Name: Semiconductor device manufacturing: process > Coating with electrically or thermally conductive material > To form ohmic contact to semiconductive material > Forming solder contact or bonding pad > Bump electrode > Plural conductive layers
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Procedure for manufacturing bottles containing fluids, particularly cosmetic, medical, pharmaceutical products or the like, and relative system and bottles
Abstract: A fluid delivery apparatus and method is provided wherein either liquid or gaseous fluid is provided from fluid dispenser manifolds, via nozzle plates associated therewith, on each side of a path of travel of articles being treated by the fluid, and wherein nozzle openings in a nozzle plates cooperate with transverse groove(s) to provide a screen flow of fluid extending transversely of the path of travel of articles, and directed toward the articles. In the case of the fluid being a liquid, the nozzle openings provide cylindrical filament-like columns of liquid which are rendered by the associated grooves into generally flat, transversely disposed semen spray of liquid. In the case of the fluid being a gas, the nozzle openings and transverse grooves cooperate to deliver the gas in transversely spaced apart, transverse, planar zones of gas directed toward the path of article travel.In the case of liquid flow, the openings are generally cylindrical, and in the case of gas flow the openings are generally spaced-apart slotted holes. In the cases of both liquid and gas fluids, one of the grooves and/or nozzles are directed upstream relative to the path of article flow. Various adjustments are provided for adjusting the positions of the nozzle plates relative to the path of flow.
1. Apparatus for fluid treatment of articles being conveyed along a predetermined generally longitudinal path, comprising means for conveying articles along a pre-determinedlongitudinal path from an upstream direction toward a downstream direction, and:
(a) a first fluid dispenser manifold arranged generally transverse to said generally longitudinal path;
(b) a second fluid dispenser manifold arranged generally transverse to said generally longitudinal path;
(c) said first and second fluid dispenser manifolds being disposed generally opposite each other with the longitudinal article path therebetween;
(d) with said first and second fluid dispenser manifolds having respectively associated first and second multi-port fluid dispenser nozzle plates disposed generally transverse of and adjacent to said path, with one said nozzle plate on each sideof said path and terminating in a nozzle plate surface nearest said path;
(e) with at least one of said first and second nozzle plates having at least one generally transverse row of nozzle openings for dispensing fluid from an associated said manifold therethrough, into contact with articles being conveyed along thepredetermined path;
(f) transverse groove means extending transverse of said longitudinal path along said nozzle plate surface, connecting the nozzle openings in said nozzle plate surface nearest said path; and
(g) with said row of nozzle openings and said transverse groove means cooperating to comprise means for providing transversely extending screen-like fluid flow from said nozzle openings.
2. The apparatus of claim 1, wherein a said nozzle plate has at least two generally transverse rows of nozzle openings, with openings in one said row together with their associated groove means being arranged to dispense fluid generallyperpendicular to the predetermined longitudinal path of articles, for impingement of fluid flow onto articles being conveyed therepast, and with the openings in another row, together with their associated groove means being arranged to dispense fluid inan upstream angled direction along said path, for impingement of fluid flow onto articles being conveyed therepast.
3. The apparatus of claim 1, wherein said at least one of said first and second nozzle plates is provided with a plurality of transversely spaced notches; and with a plurality of article-engaging roller wheels being mounted on said apparatusfor engagement with articles as they are conveyed therepast; with said wheels being partially disposed in said notches for clearance therewith.
4. The apparatus of claim 1, wherein at least one said fluid dispenser manifold is provided with means for adjustably positioning said dispenser manifold such that its nozzle openings are adjustably positionable relatively close to andrelatively away from the path of article travel.
5. The apparatus of claim 1, with a plurality of article-engaging roller wheels being mounted on said apparatus for engagement with articles as they are conveyed therepast; wherein the path of article travel is generally horizontal; andwherein said roller wheels are adapted to engage an upper surface of an article being conveyed along the path of travel, and with means facilitating vertical movement of said roller wheels to accommodate articles of various thickness.
6. The apparatus of claim 1, wherein the path of article travel is generally horizontal, and wherein said first and second fluid dispenser means are disposed above and below said path of travel.
7. The apparatus of claim 1, wherein each said fluid dispenser nozzle plate includes a plurality of generally transverse rows of nozzle openings.
8. The apparatus of claim 1, wherein a said nozzle plate has at least two generally transverse rows of nozzle openings, with openings in one said row together with their associated groove means being arranged to dispense fluid generallyperpendicular to the predetermined longitudinal path of articles, for impingement of fluid flow onto articles being conveyed therepast; and with the openings in another row together with their associated groove means being arranged to dispense fluid inan upstream angled direction, for impingement of fluid flow onto articles being conveyed therepast; wherein said at least one of said first and second nozzle plates is provided with a plurality of transversely spaced notches; and with a plurality ofarticle-engaging roller wheels being mounted on said apparatus for engagement with articles as they are conveyed therepast; with said wheels being partially disposed in said notches for clearance therewith, wherein at least one said fluid dispensermanifold is provided with means for adjustably positioning said dispenser manifold such that its nozzle openings are adjustably positionable relatively close to and relatively away from the path of article travel; wherein the path of article travel isgenerally horizontal; and wherein said roller wheels are adapted to engage an upper surface of an article being conveyed along the path of travel; and with means facilitating vertical movement of said roller wheels to accommodate articles of variousthickness; wherein each said fluid dispenser nozzle plate includes a plurality of generally transverse rows of nozzle openings; and wherein said first and second fluid dispenser means are disposed above and below said path of travel.
9. The apparatus of any one of claims 1-2, wherein said nozzle openings comprise means for disseminating generally cylindrical columns of liquid flow, and wherein said groove means comprises means for connecting said columns of liquid flow intoa generally flat, transversely disposed, planar screen spray of liquid.
10. The apparatus of claim 9, wherein said nozzle openings comprise a plurality of generally cylindrical holes in each said row.
11. The apparatus of claim 9, wherein said nozzle openings each include a cylindrical taper in the range of 100.degree. to 160.degree. across the diameter thereof, and wherein said groove means has an included angle longitudinally measured,within the range of 30.degree. to 90.degree..
12. The apparatus of claim 11, wherein said cylindrical taper is approximately 120.degree. and said included angle for said groove means is approximately 60.degree..
13. The apparatus of any one of claims 1-2, wherein said nozzle openings and associated transverse groove means comprise means for disseminating therefrom, a plurality of transversely spaced apart transverse, planar, zones of gas flow, directedtoward the path of article travel.
14. The apparatus of claim 13, wherein said nozzle openings comprise a plurality of transversely elongated slotted holes in each said row, separated by transverse spacings.
15. The apparatus of claim 14, wherein the transversely elongated slotted holes in each said row of a given fluid dispenser nozzle plate are longitudinally aligned with spacings between slotted holes in an adjacent row.
16. The apparatus of claim 14, wherein the depth of said groove means is within a range of 1 to 4 times the width of the slotted holes as measured in the longitudinal direction.
17. The apparatus of any one of claims 1-2, wherein the nozzle plate surface nearest said path, for at least one of said nozzle plates, converges toward said path in an upstream direction, and comprises means, in cooperation with said upstreamangled direction of said groove means, for creating a suction effect of fluid impingement on an article being conveyed therepast.
18. A method of fluid treatment of articles being conveyed along a pre-determined generally longitudinal path, comprising the steps of conveying articles along a pre-determined longitudinal path from an upstream direction toward a downstreamdirection, and:
(c) disposing the first and second fluid dispenser manifolds generally opposite each other with the longitudinal article path therebetween;
(d) with said first and second fluid dispenser manifolds having respectively associated first and second multi-port fluid dispenser nozzle plates; disposing the nozzle plates generally transverse of and adjacent to the path, with one nozzleplate on each side of path terminating in a nozzle plate surface nearest said path;
(e) with at least one of the first and second nozzle plates having at least one generally transverse row of nozzle openings for dispensing fluid; dispensing fluid from an associated said manifold therethrough the openings thereof, into contactwith articles being conveyed along the predetermined path;
(f) providing transverse groove means extending transverse of said longitudinal path along said nozzle plate surface and connecting the nozzle openings in said nozzle plate surface nearest said path via said groove means; and
(g) providing transversely extending screen-like fluid flow from said nozzle openings via the transverse groove means.
19. The method of claim 18, including the step of providing a said nozzle plate with at least two generally transverse rows of nozzle openings, with openings in one said row together with their associated groove means being arranged to dispensefluid generally perpendicular to the predetermined longitudinal path of articles, any impinging fluid flow onto articles being conveyed therepast, and with the openings in another row, together with their associated groove means being arranged todispense fluid in an upstream angled direction along said path, and impinging fluid flow onto articles being conveyed therepast in an upstream angled direction.
20. The method of claim 18, including the step of providing at least one of said first and second nozzle plates with a plurality of transversely spaced notches; and mounting a plurality of article-engaging roller wheels on said apparatus forengagement with articles as they are conveyed therepast; with said wheels being partially disposed in said notches for clearance therewith.
21. The method of claim 18, wherein at least one said fluid dispenser manifold is provided with means for adjustably positioning said dispenser manifold such that its nozzle openings are adjustably positionable relatively close to and relativelyaway from the path of article travel, and adjustably positioning the nozzle openings relative to the path.
22. The method of claim 18, and mounting a plurality of article-engaging roller wheels on said apparatus for engagement with articles as they are conveyed therepast; wherein the path of article travel is generally horizontal; and engaging saidroller wheels with an upper surface of an article being conveyed along the path of travel, with vertical movement of said roller wheels to accommodate articles of various thickness.
23. The method of claim 18, wherein the conveying of articles along the path of travel is generally horizontal, and wherein said first and second fluid dispenser means are disposed above and below said path of travel.
24. The method of claim 18, wherein each said fluid dispenser nozzle plate includes a plurality of generally transverse rows of nozzle openings.
25. The method of claim 18, including providing a said nozzle plate with at least two generally transverse rows of nozzle openings, with openings in one said row together with their associated groove means dispensing fluid generallyperpendicular to the predetermined longitudinal path of articles, for impingement of fluid flow onto articles being conveyed therepast; and with the openings in another row together with their associated groove means dispensing fluid in an upstreamangled direction, for impingement of fluid flow onto articles being conveyed therepast; wherein said at least one of said first and second nozzle plates is provided with a plurality of transversely spaced notches; and mounting a plurality ofarticle-engaging roller wheels on said apparatus for engagement with articles as they are conveyed therepast; with said wheels being partially disposed in said notches for clearance therewith; providing at least one said fluid dispenser manifold withmeans for adjustably positioning said dispenser manifold and adjustably positioning its nozzle opening relatively close to and relatively away from the path of article travel; wherein the path of article travel is generally horizontal; and engagingsaid roller wheels with an upper surface of an article being conveyed along the path of travel; vertically moving said roller wheels to accommodate articles of various thickness; wherein each said fluid dispenser nozzle plate includes a plurality ofgenerally transverse rows of nozzle openings; and disposing said first and second fluid dispenser means above and below said path of travel.
26. The method of any one of claims 18-19, and disseminating from said nozzle openings generally cylindrical columns of liquid flow, and connecting said columns of liquid flow, via said groove means, into a generally flat, transversely disposed,planar screen spray of liquid.
27. The method of claim 26, including the steps of providing said nozzle openings with a plurality of generally cylindrical holes in each said row.
28. The method of claim 26, including the steps of providing said nozzle openings with a cylindrical taper in the range of 100.degree. to 160.degree. across the diameter thereof, and providing said groove means with an included anglelongitudinally measured, within the range of 30.degree. to 90.degree..
29. The method of claim 28, including providing said cylindrical taper at approximately 120.degree. and providing said included angle for said groove means at approximately 60.degree..
30. The method of any one of claims 18-19, including the steps of disseminating from said nozzle openings and associated transverse groove means, a plurality of transversely spaced apart transverse, planar, zones of gas flow, directed toward thepath of article travel.
31. The method of claim 30, including the steps of providing for said nozzle openings, a plurality of transversely elongated slotted holes in each said row, separated by transverse spacings.
32. The method of claim 31, and longitudinally aligning the transversely elongated slotted holes in each said row of a given fluid dispenser nozzle plate with spacings between slotted holes in an adjacent row.
33. The method of claim 32, including providing a depth for said groove means within a range of 1 to 4 times the width of the slotted holes as measured in the longitudinal direction.
34. The method of any one of claims 18-19, and converging the nozzle plate surface nearest said path, for at least one of said nozzle plates, toward said path in an upstream direction, and creating, in cooperation with said upstream angleddirection of said groove means, a suction effect of fluid impingement on an article being conveyed therepast.
