Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
  • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
  • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
  • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
  • B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N13/00—Investigating surface or boundary effects, e.g. wetting power; Investigating diffusion effects; Analysing materials by determining surface, boundary, or diffusion effects
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N13/00—Investigating surface or boundary effects, e.g. wetting power; Investigating diffusion effects; Analysing materials by determining surface, boundary, or diffusion effects
  • G01N2013/003—Diffusion; diffusivity between liquids
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
  • G01N15/08—Investigating permeability, pore-volume, or surface area of porous materials
  • G01N2015/086—Investigating permeability, pore-volume, or surface area of porous materials of films, membranes or pellicules

Definitions

• compositions typically involve a screening and refinement process in which a large number of pharmaceutical compositions are evaluated.
• compositions typically include one or more pharmaceuticals and one or more compounds (commonly known as excipients or enhancers) that increase diffusion of the pharmaceutical(s) across the membrane of interest
• Typical systems for measuring membrane diffusion have two chambers separated by a membrane (for example, skin).
• a membrane for example, skin
• one chamber contains a pharmaceutical composition to be tested (for example, as a solution or in a transdermal patch), and the other chamber contains a recipient solution representative of serum.
• the pharmaceutical composition and the recipient solution each contact opposite surfaces of the membrane.
• the concentration of the pharmaceutical in the receiving solution is periodically measured and the diffusion rate of the pharmaceutical across the membrane determined.
• the present invention provides a system for measuring diffusion of a compound across a membrane comprising: a first base having first and second opposed surfaces and having a plurality of hollow projections extending outwardly from the first surface, each hollow projection having a tapered tip with an opening therein and a respective cavity contiguous with the ⁇ opening disposed within the projection; a second base having first and second opposed surfaces, the first surface having a plurality of recessed tapered openings therein adapted to engage the plurality of hollow projections, each recessed tapered opening being contiguous with a respective cavity that extends into the second base; and a membrane contacting the recessed tapered openings and the tips of the hollow projections, wherein the first base is fastened to the second base by a first fastening means, and wherein: a) each cavity within a hollow projection extends through the first base and forms an opening at the second surface of the first base; or b) each cavity within the second base extends through the second base and forms an opening at the second surface
• the system further comprises a retaining plate having perforations therein adapted to allow the hollow projections to pass therethrough, wherein the retaining plate is fastened to the first base by a second fastening means, wherein the membrane is disposed between the first base and the retaining plate.
• the present invention provides a method of measuring diffusion of a compound through a membrane comprising: providing a system according to the present invention; placing a first fluid composition into at least one cavity in the first base; placing a second fluid composition comprising a compound into at least one cavity in the second base, wherein the cavities in the first and second bases are in fluid communication through the membrane; and analyzing the compound content of the first fluid composition.
• the present invention provides a system, in kit form, for holding a membrane comprising: a first base having first and second opposed surfaces and having a plurality of hollow projections extending outwardly from the first surface, each hollow projection having a tapered tip with an opening therein and a respective cavity contiguous with the opening disposed within the projection; a second base having first and second opposed surfaces, the first surface having a plurality of recessed tapered openings therein adapted to engage the plurality of hollow projections, each recessed tapered opening being contiguous with a respective cavity that extends into the second base; and means for fastening the first base to the second base wherein: a) each cavity within a hollow projection extends through the first base and forms an opening at the second surface of the first base; or b) each cavity within the second base extends through the second base and forms an opening at the second surface of the second base; or c) each cavity within a hollow projection extends through the first base and forms an opening at the second surface of the first base, and each cavity
• the kit further comprises a retaining plate having perforations therein adapted to allow the hollow projections to pass therethrough, and means for fastening the retaining plate to the second base.
• membrane diffusion refers to the rate of diffusion of a compound through a membrane.
• FIG. 4 is a cross-sectional side view showing an exemplary engaged tapered projection and tapered recess;
• FIG. 5 is an exploded perspective view of one exemplary embodiment of the present invention; and
• FIG. 6 is an exploded perspective view of one exemplary embodiment of the present invention.
