An apparatus for applying pressure to a body part comprising: a first sleeve comprising a multiplicity of pressure-applying resilient protrusions configured to apply a therapeutic pressure to a surface of the body part of a patient; and a second sleeve slidably received over the first sleeve, the second sleeve configured to apply a pressure to the first sleeve, thereby increasing the therapeutic pressure applied by the first sleeve on the limb.

1. Field of the Invention
The present invention relates generally to medical devices and methods, and in particular to a device and method for removing edema fluids from a body trunk and/or extremity such as an arm or a leg.
Breast cancer is a serious disease in women, and a variety of modalities are employed in its treatment. Many of these treatments result in damage to the lymphatic and/or venous system which, in turn, can cause a condition referred to as xe2x80x9clymphedema.xe2x80x9d Lymphedema is the accumulation of excessive lymph fluid and swelling of subcutaneous tissues due to the obstruction or destruction of lymph vessels. In breast cancer patients, lymphedema occurs in the arm and results in painful swelling. Excessive fluid accumulation, referred to as edema, can also arise in the arms, legs and, trunk from a variety of other causes, including infection, radiation therapy, and other conditions which result in damage to or destruction of portions of the lymphatic and/or venous system.
2. Description of the Background Art
A variety of devices and methods have been proposed for the treatment of lymphedema in the arms and elsewhere. Many such devices utilize a sequential pump which works like a multiplicity of blood pressure cuffs extending from the shoulder to the hand, which contract and expand individually. When pressure is exerted by any one chamber or cuff, it applies a xe2x80x98blanket pressurexe2x80x99 (i.e. an annular pressure which completely circumscribes the limb or other body portion) to the skin directly underneath the area of that chamber. When the pressure upon that area is released, a similar blanket pressure is then applied to the portion of the arm covered by the next adjacent chamber, and so on up the arm. Such blanket pressures are applied sequentially from the distal to the proximal ends of the arm, with the intention of forcing the fluids up the arm and into the trunk of the body, where existing lymph nodes can process them.
Another prior mode of treatment has been a double walled sheath or stocking in which air pressure is introduced between the walls to squeeze the limb. It has been found that this and other similar systems, which rely on uniform blanket pressure application through the length of the afflicted limb or portions thereof, do not perform very well and in fact may interfere with the desired distal-to-proximal flow of lymphatic fluid.
We have found that when a uniform and/or excessive pressure is applied to an area for the purpose of moving fluid, the opposite effect may result. In particular, the application of pressure may: 1) compress the veins and lymph ducts, resulting in blockage; 2) augment capillary leak; and 3) prevent the lymphatic fluids from mobilizing.
Other approaches to treatment have included employment of a sheath that is separated into a number of longitudinally spaced inflatable air cells encircling the limb to be treated. These cells are successively inflated with uniform air pressure from the distal end to the proximal end of the sheath with the intent of promoting fluid flow in the desired direction. Such systems have been largely ineffectual, as they rely on air pressure being maintained at the same level or magnitude in any one of, or all, of the pressurized cells, producing a blanket effect. U.S. Pat. Nos. 2,533,504 and 2,781,041 disclose examples of such systems.
Prior U.S. Pat. No. 4,370,975 discloses an apparatus for treating lymphedema and similar fluid retention afflictions through the use of a multi-cell inflatable sheath which encompasses the swollen limb. Pressure is applied in the cells of the sheath in timed sequence from the distal cell to the proximal cell, the sequence of pressure applied also defining a decreasing gradient pressure from a maximum pressure applied in the distal cell to a minimum pressure applied in the proximal cell when all of the cells are pressurized. Generally, for each of the adjacent cells the more distal has applied a higher pressure than the more proximal. This application of gradient pressure from distal to proximal cells in time sequence comprises a cycle, and such cycle may be repeated indefinitely to promote the flow of lymphatic fluid from the afflicted limb in a proximal direction.
The problem with the above methods is that any form of blanket pressure such as that applied by pneumatic or hydraulic pressure to large afflicted areas will have at best a minimal result.
Carter, U.S. Pat. No. 5,063,910 shows an apparatus for treating vascular, metabolic and functional imbalance of a limb by variations in pressure of a high-density fluid, such as a mercury bath, around the limb.
The problem with this device is that the pressure applied by this means is, in fact, a blanket-pressure, which increases with the depth of the limb portion within the fluid bath, resulting in the disadvantages described above for al other pressure systems. Another disadvantage is that the patient must remain immobilized during treatment.
R. W. Lilligren et al, U.S. Pat. No. 3,454,010, shows a hollow tube-like bandage for wrapping in a spiral-like manner around the limb of a patient, into which is then applied a pneumatic pressure, which is intended to drive out excess fluids prior to surgery.
Once again the pressure applied is a uniform or blanket pressure to the skin, and so is relatively ineffective to reduce swelling.
Ewen, U.S. Pat. No. 5,257,956, shows a garment for use by post-mastectomy patients which alleviates post-operative pain and discomfort and facilitates normal activity during the recovery period. A padded vest-like garment is adapted for applying comforting pressure to the sites of removal of breast and other tissues and for holding pain relieving packages.
Again, the problem with this garment is that it applies a blanket pressure, resulting in little reduction in swelling.
Fregealle, U.S. Pat. No. 3,975,929, shows a stocking knit on a circular knitting machine which provides a gradually decreasing compressive force on the leg of the of the wearer from the ankle upwardly to the top of the stocking. Again, we believe that a uniform or blanket-pressure such as is applied by this device, is not the best method for forcing out excess lymphedema fluids.
In all of these pressure-applied methods, the patient is immobilized up to 4 hours per day, and sometimes several days in succession, suffering following treatment and soreness of the arm for many days afterwards.
It is a well established fact that special exercises following mastectomy help to mobilize lymphedema fluids; yet prior art devices contribute toward immobilizing the patient, making exercising difficult or impossible. Thus resulting in a counter-producing effect.
The cost of sequential pumps including necessary limb compression apparatus range from $500 to over $8,000. In addition, skilled technicians are necessary to operate it, thereby making treatment for lymphedema patients extremely expensive.
The following cited prior art references are relevant but distinguished from the present invention: U.S. Pat. Nos. 2,533,504, 2,699,165, 2,781,041, 2,943,859, 3,173,420, 3,454,010, 6,548,819, 3,561,435, 3,728,875, 3,845,769, 3,862,629, 3,885,554, 3,942,518, 3,975,929, 4,013,069, 4,030,488, 4,180,065, 4,320,746, 4,370,975, 4,374,518, 4,402,312, 4,552,133, 4,583,522, 4,773,397, 4,922,893, 4,938,208, 4,961,418, 5,108,426, 5,109,832, 5,117,812, 5,171,211, 5,172,689, 5,228,142, 5,233,974, 5,257,956 and 5,310,400.