In various wet processing arts involving chemical treatment, such as etching, electroplating and the like, it is known to deliver fluids onto surfaces of articles being treated. In many instances, the articles being treated are printed circuitboards and the like. Often such articles are being delivered along a generally horizontal path and are etched, cleaned, rinsed, activated, dried, coating, etc., at various stations along the path. Sometime the articles being treated, if they areprinted circuit board, have bore holes extending therethrough and it is desired to have the treatment fluid impinge not only on upper and lower surfaces of the boards, but also on bore holes. The treatment of the articles can take place via nozzlearrangements, such as that set forth in U.S. Pat. No. 4,789,405, for example. In other instances the treatments may take the form of various other fluid delivery, spraying, drying techniques, such as those disclosed in U.S. Pat. Nos. 4,576,685,4,017,982, 3,935,041, 3,905,827, or 3,776,800. Various drive techniques for driving the printed circuit boards or other articles through the various treatment stations may be used, such as those set forth in U.S. Pat. No. 4,046,248 or the like.
Accordingly, the technical field of this invention is directed to a method and arrangement for treating conductor substrates. Such treatment processes can include the removal of liquid from through-holes in conductors boards and from itssurface, drying the boards, in addition to cleaning, coating, rinsing, etching, activation and various electrolytic processes.
The present invention is directed toward efficient delivery of fluid to articles being treated, and most particularly to conductor boards and the like.
In connection with the fluid delivery, slotted tubes, for example have been used, but such are limited in development of the flow upon exiting the orifice or slot, such that the flow stream may dissipate more quickly and lose some of itsmomentum, even exponentially, as the distance from the substrate being treated increases.
Spray nozzles are also use, but such often require large amounts of energy relative to the fluid medium being processed. Additionally, in some instances spray nozzles do not provide the desired level of uniformity in terms of coverage, with ahigher percentage of flow and pressure being located at the center of the nozzle spray pattern, and a lesser percentage of flow and pressure outwardly thereof, in that flow and pressure are often substantially reduced as the distance is increasedperpendicular to the centerline of the nozzle.
Fluid jet injectors have also been used to produce tight columns of flow, but also generally fail to provide a desired level of uniform and complete coverage of the article being treated. Additionally, small injectors require substantiallyhigher pressure to maintain a desired impact of force on the article being treated, which high force impact may not always be desirable.
The present invention provides a method and apparatus for delivering a fluid to printed circuit boards or other articles being treated, as the articles are delivered along a path of travel, by impinging the fluid on the articles from both sidesof their path of travel. During such travel fluid is dispensed from nozzles and directed via the nozzles themselves and grooves that connect the nozzles, such that the fluid is provided in the form of a transverse extended screen-like fluid flow fromthe nozzle openings. The fluid delivered may be either liquid or gas. In the case of a liquid, the nozzle openings disseminate the flow into cylindrical filament-like columns of liquid flow, connected via the grooves, whereby at the orifice formed atthe junction of the cylindrical nozzles and groove, the liquid flow is transformed into a generally flat transversely disposed, planar screen spray of liquid. In the case of a gas fluid, such is provided via nozzle openings and transverse groovesconnecting rows of openings, which openings are transversely spaced apart to facilitate disseminating from the openings via the grooves separate, spaced-apart, transversely aligned planar zones of gas flow directed toward the path of article travel. Asuction effect is created by an upstream-converging surface of the nozzle, which may be optimized by the configuration of the lower surface of the nozzle.
Various adjustments are provided for the apparatus in accordance with this invention. Additionally, various preferred parameters and structural arrangements are utilized. In some cases a row of nozzle openings is directed at an angle to thepath of travel, aimed at the upstream direction of the path of travel.
Accordingly, it is a primary object of this invention to provide a novel method and apparatus for imparting fluid delivery to an article being conveyed along a predetermined path.
It is a further object of this invention to accomplish above object, wherein the fluid delivery is gas for drying an article, such as a conductor board.
It is another object of this invention to accomplish the primary object wherein the fluid delivery is a liquid fluid delivery, such as for rinsing, etching, etc.
Other objects and advantages will be readily understood upon a reading of the following brief description of the drawings, detailed description of the preferred embodiments and the appended claims.
FIG. 1 is a longitudinal sectional, schematic view, taken through a multi-station apparatus in accordance with this invention, wherein a plurality of etching, rinsing, drying, operations are illustrated, and wherein means for imparting fluiddelivery above and below articles such as circuit conductors, are illustrated.
FIG. 2 is a schematic, perspective view of a circuit board conductor being delivered along its path between upper and lower fluid dispensers in accordance with this invention, with the dispensers being of a type illustrated above and below thepath of travel in FIG. 1.
FIG. 3 is an enlarged view of upper and lower fluid delivery manifolds as shown in FIG. 1, with delivery plates thereof being shown in full lines close to the path of article travel, and in phantom lines spaced moreso from the path of articlestravel.
FIG. 4 is a view taken generally along the line of IV--IV of FIG. 3, showing the lower end of a nozzle plate surface of an upper dispenser, fragmentally illustrated.
FIG. 5 is a longitudinal section taken generally along the line V--V of FIG. 4, wherein two generally perpendicularly disposed nozzles are illustrated, with an angled nozzle being illustrated, disposed therebetween.
FIG. 5A is an enlarged detailed view of one of the nozzles and its associated groove illustrated in FIG. 5, wherein the geometric arrangement thereof is more clearly shown.
FIG. 6 is a view similar to that of the liquid dispensing nozzle plate of FIG. 4, but with the nozzle plate of FIG. 6 being specifically adapted for gas dispensing, such as drying air or the like.
FIG. 7 is a longitudinal sectional view similar to that of FIG. 5 but taken generally along the line of VII--VII of FIG. 6.
FIG. 8 is an enlarged fragmentary longitudinal sectional view taken through an alternative gas delivery pair of manifolds disposed on opposite sides of a path of travel of articles being treated, wherein the surfaces of the manifold platesclosest to the path of travel are converging in an upstream direction to facilitate suction of fluid conveyed for impinging surfaces of articles being treated.
Referring now to the drawings now in detail, reference is first made to FIG. 1, in which a fluid treatment system for articles being conveyed is generally designated by the numeral 10. In this embodiment, the articles being conveyed are printedcircuit boards or the like 11, with through-holes such as 12 extending there through, with connecting portions 13 functioning as conductors along portions of the boards, as shown in FIG. 2.
In FIG. 1, a plurality of stations 14, 15 and 16 are illustrated, with station 14 functioning perhaps as an etching chamber wherein a suitable etchant may be dispensed onto appropriate surfaces of a printed circuit board or the like, followedperhaps by a rinsing station 15, in which the ecthant liquid (or other treatment fluid) would be rinsed from the articles 11 by means of fluid dispensers 17, 18, followed by passage of the articles into another station 16, which may for example be a gastreatment station such as an air drying station wherein air is dispensed via dispensers 20, 21 which, like the dispensers 17, 18, are disposed on opposite sides of a path of travel 22 for articles being conveyed through the apparatus of the system 10, asshown, from left to right, in the direction of the arrows 23.
Each of the stations 14-16 are provided with upper and lower walls, 24, 25, side walls 26, inlet and outlet walls 27, 28 with appropriate inlet and outlet openings 30, 31, respectively.
The path 22 of travel of the articles 11 is therefore a longitudinal path of travel through the machine and in the embodiment shown, the path 22 is generally horizontal.
Appropriate drive rollers 32 are provided, generally shaft-mounted on transversely disposed shafts, which in turn are driven by any suitable means, such as a drive means for example as shown in U.S. Pat. No. 4,015,706.
In instances particularly where the treatment fluid in a given station is liquid, such as for the station 15, an appropriate liquid discharge line 33 may be provided, for discharge for recycling or the like, as desired.
With reference to FIG. 2, in particular, the article 11 is shown being delivered substantially horizontally in the direction of arrow 23, beneath a dispenser 17 and above a dispenser 18, it being understood that FIG. 2 could equally wellrepresent dispensers 20, 21 as desired.
With reference to FIG. 3, it will be seen that the upper dispenser 17 is disposed above the lower dispenser 18 for conveyance of articles 11 therebetween in a longitudinal, generally horizonal path of travel, as shown.
The dispenser 17 includes a manifold 35 which receives treatment liquid via a inlet tube 36 or the like, for delivery down through the manifold 35, through a manifold transition plate 37 having a large number of spaced apart transition holes 38therein, arranged in a row, which extends transversely, substantially between sidewalls 26 of the apparatus as shown in dotted lines in FIG. 3. The fluid thus delivered via conduit 36 and manifold transition holes 38 is thus delivered to a multi-portfluid dispenser nozzle plate 40. The nozzle plate has a plurality of fluid dispenser nozzle openings 41, 42 and 43, arranged in transverse rows, perpendicular to the longitudinal path of travel 22 for articles 11, and extending generally the transverselength of the manifold 17, substantially completely between opposed sidewalls 26 of the apparatus.
A pair of article-engaging rollers 44, 45 are provided, carded indirectly (by means not shown) by the dispenser 17, respectively shaft-mounted at 46, 47, to engage against an upper surface 48 of an article 11 being treated. The purpose of theupper and lower rollers 44, 45 is to resist the forces of impingement of fluid being delivered to an article 11 being treated via a manifold on the opposite side of the path of travel 22. Thus, fluid delivered via lower dispenser 18 would impart anupward component of motion to the article 11 being treated as shown in FIG. 3, but for the resistance applied by the rollers 44, 45 in engagement with an upper surface 48 of the article 11. Conversely, fluid delivered from upper dispenser 17 onto anupper surface 48 of the article 11, would be resisted by the presence of lower rollers (unnumbered) carried by the dispenser 180
In order to accommodate different thicknesses of article 11, the dispensers 17, 18, are vertically adjustable by any suitable means, such that their dispenser nozzle plates 40 may move, for example, between the full line positions therefor shownin FIG. 3, to the phantom line positions shown therefor, for accommodating, for example, a thicker article 11, while still maintaining a desired predetermined small spacing between the surface of the plate 40 (for example the lower surface thereof asshown in FIG. 3) and the adjacent surface of the article 11 (for example, the upper surface 48 as shown in FIG. 3).
The means for adjusting the positions of the dispensers 17, 18 toward and away from the path 22 of article travel can be any suitable means. A representative means is shown whereby an adjustable positionable member 50 is threadedly mountedthrough a fixed plate member 51, to support transversely extending posts 52 at opposite transverse ends of the dispenser 17, whereby turning the threaded member 50 may move the dispenser 17 from the full line position shown for the post 52 in FIG. 3, tothe phantom line position shown therefor also in FIG. 3, for movement of the plate 40 between the full line and phantom positions described above. It will be understood that any suitable adjustment means may be provided for changing the relativepositions of the dispensers.
In the case where the path of travel 22 is a substantially horizontal path as shown, and wherein the rollers 44, 45 for the upper manifold engage an upper surface 48 of articles 11 being treated, the weight of the rollers 44, 45 may be used toprovide the hold-down of the article 11 being treated in resisting upperwardly directed flow from the dispenser 18. In such an instance, the shafts, 46, 47 for the rollers 44, 45, respectively, may be mounted in vertical slotted holes 53, 54, as shown.
Also, it will be noted, with reference to FIG. 4 that a plurality of spaced apart notches 55, spaced generally along the plates 40 between sidewalls 26, may accommodate rollers, 44, 45, passing therethrough, as shown in FIG. 3, with clearance, soas not to engage portions of the plate 40 defined by the notches 55. Such allows close placement of the rollers 44, 45 to the openings 41, 42 and 43 and similar openings on the opposite (lower) side of the path of travel 22 in the nozzle plate of thedispenser 18.
It will be apparent from FIG. 3 that the construction, operation, adjustment, etc. of the dispenser 18 is substantially the same as that of 17, so the description thereof will not be duplicated herein. However, with the operation of thedispensers above and below the path 22 of article travel, it would generally not be necessary to provide slotted holes such as those 53 and 54 for facilitating (upward or downward) vertical movement of the posts that mount the lower rollers therein; thatthe phenomena described above with respect to the upper rollers 44, 45 and their ability to move upward in slotted holes 53, 54, is a function of utilizing gravity to assure contact of the upper rollers on the upper surface 48 of the article 11.
It will also be apparent that, except for the details of discharge of fluid through the nozzle plates, the dispensers 20, 21 will generally be constructed similar to and mounted similarly to, the dispensers 17 and 18 such that the descriptionprovided above for the dispenser 17 applies equally well here too.
With reference to the illustration for the nozzle plate 40 illustrated in FIG. 4, it will be seen that the plate 40 while being shown fragmentally cut-off at the lower end thereof, actually extends substantially completely between sidewalls 26 ofthe apparatus.
