WO2007019229A1 - Compositions exhibiting improved flowability - Google Patents
Compositions exhibiting improved flowability Download PDFInfo
- Publication number
- WO2007019229A1 WO2007019229A1 PCT/US2006/030278 US2006030278W WO2007019229A1 WO 2007019229 A1 WO2007019229 A1 WO 2007019229A1 US 2006030278 W US2006030278 W US 2006030278W WO 2007019229 A1 WO2007019229 A1 WO 2007019229A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- powder
- solid material
- modified nanoparticles
- nanoparticles
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 133
- 230000001747 exhibiting effect Effects 0.000 title abstract description 7
- 239000000843 powder Substances 0.000 claims abstract description 133
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- 238000000034 method Methods 0.000 claims abstract description 26
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- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical class O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims description 4
- 239000001506 calcium phosphate Substances 0.000 claims description 4
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- 229940124630 bronchodilator Drugs 0.000 claims description 3
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- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 1
- 229960004448 pentamidine Drugs 0.000 description 1
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229960005414 pirbuterol Drugs 0.000 description 1
- 229960004994 pirbuterol acetate Drugs 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920006294 polydialkylsiloxane Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
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- 229960002288 procaterol Drugs 0.000 description 1
- FKNXQNWAXFXVNW-BLLLJJGKSA-N procaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)[C@@H](NC(C)C)CC FKNXQNWAXFXVNW-BLLLJJGKSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- WVLAAKXASPCBGT-UHFFFAOYSA-N reproterol Chemical compound C1=2C(=O)N(C)C(=O)N(C)C=2N=CN1CCCNCC(O)C1=CC(O)=CC(O)=C1 WVLAAKXASPCBGT-UHFFFAOYSA-N 0.000 description 1
- 229960002720 reproterol Drugs 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229960001457 rimiterol Drugs 0.000 description 1
- IYMMESGOJVNCKV-SKDRFNHKSA-N rimiterol Chemical compound C([C@@H]1[C@@H](O)C=2C=C(O)C(O)=CC=2)CCCN1 IYMMESGOJVNCKV-SKDRFNHKSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical class NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- XOLBLPGZBRYERU-UHFFFAOYSA-N tin dioxide Chemical compound O=[Sn]=O XOLBLPGZBRYERU-UHFFFAOYSA-N 0.000 description 1
- 229910001887 tin oxide Inorganic materials 0.000 description 1
- 229950001669 tipredane Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- DENFJSAFJTVPJR-UHFFFAOYSA-N triethoxy(ethyl)silane Chemical compound CCO[Si](CC)(OCC)OCC DENFJSAFJTVPJR-UHFFFAOYSA-N 0.000 description 1
- JCVQKRGIASEUKR-UHFFFAOYSA-N triethoxy(phenyl)silane Chemical compound CCO[Si](OCC)(OCC)C1=CC=CC=C1 JCVQKRGIASEUKR-UHFFFAOYSA-N 0.000 description 1
- HQYALQRYBUJWDH-UHFFFAOYSA-N trimethoxy(propyl)silane Chemical compound CCC[Si](OC)(OC)OC HQYALQRYBUJWDH-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000010456 wollastonite Substances 0.000 description 1
- 229910052882 wollastonite Inorganic materials 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229910001928 zirconium oxide Inorganic materials 0.000 description 1
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
-
- 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
- A61K9/143—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 inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- compositions Exhibiting Improved Flowability
- the invention relates generally to compositions of a powder or powder mixture exhibiting substantial ease of flow.
- Achieving a uniform blend of dry bulk solids is a problem faced daily by engineers and operators in industries as varied as pharmaceuticals, foods, plastics and battery production. Even when an acceptable blend is obtained additional challenges arise in maintaining the blend through one or more pieces of downstream equipment. Poor blending or the inability to maintain an adequate blend before and during processing lead to additional and unnecessary costs, including costs associated with rejected material and decreased yields, added blending time and energy, decreased productivities, start-up delays and defective or out-of-specification products. Powder caking of raw and in-process materials, particularly during storage (in, e.g., bags or drums) can also pose significant problems. Both powder caking and an inability to achieve uniform blends and mixtures can decrease batch uniformity which, among other drawbacks, can require increased testing and sampling.
- Fumed silica is one popular powder additive that can be used to improve flow characteristics. While relatively inexpensive, fumed silica often is ineffective in preventing agglomeration of many particle types. Flowability is also a matter of degree; many, if not most, uses of fumed silica lead to some agglomeration and aggregation. Some undemanding industrial applications can tolerate a level of agglomeration not tolerated in more demanding applications. Applications involving precise metering or mixing of a powder, however, require more.
- the ability to improve powder flow can provide an increase in homogeneity with milder mixing conditions or with reduced mixing periods. Additionally, increased powder flowabilities can allow utilization of lower levels of expensive ingredients, e.g., dyes and pigments, particularly where the requirement of using a level of such ingredients correlates with the dispersibility of the materials in the powder with which they are mixed.
- expensive ingredients e.g., dyes and pigments
- compositions can be tabletted or encapsulated for oral gastrointestinal ingestion and delivery. They also can be incorporated into a dry powder inhaler for delivery to the respiratory tract. The ability to achieve homogenous blends of compositions containing relatively low levels (by weight) of pharmaceutically active ingredients is very difficult.
