A composition useful as an impregnant for the making of laminates for printed wiring boards comprises a FR4 epoxy resin which is a bisphenol A epoxy resin advanced with tetrabromobisphenol A, a crosslinking agent of a strene-maleic anhydride copolymer and a co-crosslinking agent is an optionally brominated bisphenol A and/or an optionally brominated bisphenol A diglycidyl ether.

The invention pertains to a resin composition comprising a styrene maleic anhydride copolymer as a cross-linking agent (curing agent), an epoxy resin, and a co-cross-linking agent.
The use of cross-linking agents for epoxy resin is described in BE 627,887. This patent also discloses a proposal to use copolymers of maleic anhydride and styrene (SMA) as cross-linking agent for epoxy resin. A drawback to such epoxy resin compositions is that they have low Tg and low thermal stability, rendering them unsuitable for use in prepregs, which are applied in laminates for printed wiring boards (PWBs).
The resin generally used in electrolaminates is an epoxy resin. The present practical standard is the FR4-laminate, which is based on a brominated epoxy resin prepared from a diglycidyl ether of bisphenol-A and tetrabromo-bisphenol-A, dicyanodiamide as curing agent, an organic solvent, and an accelerator. The drawback to such an epoxy resin is its low Tg (110-130xc2x0 C.), while in addition the dicyanodiamide has a tendency to crystallize in the resin and the prepreg made therefrom.
An improvement has been sought in the preparation of an interpenetrating polymeric network (IPN). Such resin compositions are known from EP 413,386. This document relates to IPNs having very favorable properties, in particular for use in the electronics industry. This is the case when the cross-linking agent used for the epoxy resin is a polybrominated phenol. In actual practice, the embodiment using anhydride cross-linking agents proves unsatisfactory. Notably, the Tg obtained is too low, and the electrical properties and the prepreg stability also leave room for improvement.
In addition, it is desired that the use of inexpensive difunctional epoxy resins should give thermal properties which are of the same standard as can be obtained using the multifunctional epoxy resins preferably employed in EP 413,386. Resins based on multifunctional epoxy compounds have been described in WO 85/03515 and WO 86/02085.
Other publications describing epoxy resin compositions employing anhydrides as cross-linking agent for the epoxy resin are U.S. Pat. No. 2,707,177; DE 3,521,506; GB 994,484; and EP 417,837. This last patent specification teaches the use of ethylenically unsaturated anhydrides, such as maleic anhydride, where the anhydride not only cross-links the epoxy resin but also takes part in the forming of the network.
A solution to the above-mentioned problems has been suggested in WO 96/07683, which discloses a resin composition where the carboxylic anhydride is a copolymer of an ethylenically unsaturated anhydride and a vinyl compound. In such a copolymer the ethylenically unsaturated portion of the anhydride is incorporated into the backbone. The carboxylic anhydride groups remain intact, and they are available as functional groups for cross-linking the epoxy resin. More specifically, those resin compositions contain triallyl cyanurate (TAC) as allyl polymerizing agent. In this type of resin TAC is necessary to obtain compositions with high Tg and acceptable thermal stability, which can be applied in prepregs.
Resin compositions which comprise dicyandiamide as co-cross-linking agent have been disclosed in DE 3,839,105. According to this document, dicyanamide is an essential constituent of the resin composition. Dicyandiamide, however, has the disadvantage that it only dissolves in toxic and expensive solvents, and it would be an advantage to find suitable co-cross-linking agents, devoid of the disadvantages of dicyandiamide.
Epoxy resin compositions containing low-molecular weight copolymers of xcex1-methylstyrene and maleic anhydride have been disclosed in U.S. Pat. No. 4,042,550. Such compositions are unsuitable for the manufacture of PWBs.
Prepregs are widely employed in the manufacture of laminates for the electronics industry, in particular for printed wiring boards. Such manufacture involves impregnating a supporting or reinforcing fabric with a resin, followed by partial curing of said resin. Such impregnated fabric is commonly referred to as prepreg. Manufacturing a printed wiring board involves laminating one or more layers of prepreg with, say, one or more layers of copper.
Processing prepregs into boards usually involves their being cut down to size and laminated. Both these process steps make stringent demands on the resin with which the fabric is impregnated. For instance, the partially cured resin has to have sufficient sturdiness and a high viscosity, yet it must be sufficiently sticky and liquid to give good adhesion when laminated, and hence good interlaminar strength. The resin may not be too highly reactive, since this will render the required partial curing impossible.
In this connection resin compositions where the epoxy resin is cross-linked with an anhydride-containing copolymer have the drawback of being too brittle to be processed as prepregs. For instance, it proves impossible to cut up such prepregs without a portion of the resin blowing about in the form of a large quantity of dry dust. This is sometimes called a xe2x80x9cmushroom effect,xe2x80x9d after mushroom spores blowing about.
It has now been found that in contrast to the previous solutions for obtaining suitable polymers for use in prepregs, IPNs are not necessary, and that epoxy resins free from TAC can be prepared having high Tg and/or improved thermal stability.
On the one hand, the invention has the object to enhance the thermal and electrical properties of resin compositions based on epoxy resin cross-linked with styrene maleic anhydride copolymer (SMA). On the other hand, the invention envisages resin compositions based on difunctional epoxy resin which have thermal and electrical properties comparable to IPNs the resin composition of which is based on multifunctional epoxy compounds. Furthermore, the invention aims to provide resin compositions where the problem of brittleness, which occurs when SMA is used as epoxy cross-linking agent, can be prevented.
To this end, the invention consists of a resin composition comprising a copolymer of styrene and maleic anhydride (SMA) as cross-linking agent, an epoxy resin, and a co-cross-linking agent, characterized in that the co-cross-linking agent is an optionally brominated bisphenol A (BPA), or an optionally brominated bisphenol A diglycidyl ether (BPADGE), or a mixture thereof, and that the composition is free from an allyl network forming compound.
It is known from WO 96/07683 that epoxy resin compositions which are free from allyl network forming compound, such as TAC, have low Tg, usually not higher than 130xc2x0 C., and low thermal stability. The present invention is based on the finding that use of BPA as co-cross-linking agent significantly improves the thermal stability of the co-polymer. To this same end it was found that BPADGE as co-cross-linking agent considerably increases the Tg, so that Tg values of 190xc2x0 C. are attainable. Preferably, the co-cross-linking agent is a brominated BPA, a brominated BPADGE, or a mixture thereof. More preferably, the co-cross-linking agent is tetrabromobisphenol A (TBBPA) or tetrabromobisphenol A diglycidyl ether (TBBPADGE). Most preferably, the co-cross-linking agent is a mixture of tetrabromobisphenol A (TBBPA) and tetrabromobisphenol A diglycidyl ether, leading to resin compositions with high thermal stability and a high Tg. Moreover, the stability of prepregs made of the resin composition of the invention is considerably improved with respect to the prior art prepregs. A further advantage is that post-curing, which is necessary with IPNs, is not longer required.
Copolymers of styrene and maleic anhydride have been described, inter alia, in Encyclopedia of Polymer Science and Engineering Vol. 9 (1987), page 225 ff. Within the framework of the invention the term xe2x80x9ccopolymerxe2x80x9d likewise refers to SMA or mixtures of SMA.
Copolymers of styrene and maleic anhydrides (SMA) are commercially available in two types. Type 2 comprises mostly high-molecular weight copolymers (MW generally higher than 100,000, for instance, 1,000,000). These are in fact thermoplasts, which are unsuitable for use in the manufacture of prepregs. Moreover, because of their low anhydride content (5-15%) they are not particularly suitable for use as a cross-linking agent for epoxy resin either. The type 1 SMA copolymers, on the other hand, which have a molecular weight in the range of about 1400 to about 50,000 and an anhydride content of more than 15% by weight, are pre-eminently suited to be used. Preference is also given to SMA copolymers having a molecular weight in the range of 1400 to 10,000. Examples of such copolymers include the commercially available SMA 1000, SMA 2000, SMA 3000, and SMA 4000. These copolymers have a styrene:maleic anhydride ratio of 1:1, 2:1, 3:1, and 4:1, respectively, and a molecular weight ranging from about 1400 to about 2000. Mixtures of these SMAs may also be used.
The amount of copolymer employed can be such as will give an anhydride and aromatic hydroxy groups:epoxy groups equivalency ratio in the range of 50 to 150% to by weight. The preferred ratio is between 75 and 125% by weight, and more preferably between 90 and 110% by weight. Optimum results are obtained when at least 10% by weight of TBBPA and at least 10% by weight of TBBPADGE are employed as co-cross-linking agents.
The term xe2x80x9cepoxy resinxe2x80x9d in this context refers to a curable composition of oxirane ring-containing compounds as described in C. A. May, Epoxy Resins, 2nd Edition, (New York and Basle: Marcel Dekker Inc.), 1988.
Examples of epoxy resins include phenol types such as those based on the diglycidyl ether of bisphenol A, on polyglycidyl ethers of phenol-formaldehyde novolac or cresol-formaldehyde novolac, on the triglycidyl ether of tris(p-hydroxyphenol)methane, or on the tetraglycidyl ether of tetraphenylethane; amine types such as those based on tetraglycidyl-methylenedianiline or on the triglycidyl ether of p-aminoglycol; cycloaliphatic types such as those based on 3,4-epoxycyclohexylmethyl-3,4-epoxycyclohexane carboxylate. The term xe2x80x9cepoxy resinxe2x80x9d also stands for reaction products of compounds containing an excess of epoxy (for instance, of the aforementioned types) and aromatic dihydroxy compounds. These compounds may be halogen substituted.
Preference is given to epoxy resins which are derivative of bisphenol A, particularly FR4, especially on account of their low price. FR4 is made by an advancing reaction of an excess of bisphenol A diglycidyl ether with tetrabromobisphenol A. Mixtures of epoxy resins with bismaleimide resin, cyanate resin and/or bismaleimide triazine resin can also be applied.
It should be noted that epoxy resins are generally represented by a single, unequivocal structural formula. The skilled person will know that this should be taken to include deviating products resulting from side reactions occurring during epoxy resin preparation. As these side products constitute a normal component of cured epoxy resins, they likewise constitute a normal component of the resins according to the invention.