The plate 40 is shown to have upper and lower surfaces 55, 56, with chamferred upstream and downstream lower surface portions 57 and 58, respectively. The chamferred surface portion 57 facilitates article inlet between a pair opposing plates 40,and the chamferred surface 58 facilitates air inlet into the partial vacuum created by an eduction effect caused by the forward or upstream directed flow from angled nozzles 60 located in rows between straight nozzles 61, 62 as will be discussed in moredetail hereinafter. Such eduction of air would be in the direction indicated by the arrow 63 in FIG. 5 to fill the partial vacuum created by liquid being discharged via angled nozzles 60, and to facilitate the flow of liquid 60 across the upper surfaceof a printed circuit board or other article being conveyed from an upstream direction to a downstream direction, pursuant to arrow 64 in FIG. 5.
The nozzles 61, it will seen, are arranged in a row extending transversely of the longitudinal path of travel, and are oriented generally perpendicular to the longitudinal path of travel 22. Each nozzle 61 in the row is comprised of a largerdiameter cylindrical blind hole zone 65 at the upper end, which joins a cylindrical tapered zone 66, therebeneath, which in turn communicates with a transverse groove 67. The transverse groove runs completely along the lower surface 56 of the plate 40,connecting the nozzle openings of nozzle zone 66, as shown in FIG. 4. The cylindrical taper "a" of zone 66 is in the range of 100.degree. to 160.degree. across its diameter, and most preferably is approximately 120.degree.. The transverse groove 67has an included angle "b" as shown in FIG. 5A, within the range of 30.degree. to 90.degree., and most preferably is approximately 60.degree..
The pressure applied to the liquid being disseminated via nozzle 61 and the spacing apart of the nozzles 61 are selected to develop the flow of liquid emanating from the group of nozzles 61 in the transverse row shown, to produce from the nozzles61 a generally cylindrical filament-like column 68 of liquid, with the groove 67 connecting a plurality of small columns of liquid into a generally flat, transversely disposed, planar screen spray of liquid, such that the groove 67 facilitates a fanspray of liquid from the individual nozzles 61 into a screen as described.
Preferably, in addition to the row of nozzles 61, there is an identical, or substantially identical row of nozzles 62 disposed downstream thereof, also downstream of angled nozzles 60 as will hereinafter be described. Each nozzle 60 is generallysimilar to the nozzle 61 having a blind bore like that 65 for the nozzle 61, which meets a cylindrical taper at the lower end thereof, which in turn meets a connecting groove 70, connecting a plurality of nozzles 60, forming an orifice, except that theconnecting groove 70 and the several zones of the nozzles 60 are angled for liquid discharge in an upstream direction, at an angle "c" to the horizontal as shown in FIG. 5, which angle is preferably about 75.degree.. It will be noted that it is theupstream directed spray via nozzles 60 that create the partial vacuum for flow of air in the direction of 63, for facilitating dissemination of liquid from the nozzles 60, 61 and 62 in an upstream direction or against the direction of flow of articlesalong their path.
With reference now to FIG. 6 and 7, the multi-port gas dispenser nozzle plates associated with the gas dispensing (generally air) station 16 are shown. Aside from the nozzle plates 74, the rest of the manifolds of dispensers of 20, 21 willgenerally be constructed along the lines of those 17,18, as aforesaid. Each nozzle plate 74, has a plurality of notches 75 which function as aforesaid for the notches 55 of the plate of FIG. 4. Additionally, each plate 74 likewise extends transverselyof the apparatus between sidewalls 26, and has upper and lower surfaces 76, 77, and lower chamferred upstream and downstream surface portions 78, 80, pursuant to the embodiment discussed above.
However, the plate 74 is provided with a plurality of slotted holes 81 arranged in a transverse row along the plate 74, as shown. The slotted holes are separated by plurality of transverse spacings 82. The slotted holes 81 are connected by atransverse, groove 83 in the lower surface 77 of the plate 74. The groove 83 is perpendicular to the longitudinal path of flow of articles passing therebeneath, and is of a depth as measured upwardly from the surface 77 that is within a range of 1 to 4times the width of the slotted holes 81 as measured in the longitudinal direction (shortest slotted hole dimension), when preferably sized.
The groove 83 facilitates maintaining the discharge of air or other gas through each of the slotted holes 81, to remain of a width that is evidenced by the dimension "d" in FIG. 6, so that air emanating downwardly therefrom as shown, in thedirection of the arrow 84, perpendicular to the path 22 of flow of articles therebeneath will be in the form of a plurality of transversely spaced apart, transversely oriented, planar zones of gas flow.
A plurality of nozzles 85 are also provided in a transverse row, as shown in FIGS. 6 and 7, similarly comprising slotted holes spaced apart from each other as shown, also arranged to emanate therefrom, with respect to each slotted hole, atransversely spaced apart transverse, planar zone of gas flow directed toward the path of article travel, of transverse dimension "d". However, the direction of flow of the air or other gas emanating from the nozzles 85, has an upstream component ofdirection, because of the orientation provided by the angled cut "e" shown in FIG. 7, whereby the groove 86 is cut into the surface 77 at an angle "e", of approximately 30.degree..
Additionally, it will be noted that the slotted holes 85 in their row aligned with groove 86, are "staggered", relative to the slotted holes 81 in their row aligned with their groove 83, such that the slotted holes 85 are longitudinally alignedwith spacings 82, and slotted holes 81 are longitudinally aligned with spacings 89. Thus an article being treated with air or other gas flow does not initially meet an unbroken singular screen of air as it passes beneath the slotted holes 81, butrather, sees a plurality of parallel vertical planar screens of air, and next sees a plurality of screens of air via the slotted holes 85, along longitudinal imaginary ribbons 90 of areas on the surface of the article being treated (see FIG. 2).
It will also be noted that in FIGS. 6 and 7, there is shown a plurality of cylindrical holes 92, connected by a groove 93 in the lower surface 77, which facilitate additional gas flow over the articles being treated. Additionally, anotheroptional row of cylindrical holes 94 may be provided on the downstream end of the plate 94, extending perpendicular to the path of flow 22 of articles passing therebeneath, also connected by a transverse groove 95, as shown in FIG. 7. It will be notedthat the holes 94 and grooves 95 are not shown in FIG. 6, in that the same are provided as an option, only.
With reference now to FIG. 8, an alternative arrangement is provided for gas or other air discharge dispensers 120, 121, in the form of upper and lower nozzle plates 174 carried by associated manifolds. The rows of slotted holes 181, 185 andtheir respective lower grooves 183, 186 are essentially the same as those for the rows of slotted holes 81, 85 and associated grooves described above with respect to the embodiment of FIGS. 6 and 7, so the same will not be duplicated herein. However, itwill be noted that the upstream orientation of air discharged via nozzle openings 185 and associated groove 186 creates a partial vacuum as shown by the arrow 190. The lower surface 177 of the plate 174 in this embodiment is sloped, rather than beingparallel to the path of flow 22 of articles being conveyed therepast, such that it converges from a downstream portion 180 thereof toward an upstream portion 178 thereof. Such convergence increases the velocity of flow of air past a through-hole 200 inthe article 111 being conveyed therepast. If the upper and lower slotted holes in upper and lower ones of the plates 174 are staggered transversely, such that a given hole is impinged upon by air being discharged from either an upper or lower slottedhole, but not both at the same time, a pumping action can be effected whereby air will pass either upwardly or downwardly through the slotted hole 200, but not in both directions at the same time. Such pumping action created by the relative placement ofupper and lower slotted holes in upper and lower plates 174, at higher velocities caused by the converging surfaces 177, and angled discharge groove 186, facilitate moving fluid upwardly and downwardly through through-holes 200.
It will be apparent from the foregoing that various modifications may be made in the details of construction, as well as in the use and operation of the apparatus and method in accordance with this invention.
The shorter dashed broken lines, in FIGS. 1-7 on the surface of the jacket, represent stitching. The remaining broken lines, which circumscribe the hood opening, the sleeve openings and waist opening, illustrate the portions of the design, which form no part of the claim.
Device and method of detecting flow rate/liquid kind, and device and method of detecting liquid kind
Expansion shell assembly and method for combining resin bonding and mechanical anchoring of a bolt in a rock formation
In various embodiments, the present invention provides pharmaceutical compositions comprising fatty acids and methods for treating subjects using same.
1. A method of increasing plasma and/or serum EPA in a subject in need thereof, the method comprising administering, daily, to the subject a pharmaceutical composition comprising at least 96%, by weight, ethyl eicosapentaenoate, about 0.2% to about 0.5% by weight ethyl octadecaletraenoate, about 0.05% to about 0.25% by weight ethyl nonadecapentaenoate, about 0.2% to about 0.45% by weight ethyl arachidonate, about 0.3% to about 0.5% by weight ethyl eicosatetraenoate, about 0.05% to about 0.32% ethyl heneicosapentaenoate and not more than 0.05% ethyl-DHA, if any, in an amount sufficient to increase plasma and/or serum EPA levels in the subject by at least about 2001% to compared to baseline.
2. The method of claim 1 wherein the composition is administered in an amount sufficient to increase plasma and/or serum EPA levels in the subject by at least 300% compared to baseline.
3. The method of claim 1 wherein the composition is administered in an amount sufficient to increase plasma and/or serum EPA levels in the subject by at least 400%, compared to baseline.
4. The method of claim 3 wherein the composition is administered to the subject daily for a period of at least about 6 weeks.
5. The method of claim 4 wherein the subject has a baseline plasma and/or serum EPA level of not more than about 50 μg/ml.
6. The method of claim 1 wherein upon administration of 2 g of the composition to the subject daily for a period of at least about 6 weeks, the subject exhibits an at least 200% increase in plasma and/or serum EPA compared to baseline.
7. The method of claim 1, wherein upon administration of 4 g of the composition to the subject daily for a period of at least about 6 weeks, the subject exhibits an at least 300% increase in plasma and/or serum EPA compared to baseline.
8. The method of claim 1 wherein upon daily administration of 4 g of the composition to the subject for a period of at least about 6 weeks, the subject exhibits an at least 400% increase in plasma and/or serum EPA compared to baseline.
9. The method of claim 1 wherein upon daily administration of the composition to the subject, the subject exhibits an increase in serum and/or plasma DPA levels and a decrease in serum and/or plasma AA, DHA and/or DGLA levels.
10. The method of claim 1 wherein upon daily administration of the composition to the subject for a period of at least 6 weeks, the subject exhibits an increase in serum and/or plasma DPA levels and a decrease in serum and/or plasma AA, DHA and/or DGLA levels compared to baseline.
11. The method of claim 1 wherein upon daily administration of the composition to the subject for a period of at least 6 weeks, the subject exhibits a decrease in plasma and/or serum DHA levels by at least 16% compared to baseline, a decrease in DGLA plasma and/or serum levels by at least 31% compared to baseline, a decrease in AA plasma and/or serum levels by at least 20% compared to baseline, and/or an increase in plasma and/or serum DPA levels of at least 130% compared to baseline.
12. The method of claim 1 wherein the composition comprises at least 96% by weight ethyl eicosapentaenoate, about 0.22% to about 0.4% by weight ethyl octadecatetraenoate, about 0.075% to about 0.20% by weight ethyl nonadecapentaenoate, about 0.25% to about 0.40% by weight ethyl arachidonate, about 0.3% to about 0.4% by weight ethyl eicosatetraenoate and about 0.075% to about 0.25% ethyl heneicosapentaenoate.
13. The method of claim 1 wherein the composition comprises at least 98% by weight, ethyl eicosapentaenoate, about 0.25% to about 0.38% by weight ethyl octadecatetraenoate, about 0.10% to about 0.15% by weight ethyl nonadecapentaenoate, about 0.25% to about 0.35% by weight ethyl arachidonate, about 0.31% to about 0.38% by weight ethyl eicosatetraenoate, and about 0.08% to about 0.20% ethyl heneicosapentaenoate.
14. The method of claim 1 wherein the composition further comprises tocopherol in an amount of about 0.1% to about 0.3%, by weight.
16. A method of increasing plasma and/or serum EPA in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising at least 96% by weight, ethyl eicosapentaenoate, about 0.2% to about 0.5% by weight ethyl octadecatetraenoate, about 0.05% to about 0.25% by weight ethyl nonadecapentaenoate, about 0.2% to about 0.45% by weight ethyl arachidonate, about 0.3% to about 0.5% by weight ethyl eicosatetraenoate, about 0.05% to about 0.32% ethyl heneicosapentaenoate, and not more than 0.05% ethyl-DHA, wherein upon daily administration of 2 g of the composition to the subject for a period of at least about 6 weeks, the subject exhibits an at least about 200% increase in plasma and/or serum EPA compared to baseline.