The present invention provides improved apparatus and methods for treating body parts of the patient, particularly the limbs, to relieve swelling due to lymphedema and other causes. The apparatus comprises a plurality of sleeves received one over another onto a patient""s limb. The innermost sleeve comprises a therapeutic pressure sleeve. In various embodiments of the present invention, a secondary sleeve, (which is slipped over the therapeutic pressure sleeve), comprises a thin fabric compression sleeve. In alternate embodiments, the secondary sleeve comprises an inflatable compression sleeve. In still further alternate embodiments, both a thin fabric compression sleeve and an inflatable compression sleeve are received over the therapeutic pressure sleeve.
When using either the thin fabric compression or inflatable compression sleeve as the secondary sleeve, the inner therapeutic pressure sleeve is first pulled into position over the patient""s limb. Thereafter, the secondary sleeve is pulled into position over the therapeutic pressure sleeve. As will be explained, the therapeutic pressure sleeve exerts a therapeutic pressure at select locations on the patient""s limb. The secondary sleeve exerts a pressure on the inner therapeutic pressure thereby increasing the therapeutic pressure on the patient""s body surface. In certain preferred embodiments, both a thin fabric compression sleeve and an inflatable compression sleeve are simultaneously used, with the inflatable compression sleeve received over the thin fabric compression sleeve. In such embodiments, the inflatable compression sleeve exerts a pressure on the thin fabric compression sleeve which in turn exerts a pressure on the therapeutic pressure sleeve, thereby increasing the therapeutic pressure applied to the patient""s limb.
In one preferred embodiment, the secondary sleeve is formed of a thin fabric sheet of elastically deformable material having a diameter somewhat smaller than the outer diameter of the therapeutic pressure sleeve. Accordingly, such a thin fabric compression sleeve is dimensioned to fit tightly around the therapeutic pressure sleeve. The thin fabric compression sleeve is circumferentially stretched when slipped into position over the therapeutic pressure sleeve. The natural elastic tendency of the thin fabric compression sleeve to constrict will exert a pressure on the therapeutic pressure sleeve, thereby increasing the therapeutic pressure exerted by the therapeutic pressure sleeve on the patient""s limb. In this embodiment of the secondary sleeve, the therapeutic pressure and thin fabric compression sleeve materials are selected such that the coefficient of friction between the therapeutic pressure sleeve and thin fabric compression sleeve is sufficiently low such that the thin fabric compression sleeve can easily be slipped on (and off) over the therapeutic pressure sleeve after the therapeutic pressure sleeve has already been slipped onto the patient""s limb. By using a therapeutic pressure and a thin fabric compression sleeve together, a higher therapeutic pressure can comfortably be applied to the patient""s limb than could comfortably be applied by one tightly fitting elastically deformable therapeutic pressure sleeve alone. This is due to the fact that should only one elastically deformable therapeutic pressure sleeve instead be used, this sleeve would have to be dimensioned to be initially tightly received over the limb, thus being difficult for the patient to comfortably slip on and off.
Another advantage of using thin fabric compression sleeves is that more than one thin fabric compression sleeve can be used simultaneously. Should two or more thin fabric compression sleeves be used, the additional outer sleeves can be received over the inner sleeves such that the addition or removal of the outer sleeves can be used as a means of pressure adjustment. Moreover, when using such thin fabric outer compression sleeves, these sleeves can be made to shorter lengths than the inner therapeutic pressure sleeve such that one or more of these shorter sleeves can be received only over particular length portions of the patient""s limb, as desired. Accordingly, bands of different therapeutic pressures can be simultaneously maintained at different locations on the patient""s limb.
In another embodiment, the secondary sleeve comprises an inflation device such as an inflatable bladder. Inflation of such a sleeve causes the inflatable compression sleeve to expand such that the inner surface of the sleeve exerts a pressure on the outer surface of the inner therapeutic pressure sleeve, thereby increasing the therapeutic pressure delivered to the patient. When initially deflated, the inflatable compression sleeve may therefore be dimensioned to be initially loosely received over the therapeutic pressure sleeve. An advantage of such a secondary inflatable sleeve received over the therapeutic pressure sleeve is that it is possible to easily adjust the therapeutic pressure applied to the limb by adjusting the inflation pressure in the inflatable compression sleeve.
In addition, when using an inner therapeutic pressure sleeve within a periodically inflating and deflating outer inflatable compression sleeve, the pressure range exerted by the inflatable compression sleeve can be attenuated, while still maintaining a therapeutic pressure on the patient""s limb. Specifically, the inner therapeutic sleeve will maintain a baseline therapeutic pressure on the limb even when the outer inflatable compression sleeve is intermittently deflated. Moreover, the inner therapeutic pressure sleeve will also operate to limit the maximum pressure applied to the limb when the inflatable compression sleeve is inflated. Furthermore, a gentler rate of increase and a gentler rate of decrease in the net pressure applied to the limb by the inflatable compression sleeve will be achieved by the use of an inner therapeutic pressure sleeve within an inflatable compression sleeve. Accordingly, a very beneficial therapeutic massaging effect can be generated.
In certain embodiments, the inflatable compression sleeve may have separate pressurized compartments such that different levels of therapeutic pressure may be applied to different portions of the patient""s limb. The pressures in the various compartments may themselves be varied such that a therapeutic massaging effect is generated.
In all of the various embodiments of the present invention, the use of a plurality of separate sleeves has numerous advantages including ease of adjusting the pressure on the patient""s limb. In particular, receiving an additional sleeve or sleeves over the therapeutic pressure sleeve will increase the pressure on the patient""s limb to various predetermined pressures dependant upon the number, dimensions, material and/or inflation pressure of the additional outer sleeve(s). Since the pressure applied to the patient""s limb can be altered by adding or removing an outer sleeve or sleeves, or by varying the inflation pressure of the inflatable compression sleeve, optimal therapeutic pressures can be tailored to each individual patient""s needs, which may vary over time and may also vary from one location to another on the patient""s limb.
Another advantage of the present use of multiple sleeves is ease of manufacturing since additional fastening elements are not required to xe2x80x9cclosexe2x80x9d or xe2x80x9ctightenxe2x80x9d the therapeutic pressure or secondary sleeves. Accordingly, the use of VELCRO straps or zippers is avoided. Rather, the dimension and construction of the sleeves themselves is itself sufficient to produce an appropriately high pressure therapeutic device.