The BPA and BPADGE may optionally be brominated, i.e. substituted with one or more bromine atoms. Brominated co-cross-linking agents are preferred because of their flame retarding properties. Preferably, the aromatic moieties of both BPA and BPADGE are substituted with two bromine atoms, to give tetrabromo substituted TBBPA and TBBPADGE, respectively. Optionally brominated novolacs can also be used as co-cross-linking agent.
Cross-linking of the epoxy resin generally proceeds with the aid of an accelerator. As suitable accelerators may be mentioned imidazoles, more particularly alkyl substituted imidazoles such as 2-methylimidazole and 2-ethyl-4-methylimidazole, and tertiary amines, e.g. benzyldimethylamine.
The amount used of such an accelerator is dependent on the type of epoxy resin, the type of cross-linking agent, and the type of accelerator. Employing a too large amount of accelerator will lead to a too highly reactive resin system. Such a system is not serviceable for making prepregs. The skilled person can easily determine within which range a resin system will be just sufficiently little reactive to allow ready processing into prepregs. In general, such a processing range will be between 0.01 and 5% by weight of accelerator, calculated on the overall weight of epoxy resin and cross-linking agent. In many cases this will be the 0.01-0.075 % by weight range. The gel time for its part is dependent on the type and amount of accelerator, the type and amount of solvent, and the type of prepreg to be manufactured. In the specific case of 2-methylimidazole (2MI) being used as accelerator, it is preferred not to use more than about 0.05% by weight of 2MI. By way of general guideline it can be said that it is advisable not to have a varnish gel time of less than 120 seconds.
The desired resin properties determine the amount of BPA and BPADGE to be incorporated into the resin. According to the invention, for instance, it has surprisingly been found that the Tg of epoxy resins cross-linked with SMA can be increased substantially by the use of at least 5% by weight of BPA. Most surprisingly of all, it is now possible, as indicated above, to obtain resins having glass transition temperatures of 130xc2x0 C. and higher even with simple difunctional epoxy compounds.
As a rule, an organic solvent is employed when preparing resins according to the invention. If a solvent is used, it must be one in which the epoxy resin, cross-linking agent, and co-cross-linking agent are soluble, while the solvent itself should be sufficiently volatile to evaporate before or during the curing.
As suitable solvents may be mentioned dimethylformamide; glycol ethers such as ethylene glycol mono-ethyl ether or propylene glycol mono-ethyl ether and their esters such as ethylene glycol mono-ethyl ether acetate; ketones such as methyl isobutyl ketone, methylethyl ketone, acetone, and methyl isopropyl ketone; and aromatic hydrocarbons such as toluene and xylene. Alternatively, mixtures of solvents can be employed. The preferred solvents are ketones, notably acetone and methylethyl ketone, or mixtures of these with ethers, notably propylene glycol mono-ethyl ether.
The invention further pertains to laminates for use in the electronics industry incorporating resins of the aforementioned type.
Laminates for use in the electronics industry (particularly for printed wiring boards) are generally produced by impregnating a supporting or reinforcing material (usually based on glass fibres, either as a woven fabric or in the form of a cross-ply laminate of unidirectionally oriented parallel filaments) with a resin, followed by the resin being cured wholly or in part. The latter process is the most common one, and a fabric impregnated with a partially cured resin is usually referred to as a xe2x80x9cprepreg.xe2x80x9d To make a printed wiring board from a prepreg fabric one or more layers of the prepreg are laminated with, say, one or more layers of copper.
The resins according to the invention are highly suitable for impregnating, e.g., woven fabric and cloth of a variety of materials such as glass, quartz, carbon, aramid, and boron fibres, more particularly to make laminates for printed wiring boards. This application preferably calls for the resin to be employed in combination with a glass fabric.
It was found that even when it is based on simple difunctional epoxy compounds, the combination of resin components according to the invention will give excellent properties for application in the electronics industry. The Tg effect has been mentioned earlier: as compared with the corresponding standard epoxy resins (cured with dicyanodiamide) the resins according to the invention have a Tg of about 30-50xc2x0 C. higher. Furthermore, it was found that resins according to the invention exhibit a much better resistance to short, intense temperature increases than do standard FR4 epoxy resin and IPNs according to EP 413,386 and have better prepreg stability. The thermal stability is demonstrated by the pressure cooker test and the solder shock test, which are known to the skilled man. The pressure cooker test is a procedure for evaluating glass epoxy laminate integrity. In this test a specimen of the laminate to be tested is placed in a pressure cooker for some time, after which the specimen is immersed in a solder bath at 260xc2x0 C. The specimen is thereafter graded on the occurrence of measles, blisters, delamination, convolution, and surface erosion. The longer the cooker time without said occurrence is, the more thermally stable the laminate will be. In the solder shock test a material is transferred abruptly from room temperature to solder having a temperature of 288xc2x0 C. The material (in this case a laminate made of a resin according to the invention) floats in the solder, and so will be subject to a temperature gradient (and hence a tension gradient). The material should be capable of withstanding these conditions for at least 30 seconds without bubble formation or delamination occurring. The longer the material can stand the test, the more serviceable it will be for use in printed wiring boards. The resins according to the invention are capable of standing the solder shock test for 10 minutes, which represents a substantial improvement over both the aforementioned known IPNs, which bear it for about 3 minutes, and FR4 epoxy resin (about 4 minutes). Furthermore, the resins according to the invention exhibit a significant reduction of dielectric loss.
Also, the resins according to the invention can be employed wherever use is made of conventional epoxy resins: as a glue, coating, molding resin, embedding resin, encapsulating resin, sheet molding compound, bulk molding compound.
In addition to being used as composites for printed wiring boards, the resins according to the invention can be employed to make composites for, inter alia, the construction, aviation, and automobile industries. The manufacture of appropriate structural composites may proceed in a known manner, e.g., by impregnating reinforcing material with molten or dissolved resin, or via resin transfer molding, filament winding, pultrusion, or RIM (reaction injection molding).
The resins according to the invention may contain the usual additives such as dyes or pigments, thixotropic agents, fluidity control agents, and stabilizers.

Epoxy resin, styrene-maleic anhydride copolymer and co-crosslinking agent


A method and apparatus for preheating golf balls prior to painting. The process includes forming golf balls with covers, heating, coating, and further heating the golf balls in a heated enclosure. The apparatus includes a ventilated holding tray that in addition to supporting the golf balls with a minimum of contact between balls and tray will allow for a thorough flow of heat about the balls for quick and uniform heating. This also will aid in reducing blemishes to the golf balls, by suspending freshly painted golf balls on conical pins set at right angles to the balls, thereby reducing the physical contact between the tray and freshly painted golf balls. The tray comprises replaceable ball support inserts. The inserts will generally be made from injection molded plastic and will be friction-fitted to the tray, and if damaged can be easily and inexpensively replaced.

The invention relates to a method of manufacturing golf balls. More specifically, the present invention relates to a method of heating golf balls prior to painting and the apparatus employed.
Conventional golf balls can be classified as one-piece, two-piece, and three-piece balls. One-piece balls are molded from a homogeneous mass of material with a dimple pattern molded therein. Two-piece balls are made by molding a cover about a solid core. Three-piece are typically, but not always wound balls which are made by molding a cover about a wound core. The core of a two-piece ball is typically formed of rubber and can be solid, semi-solid or have a liquid center. A wound core is prepared by winding a lengthy thread of elastic material about-the rubber core described above. The wound core is then surrounded with a cover material. The more recent trend in the golf ball art is towards the development of multi-component golf balls such as balls having two or more cover layers, two or more core layers or both multiple core and multiple cover layers.
Golf ball covers are presently formed from a variety of materials, such as balata, SURLYN(copyright), IOTEK(copyright), and polyurethane, depending upon the performance characteristics desired for the golf ball.
All golf balls, regardless of type, have an outer surface that contains a dimple pattern. As used herein, xe2x80x9cdimplesxe2x80x9d refer the topical relief of the outer surface of the ball, typically depressions or indentations formed into to provide desired aerodynamic effects. However, the dimple pattern may comprise of any form of topical relief on the outer surface of the golf ball formed to provide a desired aerodynamic effect to the ball, including formations such as protrusions from the outer surface.
Further to the above, golf balls are provided in a variety of colors. Conventionally they are white, but they may be manufactured in essentially any desired color, including yellow, orange and pink. The color is imparted to the ball either by applying layers of paint to the outer surface of the cover or by incorporating a pigment directly into the cover composition. Typically, in a painted ball, at least one primer layer is applied, followed by a second, finishing coat layer. After a ball has been provided with a color, identifying indicia such as a trademark, logo, identification number, model name or number and the like are hot stamped or pad printed onto the ball.
Golf balls must be capable of withstanding a variety of weather conditions such as strong sunlight, extreme temperature ranges, and immersion in water, preferably for an extended period. Further, the surface of a golf ball is flexed due to the impact every time it is struck with a club and consequently these surfaces must be able to withstand such repeated stresses. Moreover, especially with the recreational player, golf balls are susceptible to striking any of a number of hard, abrasive surfaces such as concrete, asphalt, brick, stone, etc. as a result of errant shots. It is therefore desirable for golf ball manufacturers that their golf balls be resistant to delamination or chipping of the paint layers, as such defects impact negatively upon the public perception of the quality of the golf ball. Likewise, golf ball manufacturers also seek to prevent obliteration of all or part of their trademarks, logos or other identifying indicia which identifies the brand of the ball to the playing public. Protective coatings are therefore applied to the surface of the golf ball cover. A clear primer coat and top coat layer are commonly applied to the cover to provide a high gloss and an overall enhanced appearance to the ball. In such coated balls, the various identifying indicia may be applied either to the cover, the primer coat or the topcoat.
Protective and decorative coating materials, as well as methods of applying such materials to the surface of a golf ball cover are well known in the golf ball art. Generally, such coating materials comprise urethanes, urethane hybrids, polyesters and acrylics. If desired, more than one coating layer can be used. Typical two pack polyurethane coatings include separate packages of polyol and diisocyanate. Conventionally, a primer layer such as a solvent-based or a water-based polymer may be applied to promote adhesion or to smooth surface roughness before the finish coat(s) are deposited on the golf ball. In general, a cured polyurethane top coat is most widely used as a protective coating material.
One problem encountered during golf ball coating is that each coat typically needs to be applied to the golf ball surface in a separate operation after the final molding of the golf ball cover about the core. Each of these steps is time consuming as once each coating is applied to the ball surface, there is a need to allow that coat to cure for a period of time before the next coat is applied. Also, as each of the often successive coats are applied to the golf ball, the definition of the curves on the molded golf ball are smoothed and lose their sharpness due to build-up of the coating composition on the ball""s outer surface, which also increases the outer diameter of the ball.