- Dry powder inhalation of a pharmaceutical or drug composition requires unique and challenging physical property profiles for a powder.
- two competing criteria must be balanced: 1.
- the drug particles to be delivered must be sufficiently small so that the particles can be inhaled and penetrate into the deep lung.
- the aerodynamic diameter of the particles (Equation 1 below) primarily influences this behavior, since deposition in the respiratory tract is controlled by a particle's aerodynamic size rather than its physical or geometric shape. Lung deposition improves substantially for particles less than 5 microns in aerodynamic diameter and decreases substantially for particles with effective aerodynamic diameters of greater than 5 microns.
- p is the particle density
- DPI dry powder inhaler
- powders for inhalation that are physically large (and thus effectively deagglomerated), yet are aerodynamically small (thus being more respirable).
- Some such particles for example, are hollow spherical-like particles with low density but large relative particle size. Others are significantly irregular in shape and physical character. While achieving some degree of balance between penetrability and flowability, powders of such particles, particularly when formulated in lipid/drug matrices for delivery, tend toward an amorphous state and pose potential stability drawbacks. Concerns also arise when inhaling a large amount of the excipients required to form such matrices.
- Powder handling and processing technologies today lie significantly behind the development pace of companion technologies used in liquid processes, and there remain a great many practical problems handling powders that current methods cannot effectively address. Powder compositions exhibiting enhanced flowability and processability are desired for a wide range of applications including demanding industrial and pharmaceutical uses.
- the present invention provides powder compositions exhibiting improved flowability and ease of mixing.
- Such compositions comprise at least one bulk solid phase in the form of a powder and at least an effective amount of a flow enhancing agent comprising surface-modified nanoparticles.
- the compositions can exhibit substantially free flowing characteristics and substantially increased packing densities compared with compositions that do not include the flow enhancing agent.
- compositions comprising at least one bulk solid material substantially in the form of a powder and surface-modified nanoparticles.
- the surface-modified nanoparticles are present in the compositions in an amount that is at least sufficient to improve the flowability or floodability of the bulk solid material relative to the bulk solid material substantially free of surface-modified nanoparticles.
- the invention provides pharmaceutical compositions exhibiting substantially improved flow characteristics.
- Such pharmaceutical compositions comprise at least one solid phase including one or more medicaments and an effective amount of at least one surface-modified nanoparticle.
- the present invention provides pharmaceutical compositions that exhibit substantially improved flow characteristics, where the flowability is improved by at least 5 percent.
- the compositions comprise at least one solid phase including one or more medicaments and an effective amount of at least one biocompatible surface-modified nanoparticle.
- the biocompatible particles may be biodegradable or bioadsorbable or may be inert and excreted intact as may be desirably for the selection route or method of biological exposure.
- the invention provides methods of mixing and dry blending solid compositions comprising mixing or blending one or more solid phase powders with a flow enhancing agent that contains an effective amount of at least one surface-modified nanoparticle.
- the invention provides substantially free flowing powder mixtures comprising one or more powder compositions and an effective amount of at least one surface-modified nanoparticle.
- the invention provides methods of making substantially free- flowing powder compositions, methods of using such compositions and devices incorporating such compositions.
- compositions of the invention include a flow enhancing material comprising surface-modified nanoparticles.
- the surface-modified nanoparticles are individual, unassociated (i.e., non-aggregated) particles that are mixed with, blended with or are otherwise distributed within a bulk solid material which is in powder form. While not subject to any specific physical characterization and not intending to be limited to any single characterization, one non-limiting way to identify a solid material as a powder is when it is composed principally of relatively small individual particles or relatively small groups of individual particles. Generally, such particles will have an average size (generally measured as an effective diameter) of less than or equal to 1,000 microns, more typically less than or equal to 100 microns.
- the bulk solid powder material may be distinguished from the nanoparticles by relative size, wherein the bulk solid powder material comprises particles that are larger than the nanoparticles.
- nanoparticle as used herein (unless an individual context specifically implies otherwise) will generally refer to particles, groups of particles, particulate molecules such as small individual groups or loosely associated groups of molecules, and groups of particulate molecules that while potentially varied in specific geometric shape have an effective, or average, diameter that can be measured on a nanoscale (less than 100 nanometers).
- the nanoparticles utilized in the invention enhance and/or maintain the flowability of the bulk powder materials within which they are present.
- Flowability also called free flow
- Flowability refers generally to the ability of a free-flowing material to flow steadily and consistently as individual particles or groups of individual particles such as would occur, for example, through a fine orifice.
- floodability also called floodable flow
- the surface-modified nanoparticles when present in a powder composition in accordance with the present invention, will provide an improvement in flowability and/or floodability of the powder composition when compared to the flowability and/or floodability of the bulk powder composition when substantially free of the nanoparticles.
- substantially free refers essentially to the lack or presence of a component, such as nanoparticles in the bulk powder composition.
- Such an improvement may be evidenced by at least one of the following of Examples 11- 20: (1) an increase in the tap density of the powder composition, preferably by a factor of at least 1.25 or more, preferably by a factor of at least 2.0; (2) a decrease in the angle of repose of the powder composition; (3) an increase in the Flowability Index of the powder composition; or (4) an increase in the Floodability Index of the powder composition.