• exemplary system 100 for holding a membrane comprises first base 150 having first and second opposed surfaces 152 and 154, respectively.
• a plurality of hollow projections 155 extend outwardly from first surface 152, each hollow projection 155 having an outer wall 157 and tapered tip 160 with an opening 165 therein.
• Each hollow projection 155 has a cavity 170 contiguous with opening 165 disposed therein.
• Each cavity 170 has one or more sides 175.
• each cavity 170 has a respective bottom 180. Bottoms 180 may be at the same or different depths.
• sides 175 extend into first base 150, optionally extending through the first base 150 to second surface 154 to form passages 185.
• Second base 110 has first and second opposed surfaces 112 and 114, respectively.
• First surface 112 has a plurality of recessed tapered openings 115 therein adapted to engage tapered tips 160.
• Each recessed tapered opening 115 is contiguous with a cavity
• Each cavity 120 has one or more sides 125. In one embodiment, each cavity 120 has a respective bottom 130. In another embodiment, the sides 125 extend into second base 110, optionally extending through second base 110 to second surface 114 to form passages 135. In typical use, membrane 190 is positioned between first base 150 and second base
• system 100 further comprises optional retaining plate 106, which has perforations 108 therethrough adapted to allow at least a portion of each hollow projection 155 (for example, a portion of tip 160) to pass therethrough.
• perforations 108 may be of sufficient spacing and shape to permit hollow projections 155 to simultaneously pass through perforations 108.
• the perforations 108 may be of sufficient spacing and shape to permit, for example, only a portion of tapered tips 160 to extend through perforations 108, but not allow hollow projections 155 to simultaneously pass through perforations 108.
• Retaining plate 106 is fastened to second base 110 by a second fastening means shown by screws 119, which pass through holes 116 in retaining plate 106 and engage threaded holes 118 in second base 110.
• the optional retaining plate may be positioned on either side of the membrane, and may be fastened to either the first base or the second base.
• exemplary system 200 comprises first base 250, having first and second opposed surfaces 252 and 254, respectively.
• a plurality of hollow projections 255 consisting of tapered tips 260 extend outwardly from first surface 252, each tapered tip 260 having an opening 265 therein.
• Each tapered tip 260 has a cavity 270 contiguous with opening 265 disposed therein.
• Each cavity 270 has one or more sides 275.
• each cavity 270 has a respective bottom 280.
• the sides 275 extend into first base 250, and may even extend through the first base to second surface 254, thereby forming passages 285.
• Second base 210 has first and second opposed surfaces 212 and 214, respectively.
• First surface 212 has a plurality of recessed tapered openings 215 therein adapted to engage tapered tips 260.
• Each recessed tapered opening 215 is contiguous with a cavity 220 that extends into second base 210.
• Each cavity 220 has one or more sides 225.
• each cavity 220 has a respective bottom 230.
• sides 225 extend into second base 210, and may even extend through second base 210 to second surface 214, thereby forming passages 235.
• membrane 290 is positioned between first base 250 and second base 210, and first base 250 and second base 210 are fastened together by a fastening means, shown by screws 295 (which pass through holes 296 and engage threaded holes 297).
• the first and second bases and the retaining plate may be made of any material, including, for example, metal, glass, ceramic, plastic, and combinations thereof, and may be opaque, transparent and/or translucent.
• the first and second bases may have any shape (for example, a block or plate) and/or thickness.
• Systems according to the present invention may have any number of hollow projections greater than one (for example, 2, 12, 24, 32, 64, 96, or even as many as 256 hollow projections or more).
• Hollow projections may individually have any shape including, for example, cylindrical, prismatic, or conical shapes. Hollow projections may have any, typically about equal, height relative to the base. Each hollow projection has a tapered tip, which may be of any shape as long as it generally narrows toward the outermost end of the tapered tip. Tapered tips may have any cross-sectional profile. Openings in the tapered tips may have any shape, such as for example, circular or polygonal. The area of the openings may be of any size, for example, greater than 0.01, 0.05, 0.1, 0.5, or even 1 square centimeter, or even more.