The therapeutic pressure sleeve provides a therapeutic system of applying pressure at select locations on the patient""s limbs such that lymphedema, edema and other swelling disorders are treated, as follows. The therapeutic pressure sleeve comprises a multiplicity of pressure-applying resilient protrusions such as fingers or ridges which are arranged to apply inward pressure onto a surface of the body part to relieve swelling. The protrusions will be formed from a compressible material, such as foam rubber, and pressure will be applied by wrapping or otherwise compressing or collapsing the protrusions onto the body portion so that the fingers apply a controlled level of pressure onto a localized area over the body part surface. In all embodiments, the protrusions will be spaced-apart in an array so that the tips of the fingers or ridges which engage the body part surface apply pressure in a spaced-apart manner. Surprisingly, it has been found that applying such a distributed pattern of spaced-apart pressure points or lines against the skin effectively reduces swelling resulting from lymphedema and other edemas in a simple and cost-effective manner. In particular, the method and apparatus of the present invention do not block or inhibit fluid flow within the body part, further enhancing the body""s ability to resorb the fluid responsible for swelling. An additional advantage of the device is that it is both simple and comfortable to use, enhancing patient compliance. In the treatment of lymphedema, the apparatus and method of the present invention have particularly been found to permit the release and flow back of fluid to the remaining healthy lymph nodes in a controlled manner that does not overburden such collateral lymphatic drainage.
In a specific embodiment of the present invention intended for use with the limbs of the body, i.e., the arms and legs, the resilient protrusions will have a height from a radially outward base to a radially inward tip in the range from 0.5 cm to 15 cm. The protrusions are arranged in a generally cylindrical envelope with individual fingers or ridges being aligned radially inwardly with respect to the axis of the cylindrical envelope. The length of the cylindrical envelope will depend on the body part being treated, e.g. from about 3 cm for a finger to 200 cm for trunk and legs. In an apparatus intended specifically for use with an arm, the length of the cylindrical envelope is in the range from 10 cm to 90 cm, the bases of the fingers are distributed over a generally cylindrical surface having a diameter in the range from 7.5 cm to 75 cm, and the tips of the fingers are distributed over a generally cylindrical surface having a diameter in the range from 2 cm to 15 cm. The diameters, of course, will vary widely for treatment of other body parts.
The innermost therapeutic pressure sleeve will preferably comprise at least an outer covering, preferably formed of material such as NYLON, having a low coefficient of friction. The outer covering secures the base of the fingers over the generally cylindrical outer surface. The outer covering may generally be formed from any suitable material which permits the fingers or ridges to be rolled to form the generally cylindrical envelope. The therapeutic pressure sleeve may further comprise an inner lining, preferably formed of SPANDEX. The inner lining covers the radially inward tips of the fingers over a generally cylindrical surface. The inner lining will be intended primarily for comfort and cleanliness and will be formed from any suitably soft, relatively thin material which allows the resilient fingers to apply pressure to the body part surface.
In a more specific embodiment, the resilient protrusions will be provided by a sheet of convoluted plastic foam which, when unrolled, has a plurality of protuberances projecting upwardly from a base surface thereof. The protuberances typically form cylindrical fingers or axially aligned ridges which are tapered to a smaller width in the direction away from their base. The sheet of plastic foam can be rolled into the desired cylindrical envelope configuration described above. The tapering of the protrusions is a particular advantage since it permits rolling of the foam rubber sheet with excessive compression of the inner surface of the sheet.
A principle feature of the present invention is the provision of an improved device for applying pressure to a patient""s limb for the purpose of facilitating the flow of lymphedema fluid up the limb to the shoulder or hip. This feature includes a therapeutic pressure sleeve which can be slipped over the patient""s limb and which contains a multiplicity of inwardly-pointed pressure-applying resilient fingers or ridges. The fingers are preferably arranged in rows, and the rows are arranged side-by-side such that the fingers form a grid pattern having space around each finger and between the rows. Each finger individually exerts pressure against a small area of the skin, and each small area is separated by space. The separation of individual fingers is an advantage particular in that it allows for more precise control of pressure and pressure gradient applied to the body surface.
Another feature of the present invention is that each resilient finger protrusion in the therapeutic pressure sleeve provides controlled pressure against the adjacent body surface, which in turn allows the fluid to be mobilized back to the lymphatic and venous system. It is important that the applied pressure be sufficiently great to promote flow of excess fluid from tissue back into vascular (venous and lymphatic) circulation and thereby reduce swelling. It is equally important that the applied pressure not be so large that fluid is impeded from returning to vascular circulation. It has been found that an applied pressure in the range from 5 mmHg to 60 mmHg is usually sufficient, preferably from 10 mmHg to 45 mmHg. The precise applied pressure will usually be slightly lower than venous and lymphatic outflow pressure, typically being about 1 mmHg to 10 mmHg below the individual patient""s venous pressure.
In accordance with the present invention, the therapeutic pressure sleeve can be fabricated to exert a pressure in the range of 5 mmHg to 30 mmHg, and the secondary sleeve can be formed to exhibit an additional pressure in the range of 5 mmHg to 30 mmHg, thereby increasing the total therapeutic pressure on the limb to 10 mmHg to 60 mmHg. Generally, higher maximum pressures (such as 60 mmHg) are applied to the patient""s legs, and lower maximum pressures (such as 50 mm Hg) are applied to the patient""s arms.
The devices of the present invention have been found to be particularly suitable for maintaining the desired controlled pressures needed for the treatment methods. In particular, use of the therapeutic pressure sleeve""s inner foam layer allows the compressive force to be applied while permitting significant body movement. While other devices, such as an elastic covering, could initially be set at a desired pressure, body movement such as arm flexing, would result in tight constriction of the fluid circulation. Use of the resilient protuberances is particularly preferred since it allows rolling of the device over the body part without excessive compression of the inner surface of the material. Other foam and resilient materials, however, could also be used, e.g. foams which are less dense near the surface which engages the body part.
Another feature of the present invention is the application of the apparatus to the hand in the form of a glove, or the chest or back, in the form of a vest.
Further features will become apparent in the following description of the embodiments of this invention and from the appended claims.

Multiple sleeve method and apparatus for treating edema and other swelling disorders


NF-xcexaB inhibitors are useful for treating dry eye disorders and other disorders requiring the wetting of the eye.

The present invention is directed to the treatment of dry eye disorders. In particular, the present invention is directed to the use of NF-xcexaB inhibitors in the treatment of dry eye and other disorders requiring the wetting of the eye in mammals.