- the inclusion of surface-modified nanoparticles allow for higher tap densities, where a larger concentration of a medicament may be contained in a capsule, a blister, or a reservoir-based DPI device. For example, this may contribute to more doses in a DPI device within the same sized device, rather than changing the device's shape or size.
- An improvement in powder flowability can, for example, be inferred by relative improvement as compared to compositions substantially free of the nanoparticle compositions utilized in the invention in phenomena and process parameters that are correlated with flowability.
- Relative improvements such as reductions in aggregation, agglomeration, attrition, flocculation, segregation, caking, bridging or in the ability to achieve uniform blends will all be understood to reflect an improvement in flowability as herein defined.
- a class of surface-modified nanoparticles utilized in the invention are comprised of a core material and a surface that is different or modified from the core material.
- the core material may be inorganic or organic and is selected such that, as described in more detail herein, it is compatible with the bulk solid material with which it is combined and it is suitable for the application for which it is intended.
- the selection of the core material will be governed at least in part by the specific performance requirements for the composition and any more general requirements for the intended application. For example, the performance requirements for the solid composition might require that a given core material have certain dimensional characteristics (size and shape), compatibility with the surface modifying materials along with certain stability requirements (insolubility in a processing or mixing solvent).
- Suitable inorganic nanoparticle core materials include calcium phosphate, hydroxy- apatite, and metal oxide nanoparticles such as zirconia, titania, silica, ceria, alumina, iron oxide, vanadia, zinc oxide, antimony oxide, tin oxide, alumina/silica, and combinations thereof.
- Metals such as gold, silver, or other precious metals can also be utilized as solid particles or as coatings on organic or inorganic particles.
- Suitable organic nanoparticle core materials include, for example, organic polymeric nanospheres, insoluble sugars such as lactose, trehalose, glucose or sucrose, and insoluble aminoacids.
- another class of organic polymeric nanospheres includes nanospheres that comprise polystyrene, such as those available from Bangs Laboratories, Inc. of Fishers, Indiana as powders or dispersions. Such organic polymeric nanospheres will generally have average particle sizes ranging from 20 nm to not more than 60 nm.
- the selected nanoparticle core material may be used alone or in combination with one or more other nanoparticle core materials including mixtures and combinations of organic and inorganic nanoparticle materials. Such combinations may be uniform or have distinct phases, which can be dispersed or regionally specific, such as layered or of a core-shell type structure.
- the selected nanoparticle core material whether inorganic or organic, and in whatever form employed, will generally have an average particle diameter of less than 100 nm. In some embodiments, nanoparticles may be utilized having a smaller average effective particle diameter of, for example less than or equal to 50, 40, 30, 20, 15, 10 or 5 nm; in some embodiments from 2 nm to 20 nm; in still other embodiments from 3 nm to 10 nm.
- another class of surface-modified organic nanoparticles includes buckminsterfullerenes (fullerenes), dendrimers, branched and hyperbranched "star" polymers such as 4, 6, or 8 armed polyethylene oxide (available, for example, from Aldrich Chemical Company of Milwaukee, Wisconsin or Shearwater Corporation of Huntsville, AL) whose surface has been chemically modified.
- fullerenes include C ⁇ o ?
- dendrimers include polyamidoamine (PAMAM) dendrimers of Generations 2 through 10 (G2 -GlO), available also from, for example, Aldrich Chemical Company of Milwaukee, WI.
- PAMAM polyamidoamine
- the nanoparticles utilized in the invention may be substantially spherical in shape. In other application, however, more elongated shapes by be desired. Aspect ratios less than or equal to 10 are considered preferred, with aspect ratios less than or equal to 3 generally more preferred.
- the core material will substantially determine the final morphology of the particle and thus a significant influence in selection of the core material may be the ability to obtain a desired size and shape in the final particle.
- the surface of the selected nanoparticle core material will generally be chemically or physically modified in some manner. Both direct modification of a core surface as well as modification of a permanent or temporary shell on a core material are envisioned.
- Such modifications may include, for example, covalent chemical bonding, hydrogen bonding, electrostatic attraction, London forces and hydrophilic or hydrophobic interactions so long as the interaction is maintained at least during the time period required for the nanoparticles to achieve their intended utility.
- the surface of a nanoparticle core material may be modified with one or more surface modifying groups.
- the surface modifying groups may be derived from myriad surface modifying agents. Schematically, surface modifying agents may be represented by the following general formula:
- the A group in Formula II is a group or moiety that is capable of attaching to the surface of the nanoparticle.
- the B group is a compatibilizing group with whatever solvent is used to process the nanoparticle and the bulk powder materials.
- the B group is a group or moiety that is capable of preventing irreversible agglomeration of the nanoparticle. It is possible for the A and B components to be the same, where the attaching group may also be capable of providing the desired surface compatibility.
- the compatibilizing group may be reactive, but is generally non-reactive, with a component of the bulk powder phase.
- the attaching composition may be comprised of more than one component or created in more than one step, e.g., the A composition may be comprised of an A moiety which is reacted with the surface, followed by an A" moiety which can then be reacted with B.
- the sequence of addition is not important, i.e., the A 1 A 1 B component reactions can be wholly or partly performed prior to attachment to the core.