• Cavities in the hollow projections, and/or the first and second bases may have any shape and/or depth, and their bottoms may have any shape (for example, flat and/or rounded). Referring now to FIG. 3, the cross-sectional profile of one or more tapered tips
• the cross-sectional profile of one or more tapered tips 424 may comprise a beveled portion 440.
• the cross-sectional profile of the tip comprises a beveled portion and an arcuate portion.
• recessed tapered openings may individually have any shape, but are typically chosen to have a shape that is complementary to tapered tips that they engage, in order that a tight seal may be formed with a membrane when the tip and recessed tapered opening are engaged with a membrane therebetween.
• the cross- sectional profile of recessed tapered openings 315 may comprise an arcuate portion 345.
• the cross-sectional profile of recessed tapered openings 415 may comprise a beveled portion 445.
• the cross-sectional profile of the tip may comprise both a beveled portion and an arcuate portion.
• the tapered tips are adapted to engage the recessed tapered openings fixing membrane 390 or 490, respectively, therebetween.
• the precise shape of the recessed tapered openings and the tapered tips is not important, however to prevent perforation of the membrane when assembling systems according to the present invention, the depth of the recessed tapered openings may be limited to less than 1, 0.5, 0.3, 0.2, or even less than 0.1 centimeters, and the average angle of the taper may be limited to less than 45, 30, or even less than 20 degrees from the surrounding surface.
• Fastening means utilized in the present invention may be removable or non-removable.
• Useful fastening means include mechanical, adhesive, and attractive (for example, magnetic, gravitational) means.
• Removable fastening means include, for example, screws, removable adhesives, clamps, staples, clips, nails, pins, hook and loop fasteners, weights, mushroom-type mechanical fasteners, snaps and combinations thereof.
• Non-removable fastening means include, for example, non-removable adhesives, rivets, welds, locking snap connectors, soldered joints, and combinations thereof.
• Suitable membranes are typically thin soft pliable sheets including, for example, synthetic polymer membranes (for example, cellulose acetate sheets, polymeric membranes containing ethyl cellulose, phospholipids, cholesterol, and mineral oil, polyurethane polymers containing poly(ethylene glycol) block segments, synthetic zeolites incorporated into poly(styrene), silicone rubbers, laminated polymer sheets containing alternating hydrophilic and hydrophobic sheets, filter papers or membranes loaded with organic liquids, and cultured cell membranes); hairless mouse skin; snake skin; pig skin; and cadaver skin.
• synthetic polymer membranes for example, cellulose acetate sheets, polymeric membranes containing ethyl cellulose, phospholipids, cholesterol, and mineral oil, polyurethane polymers containing poly(ethylene glycol) block segments, synthetic zeolites incorporated into poly(styrene), silicone rubbers, laminated polymer sheets containing alternating hydrophilic and hydrophobic sheets, filter papers or membranes loaded with organic
• one of the first or second bases is used as a formulation plate that contains a plurality of compositions comprising one or more compounds (for example, pharmaceuticals, excipients, dyes, chemical reagents and mixtures thereof, nutriceuticals, vitamins, cosmoceuticals) to be evaluated and the other as a receiving plate.
• the second base may be the formulation plate
• the first base may be the receiving plate, or vice versa.
• membrane 590 is positioned against formulation plate 510 thereby covering recessed tapered openings 515 (not shown) in formulation plate 510.
• Retaining plate 506, having perforations 508 therein, is fastened to formulation plate 510 by means of screws 519, which pass through holes 517 in retaining plate 506 and engage threaded holes 518 (not shown) in formulation plate 510, thereby forming subassembly 502.
• Subassembly 502 is fastened to receiving plate 550 by screws 595 that pass through holes 594 in formulation plate 510 and engage threaded holes 596 in receiving plate 550.
• subassembly 502 can be repeatedly fastened to, and unfastened from, receiving plate 550 without having to handle membrane 590.