17. The method of claim 15 wherein the subject has a baseline plasma or serum EPA level of not more than about 50 μg/ml.
18. A method of increasing plasma or serum EPA in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising at least 96%, by weight, ethyl eicosapentaenoate, about 0.2% to about 0.5% by weight ethyl octadecatetraenoate, about 0.05% to about 0.25% by weight ethyl nonadecapentaenoate, about 0.2% to about 0.45% by weight ethyl arachidonate, about 0.3% to about 0.5% by weight ethyl eicosatetraenoate, about 0.05% to about 0.32% ethyl heneicosapentacnoate, and not more than 0.05% ethyl-DHA, wherein upon daily administration of 4 g of the composition to the subject for a period of at least about 6 weeks, the subject exhibits an at least about 300% increase in plasma and/or serum EPA compared to baseline.
19. The method of claim 18 wherein the subject has a baseline plasma or serum EPA level of not more than about 50 μg/ml.
20. A method of maintaining LDL control in a subject who is on stable statin therapy and requires triglyceride lowering therapy, the method comprising identifying a subject who is on stable statin therapy and requires triglyceride lowering therapy, administering to the subject a pharmaceutically acceptable composition comprising about 1 g to about 4 g of ultra-pure E-EPA per day, wherein upon administering the composition to the subject the subject exhibits a clinically significant reduction fasting triglycerides compared to control.
[0001] This application is a continuation of U.S. patent application Ser. No. 13/040,977 filed Mar. 4, 2011, which claims priority to and the benefit of U.S. Provisional Patent Application Ser. No. 61/310,443, filed Mar. 4, 2010, all of which are incorporated herein in their entirety.
[0002] Cardiovascular disease is one of the leading causes of death in the United States and most European countries. It is estimated that over 70 million people in the United States alone suffer from a cardiovascular disease or disorder including but not limited to high blood pressure, coronary heart disease, dislipidemia, congestive heart failure and stroke. A need exists for improved treatments for cardiovascular-related diseases and disorders.
[0003] In various embodiments, the present invention provides pharmaceutical compositions and methods of using such compositions to increase plasma, serum and/or red blood cell (RBC) EPA levels and/or to treat or prevent cardiovascular-related diseases.
[0004] In one embodiment, the invention provides a pharmaceutical composition comprising, consisting of or consisting essentially of at least 95% by weight ethyl eicosapentaenoate (EPA-E), about 0.2% to about 0.5% by weight ethyl octadecatetraenoate (ODTA-E), about 0.05% to about 0.25% by weight ethyl nonaecapentaenoate (NDPA-E), about 0.2% to about 0.45% by weight ethyl arachidonate (AA-E), about 0.3% to about 0.5% by weight ethyl eicosatetraenoate (ETA-E), and about 0.05% to about 0.32% ethyl heneicosapentaenoate (HPA-E). In another embodiment, the composition is present in a capsule shell. In another embodiment, the composition contains substantially no or no amount of docosahexaenoic acid (DHA) or derivative thereof such as ethyl-DHA (DHA-E), for example not more than about 0.06%, about 0.05%, or about 0.04%, by weight.
[0005] In another embodiment, the invention provides a method of increasing serum, plasma and/or red blood cell (RBC) EPA levels comprising administering a composition as described herein to a subject in need of increased serum, plasma and/or RBC EPA levels. In a related embodiment, the subject has a baseline EPA plasma, serum and/or RBC level not greater than about 50 μg/g and upon administering the composition to the subject for a period of at least about 6 weeks, the subject exhibits at least a 100%, at least a 150%, at least a 200%, at least a 250%, at least 300%, at least 350% or at least 400% increase (change in EPA level divided by baseline EPA level) in plasma, serum and/or RBC EPA levels compared to baseline. In a related embodiment, the subject has a baseline EPA plasma, serum and/or RBC level not greater than about 50 μg/g. In another embodiment, the subject is provided with an amount of said composition effective to achieve said increases in EPA levels. In another embodiment, the subject is provided with about 2 g to about 4 g per day of said composition.
[0006] In another embodiment, the invention provides a method of treating a cardiovascular-related disease in a subject in need thereof, comprising administering a composition as described herein to the subject. In a related embodiment, the subject has a baseline EPA plasma, serum and/or RBC level not greater than about 50 μg/g and upon administering the composition to the subject for a period of at least about 6 weeks, the subject exhibits at least about a 100%, at least about a 150%, at least about a 200%, at least about a 250%, at least about a 300%, at least about a 350% or at least about a 400% increase in plasma, serum and/or RBC EPA levels compared to baseline. In a related embodiment, the subject has a baseline EPA plasma, serum and/or RBC level not greater than about 50 μg/g. In another embodiment, the subject is provided with about 2 g to about 4 g per day of said composition.
[0007] These and other embodiments of the present invention will be disclosed in further detail herein below.
[0010] While the present invention is capable of being embodied in various forms, the description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the invention, and is not intended to limit the invention to the specific embodiments illustrated. Headings are provided for convenience only and are not to be construed to limit the invention in any manner. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.
[0011] The use of numerical values in the various quantitative values specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges were both preceded by the word "about." Also, the disclosure of ranges is intended as a continuous range including every value between the minimum and maximum values recited as well as any ranges that can be formed by such values. Also disclosed herein are any and all ratios (and ranges of any such ratios) that can be formed by dividing a disclosed numeric value into any other disclosed numeric value. Accordingly, the skilled person will appreciate that many such ratios, ranges, and ranges of ratios can be unambiguously derived from the numerical values presented herein and in all instances such ratios, ranges, and ranges of ratios represent various embodiments of the present invention.
[0012] In one embodiment, the invention provides pharmaceutical compositions comprising eicosapentaenoic acid or a derivative thereof. In one embodiment, such compositions comprise eicosapentaenoic acid, or a pharmaceutically acceptable ester, derivative, conjugate or salt thereof, or mixtures of any of the foregoing, collectively referred to herein as "EPA." The term "pharmaceutically acceptable" in the present context means that the substance in question does not produce unacceptable toxicity to the subject or interaction with other components of the composition.
[0014] In another embodiment, the EPA is in the form of ethyl-EPA, lithium EPA, mono-, di- or triglyceride EPA or any other ester or salt of EPA, or the free acid form of EPA. The EPA may also be in the form of a 2-substituted derivative or other derivative which slows down its rate of oxidation but does not otherwise change its biological action to any substantial degree.
[0016] In another embodiment, a composition useful in accordance with the invention contains not more than about 10%, not more than about 9%, not more than about 8%, not more than about 7%, not more than about 6%, not more than about 5%, not more than about 4%, not more than about 3%, not more than about 2%, not more than about 1%, or not more than about 0.5%, by weight, docosahexaenoic acid (DHA) or derivative thereof such as ethyl-DHA, if any. In another embodiment, a composition of the invention contains substantially no DHA or ethyl-DHA. In still another embodiment, a composition useful in the present invention contains no DHA or derivative thereof such as DHA-E.
[0017] In another embodiment, EPA comprises at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%, by weight, of all fatty acids present in a composition according to the invention.
[0018] In another embodiment, a composition useful in accordance with the invention contains less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5% or less than 0.25%, by weight of the total composition or by weight of the total fatty acid content, of any fatty acid or derivative thereof other than EPA. Illustrative examples of a "fatty acid other than EPA" include linolenic acid (LA), arachidonic acid (AA), docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), stearadonic acid (STA), eicosatrienoic acid (ETA) and/or docosapentaenoic acid (DPA). In another embodiment, a composition useful in accordance with the invention contains about 0.1% to about 4%, about 0.5% to about 3%, or about 1 to about 2%, by weight, of total fatty acids other than EPA and/or DHA.
[0019] In another embodiment, a composition in accordance with the invention has one or more of the following features: (a) eicosapentaenoic acid ethyl ester represents at least about 96%, at least about 97%, or at least about 98%, by weight, of all fatty acids present in the composition; (b) the composition contains not more than about 4%, not more than about 3%, or not more than about 2%, by weight, of total fatty acids other than eicosapentaenoic acid ethyl ester; (c) the composition contains not more than about 0.6%, not more than about 0.5%, or not more than about OA % of any individual fatty acid other than eicosapentaenoic acid ethyl ester; (d) the composition has a refractive index (20° C.) of about 1 to about 2, about 1.2 to about 1.8 or about 1.4 to about 1.5; (e) the composition has a specific gravity (20° C.) of about 0.8 to about 1.0, about 0.85 to about 0.95 or about 0.9 to about 0.92; (e) the composition contains not more than about 20 ppm, not more than about 15 ppm or not more than about 10 ppm heavy metals, (f) the composition contains not more than about 5 ppm, not more than about 4 ppm, not more than about 3 ppm, or not more than about 2 ppm arsenic, and/or (g) the composition has a peroxide value of not more than about 5 meq/kg, not more than about 4 meg/kg, not more than about 3 meg/kg, or not more than about 2 meg/kg.
[0020] In another embodiment, the invention provides a composition comprising, consisting essentially of, or consisting of at least 95%, 96% or 97%, by weight, ethyl eicosapentaenoate, about 0.2% to about 0.5% by weight ethyl octadecatetraenoate, about 0.05% to about 0.25% by weight ethyl nonaecapentaenoate, about 0.2% to about 0.45% by weight ethyl arachidonate, about 0.3% to about 0.5% by weight ethyl eicosatetraenoate, and about 0.05% to about 0.32% ethyl heneicosapentaenoate. Optionally, the composition contains not more than about 0.06%, about 0.05%, or about 0.04%, by weight, DHA or derivative there of such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative there of such as ethyl-DHA. The composition further optionally comprises one or more antioxidants (e.g. tocopherol) or other impurities in an amount of not more than about 0.5% or not more than 0.05%. In another embodiment, the composition comprises about 0.05% to about 0.4%, for example about 0.2% by weight tocopherol. In another embodiment, about 500 mg to about 1 g of the composition is provided in a capsule shell.
[0021] In another embodiment, the invention provides a composition comprising, consisting of or consisting essentially of at least 96% by weight ethyl eicosapentaenoate, about 0.22% to about 0.4% by weight ethyl octadecatetraenoate, about 0.075% to about 0.20% by weight ethyl nonaecapentaenoate, about 0.25% to about 0.40% by weight ethyl arachidonate, about 0.3% to about 0.4% by weight ethyl eicosatetraenoate and about 0.075% to about 0.25% ethyl heneicosapentaenoate. Optionally, the composition contains not more than about 0.06%, about 0.05%, or about 0.04%, by weight, DHA or derivative there of such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative there of such as ethyl-DHA. The composition further optionally comprises one or more antioxidants (e.g, tocopherol) or other impurities in an amount of not more than about 0.5% or not more than 0.05%. In another embodiment, the composition comprises about 0.05% to about 0.4%, for example about 0.2% by weight tocopherol. In another embodiment, the invention provides a dosage form comprising about 500 mg to about 1 g of the foregoing composition in a capsule shell.
[0022] In another embodiment, the invention provides a composition comprising, consisting of, or consisting essentially of at least 96%, 97% or 98%, by weight, ethyl eicosapentaenoate, about 0.25% to about 0.38% by weight ethyl octadecatetraenoate, about 0.10% to about 0.15% by weight ethyl nonaecapentaenoate, about 0.25% to about 0.35% by weight ethyl arachidonate, about 0.31% to about 0.38% by weight ethyl eicosatetraenoate, and about 0.08% to about 0.20% ethyl heneicosapentaenoate. Optionally, the composition contains not more than about 0.06%, about 0.05%, or about 0.04%, by weight, DHA or derivative there of such as ethyl-DHA. In one embodiment the composition contains substantially no or no amount of DHA or derivative there of such as ethyl-DHA. The composition further optionally comprises one or more antioxidants (e.g, tocopherol) or other impurities in an amount of not more than about 0.5% or not more than 0.05%. In another embodiment, the composition comprises about 0.05% to about 0.4%, for example about 0.2% by weight tocopherol. In another embodiment, the invention provides a dosage form comprising about 500 mg to about 1 g of the foregoing composition in a capsule shell.