Dry eye, also known generically as keratoconjunctivitis sicca, is a common ophthalmological disorder affecting millions of Americans each year. The condition is particularly widespread among post-menopausal women due to hormonal changes following the cessation of fertility. Dry eye may afflict an individual with varying severity. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation such as is often caused by small bodies lodging between the eye lid and the eye surface. In severe cases, vision may be substantially impaired. Other diseases, such as Sjogren""s disease and cicatricial pemphigoid manifest dry eye complications.
Although it appears that dry eye may result from a number of unrelated pathogenic causes, all presentations of the complication share a common effect, that is the breakdown of the pre-ocular tear film, which results in dehydration of the exposed outer surface and many of the symptoms outlined above (Lemp, Report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes, The CLAO Journal, volume 21, number 4, pages 221-231 (1995)).
Practitioners have taken several approaches to the treatment of dry eye. One common approach has been to supplement and stabilize the ocular tear film using so-called artificial tears instilled throughout the day. Other approaches include the use of ocular inserts that provide a tear substitute or stimulation of endogenous tear production.
Examples of the tear substitution approach include the use of buffered, isotonic saline solutions, aqueous solutions containing water soluble polymers that render the solutions more viscous and thus less easily shed by the eye. Tear reconstitution is also attempted by providing one or more components of the tear film such as phospholipids and oils. Phospholipid compositions have been shown to be useful in treating dry eye; see, e.g., McCulley and Shine, Tear film structure and dry eye, Contactologia, volume 20(4), pages 145-49 (1998); and Shine and McCulley, Keratoconjunctivitis sicca associated with meibomian secretion polar lipid abnormality, Archives of Ophthalmology, volume 116(7), pages 849-52 (1998). Examples of phospholipid compositions for the treatment of dry eye are disclosed in U.S. Pat. No. 4,131,651 (Shah et al.), U.S. Pat. No. 4,370,325 (Packman), U.S. Pat. No. 4,409,205 (Shively), U.S. Pat. No. 4,744,980 and U.S. Pat. No. 4,883,658 (Holly), U.S. Pat. No. 4,914,088 (Glonek), U.S. Pat. No. 5,075,104 (Gressel et al.), U.S. Pat. No. 5,278,151 (Korb et al.), U.S. Pat. No. 5,294,607 (Glonek et al.), U.S. Pat. No. 5,371,108 (Korb et al.) and U.S. Pat. No. 5,578,586 (Glonek et al.). U.S. Pat. No. 5,174,988 (Mautone et al.) discloses phospholipid drug delivery systems involving phospholipids, propellants and an active substance.
Another approach involves the provision of lubricating substances in lieu of artificial tears. For example, U.S. Pat. No. 4,818,537 (Guo) discloses the use of a lubricating, liposome-based composition, and U.S. Pat. No. 5,800,807 (Hu et al.) discloses compositions containing glycerin and propylene glycol for treating dry eye.
Although these approaches have met with some success, problems in the treatment of dry eye nevertheless remain. The use of tear substitutes, while temporarily effective, generally requires repeated application over the course of a patient""s waking hours. It is not uncommon for a patient to have to apply artificial tear solution ten to twenty times over the course of the day. Such an undertaking is not only cumbersome and time consuming, but is also potentially very expensive. Transient symptoms of dry eye associated with refractive surgery have been reported to last in some cases from six weeks to six months or more following surgery.
Aside from efforts directed primarily to the alleviation of symptoms associated with dry eye, methods and compositions directed to treatment of the dry eye condition have also been pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) discloses the use of sex steroids, such as conjugated estrogens, to treat dry eye conditions in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen) discloses the use of finely divided calcium ion compositions to stimulate pre-ocular tear film production; and U.S. Pat. No. 4,966,773 (Gressel et al.) discloses the use of microfine particles of one or more retinoids for ocular tissue normalization.
Some recent literature reports suggest that patients suffering from dry eye syndrome disproportionately exhibit the hallmarks of excessive inflammation in relevant ocular tissues, such as the lacrimal and meibomian glands. The use of various compounds to treat dry eye patients, such as steroids [e.g. U.S. Pat. No. 5,958,912; Marsh, et al., Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjogren syndrome, Ophthalmology, 106(4): 811-816 (1999); Pflugfelder, et. al U.S. Pat. No. 6,153,607], cytokine release inhibitors (Yanni, J. M.; et. al WO 0003705 A1), cyclosporine A [Tauber, J. Adv. Exp. Med. Biol. 1998, 438 (Lacrimal Gland, Tear Film, and Dry Eye Syndromes 2), 969], and 15-HETE (Yanni et. al., U.S. Pat. No. 5,696,166), has been disclosed.
Inflammatory processes are known to involve the upregulation of several gene products by the nuclear transcription factor, NF-xcexaB. In its quiescent state NF-xcexaB exists as a heterodimer with the protein Ixcexa-Bxcex1, which masks the nuclear localization signals and DNA binding domain of the former protein. Under inflammatory conditions Ixcexa-Bxcex1 is phosphorylated, causing a conformational change which results in its tagging with multiple copies of the ubiquitin protein. Ubiquinated Ixcexa-Bxcex1 is recognized and degraded by the proteasome, which liberates NF-xcexaB. The free protein is translocated to the nucleus, where it binds to the appropriate DNA sequence and upregulates the production of several inflammatory mediators, such as COX-2, iNOS, IL-1, and TNF-xcex1. Therefore, inhibitors of the synthesis, activation, translocation or DNA binding activity of NF-xcexaB could reduce inflammation and provide therapeutic benefit to dry eye patients.
The present invention is directed to methods for the treatment of dry eye and other disorders requiring the wetting of the eye, including symptoms of dry eye associated with refractive surgery such as LASIK surgery. According to the methods of the present invention, NF-xcexaB inhibitors are administered to a patient suffering from dry eye or other disorders requiring wetting of the eye. The NF-xcexaB inhibitors are preferably administered topically to the eye.
As used herein, xe2x80x9cNF-xcexaB inhibitorsxe2x80x9d means compounds that prevent the synthesis, activation, translocation and/or DNA binding activity of NF-xcexaB. Although some steroids act as NF-xcexaB inhibitors, for purposes of the present invention xe2x80x9cNF-xcexaB inhibitorxe2x80x9d does not include any steroids.
NF-xcexaB inhibitors are known. Examples of NF-xcexaB inhibitors useful in the methods of the present invention include 2-chloro-N-[3,5-di(trifluoromethyl)phenyl]-4-(trifluoromethyl)pyrimidine-5-carboxamide (also known as SP-100030); 3,4-dihydro-4,4-dimethyl-2H-1,2-benzoselenazine (also known as BXT-51072); declopramide (also known as Oxi-104); and dexlipotam.