• Membrane 590 is typically smoothed (for example, manually) to remove wrinkles prior to fastening retaining plate 506 to formulation plate 510.
• Compositions to be evaluated (not shown) are placed into passages 535 in formulation plate 510, which are covered by tape 537 to facilitate handling and/or to reduce evaporation.
• Tape 537 may be replaced by other covering means such as, for example, a cover plate.
• Cavities 570 in hollow projections 555 of receiving plate 550 are filled with a receiving liquid (for example, serum or a synthetic version thereof, not shown). To help avoid the formation of air gaps during assembly that may, for example, lead to erroneous membrane diffusion rates, cavities 570 may be overfilled with receiving liquid to the maximum point permitted by the surface tension of the receiving liquid.
• Formulation plate 510 and receiving plate 550 are then fastened together such that tapered tips 560 engage recessed tapered openings 515, fixing membrane 590 therebetween.
• membrane 590 is typically stretched across openings 570 in tapered tips 560 and compressed between tapered tips 560 and recessed tapered openings 515, thereby ensuring a tight seal and reducing, or more typically, eliminating the possibility of crosstalk between adjacent cells.
• Elongated body portions 556 of hollow projections 555 further help to prevent crosstalk by allowing any liquids that leak out of one cell to harmlessly drain away by gravity, for example, when the system is oriented with hollow projections 555 extending vertically upward.
• Systems according to the present invention may further comprise one or more covering means, for example, as shown in FIG.
• Suitable covering means include, for example, films, sealing mats, plates, stoppers, and combinations thereof.
• the covering means may be, for example, a unitary covering means (for example, a film, tape, or cover plate) or a non-unitary covering means (for example, a plurality of films, tapes, stoppers, rubber septa, or a combination thereof).
• formulation plate 650 has hollow projections that consist of tapered tips 660. Passages 685 (not shown) extend through formulation plate 650 and form openings 665 in tapered tips 660.
• Receiving plate 610 has recessed tapered openings 615 therein adapted to engage tapered tips 660.
• Cavities 620 are contiguous with recessed tapered openings 615.
• Receiving plate 610 is fastened to formulation plate 650 by retaining bracket 672 and screws 662 that pass through holes 617 and engage threaded holes 618, such that tapered tips 660 engage recessed tapered openings 615, fixing membrane 690 therebetween.
• Receiving plate 610 is optically transparent and retaining bracket 672 has perforations 629 therethrough of appropriate spacing and alignment to permit optical detection of the contents of cavities 620.
• Optical detection methods include, for example, visual inspection, spectroscopic methods, optical scanners, and videographic and photographic methods (including digital photographic methods). Systems according to the present invention may be used in conjunction with various known collection, automated dispensing equipment, and/or autosampling equipment.
• liquid handling robots for example, such as those commercially available from Gilson, Inc., Middleton, Wisconsin and well plates (for example, having 24, 96, or 384 wells) such as, for example, those available from Weidmann Plastics Technology AG, Rapperswil, Switzerland.
• Systems according to the present invention may be provided in assembled or kit form (that is, unassembled or partially assembled), with or without a membrane.
• Various unforeseeable modifications and alterations of this invention may be made by those skilled in the art without departing from the scope and spirit of this invention, and it should be understood that this invention is not to be unduly limited to the illustrative embodiments set forth herein.

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• Pharmacology & Pharmacy (AREA)
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• Hematology (AREA)
• Sampling And Sample Adjustment (AREA)
• Investigating Or Analysing Biological Materials (AREA)

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• 2003
  • 2003-09-24 US US10/669,276 patent/US7635452B2/en not_active Expired - Fee Related
• 2004
  • 2004-07-28 WO PCT/US2004/024487 patent/WO2005036138A1/en not_active Ceased
  • 2004-07-28 JP JP2006527975A patent/JP4317224B2/ja not_active Expired - Fee Related
  • 2004-07-28 EP EP04757380A patent/EP1664733A1/en not_active Withdrawn

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