[0023] In another embodiment, the invention provides a method of increasing serum, plasma and/or red blood cell (RBC) EPA levels comprising administering a composition as described herein to a subject in need of such treatment. In one embodiment, upon orally administering a composition as set forth herein to a subject for a period of at least about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 42, about 45 or about 50 days, the subject exhibits at least about a 2-fold, at least about a 3-fold, at least about a 3.5-fold, at least about a 3.75-fold or at least about a 4-fold change (final absolute EPA level divided by baseline EPA level) in serum, plasma and/or RBC EPA. In one embodiment, the method comprises a step of identifying a patient in need of an increase in serum, plasma and/or red blood cell (RBC) EPA prior to said administration step. In a related embodiment, the subject has a baseline EPA plasma, serum and/or RBC level not greater than about 50 μg/g. In another embodiment, the subject is provided with about 2 g to about 4 g per day of said composition. In another embodiment, upon administering the composition to the subject as per above, the subject exhibits a decrease in DHA, AA and/or DGLA plasma, serum and/or RBC levels. In another embodiment, upon administering the composition to the subject as per above, the subject exhibits an increase in DPA plasma, serum and/or RBC levels. In still another embodiment, upon administering the composition to the subject as per above, DHA plasma, serum and/or RBC levels decrease by at least 16%, DGLA plasma, serum and/or RBC levels decrease by at least 31%, AA plasma, serum and/or RBC levels decrease by at least 20%, and/or DPA plasma, serum and/or RBC levels increase by greater than 130%.
[0024] In another embodiment, the invention provides a method of increasing serum, plasma and/or red blood cell (RBC) EPA levels comprising administering a composition as described herein to a subject in need of increased serum, plasma and/or RBC EPA levels. In a related embodiment, upon administering the composition to the subject for a period of at least about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 42, about 45, or about 50 days, the subject exhibits at least about a 100%, at least about a 150%, at least about a 200%, at least about a 250%, at least about a 300%, at least about a 350% or at least about a 400% increase (change in EPA level from baseline divided by baseline EPA level) in plasma, serum and/or RBC EPA levels compared to baseline. In a related embodiment, the subject has a baseline EPA plasma, serum and/or RBC level not greater than about 50 μg/g. In another embodiment, the subject is provided with about 2 g to about 4 g per day of said composition. In another embodiment, upon administering the composition to the subject as per above, the subject exhibits a decrease in DHA, AA and/or DGLA plasma, serum and/or RBC levels. In another embodiment, upon administering the composition to the subject as per above, the subject exhibits an increase in DPA plasma, serum and/or RBC levels. In still another embodiment, upon administering the composition to the subject as per above, DHA plasma, serum and/or RBC levels decrease by at least 16%, DGLA plasma, serum and/or RBC levels decrease by at least 31%, AA plasma, serum and/or RBC levels decrease by at least 20%, and/or DPA plasma, serum and/or RBC levels increase by greater than 130%.
[0025] In a related embodiment, upon orally administering about 2 to about 4 g per day of a composition as set forth herein to a subject for a period of at least about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45 or about 50 days, the subject exhibits at least about a 10 μg/g increase, at least about a 15 μg/g increase, at least about a 20 μg/g increase, at least about a 25 μg/g increase, at least about a 30 μg/g increase, at least about a 35 μg/g increase, at least about a 40 μg/g increase, at least about a 45 μg/g increase, at least about a 50 μg/g increase, at least about a 75 μg/g increase, at least about a 100 μg/g increase, or at least about a 150 μg/g increase in serum, plasma and/or RBC EPA compared to baseline. In another embodiment, upon administering the composition to the subject as per above, the subject exhibits a decrease in DHA, AA and/or DGLA plasma, serum and/or RBC levels. In another embodiment, upon administering the composition to the subject as per above, the subject exhibits an increase in DPA plasma, serum and/or RBC levels. In still another embodiment, upon administering the composition to the subject as per above, DHA plasma, serum and/or RBC levels decrease by at least 16%, DGLA plasma, serum and/or RBC levels decrease by at least 31%, AA plasma, serum and/or RBC levels decrease by at least 20%, and/or DPA plasma, serum and/or RBC levels increase by greater than 130%.
[0026] In another embodiment, the subject has not been on an omega-3 fatty acid therapy or supplement for at least 2 weeks, 3 weeks, 4 weeks, 6 weeks or 12 weeks prior to initiating therapy as described herein.
[0027] In one embodiment, the invention provides a method for treatment and/or prevention of cardiovascular-related diseases comprising administering to a subject in need of such treatment or prevention a composition as set forth herein. The term "cardiovascular-related disease" herein refers to any disease or disorder of the heart or blood vessels (i.e. arteries and veins) or any symptom thereof. Non-limiting examples of cardiovascular-related disease and disorders include hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronary heart disease, vascular disease, stroke, atherosclerosis, arrhythmia, hypertension, myocardial infarction, and other cardiovascular events.
[0028] The term "treatment" in relation a given disease or disorder, includes, but is not limited to, inhibiting the disease or disorder, for example, arresting the development of the disease or disorder; relieving the disease or disorder, for example, causing regression of the disease or disorder; or relieving a condition caused by or resulting from the disease or disorder, for example, relieving, preventing or treating symptoms of the disease or disorder. The term "prevention" in relation to a given disease or disorder means: preventing the onset of disease development if none had occurred, preventing the disease or disorder from occurring in a subject that may be predisposed to the disorder or disease but has not yet been diagnosed as having the disorder or disease, and/or preventing further disease/disorder development if already present.
[0029] In one embodiment, the present invention provides a method of blood lipid therapy comprising administering to a subject or subject group in need thereof a pharmaceutical composition as described herein. In another embodiment, the subject or subject group has hypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia and/or very high triglycerides.
[0030] In another embodiment, the subject or subject group being treated has a baseline triglyceride level (or mean or median baseline triglyceride level in the case of a subject group), fed or fasting, of about 200 mg/dl to about 500 mg/dl. In another embodiment, the subject or subject group has a baseline LDL-C level (or mean or median baseline LDL-C level), despite statin therapy, of about 40 mg/dl to about 100 mg/dl.
[0031] In one embodiment, the subject or subject group being treated in accordance with methods of the invention is on concomitant statin therapy, for example atorvastatin, rosuvastatin or simvastatin therapy (with or without ezetimibe). In another embodiment, the subject is on concomitant stable statin therapy at time of initiation of ultra-pure EPA therapy.
[0032] In another embodiment, the subject or subject group being treated in accordance with methods of the invention has a body mass index (BMI or mean BMI) of not more than about 45 kg/m2.
[0033] In another embodiment, the invention provides method of maintaining LDL control in a subject who is on stable statin therapy and requires triglyceride lowering therapy, the method comprising identifying a subject who is on stable statin therapy and requires triglyceride lowering therapy, administering to the subject a pharmaceutically acceptable composition comprising about 1 g to about 4 g of EPA per day (e.g. ultra-pure E-EPA), wherein upon administering the composition to the subject, the subject exhibits a clinically significant reduction in fasting triglycerides compared to control. In the present context, the term "clinically significant reduction in fasting triglycerides" means a reduction in triglycerides in an amount corresponding to a reduction in risk of an adverse cardiovascular event. Typically, each 10 mg/dl decline in triglycerides results in a 1.6% lower risk of death, myocardial infarction and recurrent acute coronary syndrome. See e.g. Miller et al., Impact of triglyceride level beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. ACC Vol. 51, No. 7 (2008), hereby incorporated by reference herein. Therefore, in one embodiment, a "clinically significant reduction in fasting triglycerides" means a reduction of 10 mg/dl. In the present context, the term "maintaining LDL control" means no clinically significant adverse change in LDL levels during therapy.
[0034] In one embodiment, the invention provides a method of lowering triglycerides in a subject on stable statin therapy having baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl, the method comprising administering to the subject a pharmaceutical composition comprising about 1 g to about 4 g of EPA (e.g. ultra-pure EPA), wherein upon administering the composition to the subject daily for a period of about 12 weeks the subject exhibits at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% lower fasting triglycerides than a control subject maintained on stable statin therapy without concomitant ultra-pure EPA for a period of about 12 weeks, wherein the control subject also has baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl. The term "stable statin therapy" herein means that the subject, subject group, control subject or control subject group in question has been taking a stable daily dose of a statin (e.g. atorvastatin, rosuvastatin or simvastatin) for at least 4 weeks prior to the baseline fasting triglyceride measurement (the "qualifying period"). For example, a subject or control subject on stable statin therapy would receive a constant daily (i.e. the same dose each day) statin dose for at least 4 weeks immediately prior to baseline fasting triglyceride measurement. In one embodiment, the subject's and control subject's LDL-C is maintained between about 40 mg/dl and about 100 mg/dl during the qualifying period. The subject and control subject are then continued on their stable statin dose for the 12 week period post baseline.
[0036] In another embodiment, the invention provides a method of lowering triglycerides in a subject group on stable statin therapy having mean baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl, the method comprising administering to members of the subject group a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure EPA per day, wherein upon administering the composition to the members of the subject group daily for a period of about 12 weeks the subject group exhibits at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% lower mean fasting triglycerides than a control subject group maintained on stable statin therapy without concomitant ultra-pure EPA for a period of about 12 weeks, wherein the control subject group also has mean baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl. In a related embodiment, the stable statin therapy will be sufficient such that the subject group has a mean LDL-C level about at least about 40 mg/dl and not more than about 100 mg/dl for the 4 weeks immediately prior to the baseline fasting triglyceride measurement.
[0037] In another embodiment, the invention provides a method of lowering triglycerides in subject group on stable statin therapy and having mean baseline fasting triglyceride level of about 200 mg/dl to about 500 mg/dl, the method comprising administering to members of the subject group a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure EPA, wherein upon administering the composition to members of the subject group daily for a period of about 12 weeks the subject group exhibits (a) at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% lower mean fasting triglycerides by comparison with a control subject group maintained on stable statin therapy without concomitant ultra-pure EPA for a period of about 12 weeks, and (b) no increase in mean serum LDL-C levels compared to baseline, wherein the control subject also has mean baseline fasting triglycerides of about 200 mg/dl to about 500 mg/di.
[0038] In another embodiment, the invention provides a method of lowering triglycerides in subject on stable statin therapy and having mean baseline fasting triglyceride level of about 200 mg/dl to about 500 mg/dl, the method comprising administering to the subject a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure EPA, wherein upon administering the composition to the subject daily for a period of about 12 weeks the subject exhibits (a) at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% lower fasting triglycerides by comparison with a control subject maintained on stable statin therapy without concomitant ultra-pure EPA for a period of about 12 weeks and (b) no increase in serum LDL-C levels compared to baseline, wherein the control subject also has baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl.
[0039] In another embodiment, the invention provides a method of lowering triglycerides in subject group on stable statin therapy and having mean baseline fasting triglyceride level of about 200 mg/dl to about 500 mg/dl, the method comprising administering to members of the subject group a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure EPA, wherein upon administering the composition to the members of the subject group daily for a period of about 12 weeks the subject group exhibits (a) at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% lower mean fasting triglycerides and (b) at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50% lower mean plasma or serum LDL-C levels by comparison with a control subject group maintained on stable statin therapy without concomitant ultra-pure EPA for a period of about 12 weeks, wherein the control subject also has mean baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl.
[0040] In another embodiment, the invention provides a method of lowering triglycerides in subject group on stable statin therapy and having mean baseline fasting triglyceride level of about 200 mg/dl to about 500 mg/dl, the method comprising administering to members of the subject group a pharmaceutical composition comprising about 1 g to about 4 g of ultra-pure EPA, wherein upon administering the composition to the members of the subject group daily for a period of about 12 weeks the subject group exhibits (a) at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75% lower mean fasting triglycerides and (b) at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45% or at least 50% lower mean plasma or serum LDL-C levels by comparison with a control subject group maintained on stable statin therapy without concomitant ultra-pure EPA for a period of about 12 weeks, wherein the control subject group also has mean baseline fasting triglycerides of about 200 mg/dl to about 500 mg/dl.
[0041] In another embodiment, the subject or subject group being treated in accordance with methods of the invention exhibits a fasting baseline absolute plasma level of free total fatty acid (or mean thereof) not greater than about 300 nmol/ml, not greater than about 250 nmol/ml, not greater than about 200 nmol/ml, not greater than about 150 nmol/ml, not greater than about 100 nmol/ml, or not greater than about 50 nmol/ml.
[0042] In another embodiment, the subject or subject group being treated in accordance with methods of the invention exhibits a fasting baseline absolute plasma level of free EPA (or mean thereof in the case of a subject group) not greater than about 0.70 nmol/ml, not greater than about 0.65 nmol/ml, not greater than about 0.60 nmol/ml, not greater than about 0.55 nmol/ml, not greater than about 0.50 nmol/ml, not greater than about 0.45 nmol/ml, or not greater than about 0.40 nmol/ml. In another embodiment, the subject or subject group being treated in accordance with methods of the invention exhibits a baseline fasting plasma level (or mean thereof) of free EPA, expressed as a percentage of total free fatty acid, of not more than about 3%, not more than about 2.5%, not more than about 2%, not more than about 1.5%, not more than about 1%, not more than about 0.75%, not more than about 0.5%, not more than about 0.25%, not more than about 0.2% or not more than about 0.15%. In one such embodiment, free plasma EPA and/or total fatty acid levels are determined prior to initiating therapy.