According to the methods of the present invention, a composition comprising one or more NF-xcexaB inhibitors and a pharmaceutically acceptable carrier for topical ophthalmic administration or implantation into the conjunctival sac or anterior chamber of the eye is administered to a mammal in need thereof. The compositions are formulated in accordance with methods known in the art for the particular route of administration desired.
The compositions administered according to the present invention comprise a pharmaceutically effective amount of one or more NF-xcexaB inhibitors. As used herein, a xe2x80x9cpharmaceutically effective amountxe2x80x9d is one which is sufficient to reduce or eliminate signs or symptoms of dry eye or other disorders requiring the wetting of the eye. Generally, for compositions intended to be administered topically to the eye in the form of eye drops or eye ointments, the total amount of NF-xcexaB inhibitor will be about 0.001 to 1.0% (w/v).
Preferably, the compositions administered according to the present invention will be formulated as solutions, suspensions and other dosage forms for topical administration. Aqueous solutions are generally preferred, based on ease of formulation, as well as a patient""s ability to easily administer such compositions by means of instilling one to two drops of the solutions in the affected eyes. However, the compositions may also be suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions. Suspensions may be preferred for NF-xcexaB inhibitors which are sparingly soluble in water.
The compositions administered according to the present invention may also include various other ingredients, including but not limited to surfactants, tonicity agents, buffers, preservatives, co-solvents and viscosity building agents.
Various tonicity agents may be employed to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, dextrose and/or mannitol may be added to the composition to approximate physiological tonicity. Such an amount of tonicity agent will vary, depending on the particular agent to be added. In general, however, the compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm).
An appropriate buffer system (e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid) may be added to the compositions to prevent pH drift under storage conditions. The particular concentration will vary, depending on the agent employed. Preferably, however, the buffer will be chosen to maintain a target pH within the range of pH 6-7.5.
Compositions formulated for the treatment of dry eye-type diseases and disorders may also comprise aqueous carriers designed to provide immediate, short-term relief of dry eye-type conditions. Such carriers can be formulated as a phospholipid carrier or an artificial tears carrier, or mixtures of both. As used herein, xe2x80x9cphospholipid carrierxe2x80x9d and xe2x80x9cartificial tears carrierxe2x80x9d refer to aqueous compositions which: (i) comprise one or more phospholipids (in the case of phospholipid carriers) or other compounds, which lubricate, xe2x80x9cwet,xe2x80x9d approximate the consistency of endogenous tears, aid in natural tear build-up, or otherwise provide temporary relief of dry eye symptoms and conditions upon ocular administration; (ii) are safe; and (iii) provide the appropriate delivery vehicle for the topical administration of an effective amount of one or more NF-xcexaB inhibitors. Examples or artificial tears compositions useful as artificial tears carriers include, but are not limited to, commercial products, such as Tears Naturale(copyright), Tears Naturale II(copyright), Tears Naturale Free(copyright), and Bion Tears(copyright) (Alcon Laboratories, Inc., Fort Worth, Tex.). Examples of phospholipid carrier formulations include those disclosed in U.S. Pat. No. 4,804,539 (Guo et al.), U.S. Pat. No. 4,883,658 (Holly), U.S. Pat. No. 4,914,088 (Glonek), U.S. Pat. No. 5,075,104 (Gressel et al.), U.S. Pat. No. 5,278,151 (Korb et al.), U.S. Pat. No. 5,294,607 (Glonek et al.), U.S. Pat. No. 5,371,108 (Korb et al.), U.S. Pat. No. 5,578,586 (Glonek et al.); the foregoing patents are incorporated herein by reference to the extent they disclose phospholipid compositions useful as phospholipid carriers of the present invention.
Other compounds designed to lubricate, xe2x80x9cwet,xe2x80x9d approximate the consistency of endogenous tears, aid in natural tear build-up, or otherwise provide temporary relief of dry eye symptoms and conditions upon ocular administration the eye are known in the art. Such compounds may enhance the viscosity of the composition, and include, but are not limited to: monomeric polyols, such as, glycerol, propylene glycol, ethylene glycol; polymeric polyols, such as, polyethylene glycol, hydroxypropylmethyl cellulose (xe2x80x9cHPMCxe2x80x9d), carboxy methylcellulose sodium, hydroxy propylcellulose (xe2x80x9cHPCxe2x80x9d), dextrans, such as, dextran 70; water soluble proteins, such as gelatin; and vinyl polymers, such as, polyvinyl alcohol, polyvinylpyrrolidone, povidone and carbomers, such as, carbomer 934P, carbomer 941, carbomer 940, carbomer 974P.
Other compounds may also be added to the ophthalmic compositions of the present invention to increase the viscosity of the carrier. Examples of viscosity enhancing agents include, but are not limited to: polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers. In general, the phospholipid carrier or artificial tears carrier compositions will exhibit a viscosity of 1 to 400 centipoises (xe2x80x9ccpsxe2x80x9d).
Topical ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such preservatives are typically employed at a level of from 0.001 to 1.0% w/v. Unit dose compositions of the present invention will be sterile, but typically unpreserved. Such compositions, therefore, generally will not contain preservatives.
The preferred compositions of the present invention are intended for administration to a human patient suffering from dry eye or symptoms of dry eye. Preferably, such compositions will be administered topically. In general, the doses used for the above described purposes will vary, but will be in an effective amount to eliminate or improve dry eye conditions. Generally, 1-2 drops of such compositions will be administered from once to many times per day.
A representative eye drop formulation is provided in Example 1 below.

Use of NF-xcexaB inhibitors to treat dry eye disorders


An oligomer of the formula:

1. Field of the Invention
This invention relates to silicone oligomers useful as coupling agents for curable compositions, for instance free-radically curable filler-organic elastomeric polymer compositions having special application as insulation coatings, to compositions employing the oligomers, and to cured products obtained therefrom.