Typical paints used to coat golf balls, including urethane golf balls, comprise two component polyurethane coatings, which have good impact resistance. One of the problems associated with conventional two component polyurethane coatings is that they dry slowly.
Because of the slow drying nature of conventional polyurethane coatings, the golf ball painting process requires many steps. In the conventional process for clear-coating a golf ball, the surface-prepared balls are first mechanically loaded onto a stamping machine that prints a logo or stamp on the balls. The balls are then continuously loaded onto spindles that carry the balls and travel along with a moving chain to pass by spray guns that apply a clear polyurethane top-coating to the balls. The chain then moves wet, painted balls through a heated oven to pre-cure the coating. When they reach the end of the oven, the painted balls are usually still not dry, and have to be unloaded from spindles on the moving chain onto holding trays. The holding trays with the balls are then placed into another heated oven to bake at 105xc2x0 F. to 108xc2x0 F. for as long as 16 hours or in some cases even longer in order to completely cure the coating before further processing or handling. Due to the slow-drying nature of a conventional clear coat polyurethane system, all these steps, especially the 16 hour baking process, are usually necessary.
The conventional painting process has many drawbacks. First, loading wet balls from spindles on a moving chain onto holding trays, even if done by robotic handling, often results in damage or destruction of the surface of the balls.
Secondly, there is a substantial labor cost to unload cured balls from the trays into collecting hoppers for further processing. Thirdly, oven baking for 16 hours is time-consuming and consumes a substantial amount of energy. The ovens are large and require a large amount of floor space, which is also costly. The number of steps reduces productivity substantially.
In addition, an inevitable, substantial problem is that unloading wet balls off spindles onto loading trays often leaves balls with scratches or pin marks because the balls with wet paint have to be touched by another device. These scratches or marks are major causes of quality control rejection for surface defects.
For the foregoing reasons, there is a need for an improved process that will reduce the time for drying of the paint during the necessary steps. Further, there exists a need for an apparatus that will allow for a minimum of contact damage to the ball as it is supported on the apparatus.
One embodiment of the present invention provides for a process for heating a golf ball cover from about 90xc2x0 F. to about 150xc2x0 F. for 1 to 3 hours in a heated enclosure prior to applying a coat of primer or paint to the ball. This is done to accelerate the evaporation of paint solvents, immediately after the paint is applied. The painted balls are subsequently dried in a heated enclosure at about 105xc2x0 F. to 108xc2x0 F. All additional coats of primer or paint are applied in a similar fashion, wherein the balls are painted while still in the heated state and not cooled down.
An object of the invention is to reduce the flow of paint and the resulting blemish formed during the drying process. By reducing the contact area between the freshly painted ball and the drying tray holding them, the blemish is further minimized. This is accomplished by supporting the ball on a plurality of finely pointed conical pins during the drying process.
Another object of the invention is to provide a ventilated holding tray which in addition to holding the golf balls with a minimum of contact between ball and tray, the tray will allow for a thorough flow of heat about the ball for a quick and uniform heating of the ball.
Still another object in reducing blemishes to the golf ball, is suspending the freshly painted golf ball on conical pins set at right angles to the ball, thereby reducing physical contact between the tray and the freshly painted golf ball.
A further object of the invention is to provide a tray with replaceable ball supports or inserts. The inserts will generally be made from injection molded plastic and will be friction-fitted to the tray, and if damaged can be easily and inexpensively replaced. The pins being, recessed into the inserts, provides a considerable margin of safety when the tray is manually handled.


A portable lift chair has a lightweight frame with a pair of cross members extending from opposing sides thereof from front to back in a substantially X-shaped configuration, with the cross members pivotally secured to one another and to the front portion of the frame by a pivoting linkage, a seat base, a pivotable bracket connecting the front portion of the seat base to the frame, a weight adjustable pressurized cylinder providing an upward bias to the rear portion of the seat base, a removable back rest, and a guide track with an actuator for moving the weight adjustment bracket from one anchor point to another as desired to achieve a predetermined pressure for the seat.

1. Field of the Invention
The present invention relates generally to chairs and, more specifically, to a portable lift chair comprising an extendable collapsible lightweight frame with one or more wheels fastened to the rear of the frame providing means for porting the chair to a desired location.
The seat portion is pivotally hinged toward the front of the frame with at least one hydraulic or pneumatic device applying a force toward the rear of the seat so that in the non-operative position the seat member has a positive slope providing a user with a controlled decent to a seated position and a lifting force while standing from said chair. The hydraulic or pneumatic device is connected to the front of the chair frame through a pivotal bracket that aids in folding the chair to its compact state. And is connected to a bracket on the backside of the seat. Additionally, the seat may be detachable so that other types of seat may be inserted for other purposes, such as having a seat with an aperture passing therethrough for use of a bed pan or chamber pot.
The present invention provides that the backside bracket may incorporate a plurality of attachment points providing a user selectable force during pivotal movement of the seat. The aforementioned attachment points may include a fastener and a series of spaced apart apertures with the fastener inserted through a desired aperture or the hydraulic/pneumatic device may incorporate selectable apparatus for designating a desired operative force.
Furthermore, the present invention also provides arm rests on each side of the seat to aid the user during the task of sitting and standing, and it is envisioned that the arm rests may have in whole or in part some padding thereover.
2. Description of the Prior Art
There are other chairs devices designed for lifting. Typical of these is U.S. Pat. No. 2,442,303 issued to Mayfield on May 25, 1948.
Another patent was issued to Paulson on Mar. 3, 1964 as U.S. Pat. No. 3,123,400. Yet another U.S. Pat. No. 4,884,841 was issued to Holley on Dec. 5, 1989 and still yet another was issued on Nov. 10, 1992 to DeWeese as U.S. Pat. No. 5,161,812.
Another patent was issued to Carter on Jan. 5, 1993 as U.S. Pat. No. 5,176,355. Yet another U.S. Pat. No. 5,346,280 was issued to Norman A. Deumite on Sep. 13, 1994. Another was issued to Smith on May 9, 1995 as U.S. Pat. No. Des. 356,203 and still yet another was issued on May 6, 1997 to Logan, Jr. as U.S. Pat. No. 5,626,389.
Another was published to Vaughan on Feb. 12, 2004 as U.S. Patent Application No. 2004/0026977 and still yet another was issued on Feb. 21, 2006 to Bressler et al. as U.S. Pat. No. 7,000,998.
A chair of the nature described comprising a leg frame, a cross rung between the legs thereof, a shackle link pivotally secured adjacent one end of said cross rung a vertically disposed back member pivotally mounted on the other end of said shackle link a seat pivotally secured at each end to said back and said leg frame respectively and means pivotally secured to said cross rung and said seat at each end thereof for urging the said seat arcuately upward and the said back vertically upward.
An invalid's chair including a wheeled chassis, a turntable mounted for rotation on said wheeled chassis, a chair comprising a seat and a back, a hydraulic jack between the back and the turntable, said hydraulic jack including a cylinder fixedly secured at its lower end to the turntable, a piston in said cylinder, a pump for pumping fluid within the cylinder to raise the piston, a piston rod secured to the piston, means between the piston rod and the chair back to permit limited sidewise tipping of the chair, said chair back being provided with spaced apart front and rear panels and narrow side panels joining the front and rear panels and terminating short of the lower end of the cylinder, stabilizing mechanism between the chair seat and the turntable to resist said tipping of the chair, and means conveniently located with respect to a person seated in the chair for controlling the up and down movement of the piston and the chair.
A device for assisting invalids into and from a seated position, e.g., over a toilet. The device has a frame and a seat hingedly attached at the front thereof to a support member which is vertically slidable on the frame. A stop is associated with the hinge to prevent the seat from pivoting below the horizontal attitude. An extendable arm is connected at one end to the frame and, at the other end thereof, to the seat between the hinge and the center of gravity. Control means selectively activates extension of the arm to initially vertically elevate the seat in the horizontal attitude, and then to pivot the seat upwardly to assist an individual seated thereon into a standing position; or activates retraction of the arm to initially pivot the seat into a horizontal attitude, and then to vertically lower the seat in a horizontal attitude to assist an individual into a seated position. The extendable arm may be electrically, pneumatically or hydraulically operated, and the device may be portable and adapted to be positioned over a conventional toilet.
The invention is an improved wheel chair in which the seat may be raised or lowered by a hand powered hydraulic ram mechanical means to levels that match the surface of the chair or bed to which the patient is being transferred. A commode function is also provided. The chair comprises a base having swivel casters and fixed wheels, an upper unit having a seat and backrest and a hydraulic pump, and a seat raising mechanism consisting of four pairs of interconnected levers connected by two cross bars in such a way that when the bars are pushed apart by a hydraulic ram, the separating motion is amplified to give the desired range of chair seat travel height.
The housing of an air valve, the valve controlling the height of a vehicle seat supported on a suspension having an air spring, is pivotally connected to one of the frames of the suspension supporting the seat. A manual control lever connected to the housing is operative to change the angle of inclination of the housing for selecting a desired height of the seat. A control arm of the valve is connected by a linkage to the other frame of the suspension. These connections to the air valve control the valve for selecting a desired height and for automatically restoring the height for different weights on the seat.
A chair with an automatic standing aid and a wheelchair which incorporates these features are provided. These chairs can raise or lower an occupant automatically while compensating for the change in the center of gravity with stabilizers. The stabilizers allow the chairs to be lightweight, small in size, and independent of heavy supporting bases. The chairs can be used to replace those on existing wheelchair power bases.
The ornamental design for an invalid lifter for toilets, as shown and described.
A lift seat includes a seating surface, for example, a toilet seat, mounted on a supporting frame by a four-bar linkage. The four-bar linkage includes a lower link fixed to the frame and an upper link fixed to the seat. An armrest is attached to a front link of the four-bar linkage for pivoting therewith against the bias of the spring which loads the four-bar linkage as the seat is lowered from a raised position in a seating position. Energy stored in the spring is then available to lift the person from the seating position back to the raised position. A damper is connected to the four-bar linkage to prevent abrupt movement of the seat as the four-bar mechanism collapses and expands, while a gas spring is provided to initially resist movement of the four-bar linkage from either the expanded or the collapsed condition unless the armrest is initially rotated.