[0043] In another embodiment, the subject or subject group being treated in accordance with methods of the invention exhibits a fasting baseline absolute plasma level of free EPA (or mean thereof) not greater than about 1 nmol/ml, not greater than about 0.75 nmol/ml, no greater than about 0.50 nmol/ml, not greater than about 0.4 nmol/m, no greater than about 0.35 nmol/ml, or not greater than about 0.30 nmol/ml.
[0044] In another embodiment, the subject or subject group being treated in accordance with methods of the invention exhibits a fasting baseline plasma, serum or red blood cell membrane EPA level not greater than about 150 μg/ml, not greater than about 125 μg/ml, not greater than about 100 μg/ml, not greater than about 95 μg/ml, not greater than about 75 μg/ml, not greater than about 60 μg/ml, not greater than about 50 μg/ml, not greater than about 40 μg/ml, not greater than about 30 μg/ml, or not greater than about 25 μg/ml.
[0045] In another embodiment, methods of the present invention comprise a step of measuring the subject's (or subject group's mean) baseline lipid profile prior to initiating therapy. In another embodiment, methods of the invention comprise the step of identifying a subject or subject group having one or more of the following: baseline non-HDL-C value of about 200 mg/dl to about 400 mg/dl, for example at least about 210 mg/dl, at least about 220 mg/dl, at least about 230 mg/dl, at least about 240 mg/dl, at least about 250 mg/dl, at least about 260 mg/dl, at least about 270 mg/dl, at least about 280 mg/dl, at least about 290 mg/dl, or at least about 300 mg/dl; baseline total cholesterol value of about 250 mg/dl to about 400 mg/dl, for example at least about 260 mg/dl, at least about 270 mg/dl, at least about 280 mg/di or at least about 290 mg/dl; baseline vLDL-C value of about 140 mg/dl to about 200 mg/dl, for example at least about 150 mg/dl, at least about 160 mg/dl, at least about 170 mg/dl, at least about 180 mg/dl or at least about 190 mg/dl; baseline HDL-C value of about 10 to about 100 mg/dl, for example not more than about 90 mg/dl not, not more than about 80 mg/dl, not more than about 70 mg/dl, not more than about 60 mg/dl, not more than about 60 mg/dl, not more than about 50 mg/dl, not more than about 40 mg/dl, not more than about 35 mg/dl, not more than about 30 mg/dl, not more than about 25 mg/dl, not more than about 20 mg/dl, or not more than about 15 mg/dl; and/or baseline LDL-C value of about 30 to about 300 mg/dl, for example not less than about 40 mg/dl, not less than about 50 mg/dl, not less than about 60 mg/dl, not less than about 70 mg/dl, not less than about 90 mg/dl or not less than about 90 mg/dl.
[0046] In a related embodiment, upon treatment in accordance with the present invention, for example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the subject or subject group exhibits one or more of the following outcomes:
[0072] In one embodiment, methods of the present invention comprise measuring baseline levels of one or more markers set forth in (a)-(y) above prior to dosing the subject or subject group. In another embodiment, the methods comprise administering a composition as disclosed herein to the subject after baseline levels of one or more markers set forth in (a)-(y) are determined, and subsequently taking an additional measurement of said one or more markers.
[0073] In another embodiment, upon treatment with a composition of the present invention, for example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the subject or subject group exhibits any 2 or more of, any 3 or more of, any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of, any 8 or more of, any 9 or more of, any 10 or more of, any 11 or more of, any 12 or more of, any 13 or more of, any 14 or more of, any 15 or more of, any 16 or more of, any 17 or more of, any 18 or more of, any 19 or more of, any 20 or more of, any 21 or more of, any 22 or more of, any 23 or more, any 24 or more, or all 25 of outcomes (a)-(y) described immediately above.
[0074] In another embodiment, upon treatment with a composition of the present invention, the subject or subject group exhibits one or more of the following outcomes:
[0075] (a) a reduction in triglyceride level of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline;
[0076] (b) a less than 30% increase, less than 20% increase, less than 10% increase, less than 5% increase or no increase in non-HDL-C levels or a reduction in non-HDL-C levels of at least about 1%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline;
[0077] (c) an increase in HDL-C levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline;
[0078] (d) a less than 30% increase, less than 20% increase, less than 10% increase, less than 5% increase or no increase in LDL-C levels or a reduction in LDL-C levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline;
[0079] (e) a decrease in Apo B levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) as compared to baseline;
[0080] (f) a reduction in vLDL levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0081] (g) an increase in apo A-I levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0082] (h) an increase in apo A-I/apo B ratio of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0083] (i) a reduction in lipoprotein (a) levels of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0084] (j) a reduction in mean LDL particle number of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0085] (k) an increase in mean LDL particle size of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0086] (l) a reduction in remnant-like particle cholesterol of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0087] (m) a reduction in oxidized LDL of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0088] (n) a reduction in fasting plasma glucose (FPG) of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0089] (o) a reduction in hemoglobin A1c (HbA1c) of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50% (actual % change or median % change) compared to baseline;
[0090] (p) a reduction in homeostasis model index insulin resistance of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual change or median % change) compared to baseline;
[0091] (q) a reduction in lipoprotein associated phospholipase A2 of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0092] (r) a reduction in intracellular adhesion molecule-1 of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0093] (s) a reduction in interleukin-2 of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0094] (t) a reduction in plasminogen activator inhibitor-1 of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0095] (u) a reduction in high sensitivity C-reactive protein (hsCRP) of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, or at least about 100% (actual % change or median % change) compared to baseline;
[0096] (v) an increase in plasma, serum phospholipids or RBC EPA of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 100%, at least about 200% or at least about 400% (actual % change or median % change) compared to baseline;
[0097] (w) an increase in plasma, serum phospholipid and/or RBC membrane EPA of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, r at least about 50%, at least about 100%, at least about 200%, or at least about 400% (actual % change or median % change) compared to baseline;
[0098] (x) a reduction or increase in one or more of plasma, serum phospholipid and/or RBC DHA, DPA, AA, PA and/or OA of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) compared to baseline; and/or
[0099] (y) a reduction in total cholesterol of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 75% (actual % change or median % change) compared to baseline.
[0100] In one embodiment, methods of the present invention comprise measuring baseline levels of one or more markers set forth in (a) (y) prior to dosing the subject or subject group. In another embodiment, the methods comprise administering a composition as disclosed herein to the subject after baseline levels of one or more markers set forth in (a)-(y) are determined, and subsequently taking a second measurement of the one or more markers as measured at baseline for comparison thereto.
[0101] In another embodiment, upon treatment with a composition of the present invention, for example over a period of about 1 to about 200 weeks, about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about 50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1 to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks, about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week, the subject or subject group exhibits any 2 or more of, any 3 or more of, any 4 or more of, any 5 or more of, any 6 or more of, any 7 or more of, any 8 or more of, any 9 or more of, any 10 or more of, any 11 or more of, any 12 or more of, any 13 or more of, any 14 or more of, any 15 or more of, any 16 or more of, any 17 or more of, any 18 or more of, any 19 or more of, any 20 or more of, any 21 or more of, any 22 or more of, any 23 or more of, any 24 or more of, or all 26 or more of outcomes (a)-(y) described immediately above.
[0103] In one embodiment, subjects fast for up to 12 hours prior to blood sample collection, for example about 10 hours.
[0104] In another embodiment, the present invention provides a method of treating or preventing primary hypercholesterolemia and/or mixed dyslipidemia (Fredrickson Types IIa and IIb) in a patient in need thereof, comprising administering to the patient one or more compositions as disclosed herein. In a related embodiment, the present invention provides a method of reducing triglyceride levels in a subject or subjects when treatment with a statin or niacin extended-release monotherapy is considered inadequate (Frederickson type IV hyperlipidemia).
[0105] In another embodiment, the present invention provides a method of treating or preventing risk of recurrent nonfatal myocardial infarction in a patient with a history of myocardial infarction, comprising administering to the patient one or more compositions as disclosed herein.
[0106] In another embodiment, the present invention provides a method of slowing progression of or promoting regression of atherosclerotic disease in a patient in need thereof, comprising administering to a subject in need thereof one or more compositions as disclosed herein.
[0107] In another embodiment, the present invention provides a method of treating or preventing very high serum triglyceride levels (e.g. Types IV and V hyperlipidemia) in a patient in need thereof, comprising administering to the patient one or more compositions as disclosed herein.
[0109] In another embodiment, any of the methods disclosed herein are used in treatment of a subject or subjects that consume a traditional Western diet. In one embodiment, the methods of the invention include a step of identifying a subject as a Western diet consumer or prudent diet consumer and then treating the subject if the subject is deemed a Western diet consumer. The term "Western diet" herein refers generally to a typical diet consisting of, by percentage of total calories, about 45% to about 50% carbohydrate, about 35% to about 40% fat, and about 10% to about 15% protein. A Western diet may alternately or additionally be characterized by relatively high intakes of red and processed meats, sweets, refined grains, and desserts, for example more than 50%, more than 60% or more or 70% of total calories come from these sources.
[0110] In another embodiment, any of the methods disclosed herein are used in treatment of a subject or subjects that consume less than (actual or average) about 150 g, less than about 125 g, less than about 100 g, less than about 75 g, less than about 50 g, less than about 45 g, less than about 40 g, less than about 35 g, less than about 30 g, less than about 25 g, less than about 20 g or less than about 15 g of fish per day.
[0111] In another embodiment, any of the methods disclosed herein are used in treatment of a subject or subjects that consume less than (actual or average) about 10 g, less than about 9 g, less than about 8 g, less than about 7 g, less than about 6 g, less than about 5 g, less than about 4 g, less than about 3 g, less than about 2 g per day of omega-3 fatty acids from dietary sources.
[0112] In another embodiment, any of the methods disclosed herein are used in treatment of a subject or subjects that consume less than (actual or average) about 2.5 g, less than about 2 g, less than about 1.5 g, less than about 1 g, less than about 0.5 g, less than about 0.25 g, or less than about 0.2 g per day of EPA and DHA (combined) from dietary sources.
[0113] In one embodiment, a composition as described herein is administered to a subject once or twice per day. In another embodiment, 1, 2, 3 or 4 capsules, each containing about 500 mg to about 1 g of a composition as described herein, are administered to a subject daily. In another embodiment, 1 or 2 capsules, each containing about 1 g of a composition as described herein, are administered to the subject in the morning, for example between about 5 am and about 11 am, and 1 or 2 capsules, each containing about 1 g of a composition as described herein, are administered to the subject in the evening, for example between about 5 pm and about 11 pm.
[0114] In one embodiment, a subject being treated in accordance with methods of the invention is not on fibrate or nitrate therapy.
[0115] In another embodiment, compositions useful in accordance with methods of the invention are orally deliverable. The terms "orally deliverable" or "oral administration" herein include any form of delivery of a therapeutic agent or a composition thereof to a subject wherein the agent or composition is placed in the mouth of the subject, whether or not the agent or composition is swallowed. Thus "oral administration" includes buccal and sublingual as well as esophageal administration. In one embodiment, the composition is present in a capsule, for example a soft gelatin capsule,
[0116] A composition for use in accordance with the invention can be formulated as one or more dosage units. The terms "dose unit" and "dosage unit" herein refer to a portion of a pharmaceutical composition that contains an amount of a therapeutic agent suitable for a single administration to provide a therapeutic effect. Such dosage units may be administered one to a plurality (i.e. 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) of times per day, or as many times as needed to elicit a therapeutic response.
[0117] In another embodiment, the invention provides use of any composition described herein for treating moderate to severe hypertriglyceridemia in a subject in need thereof, comprising: providing a subject having a fasting baseline triglyceride level of about 500 mg/dl to about 1500 mg/dl and administering to the subject a pharmaceutical composition as described herein. In one embodiment, the composition comprises about 1 g to about 4 g of eicosapentaenoic acid ethyl ester, wherein the composition contains substantially no docosahexaenoic acid.
[0119] The following examples are for illustrative purposes only and are not to be construed as limiting in an manner.