2. Description of the Prior Art
A substantial amount of research has been performed heretofore in connection with the treatment of fillers or reinforcing agents for the purpose of improving physical or mechanical properties of plastics, resins or rubbers reinforced with the filler. Much of this research has centered on the pretreatment of glass fiber reinforcement materials for resins and rubbers. For example, U.S. Pat. No. 3,702,783 describes the application as a size to glass fibers of a blend of 3-glycidoxypropyltrimethoxysilane and methyltrimethoxysilane. U.S. Pat. No. 3,816,235 discloses a size composition for the treatment of glass fibers wherein the size composition contains a blend of aminoalkyltriethoxysilane and methyltriethoxysilane. U.S. Pat. No. 3,944,707 discloses the use as a size for glass fiber reinforcement for plastics, blends of vinyl silane or vinyl siloxanes and a beta-haloalkoxysilane. Similarly, U.S. Pat. No. 3,993,837 discloses glass fiber size compositions containing blends of epoxyalkylsilane or siloxane and a beta-haloalkoxysilane.
U.S. Pat. No. 4,049,865 discloses glass fiber size compositions containing a blend of an aminoalkylsilane and a vinyl silane. U.S. Pat. No. 4,130,677 discloses the sizing of glass bottle surfaces with an aminoalkylsilane.
Martens et al, U.S. Pat. No. 3,148,169, discloses the pretreatment of clay filler with a silicone fluid to coat the clay particles to impart a hydrophobic character to the clay and to mask the acidic nature of the clay so that peroxides later used as crosslinking agents are not deactivated.
Pickwell et al, U.S. Pat. No. 4,550,056, describes electrical cables comprising a conductor and a coating of insulation on the conductor, the coating comprising a cured composition of
(1) an organic elastomer;
(2) an inorganic filler;
(3) a coupling composition comprising (a) an ethylenically unsaturated silane, having bonded to silicon, at least one hydroxy group and/or alkoxy group; (b) a methyl ethoxy siloxane oligomer fluid; and (c) a methyl vinyl siloxane oligomer fluid.
Rykowski, U.S. Pat. No. 4,179,537, discloses blends of an organofunctional silane, e.g., vinyltrialkoxysilanes, methacryloxyalkyltrialkoxysilanes, vinyltrihalosilanes and the like with a non-organofunctional silane, e.g., alkyltrialkoxysilanes, and the incorporation of such blends into organic resins, e.g., EPDM rubber for improving the adhesion between inorganic substrates such as clay fillers and the resin. This patent fails to disclose, teach or suggest the incorporation of siloxane oligomers in the coupling composition and suggests that the presence of siloxane oligomers in the resin-filler system could have a detrimental effect on coupling efficiency (col. 4, lines 54-63).
Use of silanes having silicon-bonded 2-methoxyethoxy groups as coupling agents, e.g., vinyl-tris-(2-methoxyethoxy)silane (col. 2, lines 44-47) is also described in U.S. Pat. No. 4,179,537. Vinyl-tris-(2-methoxyethoxy)silane, has been used industrially for many years as a coupling additive in mineral-filled EPM and EPDM wire and cable insulations. EPM is an ASTM designation for copolyrners of ethylene and propylene; EPDM is a terpolymer of ethylene, propylene and a diene monomer such as ethylidene norbornene or 1,4 hexadiene. Vinyl-tris-(2-methoxyethoxy) silane has been extensively used heretofore because it provides a unique balance of elastomer reinforcement and the degree of wet electrical stability required. However, it releases 2-methoxyethanol as a hydrolysis by-product when it is used and, unfortunately, 2-methoxyethanol is now being studied as a suspected teratogen. Consequently, coupling agent products based on vinyl-tris-(2-methoxyethoxy)silane are now facing continuing replacement pressure in the marketplace.
Commercial products used as coupling agents in elastomer/filler compositions include cohydrolysis products of dimethyl and vinylmethylchlorosilanes which are used as a filler hydrophobe treatment on calcined clays. Such products however, have a relatively high cost due to the high cost of vinylmethyldichlorosilane. Reducing the vinylmethyldichlorosilane content thereof gives inferior performance in wire cable insulation applications.
U.S. Pat. No. 4,950,779, Wengrovius, et al. (General Electric), describes mixtures comprising cyclic, linear and branched alkoxy functional silicone oligomers produced by condensation of organotrialkoxysilanes, such as methyltrimethoxysilane and vinyltrimethoxysilane, using formic acid, optionally with a strong acid catalyst.
U.S. Pat. No. 5,298,998, Horn, et al. (Hxc3xcls), describes mixtures of linear and cyclic alkoxy functional silicone oligomers produced from vinyltrialkoxysilanes using hydrogen chloride catalyst and water.
U.S. Pat. No. 5,210,168, Bergstrom, et al. (Dow Corning), describes alkoxy functional silicone oligomer mixtures produced from organotrialkoxysilanes using a carboxylic acid, such as formic acid, and a strong acid catalyst.
In U.S. Pat. No. 6,140,445, incorporated herein by reference, there are described novel alkoxy functional silicone oligomers having alkoxysilylalkyl substituents on a backbone silicon atom. Such oligomers may be produced from vinylalkoxysiloxane oligomers by hydrosilation with an alkoxyhydridosilane; by hydrosilating a vinylalkoxysilane with a hydridoalkoxy silicone oligomer; or by condensation of a bis-alkoxysilane having silicon atoms joined by other than an Si-O bond, optionally with other alkoxysilanes. Such oligomers are disclosed to be useful as coatings or adhesives, or additives therefor.
The invention is an oligomer of the formula:
[R3SiOxc2xd]m[Oxc2xdSiR2Oxc2xd]n[SiO{fraction (3/2)}R]o[SiO{fraction (4/2)}]pxe2x80x83xe2x80x83(I)
wherein
each R is selected individually from the group consisting of R1, xe2x80x94OR2 and xe2x80x94OR3; each R1 is independently a substituted or unsubstituted hydrocarbon group; each R2 is a C1-C6 alkyl group or an acyl group; and each R3 is independently an alkyl or alkenyl group having at least 8 carbon atoms;
with the provisos that
if R3 is alkenyl, there is no unsaturation within two carbon atoms adjacent to the oxygen atom of the xe2x80x94OR3 group; at least one R group is xe2x80x94OR3; at least one quarter of all R groups are xe2x80x94OR2 or xe2x80x94OR3; m=2 to 20; n=0 to 50; o=0 to 20; and p=0 to 10.
Silicone oligomers having thereon at least one C8 or higher alkoxy or alkenoxy group, preferably C10-C16 alkoxy or alkenoxy, especially dodecyloxy, have been found to hydrolyze extremely slowly. Transesterification of relatively inexpensive siliconate oligomers provides a cost effective method of providing stable silicone oligomers with lipophilic hydrocarbon functionality. While there may be some hydrolysis of the xe2x80x94OR3 groups of the oligomer over extended time periods, it does not substantially modify the overall polymer properties. Moreover, at least in the case of dodecyloxy functional oligomers, a trace level release of dodecanol can be advantageous for underground applications, such as in insulation formulations for buried cables. Dodecanol is reported as a treeing retardant in electrical insulation.