- nanoparticles in coatings can be found in Linsenbuhler, M. et. al., Powder Technology, 158, 2003, p. 3-20.
- Many suitable classes of surface-modifying agents are known to those skilled in the art and include, for example, silanes, organic acids, organic bases and alcohols, and combinations thereof.
- surface-modifying agents include silanes.
- silanes include organosilanes such as, for example, alkylchlorosilanes; alkoxysilanes, e.g., methyltrimethoxysilane, methyltriethoxysilane, ethyltrimethoxysilane, ethyltriethoxysilane, n- propyltrimethoxysilane, «-propyltriethoxysilane, i-propyltrimethoxysilane, i- propyltriethoxysilane, butyltrimethoxysilane, butyltriethoxysilane, hexyltrimethoxysilane, octyltrimethoxysilane, 3-mercaptopropyltrimethoxysilane, «-octyltriethoxysilane, isooctyltrimethoxysilane, phenyl
- polydialkylsiloxanes including, e.g., polydimethylsiloxane; arylsilanes including, e.g., substituted and unsubstituted arylsilanes; alkylsilanes including, e.g., substituted and unsubstituted alkyl silanes including, e.g., methoxy and hydroxy substituted alkyl silanes, and combinations thereof.
- silica nanoparticles include silica nanoparticles surface-modified with silane surface modifying agents including, e.g., acryloyloxypropyl trimethoxysilane, 3- methacryloyloxypropyltrimethoxysilane, 3-mercaptopropyltrimethoxysilane, n- octyltrimethoxysilane, isooctyltrimethoxysilane, and combinations thereof.
- silane surface modifying agents including, e.g., acryloyloxypropyl trimethoxysilane, 3- methacryloyloxypropyltrimethoxysilane, 3-mercaptopropyltrimethoxysilane, n- octyltrimethoxysilane, isooctyltrimethoxysilane, and combinations thereof.
- Silica nanoparticles can be treated with a number of surface modifying agents including, e.g., alcohol, organosilane including, e.g., alkyltrichlorosilanes, trialkoxyarylsilanes, trialkoxy(alkyl)silanes, and combinations thereof and organotitanates and mixtures thereof.
- organic acid surface-modifying agents include, for example, oxyacids of carbon (e.g., carboxylic acid), sulfur and phosphorus, acid derivatized poly(ethylene) glycols (PEGs) and combinations of any of these.
- Suitable phosphorus containing acids include phosphonic acids including, e.g., octylphosphonic acid, laurylphosphonic acid, decylphosphonic acid, dodecylphosphonic acid, octadecylphosphonic acid, monopolyethylene glycol phosphonate and phosphates including lauryl or stearyl phosphate.
- Suitable sulfur containing acids include sulfates and sulfonic acids including dodecyl sulfate and lauryl sulfonate. Any such acids may be used in either acid or salt forms.
- Non-silane surface modifying agents include acrylic acid, methacrylic acid, beta- carboxyethyl acrylate, mono-2-(methacryloyloxyethyl) succinate, mono(methacryloyloxypolyethyleneglycol) succinate and combinations of one or more of such agents.
- surface-modifying agents incorporate a carboxylic acid functionality such as, for example, CH3 ⁇ (CH2CH2 ⁇ )2CH2COOH (hereafter, MEEAA), 2-
- surface-modified iron oxide nanoparticles include those modified with endogenous fatty acids, e.g., steric acid, or fatty acid derivatives using endogenous compounds, e.g., steroyl lactylate or sarcosing or taurine derivatives.
- Further surface- modified zirconia nanoparticles include a combination of oleic acid and acrylic acid adsorbed onto the surface of the particle.
- Organic base surface-modifying agents may also include alkylamines, e.g., octylamine, decylamine, dodecylamine, octadecylamine, and monopolyethylene glycol amines.
- alkylamines e.g., octylamine, decylamine, dodecylamine, octadecylamine, and monopolyethylene glycol amines.
- Other non-silane surface modifying agents include acrylic acid, methacrylic acid, beta-carboxyethyl acrylate, mono-2-(methacryloyloxyethyl) succinate, mono(methacryloyloxypolyethyleneglycol) succinate and combinations of one or more of such agents.
- Surface-modifying alcohols and thiols may also be employed including, for example, aliphatic alcohols, e.g., octadecyl, dodecyl, lauryl and furfuryl alcohol, alicyclic alcohols, e.g., cyclohexanol, and aromatic alcohols, e.g., phenol and benzyl alcohol, and combinations thereof.
- Thiol-based compounds are especially suitable for modifying cores with gold surfaces.
- the surface-modified nanoparticles are selected in such a way that compositions formed with them are free from a degree of particle agglomeration or aggregation that would interfere with the desired properties of the composition.
- the surface-modified nanoparticles are generally selected to be either hydrophobic or hydrophilic such that, depending on the character of the processing solvent or the bulk material, the resulting mixture or blend exhibits substantially free flowing properties. Suitable surface groups constituting the surface modification of the utilized nanoparticles can thus be selected based upon the nature of the processing solvents and bulk materials used and the properties desired of the resultant combination.