A lifting device suitable for assisting the elderly, invalids or those recuperating from surgery to rise from a seated position to a standing position includes a rigid base (2) connected by a hinge (4) to a rigid seat (3). A closed bag (5) is interposed between and is secured to the base (2) and seat (3). By inflating the bag (5) the seat may be raised from a substantially horizontal position to a raised position to assist a seated person to rise to a standing position. A cushion (17) may be provided on the seat (3). The device may be used in reverse to assist a user in moving from a standing position to a seated position. A suitable inflation pump and control gear is provided to admit air to and remove air from the bag (5) via a tube (12).
A chair is operable between a seating position and a rise-assist position. The chair comprises a base; first and second legs; a seat pivotally connected to the first and second legs; and a back pivotally connected to the seat. The chair further comprises first and second members pivotally connected at a first end to the legs, and pivotally connected at a second end to the back. At least portions of the legs, first and second members, back and seat form first and second four-bar linkages, respectively. At least one biasing member is pivotally connected at a first end to one of the base and at least one of the legs and pivotally connected at a second end to at least one of the four-bar linkages. The at least one biasing member operates to assist movement of the chair between the seating position and the rise-assist position.
While these chairs may be suitable for the purposes for which they were designed, they would not be as suitable for the purposes of the present invention, as hereinafter described.


Described herein is a nutritional supplement to be incorporated into the diet of a type 2 diabetic or an individual having lipodystrophy. The supplement provides active food-grade ingredients to improve the management of blood glucose and blood lipid levels. The supplement additionally aids in the improvement of the effects of platelet aggregation. The supplement should be taken daily during or at the end of the two largest meals, where most of the fat and cholesterol are likely to be ingested.

Type 2 diabetes mellitus affects 100 to 120 million people globally and 16 million nationally, about half of whom are unaware that they have the condition. Diabetes is a metabolic disorder defined by elevated blood glucose concentrations due to insulin dysfunction. The concomitant effects of the disease are defective insulin secretions, relative (rather than absolute) insulin deficiency, insulin resistance, and abnormal blood lipid levels. The specific etiologies of the type 2 diabetes are unknown, but autoimmune destruction of xcex2-cells does not occur as seen in type 1 diabetes. Insulin levels may be normal or elevated, but the insulin itself is defective and unable to control blood glucose concentrations. The risk of developing microvascular complications from diabetes is related to hyperglycemia, and this increases with slight increases in hemoglobin Alc (Hgb Alc) and with prolonged exposure to high glucose concentrations. Hyperglycemia is also implicated in causing macrovascular complications such as coronary artery disease, peripheral vascular disease, and stroke, but the relationship is less clear.
Postprandial hyperglycemia contributes substantially to overall glycemic control, and its role on the pathogenesis of the long-term microvascular and macrovascular complications of diabetes has generally been under-appreciated. Once diabetes is diagnosed, there is a progressive worsening of hyperglycemia in both the fasting and postprandial state. Since neither the oral agents (sulfonylureas) nor insulin can create the brief rise in insulin that normally accompanies a meal to mitigate this problem, the first line of therapy in type 2 diabetes is nutritional management, which as been recently referred to as xe2x80x9cmedical nutrition therapyxe2x80x9d (MNT) (American Diabetes Association, Diabetes Care, 23(1):543-546 (2000)). This is integral to total diabetes management and is most effective if it involves an individualized plan devised by a registered dietitian or a nurse-dietitian team, and includes self-management training. Usually, the goals of MNT include maintenance of near-normal blood glucose levels by balancing food and blood glucose regulation medications (if prescribed), achievement of optimal serum lipid levels and blood pressure, provision of adequate calories for maintaining ideal weight, prevention and treatment of complications, and improvement in overall health.
Metabolic disorders such as hypertriglyceridemia, hypercholesterolemia and hyperglycemia are prevalent among HIV-infected individuals. Morphological changes accompany these metabolic disorders and have been referred to as lipodystrophy syndrome, although it is thought that there are two distinct syndromes. Affected individuals show fat redistribution, such as fat loss (e.g., in face) or fat accumulation (e.g., in abdominal area). These metabolic disorders may be attributed to high active antiretroviral therapy (HAART). Left untreated, the downstream adverse consequences of lipodystrophy include atherogenesis and atherosclerotic vascular disease. Thus, there is a need to provide nutritional supplementation to manage these metabolic disorders.
The invention relates to a nutritional supplement containing bioactive food-grade ingredients, which can help with the management of type 2 diabetes mellitus and metabolic disorders associated with lipodystrophy.
The nutritional supplement comprises a low glycemic index carbohydrate source, a source of protein, a source of fat, a source of sterol and/or stanol, a source of chromium, a source of salicylic acid, and a source of ginseng. In preferred embodiments, the nutritional supplement comprises, for a 45 kcal serving, from about 1 to about 25 grams carbohydrate (preferably as a combination of low glycemic index carbohydrates such as konjac, fructose, barley flakes, psyllium), from about 1 to about 10 grams protein, from about 1 to about 10 grams fat, from about 0.5 to about 4 grams plant sterol, from about 1 to about 2000 micrograms chromium (e.g., as chromium picolinate), from about 1 to about 325 milligrams salicylic acid (e.g., from a natural source like willow bark), and from about 1 mg to about 5 grams ginseng. The ranges used herein are based upon a single serving, where two servings are needed per day. Vitamins and minerals in amounts recommended daily to supplement the diet can also be optionally added.
The nutritional supplement can be made in a variety of forms, such as pharmaceutical compositions (e.g., tablet, powder, suspension, liquid, capsule, gel), nutritional beverages, puddings, confections (i.e., candy), ice cream, frozen confections and novelties, or non-baked, extruded food products such as bars. The preferred forms of the nutritional supplement are as a nutritional beverage and as a bar, such as a non-baked, extruded snack bar. In another embodiment, the ingredients of the nutritional supplement can be administered separately, such as by incorporating certain components (e.g., bitter tasting ones) into a capsule or tablet and the remaining ingredients are provided as a powder or nutritional bar. The supplement can be formulated for single or multiple daily administration, preferably twice daily, during or following the two meals in which the greatest amount of carbohydrate, cholesterol and fats are to be consumed.
The invention flier pertains to therapeutic methods for managing conditions associated with type 2 diabetes. In another embodiment, the nutritional supplement can be administered to HIV-infected individuals to prevent and/or treat metabolic disorders associated with lipodystrophy, such as insulin resistance, atherogenesis and cardivascular disease. The nutritional supplement can be administered to an individual to aid in the management of blood glucose levels and/or blood glucose levels. The risk of developing microvascular and macrovascular complications, such as atherogenesis and aterosclerotic vascular disease, associated with type 2 diabetes and lipodystrophy are lessened.
The invention pertains to a nutritional supplement that provides nutritional support for people with type 2 diabetes mellitus. The invention further pertains to methods for effectively managing three aspects of type 2 diabetes [i.e., blood sugar (e.g., lowers postprandial and fasting blood glucose), blood lipids (e.g., total cholesterol fand LDL-cholesterol), and platelet aggregation] for a patient in need thereof. In another embodiment, the nutritional supplement can be administered to HIV-infected individuals to prevent and/or treat the metabolic changes associated with lipodystrophy, such as insulin resistance, atherogenesis and cardiovascular disease. Use of the nutritional supplement is not intended to take the place of the prescribed diet, exercise, and medication regimen, recommended for individuals having type 2 diabetes or lipodystrophy; rather it works as an adjunctive therapy in those patients who are compliant with their healthcare providers""suggestions.
The nutritional supplement can be made in a variety of forms such as a pharmaceutical composition (e.g., tablet, powder, suspension, liquid, capsule, gel), nutritional beverages, puddings, confections (i.e., candy), ice cream, frozen confections and novelties, or non-baked, extruded food products such as bars, to assist patients with the management of diabetes.
The nutritional supplement of the invention, suitable for individuals with type 2 diabetes mellitus or lipodystrophy, comprises a low glycermic index carbohydrate sources, a source of protein, a source of fat, a source of sterol and/or stanol, a source of chromium, a source of salicylic acid, and a source of ginseng. In particular, the nutritional supplement includes the following components: total carbohydrates, from about 1 to about 25 grams; protein, from about 1 to about 10 grams; fat, from about 1 to about 10 grams; plant sterol, from about 0.5 to about 4 grams; chromium, from about 1 to about 2,000 micrograms; willow bark or aspirin, from about 1 to about 325 milligrams; salicylic acid and ginseng, from about 1 mg to about 5 grams.
In a preferred embodiment, the nutritional supplement should approximately be comprised of (with about 20 to about 40 grams being preferred and 40 g being most preferred) about 10 g to about 15 g powder in 8 oz. water, from about 2 to about 10 grams of total carbohydrate, from about 1 to about 5 grams protein, from about 1 to about 5 grams fat, from about 0.5 to about 2 grams plant sterol, from about 50 to about 1000 micrograms chromium, from about 20 to about 80 milligrams salicylic acid source, and from about 100 to 200 milligrams ginseng.
In another embodiment, additional ingredients can be incorporated into the nutritional supplement for patients with lipodystrophy. In addition to the ingredients provided above, the nutritional supplement further comprises from about 1 to about 80 grams glutamine (with about 20 to about 40 grams being preferred; and 40 g being most preferred), from about 100 mg to about 20 grams N-acetyl cysteine (NAC; with about 1 to about 2 grams being preferred; and 1 gram being most preferred), from about 0.5 to about 25 grams of whey protein and from about 1 to about 2xc3x97RDI of antioxidants.
The nutritional supplement can be formulated into a snack to be taken as part of the diet or it can be formulated as a meal replacement. For a snack, the nutritional supplement should provide from about 1 to about 250 kcal per serving; from about 20 to about 100 kcal being preferred; and from about 45 to about 50 kcal being most preferred. As a meal replacement, the nutritional supplement will provide from about 300 kcal to about 350 kcal per serving.
