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
  • A61K9/14—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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Definitions

• the present invention relates to crystalline drug particles and in particular relates to crystalline drug particles prepared, using a controlled, precipitation process.
• Bioavailability is a term meaning the degree to which a pharmaceutical product, or drug, becomes available to the target tissue after being administered to the body. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is poorly soluble in water. Poorly water soluble drugs tend to be eliminated from the gastrointestinal tract before being absorbed into the circulation.
• U.S. Patent 5,716,642 teaches the use of an acid-base precipitation method. However, the method described in the '642 patent results in a large concentration of salt which must be removed via dialysis in order to obtain relatively pure drug particles. Examples of solvent precipitation methods are described in U.S. Patent Nos. 4,826,689 and 6,221,398 Bl, in Hasegawa et al, "Supersaturation Mechanism of Drugs from Solid Dispersions with Enteric Coating Agents, Chem. Pharm. Bull. Vol. 36, No. 12, p. 4941 (1988), and Frederic Ruch and Egon Matijevic, Preparation of Micrometer Size
• the crystal lattice is generally recognized to be a highly ordered structure which repeats itself regularly in three dimensions.
• crystal lattice imperfections developed during the crystal growth step may cause dislocations within the crystal which are considered to be thermodynamically instable, resulting in an increase in free energy and a reduction in the activation energy for dissolution at points where the dislocations emerge on the crystal surface.
• the present invention is particles comprising a plurality of crystalline domains, wherein each crystalline domain is oriented differently than any of the adjacent domains; and a plurality of interfacial regions surrounding the crystalline domains; wherein the crystalline domains comprise a drug substance, and wherein the interfacial regions comprise at least one stabilizer.
• the present invention is drug particles prepared according to a process comprising the steps of: (a) dissolving a drug substance in a solvent; and (b) adding the product of step (a) to water to form precipitated drug particles; wherein the drug particles comprise: a plurality of crystalline domains, each domain being oriented differently than any of the adjacent domains, wherein the domains comprise a drug substance; and a plurality of interfacial regions surrounding the crystalline domains, the interfacial regions comprising at least one stabilizer.
• the particles of the present invention exhibit relatively fast dissolution times as compared to particles prepared by processes described in the prior art.
• Figure 1 is an enlarged cross-sectional view of a particle of the present invention.
• Figure 1 illustrates one embodiment of a particle 10 of the present invention.
• Particle 10 comprises a plurality of crystalline domains 11, 12, and 13.
• the lines in each of the crystalline domains 11, 12, and 13 depict the orientation of the crystal lattice within each of the domains.
• the orientation of the crystal lattice in crystalline domain 11 is in a different direction than the orientation of the crystal lattice in crystalline domain 12, and the orientation of the crystal lattice in crystalline domain 11 is also in a different direction than the orientation of the crystal lattice in crystalline domain 13.
• Each crystalline domain is oriented differently than any of the adjacent domains.
• the crystalline domains comprise a drug substance.
• the drug substance is poorly soluble in water.
• Suitable drug substances can be selected from a variety of known classes of drugs including, for example, analgesics, anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, antibiotics (including penicillins), anticoagulants, antidepressants, antidiabetic agents, antiepileptics, antihistamines, antihypertensive agents, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, immunosuppressants, antithyroid agents, antiviral agents, anxiolytic sedatives (hypnotics and neuroleptics), astringents, beta-adrenoceptor blocl ing agents, blood products and substitutes, cardiacinotropic agents, contrast media, corticosterioids, cough suppressants (expectorants and mucolytics), diagnostic agents, diagnostic imaging agents, diuretics, dopaminergics (antiparkinsonian agents), haemostatic
• the crystalline domains are preferably less than 500 Angstroms in size. More preferably, the crystalline domains are less than 450 Angstroms, and even more preferably less than 400 Angstroms.
• a plurality of interfacial regions 14 surround the crystalline domains 11, 12, and 13. As shown in Figure 1, the interfacial regions 14 are in between each of the crystalline domains 11, 12, and 13, and the interfacial regions 14 are also on the outside surface of the particle 10.
• the interfacial regions 14 comprise at least one stabilizer.
• the stabilizer should be chosen so as to reduce crystal growth so the crystalline domain size stays relative small and so that big crystals do not result. However, the stabilizer should also be chosen such that crystal growth is not prevented altogether, in order to ensure that some stabilizer is incorporated into the interfacial regions 14. Moreover, the stabilizer should be chosen so as not to prevent crystallization altogether, resulting in supersaturated solutions of the drug molecules. While not wishing to be bound by theory, incorporation of the stabilizer into the interfacial regions is what causes the particles of the present invention to exhibit relatively fast dissolution times.