- a processing solvent is hydrophobic
- hydrophobic for example, one skilled in the art can select from among various hydrophobic surface groups to achieve a surface-modified particle that is compatible with the hydrophobic solvent; when the processing solvent is hydrophilic, one skilled in the art can select from various hydrophilic surface groups; and, when the solvent is a hydrofluorocarbon or fluorocarbon, one skilled in the art can select from among various compatible surface groups; and so forth.
- the nature of the bulk material and the desired final properties can also affect the selection of the surface composition.
- the nanoparticle can include two or more different surface groups (e.g., a combination of hydrophilic and hydrophobic groups) that combine to provide a nanoparticle having a desired set of characteristic.
- the surface groups will generally be selected to provide a statistically averaged, randomly surface-modified particle.
- the surface groups will be present on the surface of the particle in an amount sufficient to provide surface-modified nanoparticles with the properties necessary for compatibility with the bulk material.
- the surface groups are present in an amount sufficient to form a monolayer, and in another embodiment, a continuous monolayer, on the surface of at least a substantial portion of the nanoparticle.
- a variety of methods are available for modifying the surfaces of nanoparticles.
- a surface modifying agent may, for example, be added to nanoparticles (e.g., in the form of a powder or a colloidal dispersion) and the surface modifying agent may be allowed to react with the nanoparticles.
- the reactive group/linker may be reacted with the nanoparticle followed by reaction with the compatibilizing group.
- the reactive group/linker may be reacted with the compatibilizing group followed by reaction with the nanoparticle.
- Other surface modification processes are described in, e g., U.S. Patent Nos. 2,801,185 (Her) and 4,522,958 (Das et al.), whose descriptions are incorporated herein by reference for such purpose.
- Surface-modified nanoparticles or precursors to them may be in the form of a colloidal dispersion.
- Some such dispersions are commercially available as unmodified silica starting materials, for example those nano-sized colloidal silicas available under the product designations NALCO 1040, 1050, 1060, 2326, 2327, and 2329 colloidal silica fromNalco Chemical Co. of Naperville, IL.
- Metal oxide colloidal dispersions include colloidal zirconium oxide, suitable examples of which are described in U.S. Patent No. 5,037,579 (Matchett) (whose description is incorporated by reference herein), and colloidal titanium oxide, examples of which are described in U.S. Patent Nos. 6,329,058 and 6,432,526 (Arney et al.), whose descriptions are also incorporated by reference herein.
- the bulk powder phase (i.e., the bulk solid material) may contain any one or mixture of particles for which a desired degree of flowability is desired.
- the bulk phase particulate powders will have median particle size diameters less than 200 micrometers, but greater than 100 ran. In some instances, the bulk phase particulate powders may have median particle size diameters less than 100 ran in size, but larger than the surface-modified nanoparticles. In one embodiment, the bulk phase particulate powders will have median particle size diameters ranging from 0.5 micrometer to 200 micrometers, preferably from 1 micrometer to 200 micrometers, and more preferably from 1 micrometer to 100 micrometers.
- the bulk phase particulate powders may be inorganic, organic or any combination thereof.
- Examples of bulk phase powders include polymers; medicaments; pigments; abrasives; additives; ceramic (e.g., glass, crystalline ceramic, glass-ceramic, and combinations thereof) bubbles; ceramic microspheres; silicates (e.g., talc, clay, sericite); fillers such as carbon black, titanium dioxide, calcium carbonate, nepheline ("MINEX", Unimin Corp, New Canaan, CT), Feldspar and Wollastonite; excipients such as microcrystalline cellulose (and other natural or synthetic polymers), dicalcium phosphate, lactose monohydrate and other sugars; exfolients; cosmetic ingredients; aerogels; foodstuffs; glass materials and toner materials.
- Suitable ceramic bubbles and ceramic microspheres are exemplified in U.S. Patent Nos. 4,767,726 (Marshall), and 5,883,029 (Castle), herein incorporated by reference.
- glass bubbles examples include those marketed by 3M Company under the trade designation "3MTM SCOTCHLITE GLASS BUBBLES” (e.g., grades Kl, K15, S15, S22, K20, K25, S32, K37, S38, K46, S60/10000, S60HS, A16/500, A20/1000, A20/1000, A20/1000, H50/10000 EPX, and H50/10000 (acid washed)); glass bubbles marketed by Potter Industries, Valley Forge, PA, under the trade designation "SPHERICEL” (e.g., grades 110P8 and 60P18), "LUXSIL", and "Q-CEL” (e.g., grades 30, 6014, 6019, 6028, 6036, 6042, 6048, 5019, 5023, and 5028); hollow glass microspheres marketed under the trade designation "DICAPERL” by Grefco Minerals, BaIa Cynwyd, PA, (e.g.,
- Ceramic microspheres examples include ceramic hollow microspheres marketed by SphereOne, Inc. under the trade designation, 11 EXTENDOSPHERES 11 (e.g., grades SG, CG, TG, SF-IO, SF-12, SF-14, SLG, SL-90, SL- 150, and XOL-200); and ceramic microspheres marketed by 3M Company under the trade designation "3MTM Ceramic Microspheres” (e.g., grades G-200, G-400, G-600, G-800, G- 850, W-210, W-410, and W-610).