[0120] A single center, double blind, randomized, parallel-group, placebo controlled dose-ranging study of E-EPA in subjects with age-associated impairment (AAMI) was performed. The primary goal was to examine the effect of ethyl-EPA versus placebo on cognitive performance in subjects with AAMI as measure by the power of attention tasks in a computerized test batter over a period of 6 weeks. Secondary objectives were to:
[0121] (1) examine the effect of E-EPA versus placebo over 6 weeks on the following tests in the computerized cognitive battery: Continuity of attention tasks; Quality of working memory tasks; Quality of episodic memory tasks; Speed of attention tasks;
[0122] (2) to assess the safety and tolerability of E-EPA versus placebo from routine clinical laboratory tests, adverse events (AE) monitoring and vital signs; and
[0123] (3) assess the potential dose-effect relationship of E-EPA on the cognative endpoints by measurement of essential fatty acids in plasma and red blood cell membranes. 94 subjects were randomized.
[0124] The study plan was to enroll 96 subjects who would be randomly allocated to 1 of 4 possible treatment groups for 6 weeks, in a balanced block design (24 subjects per group), as follows:
[0129] Ethyl-EPA was provided as 500 mg soft gel capsules providing ethyl-EPA of >96% purity, 0.25% to 0.38% by weight ethyl octadecatetraenoate, 0.075% to 0.15% by weight ethyl nonaecapentaenoate, 0.25% to 0.35% by weight ethyl arachidonate, 0.3% to 0.4% by weight ethyl eicosatetraenoate (ETA-E), 0.075% to 0.15% ethyl heneicosapentaenoate and 0.2% dl-tocopherol as an antioxidant. Matching placebo capsules contained 467 g of liquid paraffin and 0.2% dl-tocopherol. The placebo group was further randomized so that an equal number of subjects (8) was allocated 1 g, 2 g or 4 g placebo. Study drug was taken twice daily (BID) as a divided dose (e.g. for the 1 g dose, 500 mg was given in the morning and a further 500 mg was given in the evening) with a light snack or meal.
[0130] The study consisted of a screening visit, a training visit and 4 study visits. At the screening visit, subjects' eligibility was determined through cognitive tests (verbal paired associated learning [PAL] subscale, vocabulary subtext, Memory Assessment Clinics Questionnaire [MAC-Q], mini mental state evaluation [MMSE] and MINI [mini international neuropsychiatirc interview; sections 1 and 2 of Diagnostic and Statistical Manual of Mental Disorders, 4th Ed. (DSM-IV) plus dysthymia]), haematology, clinical chemistry and 12-lead electrocardiogram (ECG). At the training visit, subjects were shown how to use the CDR computerized system. Subjects took study drug for 6 weeks and on Days 0, 14, 28 and 42, subjects underwent the CDR cognitive test battery.
[0134] 3. Self-reported complaints of memory loss reflected in such everyday problems as difficulty remembering names of individuals following introduction, misplacing objects, difficulty remembering multiple items to be purchased or multiple tasks to be performed, problems remembering telephone numbers or postal codes and difficulty recalling information quickly or following distraction as determined by a score of 25 or higher on the MAC-Q questionnaire. Onset of memory loss was to be described as gradual without sudden worsening in recent months.
[0135] 4. Possession of subjective and objective cognitive impairment with a score of at least 1 standard deviation (SD) below that of the mean for age-matched elderly population as determined by the total score of between 13 and 20 from the PAL subset of the Wechsler Memory Scale.
[0136] 5. Evidence of adequate intellectual function as determined by a scaled score of at least 9 (raw score of at least 32) on the Vocabulary subtest of the Wechsler Adult Intelligence Scale (WAIS).
[0139] 8. Was able to travel to the centre and judged by the Investigator as likely to be able to continue to travel for the duration of the study and comply with the logistical aspects of the study.
[0144] 3. Past or current history of a neurological or psychiatric disorder that could have affected cognitive function.
[0145] 4. Past or current history of inflammatory gastrointestinal disease such as Crohn's Disease or ulcerative colitis.
[0148] 7. Any history or evidence of clinically significant cardiac abnormality as measured by 12-lead ECG.
[0149] 8. Any other medical condition or intercurrent illness not adequately controlled, which, in the opinion of the Investigator, may have put the subject at risk when participating in the study or may have influenced the results of the study or affected the subject's ability to take part in the study.
[0150] 9. Clinically significant abnormal screening laboratory results (haematology, biochemistry) on screening or vital signs that fell outside the normal range for this population, which in the opinion of the Investigator affected the subject's suitability for the study.
[0151] 10. Any changes to prescribed medication for a medical condition within 4 weeks of the baseline visit.
[0152] 11. Omega-3 supplementation within 4 weeks of the baseline visit or during the study treatment period.
[0154] 13. Cough or cold flu remedies containing opiates or antihistamines, within 2 weeks of the baseline visit or during the 6-week treatment period.
[0156] Any subject could withdraw from the study at any time at their or their legal guardian's request, or at the discretion of the investigator, if the subjects continued inclusion was not in their best interest, or in the event of a serious or unexpected AE. Every reasonable effort was made to document subject outcome and reasons for withdrawal. Any ongoing AEs were followed-up until the event had resolved, stabilised or was otherwise explained. Subjects who were withdrawn were not replaced. Subjects were assigned unique identification numbers according to a predetermined randomization list generated by Catalent Pharma Solutions and used in the drug packaging.
[0157] Study drug was administered orally BID as a divided dose with food, for 6 weeks. Subjects were randomized to 1 of 6 possible treatment groups (Table 1).
[0158] Study drug was dispensed at Visits 3, 4 and 5; the maximum period between Visit 3 and each subsequent visit was:
[0162] All treatment packs were identical in appearance, in order to maintain subject and investigator blind throughout the study. The investigator, Sponsor/clinical research organization personnel and subjects remained blinded throughout this study. The investigator was permitted to un-blind individual subjects if it was considered medically imperative. The process for breaking the blind is outlined below.
[0163] Omega-3 supplements had to be discontinued at least 4 weeks prior to the baseline visit (Visit 3). Cough and influenza remedies containing opiates or antihistamines had to be discontinued 2 weeks prior to the baseline visit (Visit 3) and were not permitted for the duration of the study.
[0164] Existing medication had to have been stable for 4 weeks prior to the baseline visit (Visit 3) and the dose maintained for the duration of the study. Where a dose change was absolutely necessary this was recorded in the electronic case report form (eCRF).
[0165] Subjects who required anticoagulant medication during the study were to be withdrawn. Psychological counseling or therapy was not permitted for the duration of the study, as these could have interfered with the outcome of the study. Unused study drug was returned to the study site. Subjects who used less than 80% of the prescribed dose were considered non-compliant.
[0166] At screening cognitive testing and suitability for the study were assessed using the Verbal Paired Associates 1 (Wechsler Memory Scale), Vocabulary Subtest of the WAIS, MAC-Q, MMSE and MINI (DSM-IV Sections 1 and 2 plus Dysthymia).
[0167] A selection of tasks from the CDR computerized cognitive assessment system were administered (Appendix 8 of protocol) at Visit 2 (training visit), Visit 3 (baseline), Visit 4 (Day 14), Visit 5 (Day 28) and Visit 6 (Day 42). Parallel forms of the tests were presented at each testing session. AH tasks were computer-controlled, the information presented on high resolution monitors, and the responses recorded via a response model containing 2 buttons 1 marked `no` the other `yes`. Five CDR composite scores were used as the primary/secondary outcome variables.
[0169] To ensure consistency of approach, full training on the cognitive tests and CDR test battery was provided to study site staff and study subjects. The results of each variable were automatically recorded using the machine interface developed by CDR.
[0170] An AE was defined as any untoward medical occurrence temporally associated with the use of a medicinal product whether or not considered related to the medicinal product.
[0171] The investigator was responsible for the detection and documentation of AEs. At each visit the subject was asked about AEs by means of non-leading questions. AEs were recorded from the time a subject provided a written informed consent and deemed eligible to participate until completion of the treatment period. AEs ongoing at the end of the treatment period were followed until resolution or return to baseline or normal value or if the event was considered unrelated to study drug.
[0177] Other events were considered SAEs if they jeopardized the subject or required medical or surgical intervention to prevent one of the outcomes listed above.
[0178] Regardless of the above criteria, any AE that the Sponsor or investigator considered serious was to have been immediately reported as a SAE. Any death or SAE experienced by the patient while receiving or within 30 days of last dose of Investigational Medicinal Product must be promptly reported (within 24 hours of learning of the event) to pharmacovigilance. All AEs (including SAEs) are to be accurately recorded on the adverse event page of the subject's eCRF, beginning from first administration of Investigational Medicinal Product until 30 days after the last dose.
[0179] Blood samples for the laboratory assessments for haematology (a 5 mL blood sample) and clinical chemistry (a 10 mL blood sample) listed in Table 2, were collected at the screening visit (Visit 1). Samples were processed and analyzed by Simbec Laboratories Ltd.
[0181] Blood samples (10 mL) were collected at Visit 1 (screening) and at Visits 4, 5 and 6. Analysis was performed by MSR Lipid Analysis, Scottish Crop Research Institute, Dundee, UK. The screening sample acted as baseline for the EFA measurements.
[0182] Lipid was extracted from plasma, serum and RBC suspensions and converted into fatty acid methyl esters which were analysed by gas chromatography to give fatty acid profiles as micrograms fatty acid per gram of sample (μgFA/g) and normalised area percent. The CDR computerized system has been used to measure the effects of pharmaceuticals on cognitive function in a variety of clinical trials. Efficacy was assessed by a battery of cognition tests designed by CDR. Safety data were analysed by Quanticate.
[0184] Intent to Treat (ITT) Population: All randomised subjects with at least 1 visit post-baseline were included in this population, regardless of treatment actually received.
[0185] Per Protocol Population (PP): All randomised subjects that completed the study, excluding significant protocol deviators, were defined as the Safety PP population. An Efficacy PP population was based on the Efficacy completers. The intercept of the Safety and Efficacy PP populations defined the Study PP Population.
[0186] Safety Population: All randomised subjects that received at least 1 dose of study medication.
[0187] Summary statistics were provided for the ITT and Study PP Populations separately for all composite scores, major and supportive variables. Summary statistics were performed for both the unadjusted and difference from baseline data (Le, the difference from the time matched predose assessments on Day 0). Summary statistics were calculated by treatment, day and time-point. The summary statistics comprised n, mean, median, SD, standard error of mean (SEM), minimum and maximum values.
[0188] Difference from baseline data for each major variable was evaluated by an Analysis of Covariance (ANCOVA) using SAS® PROC MIXED Version 8.2.
[0189] Fixed effects for treatment, day, time point, treatment by day, treatment by time point, treatment by day by time-point were fitted. Subject within treatment was fitted as a repeated effect using the repeated statement. The compound symmetry covariance structure was used. Subjects' time-matched predose assessments on Day 0 were used as a covariate in the analysis. Least squares means (LS means) were calculated for treatment by day, treatment by time-point and treatment by day by time-point interaction. This formal analysis was conducted for the ITT and Study PP Populations separately.
[0190] Safety evaluations were based on the safety population. Safety and tolerability were assessed in terms of AEs, vital signs, 12-lead ECG, clinical laboratory data, medical history, and study drug compliance. Safety and tolerability data were presented by treatment group. All safety data were listed individually by subject.
[0191] RBC and plasma EFA data were collected at baseline, Day 14, 28 and 42 and summarised by visit for each treatment group. Change from baseline and percent change from baseline were also summarised. ANCOVA comparison of ethyl-EPA dose groups and ethyl-EPA versus placebo was performed.
[0192] The sample size calculation was based on Power of Attention. Ispronicline (50 mg), a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with AAMI on Day 21 of repeated dosing in an earlier study showed a benefit of 61 msec (50 mg mean=-32.54, SD=61.22; placebo mean=28.25, SD=49.64) to Power of Attention. Using a pooled SD, a sample size of 15 subjects per treatment arm was considered sufficient to detect a difference of 61 msec, with 80% power and 5% significance level (no adjustment for multiple testing). As there was no prior experience with the compound or mechanism of action with these cognitive measures, a sample size of 24 subjects per treatment arm was chosen as sufficient to allow for early withdrawals.
[0193] There were no changes to the conduct of the study. The following changes were made to the planned analyses: The equation to calculate Speed of Memory was changed to SPEEDMEM (speed of memory)=SPMRT (spatial working memory speed)+NWMRT (numeric working speed)+DRECRT (word recognition speed)+DPICRT (picture recognition speed).
[0194] Subject's time-matched pre-dose assessments on Day 0 were used as a covariate in the analysis.
[0195] Day 0 was removed from Day values in the list of ANCOVA variable values. Covariate=Baseline was changed to Covariate=Time matched predose assessments on Day 0 in the list of ANCOVA variable values.
[0199] Figures were included for Treatment, Treatment by Day, Treatment by Time-point, Treatment by Day by Time-point effects for ANCOVA LS means.
[0200] Figures were added for ANCOVA LS means differences to placebo (95% confidence interval [CI]).