In the formula (I), above, R1 is independently a substituted or unsubstituted hydrocarbon group. For instance R1 may be a saturated or unsaturated aliphatic or aromatic hydrocarbon of 1 to 16 carbon atoms, e.g., alkyl (linear or branched), or cycloalkyl. Exemplary unsubstituted R1 groups are methyl, ethyl, 1i-propyl, 1-butyl, t-butyl, pentyl, cyclohexyl, octyl, decyl, dodecyl, phenyl, benzyl or napthyl. Methyl, ethyl and phenyl are preferred R1 groups which are unsubstituted hydrocarbon groups.
The R1 groups also may contain ethylenic or acetylenic unsaturation.
Examples of such R1 groups include vinyl, allyl, propargyl, acryloxyalkyl, methacryloxyalkyl, crotyloxyalkyl, styryl, n-octenyl, linolyl, lineoyl, etc. Vinyl, acryloxypropyl and methacryloxypropyl are preferred.
Other R1 groups may be monovalent organic radicals linked to the Si atom of the siloxane oligomer backbone by an Sixe2x80x94C bond, and which has one or more, ether, ester, carbamate, isocyanurate, thioether, polysulfide, blocked mercaptan, amide, cyano, epoxy or oximato group thereon.
Exemplary ether-containing groups include alkoxyethyl or alkoxypropyl and polyether groups, especially those obtained as a result of hydrosilation of an allyl-started poly(ethylene oxide), allyl-started polypropylene oxide or allyl-started EO/PO copolymer. Ether groups may also be provided by etherification of silylalkylhydroxides.
Exemplary ester containing groups are acetic acid, propionic acid, octanoic acid, benzoic acid, fatty acid, or acid terminated polyester, esters of hydroxyalkyl groups, for instance acetyloxypropyl, propionyloxypropyl, benzoyloxyethyl, and the like.
Exemplary carbamate containing groups may be groups obtained by reaction of silylalkylisocyanates with alcohols, and may include polyurethane as well an mono-carbamato structures. Specific such groups include propyl-N-carbamatoethyl; propyl-N-carbamatomethyl, ethyl-N-carbamatoethyl and propyl-N-carbamatoisopropyl.
Exemplary amide containing groups are suitably derived from aminoalkyl groups, amidized with a carboxylate ester such as methyl acetate, methyl propionate or a fatty acid ester, and the like. Specific such groups include 3-acetamidopropyl, 2-propionamidoethyl, 3-cocoamidopropyl.
Polysulfide encompasses groups having the functionality xe2x80x94Snxe2x80x94 therein where n is 2-8, preferably 2-4, especially disulfide and tetrasulfide. Specific such groups include: C4H9xe2x80x94SSxe2x80x94C3H6xe2x80x94 and C2H5xe2x80x94SSxe2x80x94C2H4xe2x80x94.
Blocked mercaptans are functional groups produced by reaction of a mercapto group with a subsequently removable blocking agent. Exemplary blocked mercaptan groups include thioester and other groups disclosed in copending application PCT/US98/17391, filed Aug. 21, 1998, designating US.
Representative examples of silanes which may be incorporated into the oligomers to provide blocked mercaptan groups include 3-methyldiethoxysilylpropyl thioacetate, 3-trimethoxysilylpropyl thioacetate, 3-triethoxysilylpropyl thioacetate, 3-trimethoxysilylpropyl thiopropionate, 3-triethoxysilylpropyl thiobenzoate; 3-triethoxysilylethyl thioacetate, 3-triethoxysilylmethyl thioacetate, 3-triethoxysilylpropyl thiooctanoate, and other compounds listed in PCT/US98/17391, filed Aug. 21, 1998.
Cyano containing groups are exemplified by 3-cyanopropyl.
Epoxy-containing groups are exemplified by glycidoxypropyl and xcex2-(3,4-epoxycyclohexyl)ethyl.
The R1 groups may also be substituted by a silyl group. For instance, R1 may be a group, xe2x80x94Axe2x80x94W, which comprises a silyl group W and a divalent linking group A which is attached by an Sixe2x80x94C bonds to group W and to a silicon atom of the siloxane oligomer. Preferably such a group is internal (i e. non-terminal) to the oligomer. The divalent linking group A creates a non-siloxane bridge between the siloxane oligomer and the silyl group W. The linking group A may contain hetero atoms in the structure so long as Sixe2x80x94C bonds are used at the ends of the linking group to form the respective connections the oligomer and to the silyl group W. The linking group may be linear, branched or cyclic and may be olefinically or aromatically unsaturated. The linking group may be, for instance, alkylene, alkarylalkylene or alkarylene, or it may be alkylene which is interrupted by hetero-atom containing organic structures such as ether, including polyether; ester, including polyester; carbamate, including polyurethane; isocyanurate; thioether; polysulfide, including disulfide and tetrasulfide; or the like. Preferably the linking group is an alkylene of 2 to 12 carbon atoms. The linking group A may be substituted with silyl or siloxy functions, as well as unsaturated groups. Indeed, group A may form part of a backbone with relatively linear siloxane chains attached to either end of the group. Examples of linking groups A include cycloaliphatic groups such as 1,4-diethylenecyclohexylene:
or 1,3,-diethylene-5-triethoxysilylethylcyclohexylene:
branched or linear aliphatic groups such as ethylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, 1,3-butylene, 1,2-butylene or 2,2-dimethyl-1,3-propylene; arylene groups such as 1,4-phenylene; alkarylalkylene groups such as 1,4-diethylenephenylene:
divalent polyether groups of the formula:
xe2x80x94CrH2rxe2x80x94(OCsH2s)qxe2x80x94
where q is 1-50, preferably 1-5; r and s are integers of 2-6; and divalent thioether or polysulfide-containing groups of the formula:
xe2x80x94CtH2txe2x80x94Suxe2x80x94CtH2txe2x80x94
where t is 2-16, preferably 2-4, and u is 1-8, preferably 2-4. Preferably the linking group is an alkylene of 2 to 12 carbon atoms, more preferably 2-3 carbon atoms.
The silyl functional group W in the structure xe2x80x94AW may be a silyl group having hydrolyzable functionality, such as alkoxy or acetoxy functionality. Alternatively, the group W may be a silicon linked organosiloxane or polyorganosiloxane group. Preferably, the silyl group W is an alkoxysilyl group or a further siloxane oligomer of alkoxy silane monomers, more preferably a dialkoxysilyl and most preferably a trialkoxysilyl group.