- 11 EXTENDOSPHERES 11 e.g., grades SG, CG, TG, SF-IO, SF-12, SF-14, SLG, SL-90, SL- 150, and XOL-200
- 3MTM Ceramic Microspheres e.g., grades G-200, G-400, G-600, G-800, G- 850, W-210, W-410, and W
- Surface-modified nanoparticles are present in the bulk solid materials utilized in the invention (which may comprise a mixture of one or more bulk materials) in an amount effective to enhance the flowability or floodability of the bulk material by reducing or minimizing the degree of aggregation, agglomeration or flocculation of the bulk material.
- the amount of surface-modified nanoparticle effective to achieve this purpose will depend, inter alia, on the composition of the bulk material, the chosen nanoparticle, the presence or absence of other adjuvants or excipients and on the particular needs and requirements of the application for which the bulk material is to be used.
- the nature of the nanoparticle surface, the morphology of the particle and particle size may each influence the desired properties of the composition and influence the selection of a nanoparticle and the amount or concentration of nanoparticle used.
- the presence of as little as 0.001 percent of nanoparticle by weight of the combined composition can achieve an improvement in flowability.
- the nanoparticle will be present in an amount of less than or equal to 10 weight percent; in some embodiments less than or equal to 5 weight percent; less than or equal to 1 weight percent; or less than 0.1 weight percent.
- the amount of surface-modified nanoparticles is from 0.001 to 20 percent; from 0.001 to 10 percent; from 0.001 to 1 percent; from 0.001 to 0.01 percent; or from 0.01 to 1 percent, by weight of the composition.
- the selected nanoparticles be substantially spherical.
- the toxicology and biocompatibility of a selected nanoparticle will be particularly relevant and important for pharmaceutical applications. It will be understood that such selection and optimization of component compositions will be within the skill of those in the art who are familiar with the physical properties required for the composition in a given use or application.
- the surface-modified nanoparticles will not irreversibly associate with one another.
- Medicaments include antiallergics, analgesics, bronchodilators, antihistamines, therapeutic proteins and peptides, antitussives, anginal preparations, antibiotics, anti-inflammatory preparations, diuretics, hormones, or sulfonamides, such as, for example, a vasoconstrictive amine, an enzyme, an alkaloid or a steroid, and combinations of any one or more of these.
- medicaments include the following: isoproterenol, phenylephrine, phenylpropanolamine, glucagon, adrenochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, heparin, morphine, dihydromorphinone, dihydromorphine, ergotamine, scopolamine, methapyrilene, cyanocobalamin, terbutaline, rimiterol, salbutamol, isoprenaline, fenoterol, oxitropium bromide, reproterol, budesonide, flunisolide, ciclesonide, formoterol, fluticasone propionate,
- antibiotics such as neomycin, cephalosporins, streptomycin, penicillin, procaine penicillin, tetracycline, chlorotetracycline and hydroxytetracycline; adrenocorticotropic hormone and adrenocortical hormones, such as cortisone, hydrocortisone, hydrocortisone acetate and prednisolone; antiallergy compounds such as cromolyn sodium, nedocromil protein and peptide molecules such as insulin, pentamidine, calcitonin, amiloride, interferon, LHRH analogues, IDNAase, heparin, and others.
- antibiotics such as neomycin, cephalosporins, streptomycin, penicillin, procaine penicillin, tetracycline, chlorotetracycline and hydroxytetracycline
- adrenocorticotropic hormone and adrenocortical hormones
- the medicaments may be used as either a free base or as one or more salts known to the art.
- the choice of a free base or salt will be influenced by the biological impact as well as the chemical and physical stability (e.g., its tendency toward solvates, multiple polymorphs, friability, etc.) of the medicament in a given formulation.
- salts of medicaments in the present invention are the following: acetate, benzenesulphonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphatediphosphate, polygalacturonate, salicylate, stearate,
- Cationic salts of a medicament may also be used.
- Suitable cationic salts include the alkali metals, e.g., sodium and potassium, and ammonium salts and salts of amines known in the art to be pharmaceutically acceptable, e.g., glycine, ethylene diamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, l-amino-2- propanol-amino-2-(hydroxymethyl)propane- 1 ,3-diol and 1 -(3,4 ⁇ dihydroxyphenyl)-2 isopropylaminoethanol.
- the particle size of a medicament powder will generally be no greater than 100 micrometers in diameter. In other embodiments, the particle size will be less than 25 micrometers in diameter. Desirably, the particle size of the finely-divided solid powder should for physiological reasons be less than 25 micrometers in diameter and in other embodiments, less than 10 micrometers in diameter, and in other embodiments, less than 5 micrometers. Pharmaceutical formulations frequently will consist of blends of one or more medicaments with one or more excipients that are used as intermediate materials (isolated or in-process) before the final product is manufactured.
- Suitable excipients are listed in the Handbook of Pharmaceutical Excipients (Rowe, et al., APhA Publications, 2003) and are exemplified by microcrystalline cellulose, dicalcium phosphate, lactose monohydrate, mannose, sorbitol, calcium carbonate, starches and magnesium or zinc stearates.
- the surface- modified nanoparticles may have many potential benefits in the preparation of these excipients/medicament blends, including reducing mixing times, reducing attrition during processing and improving the homogeneity of the blend.
- a pharmaceutical inhalation powder formulation will consist of a medicament, an optional excipient, and surface-modified nanoparticles. It may be desirable for the medicament particles to be less than 10 micrometers in size such that they can be inhaled into the lung of a patient.