• stabilizer or stabilizers will depend upon the drug molecule. Generally, polymeric stabilizers are preferred. Examples of particle stabilizers include phospholipids, ⁇ surfactants, polymeric surfactants, vesicles, polymers, including copolymers and homopolymers and biopolymers, and/or dispersion aids.
• Suitable surfactants include gelatin, casein, lecithin, phosphatides, gum acacia, cholesterol, tragacanth, fatty acids and fatty acid salts, benzalkonium chloride, glycerol mono and di fatty acid esters and ethers, cetostearyl alcohol, cetomacrogol 1000, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, for example, the commercially available Tweens, polyethylene glycols, poly(ethylene oxide/propylene oxide) copolymers, for example, the commercially available Poloxomers or Pluronics, polyoxyethylene fatty acid ethers, for example, the commercially available Brijs, polyoxyethylene fatty acid esters, sorbitan fatty acid esters, for example, the commercially available Spans, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,
• the drug particles of the present invention are essentially crystalline.
• essentially crystalline is defined to mean that the particles are at least 90% crystalline as measured using X-ray diffraction techniques.
• the size of particle 10 as determined by light scattering techniques is not critical. In a preferred embodiment, however, the particles of the present invention are relatively small. More preferably, the particles of the present invention have a mean particle size of less than 20 microns, even more preferably less than 10 microns, and yet even more preferably less than 5 microns.
• the particles of the present invention exhibit relatively fast dissolution rates.
• the preferred method for measuring dissolution rates for the particles of the present invention is a turbidity method.
• Turbidity gives a quantitative measurement of the change of intensity of light passing through a suspension of drug particles, caused by absorptive interactions resulting in energy transfer to the drug particles and by scattering from optical inhomogeneities in the drug particles.
• “Absorbance” is also a term that is used interchangeably with turbidity.
• the turbidity method useful for determining the percent of dissolved material for the particles of the present invention comprises the following steps: determining the initial concentration of drug particles suspended in a liquid medium (i); determining the dynamic solid concentration (d) of drug particles in liquid medium; and calculating the percent dissolved material according to the formula: [(i - d)/i] x 100. Turbidity measurements are used to determine (i) and (d).
• any liquid medium can be used to measure turbidity, so long as the liquid medium is transparent in visible light and has a sufficiently different refractive index from the solid material such that it scatters light.
• the liquid medium should be chosen such that the equilibrium solubility of the drug particles in the liquid medium is between 5 and 500 mg/L.
• equilibrium solubility is defined herein to mean the maximum amount of drug particles that can be completely dissolved within 120 minutes in the liquid medium using this technique. To determine dissolution rates using turbidity measurements, one would need to develop a calibration curve showing turbidity versus a known concentration for the particular drag particles used.
• the particles of the present invention When added to a liquid medium at a concentration that is from 25-95% of the equilibrium solubility, the particles of the present invention demonstrate complete dissolution in less than 5 minutes, as measured by the turbidity technique described above.
• equilibrium solubility is described above. More preferably, the drug particles can be added to the liquid medium at a concentration that is from 40-80% of their equilibrium solubility and still maintain complete dissolution in less than 5 minutes.
• complete dissolution means that 95% of the particles are dissolved, as demonstrated by a 95% reduction in turbidity.
• the particles of the present invention can be prepared using any method suitable for malcing small particles of poorly water soluble drag substances.
• the particles are prepared by way of a controlled precipitation process.
• a "controlled precipitation process” is defined herein to mean a process comprising the following steps: (a) dissolving a drug substance in a solvent; and (b) adding the product of step (a) to water to form precipitated drag particles.
• a stabilizer such as those described above, is present in the solvent, in the water or in both the solvent and the water.
• the solvent into which the drag is dissolved in step (a) can be any organic solvent or water/organic solvent blend which dissolves the drug adequately.
• the solvent should be miscible in water.
• the selected solvent exhibits ideal mixing behavior with water so that the solution can be instantaneously distributed throughout the water when added to the water in step (b).
• Suitable organic solvents include but are not limited to methanol, ethanol, isopropanol, 1-butanol, t-butanol, trifluoroethanol, polyhydric alcohols such as propylene glycol, PEG 400, and 1,3-propanediol, amides such as n-methyl pyrrolidone, N,N-dimethylformamide, tetrahydrofuran, propionaldehyde, acetone, n- propylamine, isopropylamine, ethylene diamine, acetonitrile, methyl ethyl ketone, acetic acid, formic acid, dimethylsulfoxide, 1,3-dioxolane, hexafluoroisopropanol, and combinations thereof.
