred until all the solids were wetted. A second suspension was prepared in the same manner but without adding the raw material itraconazole (unseeded sample). Both suspensions were homogenized at approximately 18,000 psi for 30 minutes. Final temperature of the suspensions after homogenization was approximately 30°C. The suspensions were then centrifuged and the solids dried for approximately 16 hours at 30°C.
- FIG. 15 shows the DSC traces of the seeded and unseeded samples. The heating rate for both samples was 2 min to 180°C in hermetically sealed aluminum pans.
- the trace for the unseeded sample shows two endotherms, indicating that a mixture of polymo ⁇ hs is still present after homogenization.
- the trace for the seeded sample shows that seeding and homogenization causes the conversion of the solids to the stable polymo ⁇ h. Therefore, seeding appears to influence the kinetics of the transition from the less stable to the more stable polymo ⁇ hic form.
- Example 17 Seeding during Precipitation to Preferentially Form a Stable Polvmo ⁇ h Sample preparation.
- An itraconazole-NMP drug concentrate was prepared by dissolving 1.67g of itraconazole in lOmL of NMP with stirring and gentle heating. The solution was filtered twice using 0.2 ⁇ m syringe filters. Itraconazole nanosuspensions were then prepared by adding 1.2 mL of the drag concentrate to 20 mL of an aqueous receiving solution at approx. 3°C and stirring at approx. 500 ⁇ m.
- a seeded nanosuspension was prepared by using a mixture of approx. 0.02g of raw material itraconazole in distilled water as the receiving solution.
- An unseeded nanosuspension was prepared by using distilled water only as the receiving solution. Both suspensions were centrifuged, the supernatants decanted, and the solids dried in a vacuum oven at
- FIG. 16 shows a comparison of the DSC traces for the solids from the seeded and unseeded suspensions. The samples were heated at
- the dashed line represents the unseeded sample, which shows two endotherms, indicating the presence of a polymo ⁇ hic mixture.
- the solid line represents the seeded sample, which shows only one endotherm near the expected melting temperature of the raw material, indicating that the seed material induced the exclusive formation of the more stable polymo ⁇ h.
- Example 18 Polvmo ⁇ h control by seeding the drag concentrate Sample preparation.
- the solubility of itraconazole in NMP at room temperature (approximately 22°C) was experimentally determined to be 0.16 g/mL.
- a 0.20 g/mL drag concentrate solution was prepared by dissolving 2.0 g of itraconazole and 0.2 g Poloxamer 188 in 10 mL NMP with heat and stirring. This solution was then allowed to cool to room temperature to yield a supersaturated solution.
- a microprecipitation experiment was immediately performed in which 1.5 mL of the drug concentrate was added to 30 mL of an aqueous solution containing 0.1% deoxycholate, 2.2% glycerol.
- the aqueous solution was maintained at ⁇ 2°C and a stir rate of 350 ⁇ m during the addition step.
- the resulting presuspension was homogenized at ⁇ 13,000 psi for approx. 10 minutes at 50°C.
- the suspension was then centrifuged, the supernatant decanted, and the solid crystals dried in a vacuum oven at 30°C for 135 hours.
- the supersaturated drag concentrate was subsequently aged by storing at room temperature in order to induce crystallization. After 12 days, the drug concentrate was hazy, indicating that crystal formation had occurred.
- An itraconazole suspension was prepared from the drug concentrate, in the same manner as in the first experiment, by adding 1.5 mL to 30 mL of an aqueous solution containing 0.1% deoxycholate, 2.2% glycerol. The aqueous solution was maintained at ⁇ 5°C and a stir rate of 350 ⁇ m during the addition step. The resulting presuspension was homogenized at ⁇ 13,000 psi for approx. 10 minutes at 50°C. The suspension was then centrifuged, the supernatant decanted, and the solid crystals dried in a vacuum oven at 30°C for 135 hours.
- Example 19 Microprecipitation and Homogenization Processes for Making Paclitaxel Particles
- Example A A solution of paclitaxel in NMP was precipitated in a surfactant solution containing 0.5% poloxamer 188 and 0.05% mPEG-DSPE (with 2% glycerin as a tonicity agent), at low temperature ( ⁇ 10°C). The total suspension volume was 10 mL, with a drug concentration of 1% (w/v). High pressure homogenization was carried out immediately after precipitation, at a pressure of ⁇ 25,000 psi at a temperature of 40°C. After homogenization (20 minutes), particle size of the suspension was examined using light scattering. Mean particle size was 186 nm.
- Example B A solution of paclitaxel in NMP was precipitated in a surfactant solution containing 0.5% w/v poloxamer 188 and 0.05% w/v mPEG-DSPE (with 2% w/v glycerin as a tonicity agent), at low temperature ( ⁇ 10°C). The total suspension volume was 20 mL, with a drag concentration of 1% (w/v). High pressure homogenization was carried out immediately after precipitation, at a pressure of ⁇ 25,000 psi at a temperature of 40°C. After 30 minutes homogenization, particle size of the suspension was examined using light scattering. Mean particle size was 204 nm.