- the optional excipient may consist of a sugar, such as lactose monohydrate, and may have particle sizes substantially larger than 10 microns.
- the surface-modified nanoparticles may be configured in such a way that they are arranged on the surface of the medicament and/or optional excipient particles.
- the surface-modified nanoparticles may be primarily contained on the surface of large excipient particles, such that when the patient inhales the formulation, a substantial fraction of the respirable medicament particles deposit in the patient's lung, whereas the large excipient particles, and the nanoparticles on the surface of the large excipient particles collect in the patient's mouth and throat. In this way, the amount of nanoparticles reaching the patient's lung may be minimized.
- the dry power inhalers may have the powder stored in a storage device prior to dosing.
- This storage device may comprise a reservoir, capsule, blister, or dimpled tape.
- the drug powder used in the formulation is a micronized crystalline powder, but may also be an amorphous powder from a process such as spray drying. Additionally, the drug may be contained in particles that are a matrix of drug and some excipient.
- the DPI may be a multi-dose device or may be a single dose device.
- a further embodiment of this invention is a method to decrease the flow rate sensitivity of dry powder inhaler drug delivery. Delivery from DPIs often is highly dependent on the flow rate through the inhaler.
- the powder formulations of this invention are used in dry powder inhalers, particularly passive dry powder inhalers, the flow rate sensitivity of the drug delivery from the DPIs is reduced.
- the DPIs described may be used for delivery to patients who are unable to achieve a high respiratory flow rate, i.e., asthmatics, elderly, and young children.
- the pharmaceutical powder formulation may be used for nasal drug delivery.
- compositions of the invention will find utility in any application where an increase or improvement in flow properties of a powder material is desired.
- Some specific applications, including those outside pharmaceutical applications, for the compositions and methods of the invention include: (a) In the weighing, metering and mixing of powders where accurate measurements and or increased homogeneities are required;
- DPI dry powder inhaler
- compositions of the invention that comprise a bulk solid material (that includes one or more pharmaceutically active ingredients) and nanoparticles may be placed in the powder containment system; (i) To improve the accuracy and/or homogeneity of pharmaceutical compositions that are filled into capsules or formed into tablets; and (j) To prepare high tap density powders for use in rapid dissolve tablets, such as described in U.S. Pat. No. 6,051,252 (Liebowitz et al.), herein incorporated by reference.
- compositions of the present invention will generally be prepared by mixing the bulk powder material with the surface-modified nanoparticles using any suitable, conventional mixing or blending process.
- the surface-modified nanoparticle is prepared as a dispersion in an organic solvent and the bulk powder material is added to the dispersion.
- Typical solvents include, for example, toluene, isopropanol, heptane, hexane, and octane.
- the surface-modified nanoparticles and the bulk powder material are blended as powders, e.g., dry blended.
- powders e.g., dry blended.
- silica nanoparticles modified with isooctyltrimethoxysilane ('isooctyl'), methyltrimethoxysilane ('methyl'), or octadecyltrimethoxysilane ('octadecyl') groups, were prepared using the method described in U.S. Patent No. 6,586,483, which is incorporated herein by reference for such purpose.
- NALCO 2326 colloidal silica was used as the core for 5 nm size particles and NALCO 2327 was used as the core for 20 nm size particles.
- the dry powders (500 g in each of Examples 1-9) were combined with a suspension of the nanoparticles in toluene to provide a mixture in which the dry weight percentage of nanoparticles was 0.01, 0.1, 0.5, or 1.0. Measured aliquots of a 1 weight percent dispersion of the surface-modified nanoparticles in toluene were combined with additional toluene to make 500 g of dispersion containing a sufficient mass of surface-modified nanoparticles to prepare each desired mixture with each of the powders. Each mixture was thoroughly combined using a Silverson Model L4R (Silverson Machines, Inc., East Longmeadow, MA) homogenizer for 30 minutes.
- Silverson Model L4R Silverson Model L4R (Silverson Machines, Inc., East Longmeadow, MA) homogenizer for 30 minutes.
- each mixture was then dried overnight in a forced air oven at 150 0 C.
- the composition of each mixture is given in Table 1.
- no surface- modified nanoparticles were combined with the powders; the powders were combined with toluene and were mixed and dried as described above.
- " — " indicates "none,” i.e., that no surface modified nanoparticles were combined with the powders.
- the albuterol sulfate powder was added to isopropanol to make a 1 weight percent dispersion. This dispersion was combined with a 1 weight percent dispersion of the surface-modified nanoparticles in isopropanol. The mixture was spray dried to afford a dry powder.
- Example 20 the mixture of albuterol sulfate and surface-modified nanoparticles of Example 10 was placed in the reservoir of a TURBUHALER dry powder inhaler device ("DPI" device, manufactured by Astra Pharmaceuticals, London, United Kingdom).
- DPI TURBUHALER dry powder inhaler device
- Comparative Example 7 the reservoir of another TURBUHALER dry powder inhaler device was charged with albuterol sulfate powder.
- MMI Model 160 Marple Miller Impactor
- USP throat United States Pharmacopeia, USP 24 ⁇ 601> Aerosols, Metered Dose Inhalers, and Dry Powder Inhalers, Figure 4
- a suitable coupler was affixed to the USP induction port to provide an air-tight seal between the DPI device and the induction port.