For the purposes of this invention, a preferred nutritional supplement comprises the components described above as a single serving (serving unit), whereby one or a plurality (preferably, two) of these supplement(s) is(are) consumed daily. Preferably, two servings (e.g., 8 oz. water with 10-15 g powder) should make up 90 kcal and 1 bread exchange. In a preferred embodiment, each serving (serving size) contains 45 kcal and is comprised of macronutrient percentages in concert with the dietary recommendations of the American Diabetic Association. Other serving sizes are contemplated in the invention. The total amount of each ingredient should be appropriately adjusted. The supplement is most effective if taken during or after the midday and the evening meal, because after these, postprandial blood glucose levels are highest. The product contains active food compounds that help minimize hyperglycemia and hyperlipidemia. These conditions have been identified by the leaders in the field of diabetes as the major health risks associated with the condition. Fortunately, they can be effectively managed through food.
The use levels for ingredients incorporated into the nutritional supplement are illustrated in the chart below in relation to an about 10 to about 15g size serving of powder in 8 oz. water, and represents broadest, preferred and most preferred embodiments (all ingredients are qualified with the term xe2x80x9caboutxe2x80x9d).
The ingredients that make up the nutritional supplement are further described in detail below and with regard to their relative role each contributes to therapeutic advantages of the invention.
Carbohydrates
Too much glucose released into the blood at once raises insulin and serotonin levels, which could decrease appetite or the desire for carbohydrate-rich foods at the next meal. Use of low-glycemic-index foods seems to be associated with better glucose control. Simple sugars usually cause a greater rise in blood glucose than starchy foods (Anderson, J. S. et al., Modern Nutrition in Health and Disease, pp.1259-86 (1994)). Bread and potatoes raise blood glucose more than beans. Other non-carbohydrate containing food ingested at the same time as carbohydrates (e.g., fat, fiber, protein) reduce postprandial blood glucose and insulin levels. The glycemic index is the area under the curve (AUC) in a plot of blood sugar measurements versus time, wherein the blood sugar measurements are taken over a period of time after a carbohydrate meal. Thus, the glycemic index of a carbohydrate is a relative measure of the rate and amount of glucose released into the blood from a carbohydrate.
In a preferred embodiment, the nutritional supplement contains one or more carbohydrates having a low glycemic index (e.g., from less than about 70). In a preferred embodiment the carbohydrate has a low glycemic index (e.g., konjac mannan, fructose, barley flakes (e.g., hulless)) and the carbohydrate provides a source of fiber (e.g., whey bran, cellulose, oat bran, guar, pectin, psyllium) comprising about 2 to about 10 g carbohydrate per serving, of which two are recommended per day.
Patients with type 2 diabetes consuming very high fiber diets (50 g versus the recommended 24 g) had significantly lower mean daily postprandial plasma glucose concentrations and mean daily urinary glucose excretions (Chandalia, M., N. Engl J. Med., (342): 1392-1398 (2000)). The overall decrease in plasma glucose was similar to that typically achieved with an oral hypoglycemic drug (Rendell, M., N. Engl. J. Med., (342): (2000)). Blood lipids (total cholesterol, triglycerides, and very-low density lipoprotein cholesterol concentrations) were also significantly lower than in the lower fiber group.
Psyllium husk fiber is a viscous, mostly water-soluble fiber prepared from blonde psyllium seed (Plantago ovata). Strong support exists from a meta-analysis showing that about 10 g of psyllium per day significantly lowers both total cholesterol (4%; p less than 0.0001) and low density lipoprotein (LDL) cholesterol (7%; p less than 0.0001) (Anderson J. W. et al., Am. J. Clin. Nutr., (71): 472-9 (2000)). This prompted the FDA to grant a xe2x80x9chealth claimxe2x80x9d for the use of psyllium to reduce the risk of cardiovascular disease. Later, Anderson and colleagues observed similar effects of psyllium on the blood lipid levels of patients with primary hypercholesterolemia after long-term use (26 weeks) (Anderson, J. W. et al., Am. J. Clin. Nutr., (71): 1433-8 (2000)). Psyllium may offer an effective adjunct to diet therapy and provide an alternative to drugs in patients with mild hypercholesterolemia.
The data regarding the use of psyllium as a means of lowering blood glucose in type 2 diabetes are less convincing (Anderson, J. W. et al., Am. J. Clin. Nutr., (70): 466-73 (1999)). Fifty-six patients with type 2 diabetes and hypercholesterolemia were randomly assigned to consume 10.2 g of psyllium for 8 weeks or to a cellulose placebo along with a traditional diet for diabetes. The fibers were consumed 20 to 30 minutes before the morning and evening meals. Significant improvements were observed in serum lipids (both total cholesterol, p less than 0.05, and LDL-cholesterol, p less than 0.07) and these changes were similar to other studies (Anderson, J. W. et al., Am. J. Clin. Nutr., 71: 1433-8 (2000); Anderson, J. W. et al., Am. J. Clin. Nutr., (71): 472-9 (2000)). The all day glucose and postlunch glucose concentrations were 11% (p less than 0.05) and 19.2% (p less than 0.01) lower, respectively in the psyllium group. Thus, it appears that an efficacious dose of psyllium to lower blood lipids is the same as for lowering blood glucose.
In the nutritional supplements of the invention, a serving should provide from about 0.5 to about 5 g psyllium, with about 1 g of psyllium per serving (8 oz. water and 10-15 g dry mix) being particularly preferred. The daily allowance of psyllium should be from about 0.5 g to about 11 grams. The term xe2x80x9cdaily allowancexe2x80x9d as defined herein should be understood as the amount of an ingredient, such as psyllium, provided to an individual in a single daily serving or as multiple daily servings, e.g., two daily servings. The addition of more psyllium beyond the ranges described herein will adversely affect the taste of the nutritional supplement and require the addition of calorie-containing nutrients to compensate. Further, higher use levels of psyllium also cause the liquid to gel after a few minutes, making it difficult to drink.
Fructose is a preferred carbohydrate for sweetening the nutritional supplement. It is sweeter than ordinary table sugar (sucrose), derived from beet or cane sugars, and has a low glycemic index (GI=32). Taken as part of a meal, fructose produces a smaller incremental rise in plasma glucose level does sucrose, glucose, potato starch, or wheat starch. From about 0.5 g to about 11 g fructose can be used; with about 2 g fructose per serving being perferred.
In preferred embodiments, it is desirable to incorporate barley (e.g., barley flakes) into the nutritional supplement as a carbohydrate and fiber source. Of all the grains, certain forms of barley have some of the lowest glycemic indexes. Pearled barley (GI=36) and cracked barley (GI=72) have lower glycemic indexes than sweet corn (GI=78), rolled barley (GI=94), and instant white rice (GI=128). Further, it is desirable to use barley with its bran still on it (referred to as xe2x80x9chulless barleyxe2x80x9d), so that the naturally occurring fiber remains. From about 0.5 g to about 11 g of barley per serving based upon a 10-15 g serving can be used; with about 1 g per serving being particularly preferred. Thus, it provides a low glycemic source of carbohydrate and a source of fiber (14%), both of which are advantageous in maintaining good glucose and weight control.
Konjac flour, which comes from a perennial tuber called Amorphophallus konjac, is a dietary fiber (90%) and a polysaccharide with a very high molecular weight. In addition, this glucomannan hydrocolloid has the ability to increase the viscosity of the intestinal fluid (digesta), thereby limiting the transport of glucose into the bloodstream (Vuksan, V. et al., submitted for publications, (2000)). Konjac mannan also has a low glycemic index, promoting weight loss by increasing satiety in obese and non-obese patients with type 2 diabetes (Doi, K. et al., Progress in Obesity Research, ch. 80: 507-14, (1990)). In preferred embodiments, the nutritional supplement should provide from about 0.5 g to about 11 g konjac per serving; with about 1 g of konjac mannan being preferred.
Protein
Sources of protein can be any suitable protein utilized in nutritional formulations and can include all high biological value proteins such as whey protein, whey protein concentrate, whey powder, egg, soy protein, soy protein isolate, caseinate (e.g., sodium caseinate, sodium calcium caseinate, calcium caseinate, potassium caseinate), animal and vegetable protein and mixtures thereof. When choosing a protein source, the biological value of the protein should be considered first, with the highest biological values being found in caseinate, whey, lactalbumin, soy, delactosed milk solids, egg albumin and whole egg proteins These proteins have high biological value; that is, they have a high proportion of the essential amino acids.
In a preferred embodiment, the protein is whey protein concentrate or other protein with a high biological value (e.g., casein, soy, milk, egg) comprising from about 1 to about 5 grams protein per serving. The preferred amount of protein is approximately 2 grams per serving.
In the case of lipodystrophy, the individual will need additional protein than required for type II diabetics and as such all high biological value proteins can be used in the formulation in amounts of from about 0.5 grams to about 25 grams protein, with from about 0.5 grams to about 5 grams protein being preferred, and about 1.5 grams being most preferred. Preferably the protein source is whey protein.
Chromium
Chromium in an essential trace element that participates in carbohydrate and lipid metabolism (Cataldo, C. B. et al., Nutrition and Diet Therapy, (N.Y.: West Publishing Company), pp. 205-6 (1995)). It is widespread in the diet and found in unrefined foods like liver, whole grains, nuts and cheeses. However, as the intake of refined foods increases, there is an increased chance of developing a deficiency. The Estimated Safe and Adequate Nutritional Intake for chromium is 50 to 200xcexcg per day. Most people are unable to achieve the minimum amount of chromium intake. Several studies have demonstrated that men take abut 33xc2x13 xcexcg and women take about 25xc2x11 xcexcg per day (Anderson, R. A. Am. Coll. Nutr., (17): 548-55 (1998)).
One form, chromium picolinate, has been studied extensively for its effect on blood glucose management and weight loss. Chromium as picolinate appears to have a beneficial effect on fasting plasma glucose concentrations at doses between 200 and 1,000 xcexcg daily. Most studies have shown the greatest benefit from at least 400 xcexcg or more, and it seems to work whether it is given once or twice a day (Anderson, R. A., Am. Coll. Nutr., (17): 548-55 (1998)). The proposed mechanism of action is that chromium increases the ability of insulin to bind to cells. It has been shown to maintain lean body mass during weight loss (Kaats, G. R. et al., Curr. Ther. Res., 51: 261-74 (1992)). Chromium supplementation is not efficacious until it has been used for six weeks, and with long term use it continues to be effective.
Each serving of the nutritional supplement of the invention should provide the preferred range from about 50 to 1000 xcexcg chromium per serving. The most preferred amount of chromium for the nutritional supplement is approximately 100 xcexcg of chromium picolinate per serving, with two daily servings being preferred. Alternatively, chromium chloride may be used, but the picolinate form is preferred due to its beneficial effects on fasting plasma glucose (FPG) concentrations. Since the nutritional supplement is intended to supplement the diet of an individual, the daily allowance of chromium provided by the invention is intended to be less than the efficacious amount. The difference in the amount of chromium will likely be made up from the diet (e.g., nutritional supplements, foods, pharmaceutical compositions), which may comprise an additional 200 xcexcg per day.