- Example C A solution of paclitaxel in NMP was precipitated in a surfactant solution containing 0.5% poloxamer 188 and 0.05% mPEG-DSPE (with 2% glycerin as a tonicity agent), at low temperature ( ⁇ 10°C). The total suspension volume was 10 mL, with a drag concentration of 1% (w/v). High pressure homogenization was carried out immediately after precipitation, at a pressure of ⁇ 25,000 psi at a temperature of 70°C. After homogenization, particle size of the suspension was examined using light scattering. Mean particle size was 158 nm. About 45% of particles were under 150 nm.
- Example D A solution of paclitaxel in NMP was precipitated in a surfactant solution containing 0.05% mPEG-DSPE (with 2% glycerin as a tonicity agent), at low temperature ( ⁇ 10°C). The total suspension volume was 10 mL, with a drag concentration of 1% (w/v). High pressure homogenization was carried out immediately after precipitation, at a pressure of ⁇ 25,000 psi at a temperature of 40°C. After homogenization, particle size of the suspension was examined using light scattering. Mean particle size was 244 nm.
- Example 20 Dissolution Characteristics of Paclitaxel Submicron Particles
- One of the desirable characteristics of submicron formulations of antineoplastic drags is that they do not dissolve in order to facilitate long circulation when administered to a subject.
- Two formulations of paclitaxel particles prepared by the methods described in Example 19 were tested for their solubility by dissolution kinetics using % transmission at 400 nm as a measure for dissolution. The particles are not soluble if % transmission does not return to 100% after addition of suspension.
- One formulation contains the surface modifiers poloxamer 188 (PI 88) and mPEG- DSPE.
- the other formulation contains the surface modifier of mPEG-DSPE only. The results are shown in FIG. 18. In both cases, % transmission did not rise after the initial drop to about 60%, indicating that the particles do not dissolve.
- Example 21 Stability of Paclitaxel Submicron Particles Under Stressed Conditions and Upon Storage Stability of the submicron paclitaxel particles prepared in Example A of Example 19 was tested using accelerated stress testing as well as storage at 5°C for one month. As shown in FIGs. 19 and 20, the mean particle size and the 99 th percentile both remained virtually unchanged. No aggregation was observed for the formulation either, even after all the stress tests. Aggregation was estimated by measuring particle size before and after 1 minute sonication and comparing the difference via the following equation: % Aggregation where P99 represents 99 th percentile of the particle size distribution before sonication, and P 99S represents 99 th percentile of the particle size distribution after sonication.
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Abstract
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DK04810266.9T DK1682116T3 (en) | 2003-11-07 | 2004-11-03 | Process for producing submicron particles of paclitaxel or docetaxel |
PL04810266T PL1682116T3 (en) | 2003-11-07 | 2004-11-03 | Method for preparing submicron particles of paclitaxel or docetaxel |
EP04810266A EP1682116B1 (en) | 2003-11-07 | 2004-11-03 | Method for preparing submicron particles of paclitaxel or docetaxel |
ES04810266T ES2388924T3 (en) | 2003-11-07 | 2004-11-03 | Method for preparing submicron particles of paclitaxel or docetaxel |
AU2004289233A AU2004289233B2 (en) | 2003-11-07 | 2004-11-03 | Method for preparing submicron particles of paclitaxel |
JP2006538455A JP2007510657A (en) | 2003-11-07 | 2004-11-03 | Process for preparing submicron particles of paclitaxel |
BRPI0416239-0A BRPI0416239A (en) | 2003-11-07 | 2004-11-03 | method for preparing paclitaxel submicron particles |
NZ546439A NZ546439A (en) | 2003-11-07 | 2004-11-03 | Method for preparing submicron particles of paclitaxel |
CA002540383A CA2540383A1 (en) | 2003-11-07 | 2004-11-03 | Method for preparing submicron particles of paclitaxel |
IL174031A IL174031A (en) | 2003-11-07 | 2006-03-01 | Method for preparing submicron particles of paclitaxel |
KR1020067008686A KR101152458B1 (en) | 2003-11-07 | 2006-05-04 | Method for preparing submicron particles of paclitaxel |
NO20062552A NO20062552L (en) | 2003-11-07 | 2006-06-02 | Process for the preparation of submicrometer-sized particles of paclitaxel |
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US10/703,395 US8067032B2 (en) | 2000-12-22 | 2003-11-07 | Method for preparing submicron particles of antineoplastic agents |
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- 2004-11-03 JP JP2006538455A patent/JP2007510657A/en active Pending
- 2004-11-03 EP EP04810266A patent/EP1682116B1/en active Active
- 2004-11-03 RU RU2006119916/15A patent/RU2402313C2/en not_active IP Right Cessation