• polyhydric alcohols such as propylene glycol, PEG 400, and 1,3-propanediol
• amides such as n-methyl pyrrolidone, N,N-d
• the concentration of drug dissolved in the solvent in step (a) is preferably as close as practical to the solubility limit of the solvent at room temperature. Such concentration will depend upon the selected drug and solvent but is typically in the range of from 0.1 to 20.0 weight percent.
• excipients are added to the solvent, to the water, or to both the solvent and the water.
• An excipient is defined herein as meaning something that changes the crystallization behavior of the molecules but is not incorporated into the resulting particles.
• Suitable excipients include organics, inorganics, acids, bases, salts, or mixtures thereof. Other suitable excipients are described in detail in the Handbook of
• the controlled precipitation process further comprises the step of mixing the product of step (b).
• Any external device which imparts intense mixing of the drug/solvent in the water can be used.
• "Intense mixing” is defined herein as meaning that a uniformly supersaturated mixture is formed prior to particle nucleation. The mixing should be sufficiently intense so as to result in nearly instantaneous dispersion of the drug/solvent solution across the water before new particle growth occurs. Such intense mixing results in supersaturation of the drug substance in the solvent and liquid mixture, causing drag particles to precipitate into small particles having a crystalline structure.
• Examples of devices which may be used to mix the product of step (b) include a stir bar, and agitator, a homogenizer, and a colloid mill.
• the controlled precipitation process further comprises the step of recovering the precipitated drug particles.
• recovering the drug particles comprises removing the solvent first and then subsequently removing the water.
• the solvent and water can be removed simultaneously from the particles.
• the choice will depend upon the concentration of solvent and the chosen method to remove the water.
• Removing the solvent can be performed using any desirable means including evaporation, dialysis and the like.
• Removing the water can be performed using any desirable means, including spray drying, spray freezing, gellation, (defined as gelling the particles with a polymer), lyophilization, or filtration.
• the temperature of the product of step (b) is optimally controlled at a reduced temperature.
• the temperature is controlled at less than 65 °C, more preferably less than 30 °C, even more preferably less than 23 °C, and most preferably less than 10 °C.
• the lower limit of the temperature of the dispersion is the freezing point of water. Temperatures which are too high could lead to undesirable particle growth.
• F-68 means Pluronic ® polyethylene oxide/polypropylene oxide (EO x -PO y -EO x ) copolymers of different x:y ratios.
• Teween 20 means polyoxyethylene 20 sorbitan monolaurate.
• PEG 150-C18 means polyoxyethylene 150 monostearate.
• PEG 150-diC18 means polyoxyethylene 150 distearate.
• PVP means polyvinylpyrrolidone.
• PVA polyvinyl alcohol
• DCNa deoxycholic acid sodium salt
• Examples 1 through 21 Drag particles prepared using a controlled precipitation process.
• 0.3 g of the drug was dissolved in 6 ml of the organic solvent, which may contain 0.3 g of a stabilizer.
• the organic solution was injected at 2 degrees C with vigorous stirring into 30.0 g of the aqueous phase, which may contain a second stabilizer.
• the solvent was stripped from the resulting slurry, and the slurry freeze dried to yield a powder.
• X- ray diffraction patterns indicated that all samples were essentially crystalline. Average size of the crystalline domains was determined using X-ray diffraction as known by those skilled in the art of particle size measurement, using Jade XRD pattern processing software (v.6).
• Dissolution was then monitored by the loss in turbidity.
• the time to completely dissolve was the point at which there was a 95% reduction in the turbidity measurement.
• Comparative Examples 22 through 24 Drag particles as received.
• Comparative Examples 25 through 26 Drug particles prepared using a wet milling process.

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• 2002
  • 2002-08-06 US US10/213,907 patent/US20040028746A1/en not_active Abandoned
• 2003
  • 2003-07-14 AU AU2003249195A patent/AU2003249195A1/en not_active Abandoned
  • 2003-07-14 JP JP2004526104A patent/JP2005536525A/ja active Pending
  • 2003-07-14 CN CNB038187817A patent/CN100356905C/zh not_active Expired - Fee Related
  • 2003-07-14 WO PCT/US2003/021882 patent/WO2004012710A1/en not_active Ceased
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