Ginseng
Ginseng (e.g., Panax ginseng) is a slow-growing perennial herb native to mountainous-forested areas in China, Korea, and parts of Russia. Its early therapeutic uses in Asian medicine included revitalization of energy, reduction of susceptibility to illness, and promotion of longevity. The active compounds are ginsenosides, and most commercially available products are standardized to a known concentration. More recently, ginseng was officially recognized by the German Pharmacopeia and approved in the Commission E monographs for use in geriatric remedies and tonics for invigoration and fortification.
Ginseng has also been shown to influence blood glucose concentrations (Sotaniemi, E. A. et al., Diab. Care, 18: 1373-75 (1995); Vuksan, V. et al., Arch. Intern. Med., 160: 1009-13 (2000)). The Finns evaluated the effect of two doses of ginseng (100 mg and 200 mg) on glucose balance, serum lipids, and physical performance (Sotaniemi, E. A. et al., Diab. Care, 18: 1373-75 (1995)). Thirty-six newly diagnosed, non-insulin-dependent subjects with diabetes were randomized to one of the treatments or a placebo for 8 weeks. Both groups receiving the ginseng experienced a significant reduction in fasting plasma glucose (p less than 0.05). For the higher ginseng dose, but not the lower one, Hgb Alc was significantly reduced (p less than 0.05). In the two ginseng-treated groups, energy levels improved but serum lipids did not change.
In a more recent study, ginseng was administered to 9 subjects with type 2 diabetes in a large dose (3 g of Panax quinquefolius L) before or together with a glucose-containing solution, used for a glucose tolerance test (25 g oral glucose load) (Vuksan, V. et al., Arch. Intern. Med., 160: 1009-13 (2000)). Compared to a placebo, ginseng significantly reduced the area under the curve (AUC) of glucose (p less than 0.008 over 120 minutes). The AUC was significantly lower (p less than 0.05) in the ginseng groups compared whether the ginseng was taken before (19xc2x122%) or during (22xc2x111%) the glucose administration.
The mechanism by which ginseng lowers blood glucose concentrations is unknown, although several have been proposed (Vuksan, V. et al., Arch. Intern. Med., 160: 1009-13 (2000)). It has been proposed that ginseng slows the digestion of food, thereby decreasing the rate of carbohydrate absorption in the portal hepatic circulation. Ginseng has been shown to increase glucose transporter-2 protein in the liver of normal and hyperglycemic mice; glucose uptake also increases via the same transporter in sheep erythrocytes. Finally, ginseng may modulate insulin secretion. The action of the transporter-2 protein and insulin secretion appear to be modulated by nitric oxide, which may be stimulated by ginseng.
The nutritional supplement should contain from about 100 to 200 mg ginseng per serving in a concentrated form; less concentrated ginseng should be provided in amounts of from about 1 mg to about 5 g. Preferably, the nutritional supplement should provide approximately 100 mg of ginseng per serving. The amount is based on the treatment used in the Finnish study, whose conditions approximated usual care (i.e., showing the effect on FPG and Hgb Alc over a long period of time).
Sterols and Stanols
Phytosterols are naturally occurring constituents of plants. The most abundant is xcex2-sitosterol, although others include campesterol and stigmasterol. Numerous reports exist in the medical literature describing the cholesterol-lowering effects of plant sterols and stanols (Jones, P. J. H. et al., Metabolism, 47: 751-6 (1998); Jones, P. J. H. et al., Can. J. Physiol. Pharmacol., 75: 217-27 (1997); Halikainen, M. A. et al., J. Nutr., 130: 767-76 (2000); Gylling, H. et al., Circulation, 96: 4226-31 (1997); Halikainen, M. A. et al., Am. J. Clin. Nutr., 63: 403-10 (2000)). Although these compounds are normally consumed from plants, a typical diet only contains about 200 to 400 mg/day (Jones, P. J. H. et al., Can. J. Physiol. Pharmacol., 75: 217-27 (1997)). A review of the literature supports the use of 1.6 to 3.0 g per day to achieve a significant reduction in total-and LDL-cholesterol levels. With these doses, total cholesterol has been shown to decrease 0.5 to 26% and LDL-cholesterol by 2 to 33%. The HDL-cholesterol is not affected by sterol ingestion.
A recent report showed that 1.6 g of a stanol ester for 4 weeks was sufficient to significantly decrease total cholesterol (6.8%; p less than 0.001) and LDL-cholesterol (5.6%; p 0.05) in hypercholesterolemic men and women (Halikainen, M. A. et al., J. Nutr., 130: 767-76 (2000)). Increasing the dose to 2.4 or 3.2 g per day did not provide additional clinical benefit. When phytosterol levels are increased in the blood, nutritional cholesterol is inefficiently absorbed and cholesterol synthesis reduced. Both of these actions cause serum cholesterol levels to decrease (Jones, P. J. H. et al., Can. J. Physiol. Pharmacol., 75: 217-27 (1997)).
The nutritional supplement should provide from about 0.5 to about 2 grams sterol, stanol or derivative of these, preferably a plant sterol or stanol. The sterol or stanol can be provided in the form of an ester and/or attached to a lecithin micelle. The supplement preferably provides 0.8 g of a plant (e.g., from soy, tall, with soy being preferred) sterol as a lecithin micelle in each serving so that use of the product twice a day will give the desired effect on blood lipids. It is recommended that each serving be taken with or at the completion of the two largest (e.g., lunch and dinner) meals so that the sterol can exert its maximum effect on the cholesterol-containing food. It has been reported that there is no therapeutic difference between plant stanol esters and plant sterol esters (Brief Critical Review, Nutr.Rev., 56: 245-252 (1998)), so a plant stanol ester may alternatively be used.
In a particularly preferred embodiment, the sterol or stanol is incorporated into a micelle. The micelle can be produced using lecithin or other emulsifying agent. Known methods for producing lecithin micelles can be used. This should create at least the same cholesterol-lowering effect, if not more, because lecithin itself may reduce cholesterol levels (Knuiman, K. T. et al., Am. J. Clin. Nutr., 49: 266-8 (1989); Polichetti et al., Br. J. Nutr., 75: 471-8 (1996)). Nonetheless, sterol as a lecithin micelle should at least be as good as the ester form in a high-fat medium (e.g., margarine), the typical commercially available form, because a sterol-lecithin micelle has already been shown to be effective at reducing cholesterol absorption, thus theoretically lowering serum lipid levels in hypercholesterolemic patients (Ostlund, R. E. et al., Am. J. Cl in. Nutr., 70: 826-31 (1999) and Ostlund, U.S. Pat. No. 5,932,562).
Other Cholesterol Lowering Agents
In addition to or alternative to the ingredients described above for cholesterol loweirng, other cholesterol-lowering agents may be used such as red yeast rice (about 1 to 20 grams; with about 1 to about 5 grams being preferred; and about 2.4 g/day of a 0.4% preparation being most preferred), oat or yeast xcex2-glucan (about 1 to 20 grams; with about 1 to about 5 grams being preferred; and about 3 g/day being most preferred), or increasing the amount of psyllium (about 1 to 100 grams; with about 10 to about 50 grams being preferred; and about 10 to about 15 g/day being most preferred).
Lipid Source
Nutritional fish oil can be added to the nutritional supplement because it is a potent means of reducing serum triglycerides and is an anti-platelet aggregator (Gorlin, R., Arch. Intern. Med., 148: 2043-8 (1988); Drevon, C. A., Nutr. Rev., 50: 38-45(1992); Norum, K. R., Nutr. Rev., 50: 30-37 (1992); Simopoulos, A. P., Am. J. Clin. Nutr., 54: 438-63 (1991)). Patients with type 2 diabetes are often hypertriglyceridemic. Plasma triglyceride levels vary with the amount and type of fat in the diet (Norum, K. R., Nutr. Rev., 50: 30-7 (1992)). Saturated fats increase triglycerides in the plasma whereas unsaturated (mono and poly) fats do not. A low-fat diet, rich in carbohydrates, also raises triglyceride levels.
The mechanism of action for lowering triglyceride levels is unknown, but the fish oil appears to slow the production of very low density lipoproteins produced in the liver through inhibition of apoprotein B synthesis (Gorlin, R., Arch. Intern. Med., 148: 2043-8 (1988)). Hemodialyzed, hypertriglyceridemic patients consuming 2.5 to 3 g of omega-3 fatty acids experienced a 30% reduction in plasma triglycerides (Bonanome, A. et al., Am. J. Clin. Nutr., 63: 261-6 (1996)). For changes in serum triglyceride levels to occur, more than 2 to 3 g of omega-3 fatty acids need to be ingested daily (Drevon, C. A., Nutr. Rev., 50: 38-45 (1992)). Most commercial fish oil is 30% omega-3 fatty acids, so at least 6 g need to be consumed to meet this need. Continued consumption of the fish oil for years proves to be effective (Simopoulos, A. P., Am.J. Clin. Nutr., 54: 438-63(1991)).
Fish oil also prolongs bleeding time, a measurement of platelet and vessel wall interaction (Gorlin, R., Arch. Intern. Med., 148: 2043-8 (1988)). It is likely that platelet behavior is inhibited through the alteration of production of thromboxane A2, when eicosapentanoic acid competes with arachidonic acid for space on the fatty acid chain of the phospholipids residing on the cell membrane. For changes to occur, at least 3.6 g of omega-3 fatty acids are needed for at least two weeks. (Gorlin, R., Arch. Intern. Med., 148: 2043-8 (1988)). However, the combination of aspirin and fish oil increase bleeding time (an indication of less platelet aggregation) by more than the sum of the increases in bleeding time caused by aspirin or fish oil separately (Gorlin, R., Arch. Intern. Med., 148: 2043-8 (1988)).