- 2004-11-03 DK DK04810266.9T patent/DK1682116T3/en active
- 2004-11-03 ES ES04810266T patent/ES2388924T3/en active Active
-
2006
- 2006-03-01 IL IL174031A patent/IL174031A/en active IP Right Grant
- 2006-05-04 KR KR1020067008686A patent/KR101152458B1/en active IP Right Grant
- 2006-05-04 ZA ZA200603547A patent/ZA200603547B/en unknown
- 2006-06-02 NO NO20062552A patent/NO20062552L/en not_active Application Discontinuation
-
2011
- 2011-09-23 US US13/242,894 patent/US20120070498A1/en not_active Abandoned
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Cited By (26)
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WO2006110862A3 (en) * | 2005-04-12 | 2007-07-05 | Wisconsin Alumni Res Found | Micelle composition of polymer and passenger drug |
US8173167B2 (en) | 2005-04-12 | 2012-05-08 | Wisconsin Alumni Research Foundation | Micelle composition of polymer and passenger drug |
WO2006110862A2 (en) * | 2005-04-12 | 2006-10-19 | Wisconsin Alumni Research Foundation | Micelle composition of polymer and passenger drug |
US9107814B2 (en) | 2005-04-12 | 2015-08-18 | Wisconsin Alumni Research Foundation | Micelle composition of polymer and passenger drug |
JP2009542761A (en) * | 2006-07-13 | 2009-12-03 | ユニリーバー・ナームローゼ・ベンノートシヤープ | Improvements related to antiparasitic compositions |
JP2009542793A (en) * | 2006-07-13 | 2009-12-03 | ユニリーバー・ピーエルシー | Preparation of pharmaceutical composition |
US8795634B2 (en) | 2008-09-12 | 2014-08-05 | Critical Pharmaceuticals Limited | Absorption of therapeutic agents across mucosal membranes or the skin |
WO2010138660A1 (en) * | 2009-05-27 | 2010-12-02 | Sanofi-Aventis | Anticancer pharmaceutical formulation |
US10945948B2 (en) | 2012-05-03 | 2021-03-16 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US10857096B2 (en) | 2012-05-03 | 2020-12-08 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US9737491B2 (en) | 2012-05-03 | 2017-08-22 | The Johns Hopkins University | Nanocrystals, compositions, and methods that aid particle transport in mucus |
US9827191B2 (en) | 2012-05-03 | 2017-11-28 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US10646437B2 (en) | 2012-05-03 | 2020-05-12 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US10646436B2 (en) | 2012-05-03 | 2020-05-12 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US10688041B2 (en) | 2012-05-03 | 2020-06-23 | Kala Pharmaceuticals, Inc. | Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus |
US10688045B2 (en) | 2012-05-03 | 2020-06-23 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US10736854B2 (en) | 2012-05-03 | 2020-08-11 | The Johns Hopkins University | Nanocrystals, compositions, and methods that aid particle transport in mucus |
US11878072B2 (en) | 2012-05-03 | 2024-01-23 | Alcon Inc. | Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus |
US11872318B2 (en) | 2012-05-03 | 2024-01-16 | The Johns Hopkins University | Nanocrystals, compositions, and methods that aid particle transport in mucus |
US10993908B2 (en) | 2012-05-03 | 2021-05-04 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US11219597B2 (en) | 2012-05-03 | 2022-01-11 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US11219596B2 (en) | 2012-05-03 | 2022-01-11 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
US11318088B2 (en) | 2012-05-03 | 2022-05-03 | Kala Pharmaceuticals, Inc. | Compositions and methods utilizing poly(vinyl alcohol) and/or other polymers that aid particle transport in mucus |
US11642317B2 (en) | 2012-05-03 | 2023-05-09 | The Johns Hopkins University | Nanocrystals, compositions, and methods that aid particle transport in mucus |
DE102012221219A1 (en) | 2012-11-20 | 2014-05-22 | Jesalis Pharma Gmbh | Process for increasing the particle size of crystalline drug microparticles |
WO2014079801A1 (en) | 2012-11-20 | 2014-05-30 | Jesalis Pharma Gmbh | Method for increasing the particle size of crystalline active micro-particles |
Also Published As
Publication number | Publication date |
---|---|
KR101152458B1 (en) | 2012-06-01 |
US20040245662A1 (en) | 2004-12-09 |
EP1682116B1 (en) | 2012-05-30 |
AU2004289233A1 (en) | 2005-05-26 |
CN100551365C (en) | 2009-10-21 |
PL1682116T3 (en) | 2012-10-31 |
EP1682116A1 (en) | 2006-07-26 |
NO20062552L (en) | 2006-06-02 |
US20120070498A1 (en) | 2012-03-22 |
ZA200603547B (en) | 2007-04-25 |
BRPI0416239A (en) | 2007-01-09 |
IL174031A0 (en) | 2006-08-01 |
JP2007510657A (en) | 2007-04-26 |
ES2388924T3 (en) | 2012-10-19 |
RU2402313C2 (en) | 2010-10-27 |
IL174031A (en) | 2012-04-30 |
KR20060118455A (en) | 2006-11-23 |
RU2006119916A (en) | 2007-12-20 |
DK1682116T3 (en) | 2012-09-03 |
NZ546439A (en) | 2010-04-30 |
US8067032B2 (en) | 2011-11-29 |
CN1870987A (en) | 2006-11-29 |
AU2004289233B2 (en) | 2010-10-21 |
CA2540383A1 (en) | 2005-05-26 |
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