[0201] A post-hoc analysis was performed which compared the individual placebo groups (1 g, 2 g and 4 g paraffin oil) with the corresponding ethyl-EPA dose rather than to a pooled placebo group.
[0202] Ninety-one subjects completed the study, three subjects discontinued; 2 subjects from the ethyl-EPA 2 g treatment group (1 subject due to an SAE considered unrelated to the study drug and 1 due to a protocol violation and 1 subject from the placebo 2 g group due to an AE.
[0203] For Power of Attention, there was no statistically significant effect of treatment, nor any treatment by day, treatment by time-point or treatment by day by time-point interactions. There was no LS mean difference between active treatment and placebo at any time-point. For Choice Reaction Time there were statistically significant benefits for ethyl-EPA 1 g and 2 g on Day 28, and some trends for benefit for 1 and 4 g ethyl-EPA on Day 42, versus placebo; however no clear treatment-related pattern was observed.
[0204] Continuity of Attention did not show a difference between placebo and ethyl-EPA, except for an overall decrease for 2 g ethyl-EPA that was only visible in the ITT population. The subtask Digit Vigilance Targets Detected showed isolated decreases for active treatment versus placebo, but there was no obvious treatment-related pattern.
[0205] Quality of Working Memory was the only composite score that showed a statistically significant treatment by day interaction in the F-ratio. However, there were only isolated statistically significant decreases for ethyl-EPA 1 g and 2 g versus placebo on Days 14 and 28, and these were most likely to be due to chance and not treatment related.
[0206] Quality of Episodic Secondary Memory showed statistically significant decreases for ethyl-EPA versus placebo at various time-points. However, it seems unlikely to be an effect of active treatment as the unadjusted data showed pre-existing differences between the treatment groups that was most notable on Day 0 in the first assessment session. In difference from Baseline data that were calculated prior to ANCOVA analysis, these differences were no longer apparent. This suggests that the ANCOVA model fitted a strong negative correlation with the baseline values. This is often the case when the variability within subjects overlaps the variability between subjects.
[0207] Speed of Memory and the subtasks Spatial and Numeric Working Memory Speeds and Word and Picture Recognition Speed showed no differences in performance, in the F-ratio statistics, between Ethyl-EPA and placebo.
[0208] For Self-rated Alertness, there was no apparent difference in ratings between ethyl-EPA and placebo. There were isolated decreases in ratings for active treatment versus placebo that were unlikely to be compound related,
[0209] Self-rated Contentment showed statistically significant decreases in ratings for ethyl-EPA 2 g on Day 28. However, these individual decreases were not statistically significant. It is unlikely that this was a treatment-related effect as it was restricted to a single day and no other dose level showed a similar pattern on any other day. For Sell-rated Calmness there was no difference in ratings between active treatment and placebo.
[0210] When the results of each ethyl-EPA dose and their corresponding placebo were compared (post-hoc analysis), it appeared that ethyl-EPA 4 g improved the subjects' reaction times in the attention tasks (Power of Attention, Simple Reaction Time and Choice Reaction Time). This was seen most clearly for Choice Reaction Time, where a pattern of gradual improvement over the assessment day for 4 g was seen. It is possible that a longer period of administration would clarify the effects of ethyl--EPA on these parameters.
[0211] EPA (shown in Table 3), DPAn-3 and EPA/AA ratio (data not shown) plasma and RBC values increased substantially from baseline to Day 42 for the AMR-101 1, 2, and 4 g treatment groups. AA, DHA and DGLA values decreased substantially from baseline (data not shown).
[0212] As can be seen in Table 3, at the 2 g per day AMR101 dose, plasma EPA levels increased 297% after 42 days and at the 4 g per day AMR101 dose, plasma EPA levels increased by 417% compared to baseline.
[0213] Grimsgaard et al. previously published an article describing serum phospholipid levels at baseline and alter 7 weeks of supplementation with 4 g per day of 90% ethyl-DHA, 4 g per day of 95% ethyl-EPA with some DHA present, or corn oil. Am. J. Clin. Nutr. 1997; 66:649-59(1997). The complete profile of additional fatty acids and ingredients present in these compositions is unknown. After supplementation over a period of 7 weeks, subjects exhibited only a 297% increase in serum phospholipid EPA compared to the increase of 417% shown above with an inventive composition. A comparison of other changes in plasma/serum fatty acids is shown in Table 4.
[0214] Furthermore, in the Japanese Eicosapentaenoic Acid (EPA) Lipid Intervention Study (JELIS), Yokoyama et al. reported that they followed over 18,000 patients randomly assigned to received either 1800 mg of EPA composition (Epadel) with statin, or statin only with a 5-year follow-up. Lancet 2007; 369:1090-98. After 5 years of treatment, subjects exhibited an increase in plasma EPA of only 70% (from baseline of 93 mg/L to 169 mg/L).
[0215] FIGS. 1 and 2 and show a comparison of the change in plasma/serum EPA levels observed with AMR101 treatment in the current study compared to those observed with different EPA compositions in the JELIS study and by Grimsgaard. As will be noted, at ˜2 g per day, AMR101 achieved much greater plasma EPA increase compared to baseline (˜4-fold) after just 6 weeks than the JELIS study observed (<2-fold) after 5 years of treatment. Moreover, at the 4 g per day dose, AMR101 treatment for 6 weeks achieved much higher (>250 μg/g) plasma EPA levels than reported by Grimsgaard after 7 weeks of treatment (87.66 μg/g serum). Overall, the 4 g per day dose of AMR101 resulted in a greater than 5-fold increase in plasma EPA over baseline while the 4 g per day dose of Grimsgaard's composition resulted in less than a 3-fold increase in serum EPA. These results were unexpected.
[0216] A mufti-center, randomized, double-blind, placebo-controlled trial was conducted in North America to determine whether 1 gram twice daily of EPA for 6 months improves motor performance in Huntington's patients. A post-hoc analysis was performed to evaluate the effect of EPA on non-fasting triacylglycerols.
[0217] Study of the effects of ethyl-EPA on the progression of Huntington Disease enrolled study participants at 41 sites in Canada and the United States. Based on the results of the earlier study, the study entry criteria were designed to enrich the participation of individuals with Huntington disease with a GAG repeat less than 45, without requiring genetic testing to reveal the length of expansions to research participants or investigators. To participate in the study, individuals had to have the clinical features of HD and either a confirmatory family history or a known GAG expansion. Eligibility criteria included a minimum age of 35, a total functional capacity of at least 7, minimal dystonia (not exceeding 2 on the UHDRS in either the trunk or extremities), minimal bradykinesia (not exceeding 2 on the UHDRS item for bradykinesia), the use of adequate birth control, the ability to take oral medications, and the willingness and ability to comply with study requirements. Individuals were not eligible to participate if, within 60 days of the baseline visit, they had used omega-3 fatty acid supplements, tetrabenazine or reserpine, high or variable doses of oral anti-psychotic medications (e.g., haloperidol), steroids other than topical preparations, high dose selenium supplements, lithium, high doses of benzodiazepines, anti-coagulation medication (e.g., coumadin), high doses (greater than 325 mg per day) of aspirin, unstable does of NMDA receptor antagonists (e.g., memantine), unstable doses of anti-epileptic medications, or if they had participated in other investigational drug studies. Additional exclusion criteria were the use of depot neuroleptics within 6 months of the baseline visit, a history of tardive dyskinesia, unstable medical or psychiatric illness, major depression (defined as a score greater than 20 on the Beck Depression Inventory II), suicidal ideation, clinically significant substance abuse within 12 months of the baseline visit, women who were pregnant or lactating, known allergy to ethyl-EPA or placebo, or previous participation in an investigational study of EPA.
[0218] This was a randomized, double-blind, placebo-controlled, parallel group study of EPA (1 gram twice/day). The institutional review board at each participating site approved the research plan and consent documents. Eligible study participants provided written consent. At the baseline visit, participants were randomized according to a block-balanced computer-generated randomization plan that was stratified by site and generated by the Biostatistics Center at the University of Rochester. Individuals were randomized in a 1:1 ratio to receive either active drug (n=158) in the form of two 500 mg capsules of AMR101 orally or placebo (n=154) in the form of two 500 mg capsules containing light paraffin oil and 0.2% dl-alpha-tocopherol twice daily orally for 6 months. After 6 months, all TREND-HD participants were treated with AMR101 for 6 months in an open-label fashion. Only data from the first 6 months were used to evaluate the effects of AMR101 on lipids.
[0219] The outcome measure of this study was the change in non-fasting triacylglycerol (TG) levels in those on AMR101 compared to those on placebo.
[0220] Safety was assessed at all study visits, including evaluation and assessment of adverse events and serious adverse events and review of clinical laboratory tests (complete blood count, serum chemistry, and urine pregnancy tests). The safety of research participants was monitored in a blinded manner by a medical monitor from both the sponsor and from the Huntington Study Group. In addition, an independent Safety Monitoring Committee that had access to treatment assignments reviewed safety data throughout the study to determine if any modifications were needed to the trial's conduct.
[0221] Changes in lipid levels were compared using an analysis of covariance (ANCOVA) with treatment group as the factor of interest, site as a stratification factor, and baseline value as a covariate. All individuals who received study medication were included in the safety analysis. For each type of adverse event, the treatment groups were compared regarding the occurrence of at least one event using Fisher's exact test. Continuous measures of safety such as laboratory test results and vital signs were analyzed using methods similar to those described above for the primary outcome variable (ANCOVA). No corrections were made for multiple comparisons in evaluating safety data.
[0222] One hundred forty-five subjects on AMR101 (92% of those assigned) and 141 of those on placebo (92% of those assigned) had red blood cell content of EPA determined at baseline and 6 months. Baseline red blood cell content of 20:5n3 (EPA) increased significantly after 6 months in those on AMR101 (from a mean of 0.52% to 3.07%) but decreased in those on placebo (from a mean of 0.61% to 0.55%); p<0.0001). After 6 months, individuals taking AMR101 had a 26 mg/dL decrease in TGs from a baseline of 171 compared to a decrease of 11 mg/dL from a baseline of 187 mg/dL in those on placebo; p=0.007. Total cholesterol was reduced significantly more in those taking AMR101 (9.5 mg/dL) from a baseline of 204 mg/dL than in those taking placebo (2.5 mg/dL) from a baseline of 208 mg/dL; p=0.009. Lipid and Motor Scoer data are shown in Tables 5 and 6, respectively.
[0223] By comparison with these data for AMR101 Grimsgaard reported a decrease (from baseline) of only 12% in serum triglycerides in the EPA group after 7 weeks of treatment. Furthermore, addition of the Epadel EPA composition to existing statin therapy in the JELIS study resulted in only a 9% reduction in triglycerides after 5 years of treatment.
[0224] A study was performed to evaluate and compare the content of Epadel capsules with AMR101 capsules. Six capsules of each composition were selected for analysis by gas chromatography. Averages of the six capsules for each of the two compositions are shown in Table 7.
[0225] A phase multiple dose pharmacokinetic study in healthy male volunteers was carried out at a single center. Twenty four subjects were divided into two treatment groups of 12 subjects each (groups A and B). Both groups received the same total daily dose of AMR101 but the dosing regiments were different. AH subjects received a single oral dose of 2 g AMR101 on Day 1. Treatment Group A received 28 continuous once daily doses of 2 g AMR101. Treatment Group B received 27 continuous twice daily doses of 1 g AMR101 and a single does of 2 g of AMR101 on day 30.
[0226] Levels of EPA and other essential fatty acids were determined in plasma and red blood cells Blood samples for pharmacokinetic analysis were taken at the following time points for Treatment groups A and B:
[0233] Using a corrected value obtained by subtracting the pre-administration concentration from the concentrations at each sampling, a single oral dose of 2 g of AMR101 resulted in a rapid rise in plasma lipid EPA. Maximum values were observed at 5 hours post-administration with EPA levels remaining above baseline at 48 hours post-administration. The half-life of removal of EPA from plasma lipids was 87±65 h (non-baseline subtracted) and 42±31 h (baseline subtracted). Summary pharmacokinetic data are shown in Table 8.
2015-09-24 Pharmaceutical composition comprising omega-3 fatty acid and hydroxy-derivative of a statin and methods of using same
The annual EAA Young Eagles First Flight Day introduces 100+ local children (ages 8-17) to aviation by showing them what pilots do both on ground and in the air. Each child will enjoy a pancake breakfast before going through a pre-flight session. Upon completion, the children will enjoy a free 20-minute flight with EAA-certified pilots.
For most children, this will be the first time flying. An open house will also take place for the children and their families, featuring interactive displays and demonstrations in the areas of aviation, aerospace, and unmanned aerial systems.