The nutritional supplement may contain a source of fat that provides from about 10% to about 80% omega-3 fatty acids in amounts of from about 0.5 g to about 5 g per serving. Examples of suitable fats included but are not limited to fish oil (e.g., from menhaden or sardines) and non-atherogenic oils such as vegetable oil (e.g., canola, olive, soy, safflower, sunflower, corn) and combinations thereof. In an embodiment, approximately 1 g of fish oil (30% omega-3 fatty acids) can be used, with two servings recommended per day. This dose alone will not achieve the desired biological effects of lowering triglyceride levels and reducing platelet aggregation, but it is assumed that the diet will supply the remaining omega-3 fatty acids and that the addition of a natural source of aspirin (described in detail below) will assure efficacy. In another preferred embodiment, the source of fat will be provided as a combination of fish oil and a non-atherogenic oil, such as a 1:1 mixture. In the most preferred emobodiment, only a nonatherogenic fat source is used, e.g., canola oil.
Salicylic Acid
Aspirin therapy is beneficial for patients with type 2 diabetes who are at risk of developing cardiovascular disease (American Diabetes Association, Diab. Care, (23): 1772-1773 (2000); Kajubi, S. K., Arch. Intern. Med., 160: 3945 (2000)). Patients should take one children""s aspirin daily to supply 81 mg of acetylsalicylic acid. However, compliance with medications wanes as the number of drugs increase, and most people with diabetes are taking several. To overcome this phenomenon, willow bark (Salix alba) can be incorporated into the supplement of the invention, which contains a natural source of acetylsalicylic acid, the active compound known as aspirin. Thus, patients who consume the nutritional supplement twice daily will get sufficient willow bark to favorably modulate platelet function. Willow bark is officially recognized in the German Pharmacopeia and approved in the Commission E monographs for use as an analgesic.
In a preferred embodiment, the nutritional supplement can contain from about 20 to about 80 mg salicylic acid source. For example, a dose of 4 to 8 g willow bark in the form of dried bark, tincture, dry extract, etc. is equivalent to 40 to 80 mg of total salicin. The dose of willow bark should be added in amounts that supply 40 mg of the active compound, actetylsalicylic acid, per serving. Aspirin can also be used, particularly for pharmaceutical compositions.
Glutamine
Glutamnine has been shown to benefit bowel and immune function in these patients (Shabert J., Ehrlich N., The Ultimate Nutrient Glutamine, Garden city Park, N.Y.; Avery Publishing Group, 1994). In one embodiment, the nutritional supplement can contain from about 1 gram to about 80 grams of glutamine. In another embodiment, the amount of glutamine can be from about 20 grams to about 40 grams, with about 40 grams being most preferred.
Further Ingredients
The nutritional supplement can also contain other ingredients such as one or a combination of other vitamins, minerals, antioxidants, herbs (e.g., ginkgo biloba), fiber and other nutritional supplements. Selection of one or several of these ingredients is a matter of formulation design, consumer and end-user preference. The amount of these ingredients added to the nutritional supplements of this invention are readily known to the skilled artisan and guidance to such amounts can be provided by the RDA and DRI (Dietary Reference Intake) doses for children and adults. Vitamins and minerals that can be added include, but are not limited to, calcium phosphate or acetate, tribasic; potassium phosphate, dibasic; magnesium sulfate or oxide; salt (sodium chloride); potassium chloride or acetate; ascorbic acid; ferric orthophosphate; niacin amide; zinc sulfate or oxide; calcium pantothenate; copper gluconate; riboflavin; beta-carotene; pyridoxine hydrochloride; thiamin mononitrate; folic acid; biotin; chromium chloride or picolinate; potassium iodide; selenium; sodium selenate; sodium molybdate; phylloquinone; Vitamin D3; cyanocobalamin; sodium selenite; copper sulfate; Vitamin A; Vitamin E; vitamin B6 and hydrochloride thereof; Vitamin C; inositol; Vitamin B12; potassium iodide.
The amount of other additives per unit serving are a matter of design and will depend upon the total number of unit servings of the nutritional supplement daily administered to the patient. The total amount of other ingredients will also depend, in part, upon the condition of the patient. Preferably the amount of other ingredients will be a fraction or multiplier of the RDA or DRI amounts. For example, the nutritional supplement will comprise 50% RDI (Reference Daily Intake) of vitamins and minerals per unit dosage and the patient will consume two units per day.
Flavors, coloring agents, spices, nuts and the like can be incorporated into the product. Flavorings can be in the form of flavored extracts, volatile oils, chocolate flavorings (e.g., non-caffeinated cocoa or chocolate, chocolate substitutes such as carob), peanut butter flavoring, cookie crumbs, crisp rice, vanilla or any commercially available flavoring. Flavorings can be protected with mixed tocopherols. Examples of useful flavorings include but are not limited to pure anise extract, imitation banana extract, imitation cherry extract, chocolate extract, pure lemon extract, pure orange extract, pure peppermint extract, imitation pineapple extract, imitation rum extract, imitation strawberry extract, or pure vanilla extract; or volatile oils, such as balm oil, bay oil, bergamot oil, cedarwood oil, cherry oil, walnut oil, cinnamon oil, clove oil, or peppermint oil; peanut butter, chocolate flavoring, vanilla cookie crumb, butterscotch or toffee. In a preferred embodiment, the nutritional supplement contains berry or other fruit flavor. The food compositions may further be coated, for example with a yogurt coating if it is as a bar.
Emulsifiers may be added for stability of the final product. Examples of suitable emulsifiers include, but are not limited to, lecithin (e.g., from egg or soy), and/or mono-and di-glycerides. Other emulsifiers are readily apparent to the skilled artisan and selection of suitable emulsifier(s) will depend, in part, upon the formulation and final product.
Preservatives may also be added to the nutritional supplement to extend product shelf life. Preferably, preservatives such as potassium sorbate, sodium sorbate, potassium benzoate, sodium benzoate or calcium disodium EDTA are used.
In addition to the carbohydrates described above, the nutritional supplement can contain artificial sweeteners, e.g., saccharides, cyclamates, aspartamine, aspartame, acesulfame K, and/or sorbitol. Such artificial sweeteners can be desirable if the nutritional supplement is intended for an overweight or obese individual, or an individual with type II diabetes who is prone to hyperglycemia.
Manufacture of the Nutritional Supplement
The nutritional supplements of the present invention may be formulated using any pharmaceutically acceptable forms of the vitamins, minerals and other nutrients discussed above, including their salts. They may be formulated into capsules, tablets, powders, suspensions, gels or liquids optionally comprising a physiologically acceptable carrier, such as but not limited to water, milk, juice, soda, starch, vegetable oils, salt solutions, hydroxymethyl cellulose, carbohydrate. In a preferred embodiment, the nutritional supplements may be formulated as powders, for example, for mixing with consumable liquids, such as milk, juice, sodas, water or consumable gels or syrups for mixing into other nutritional liquids or foods. The nutritional supplements of this invention may be formulated with other foods or liquids to provide premeasured supplemental foods, such as single serving beverages or bars, for example.
In a particularly preferred embodiment, the nutritional supplement will be formulated into a nutritional beverage, a form which has consumer appeal, is easy to administer and incorporate into one""s daily regimen, thus increasing the chances of patient compliance. To manufacture the beverage, the ingredients are dried and made readily soluble in water.
To manufacture such a food bar, the dry ingredients are added with the liquid ingredients in a mixer and mixed until the dough phase is reached; the dough is put into an extruder and extruded; the extruded dough is cut into appropriate lengths; and the product is cooled.
For manufacture of other foods or beverages, the ingredients comprising the nutritional supplement of this invention can be added to traditional formulations or they can be used to replace traditional ingredients. Those skilled in food formulating will be able to design appropriate foods/beverages with the objective of this invention in mind.
The nutritional supplement can be made in a variety of forms, such as puddings, confections, (i.e., candy), nutritional beverages, ice cream, frozen confections and novelties, or non-baked, extruded food products such as bars. The preferred form is a powder to add to a beverage or a non-baked extruded nutritional bar.
In another embodiment, the ingredients can be separately assembled. For example, certain of the ingredients (e.g., the bitter tasting ones) can be assembled into a tablet or capsule using known techniques for their manufacture. The remaining ingredients can be assembled into a powder or nutritional bar, as described herein. The two assembled forms comprise the nutritional supplement and can be packaged together or separately, such as in the form of a kit, as described below. Further, they can be administered together or separately, as desired.
Use of the Nutritional Supplement
The ingredients described above aid in the management of blood glucose levels, blood lipid levels, and platelet aggregation. The importance of managing blood glucose levels through foods and regulation of insulin contribute to the management of hyperglycemia and overweight, both seen in type 2 diabetics (Slabber, M. et al., Am. J. Clin. Nutr., 60: 48-53 (1994)). In addition, patients with type 2 diabetes typically have abnormally high total- and LDL-cholesterol, low high density lipoprotein (HDL) cholesterol, and are hypertriglyceridemnicxe2x80x94conditions that give diabetics a two to fourfold excess risk of coronary heart disease. Diabetics also suffer from abnormal platelet function, specifically, platelet aggregation, which leads to atherosclerosis and vascular thrombosis, precursors of cardiovascular disease and premature death (American Diabetes Association, Diab. Care, (23): 1772-1773 (2000)). Early incorporation of the food ingredients contained in the preferred embodiment of the invention may delay the need for lipid-lowering and anti-platelet-aggregating drugs.
The nutritional supplement can provide benefits to HIV-infected individuals with lipodystrophy. The metabolic changes associated with lipodystrophy can be minimized, reduced and/or prevented by administration of the nutritional supplement of this invention. The metabolic changes are similar to those seen in diabetics, namely insulin resistance, abnormal lipid and trygliceride levels, glucose intolerance accelerated atherosclerosis and enhanced cardiovascular risks. Thus, the benefits of the invention to diabetics can be applicable to individuals with lipodystrophy. Further, control of these metabolic changes may reduce, minimize or prevent the body composition changes (e.g., fat accumulation, fat redistribution) typically associated with lipodystrophy. HIV-infected individuals on antiretroviral therapy (HAART), particularly those receiving protease inhibitors, should benefit from the nutritional supplement as these therapies are thought to be a cause of lipodystrophy. Diet and exercise coupled with the use of the nutritional supplement of the invention should provide a therapeutic regimen to reduce the risks associated with lipodystrophy.
The composition and nutritional supplements of the invention are intended to be orally administered daily. Based on the serving size of 10-15 g powder in 8 oz. water, the recommended dosage is twice daily. For example, if the supplement is in the form of a beverage or food bar, then the patient would consume one after or during each of the two largest meals, where the greatest amounts of fats and cholesterol are likely to be consumed. The recommended daily amounts of each ingredient, as described above, serve as a guideline for formulating the nutritional supplements of this invention. The actual amount of each ingredient per unit dosage will depend upon the number of units daily administered to the individual in need thereof. This is a matter of product design and is well within the skill of the nutritional supplement formulator.