- the stage cups of the MMI were coated with a surfactant to prevent particle bounce and re- entrainment.
- the amount of drug collected on each component of the MMI testing apparatus was determined by rinsing the component with a measured volume of an appropriate solvent and subjecting the rinsed material to HPLC analysis to determine albuterol sulfate concentration. Data that was returned from HPLC analysis was analyzed to determine the average amount of drug collected per delivered dose. The resulting mass values were then normalized to the fraction of delivered dose collected in each individual component of the testing assembly.
- Throat deposition is defined as the percent of the total delivered dose that deposits in the USP throat.
- Respirable mass is defined as the percentage of the total delivered dose that is measured to be smaller than the respirable limit of 4.7 micrometers in aerodynamic diameter.
- Respirable fraction is defined as the percentage of a delivered dose that reaches the entry of the throat and is smaller than the respirable limit.
- Example 20 the device delivered 199 micrograms of powder per actuation and it was determined that 54% of the albuterol sulfate particles had an aerodynamic diameter less than 4.7 microns.
- Comparative Example 7 the device delivered 68 micrograms per actuation and it was determined that 50% of the albuterol sulfate particles had an aerodynamic diameter less than 4.7 microns.
- a stock dispersion of surface-modified nanoparticles (5 run size, isooctyl/methyl surface modified) with a concentration of 0.005 g/mL was prepared by adding surface- modified nanoparticles (1.0 g) to a 200 niL volumetric flask and filling the remainder of the volume with heptane. A stir bar was placed in the flask and the mixture was stirred on a stir plate until the nanoparticles became fully dispersed based on visual appearance.
- Drug powder (5.O g of albuterol base, flunisolide hemihydrate, and pirbuterol acetate, respectively) and stock nano-particle dispersion (10 mL) were added to a round bottom flask (1.0 L).
- Heptane was then added to the flask to bring the total volume to approximately 200 mL.
- the flask was sealed with a rubber stopper and the mixture was deagglomerated by sonication and hand swirling for approximately 3 to 5 minutes and until no agglomerated material could be seen sticking on the sides of the flask.
- the flask was then placed onto a rotary evaporator to remove the solvent.
- the rotary evaporator was set to a nominal temperature of 50°C and operated under vacuum. After removal of all the solvent, the remaining powder was caked on the flask sides.
- the flask was then placed in a vacuum oven at 45° C for approximately 1 hour to further remove any residual solvent.
- the modified drug powder composition had a nominal concentration of surface-modified nanoparticles of 1.0 percent.
- Aerolizer® DPI device from a Foradil® Aerolizer® product, available from Schering Plough Co. was used to deliver the powder from Shionogi Quali-V® (hypromellose, also known as hydroxypropyl methylcellulose) capsules (Shionogi Qualicaps, Madrid, Spain).
- Shionogi Quali-V® hyperromellose, also known as hydroxypropyl methylcellulose
- An Aerolizer® DPI device containing an empty capsule was coupled to the USP inlet and the APS Aerosol Pressure Drop on the Model 3306 Impactor Inlet was adjusted to 0.3 inches of water per manufacturer calibration instructions.
- the Aerolizer® DPI device was then removed from the coupler, but the coupler was left attached to the USP Inlet. The opening of the coupler (that the Aerolizer® is inserted into) was partially restricted in order to maintain the 0.3 inches of water APS Aerosol Pressure Drop when the Aerolizer® DPI device was not present.
- the APS sampling time was set to 10 seconds. Approximately 5 mg of powder was loaded into a capsule and placed into the Aerolizer® DPI device. The capsule was punctured immediately prior to testing using the piercing mechanism of the Aerolizer® DPI device. The APS sampling was then started without the device in place. After five seconds of sampling, the coupler restriction was removed and the Aerolizer® DPI device with loaded capsule was immediately inserted into the opening in the coupler in order to deliver the drug from the DPI. The APS measured the total concentration of the powder from the sample, as shown in Table 4. The concentration of powder with aerodynamic diameters less than approximately 4.7 microns was determined from the APS measurement and is representative of particles likely to reach the deep lung of a patient. The results below are an average of three measurements for each powder type. Results are shown for the modified drug powder composition containing 1.0% surface-modified nanoparticles, as well as comparative examples ('CE') with unmodified drug powders.
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JP2008525187A JP5694643B2 (en) | 2005-08-05 | 2006-08-04 | Composition exhibiting improved fluidity |
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Cited By (41)
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Also Published As
Publication number | Publication date |
---|---|
CA2617909C (en) | 2014-02-04 |
US20080286362A1 (en) | 2008-11-20 |
US8062670B2 (en) | 2011-11-22 |
CN101243130A (en) | 2008-08-13 |
CA2617909A1 (en) | 2007-02-15 |
JP2009503104A (en) | 2009-01-29 |
JP2013100352A (en) | 2013-05-23 |
CN101243130B (en) | 2011-12-07 |
JP5694643B2 (en) | 2015-04-01 |
EP1917301A1 (en) | 2008-05-07 |
EP1917301B1 (en) | 2014-04-23 |
AU2006278571B2 (en) | 2011-11-24 |
AU2006278571A1 (en) | 2007-02-15 |
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