The ingredients can be administered in a single formulation or they can be separately administered. For example, it may be desirable to administer the bitter tasting ingredients in a form that masks their taste (e.g., capsule or pill form) rather than incorporating them into the nutritional composition itself (e.g., powder or bar). Thus, the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the nutritional compositions of the invention (e.g., nutritional supplement in the form of a powder and capsules containing herbs and aspirin). Optionally associated with such container(s) can be a notice in the form prescribed by a government agency regulating the manufacture, use or sale of pharmaceutical products, which notice reflects approval by the agency of manufacture, use of sale for human administration. The pack or kit can be labeled with information regarding mode of administration, sequence of administration (e.g., separately, sequentially or concurrently), or the like. The pack or kit may also include means for reminding the patient to take the therapy. The pack or kit can be a single unit dosage of the combination therapy or it can be a plurality of unit dosages. In particular, the agents can be separated, mixed together in any combination, present in a formulation or tablet. Agents assembled in a blister pack or other dispensing means is preferred.
All references provided cited are incorporated by reference in their entirety.

Nutritional supplement for patients with type 2 diabetes mellitus for lipodystrophy


A method for treating patients having calcium related disorders includes using di- or tripeptide derivatives of bisphosphonates to enhance oral bioavailability of such compounds.

Calcium-related disorders in general and osteoporosis in particular are a major public health problem in developed countries. Several important pathological conditions are calcium-related and involve irregularities in calcium metabolism: Paget""s disease, osteoporosis, hypercalcemia of malignancy, and osteolysis front bone metastases, etc. Bisphosphonates are a relatively new family of drugs used clinically in various calcium-related disorders including tumor osteolysis, and are undergoing clinical trials for osteoporosis. They are poorly absorbed following oral administration probably due to their high polarity and charge. IV and IM administration is a serious obstacle to their wide-spread use.
In the patent of Bosies et al. (U.S. Pat. No. 4,666,895 May 19, 1987) peptidyl diphosphonic acid derivatives are described. Bosies et al. Patent hypothesize that some peptidyl compounds will have better activity on bone: xe2x80x9cIn particular, they can be used in cases where the formation and breakdown of bone is disturbed, for example in cases of osteoporosisxe2x80x9d. Nothing is claimed, regarding the absorption of such compounds from the gastrointestinal tract following oral administration. The dosage recommended is much higher than that needed when effective oral absorption takes place. The dosage range recommended (see column 6) is from . . . xe2x80x9c1 mg to 1000 mg, and preferably from 10 to 200 mg.xe2x80x9d Such doses are typical for non-absorbable bisphosphonates such as etidronate and pamidronate. The daily oral recommended dose of a recently approved bisphosphonate in the US, alendronate (Fosamax) is 10 mg and 40 mg, in the treatment of osteoporosis and Paget""s disease, respectively (American Hospital Formulary Service AHFS Drug Information, section 92:00, 1995). As is known widely, this drug is 100 to 1000 times more effective than etidronate, the drug chosen by Bosies et al, for comparison. Typical absorption of such bisphosphonates in humans is in the range of 1%. Effective hydrolysis of the prodrug to the parent drug, for e.g., pamidronate or alendronate, is achieved following oral administration in the cytosol (intestinal cells). It is clear that if a peptidyl derivative of such a drug is administered to humans the dose should be reduced by 50 to 100 times, in order not to be lethal, due to the enhanced absorption of about 50 to 100 times of the prodrug. Bosies relates only to subcutaneous injections, in comparison to a first generation bisphosphonate, etidronate. Furthermore, selection of the peptidyl derivatives is not based on recognition by the transporter system nor on the possibility for hydrolysis to the parent drug. In their patent they seed a new compound, the administered drug being the active drug at the site of action (bone). The present invention relates specifically to the activity of the parent drug yielded form the prodrug following oral absorption.
The results are described ambiguously (+ and xe2x88x92system), and the activity of the compounds is compared to first generation bisphosphonate, etidronate (a non-nitrogen containing compound) rather than a more appropriate comparison to nitrogen-containing drugs such as pamidronate, known to be more effective (pamidronate and alendronate, nitrogen containing bisphosphonates, in clinical use are 10 to 1000 times more effective than etidronate. To the best of our knowledge no further development (since 1987) nor a scientific report is available for such compounds claimed by Bosies et al.
Bisphosphonates
Bisphosphonates have been approved for clinical use in Paget""s disease, tumor osteolysis, and hypercalcemia of malignancy and approved in some countries for osteoporosis therapy. Most bisphosphonates are disodium salts of tie tetraacids (M.W. approximately 250), and are poorly absorbed from the GI tract (approximately 1% of the oral dose is absorbed). Chronic IM or SC administration of bisphosphonates causes irritation and necrosis, and the oral route has been associated with GI disturbances, resulting in poor patient compliance and side effects. For example, the treatment protocol of pamidronate in tumor osteolyis is 1-day slow and diluted IV infusion to avoid thrombophlebitis, but treatment is repeated if normocalcemia is not attained. Another example is the chronic therapy (years) required in osteoporosis.
Absorption Barriers
Clinically, the oral route is the most common and accepted one for delivering drugs of a low molecular weight, of up to 400-600. However, the low permeability of the intestinal epithelia towards highly polar and charged molecules impedes the effective absorption of many low molecular weight drugs. Many such drugs must be delivered parenterally by frequent injections. This is highly risky without close medical supervision. The problem is particularly acute in cases of drugs used for treatment of various chronic diseases such as cancer and age-related diseases, such as osteoporosis, which require prolonged drug treatment.
New Drugs for Calcium-related Disorders
Drugs require a degree of lipophilicity to pass through the GI barrier. In order to increase oral absorption of drugs with low membrane permeability, nonpolar prodrugs are often utilized. Due to the wide variety of esterases present in the target tissue for oral prodrug-regeneration, esters are the most common prodrugs when GI absorption is considered. Acyloxymethyl esters of bisphosphonic acids were proposed however this did not lead to a useful drug (European Patent EP 0 416 689 A2, date of filing Aug. 29, 1990). Similarly, Fels et al. proposed pharmaceutical compositions comprising bisphosphonates and sodium lauryl sulfate for increased oral absorption (U.S. Pat. No. 4,980,171, Dec. 25, 1990).
One way to increase membrane permeability of drugs is by utilization of the peptide carrier system (G. L. Amidon et al., Absorption of difficult drug molecules: Carrier-mediated transport of peptides and peptide analogues, Novel drug delivery and its therapeutic application, L. F. Prescott and W. S. Nimmo, Eds., John Wiley and Sons (1989) pp. 45-56).
The hypothesis of the present patent is completely different from the working hypothesis of Bosies et al. By carefully selecting specific di and/or tripeptide derivatives of bisphosphonates, enhanced oral bioavailability can be achieved due to the recognition by the active carrier transporter of the intestinal mucosae and the hydrolysis to the parent drug following oral administration.
Thus, the prodrug in our invention is a delivery system rather than a new compound for bone diseases. Therefore, the present selection of new compounds is based on enhanced absorption for the GI tract and hydrolysis to the parent compound resulting in improved oral, clinical treatment by a low dose. The selection of the di/tri-peptidyl moiety is based on transporter recognition and hydrolysis and not, as in Bosies et al patent, on resorbing activity on the bone.
Thus, the present invention relates to novel compounds of the general formula
wherein Z is
wherein Z1 and Z2 are independently a side chain of an amino acid or hydrogen,
wherein Z4 is hydrogen or Z4 and Z1 together with xe2x80x94Nxe2x80x94CHxe2x80x94CO represent a proline residue.
where Q is
where Z3 is a bond or a spacer group selected from NH, CO, NHCO, NHCO(CH2)qxe2x80x94CO, (CH2)rCO where r is zero or an integer,
and where q is an integer or zero,
m is 2, 3 or 4,
n is greater than or equal to 0
X is xe2x80x94H or xe2x80x94OH,
Y is xe2x80x94H or xe2x80x94NR2R3,
where A designates a 5- or 6-membered heterocyclic ring which contains 1, 2 or 3 nitrogen atoms, zero, 1 or 2 oxygen atoms and which may contain a sulfur atom, which contains up to and including 3 double bonds, where R2 and R3 are independently hydrogen, lower alkyl, lower alkenyl, lower alkoxy, (di)alkylaminoalkyl, alkoxyalkyl and where the ring A may be substituted by one or more conventional substituents, and to pharmaceutical compositions of improved absorption from the gastro-intestinal tract which contain as active ingredient an efficient quantity of a compound defined above.
Preferred compounds are of the formula
wherein
n designates zero or an integer,
m designates 2, 3 or 4; and where
Z1 and Z2, which may be identical or different, each designates a side chain of an amino acid.
The compounds defined above are aminoacyl derivatives when n is zero, and they are peptidyl-bisphosphonates when n is an integer as defined above.
A wide range of amino acids can be used, and preferred ones for use in the peptidyl chain according to the invention are:
proline
phenylalanine
alanine
lysine
arginine
aspartic acid
glutamic acid
The invention furthermore relates to a method for the production of derivatives defined above, or their salts which comprises linking a desired bisphosphonate compound, of the Pamidronate or Alendronate type, to one or more amino acids.
The invention further relates to pharmaceutical compositions, for oral administration, which contain an effective quantity of a novel derivative defined above. The compositions according to the present invention are characterized by high absorption from the gastrointestinal tract.
The dosage in humans is dependent on various factors including drug potency, age, disease type and state, and the mode of administration. Since the present invention provides significantly enhanced oral absorption the dosage should be determined according to the extent of absorption of a specific peptidyl-bisphosphonate derivative. Therefore, the dose of the prodrug is typically about 20 to 100 times lower than the one usually prescribed for oral administration. One should also recall that the MW of a prodrug is higher than the active drug. The effective dosage range is form about 0.001 mg to about 100 mg per patient per day, a preferred range being of the order of about 0.02 mg to 1 mg per patient, per day in oral administration.

Phosphonates, biphosphonates and pharmaceutical compositions containing them

Yissum Research Development Company of the Hebrew University Jerusalem