A preferred group xe2x80x94Axe2x80x94W may be represented as xe2x80x94CfH2fxe2x80x94SiR1g(X)3-g wherein the structure xe2x80x94CfH2fxe2x80x94 corresponds to A and the structure xe2x80x94SiR2g(X)3-g corresponds to W. Suitably, f=2 to 12, g=0 to 2, X is a hydrolyzable group such as halogen, oxime, alkoxy, aryloxy, alkenoxy or acetoxy and R1 is as previously defined. More preferably f=2 to 6, g=0-1, X is methoxy, ethoxy or acetoxy, and R1 is methyl. Exemplary such groups are xe2x80x94C2H4Si(OCH3)3; xe2x80x94C2H4Si(OC2H5)3; xe2x80x94C2H4Si(OCH3)2(CH3); xe2x80x94C2H4Si(OCH3)2Cl; xe2x80x94C2H4(C6H9)(C2H4Si(OCH3)3)2; xe2x80x94C2H4(C5H8)C2H4Si(OC2H5)3; and xe2x80x94C2H4Si(OCH3)2(OSi(OCH3)3).
R2 is a C1-C6 alkyl group or an acyl group. Exemplary R2 groups are methyl, ethyl, 1i-propyl, n-propyl, 1-butyl, t-butyl, pentyl, cyclohexyl, octyl, acetyl, benzoyl and propionyl. Preferably R2 is lower alkyl (C1-C6), more preferably methyl or ethyl.
R3 is a C8 or higher alkyl or alkenyl group. Examples include octyl, nonyl, decyl, dodecyl and alkyl groups derived from fatty acids, which may be saturated or unsaturated, for instance myristyl, palmityl, stearyl, palmitoleyl, oleyl, linoleyl, and mixtures such as coco alkyl, tallow alkyl, etc. Preferred R3 groups are C10-C16 saturated hydrocarbon groups, especially dodecyl.
Preferably m+n+o+p less than 50, more preferably xe2x89xa645, even more preferably  less than 30 and most preferably  less than 15. In its broadest aspect, m=2 to 20, n=0 to 50, o=0 to 20 and p=0 to 10. Preferably, m=2 to 10, n=0 to 20, o=0 to 20 and p=0 to 10. More preferably m=2 to 10, n=0 to 20, o=0 to 10 and p=0 to 5. Even more preferably m is 2 to 4, n is to 1 to 15, o is 0 to 2 and p is 0 to 1, though it is understood there may be distributions of the number of siloxy units within a given oligomer batch. This preference will also depend on the oligomer structure itself. It should also be noted from the foregoing that while linear structures are among the even more preferred structures, linearity is not necessary. The preferred, more preferred and even more preferred structures may also include branched structures.
Preferably there are multiple xe2x80x94OR2 groups available on the oligomer so that upon curing these oligomers may cross-link with each other and/or the inorganic filler, if present. Thus, R is xe2x80x94OR2, more preferably ethoxy or methoxy, in at least one quarter of the R groups, while the remainder of the R groups are R1 or xe2x80x94OR3 groups. More preferably at least half of the R groups are xe2x80x94OR2 or xe2x80x94OR3 groups. Also preferably, with respect to the individual M (terminal) or D (linear) units of the oligomer, if one R is R1 it is preferred that the other R group or groups on such unit are xe2x80x94OR2 and/or xe2x80x94OR3.
It is preferred that the oligomer has a viscosity of 0.5 to 500 csks or more preferably 0.5 to 200 csks (25xc2x0 C.). As is clear to one of skill in the art, the viscosity of the oligomer may be adjusted by adjusting the number of siloxy groups in the oligomer. In most applications the viscosity will be adjusted for a specific application to ensure that the composition containing the oligomer will spread over a specific substrate or be sprayable.
Oligomer Manufacture
The oligomers may be formed by condensation reactions of one or more silane compounds having an average of 2 or more xe2x80x94OR2 groups per molecule, in a manner such that at least one xe2x80x94OR2 group remains on the oligomer, and then fully or partially transesterifying the oligomer xe2x80x94OR2 groups with a C8 or higher alcohol. The individual silane compounds used to prepare the oligomers have at least one alkoxy group or acyloxy group, but preferably are di- or tri-alkoxy silanes.
The condensation may be performed according to any of the procedures disclosed in the previously identified patents, U.S. Pat. No. 4,950,779, Wengrovius, et al., U.S. Pat. No. 5,298,998, Horn, et al., U.S. Pat. No. 5,210,168, Bergstrom, et al., and in U.S. Pat. No. 6,323,277 and WO Application No. PCT/US99/08533, all of which documents are incorporated herein by reference.
Representative examples of alkoxysilanes which may be used in the condensation reaction include: vinyltrimethoxysilane, vinylmethyldimethoxysilane, vinyldimethylmethoxysilane, vinyltriethoxysilane, vinyltriisopropenoxysilane, methacryloxypropyltriethoxysilane, methacryloxypropyltrimethoxysilane, acryloxypropyltrimethoxysilane, acryloxypropyltriethoxysilane, acryloxyethyltrimethoxysilane, trimethoxysilylpropyl methyl maleate, styryloxypropyltriethoxysilane, allyltrimethoxysilane, allyloxypropyltriethoxysilane, allyl-N-(3-trimethoxysilylpropyl)carbamate, methacrylamidopropyltriethoxysilane, methacryloxypropyleneoxypropylmethyldimethoxysilane, crotyloxypropyltrimethoxysilane, 1,4-bis-(triethoxysilylethyl)cyclohexane; 1,3,5-tris-(triethoxysilylethyl)cyclohexane; bis-(triethoxysilylethyl)benzene; tris-triethoxysilylethyl isocyanurate, 1,4-bis-(triethoxysilyl)butane, phenyltrimethoxysilane, phenylmethyldimethoxysilane, napthyltrimethoxysilane, cyanopropyltriethoxysilane, glycidoxypropyltriethoxysilane, beta-(3,4-epoxycyclohexyl)trimethoxysilane, (polyethyleneoxy)propyltrimethoxysilane, (poly(ethyleneoxy)(propyleneoxy))propyltriethoxysilane, 3-trimethoxysilylpropyl acetate, 3-methyldiethoxysilylpropyl acetate, phenyl N-(3-trimethoxysilylpropyl)carbamate, 3-triethoxysilylpropyl N-phenylcarbamate, methyl N-(3-trimethoxysilylpropyl)carbamate, 3-methyldiethoxysilylpropyl thioacetate, 3-trimethoxysilylpropyl thioacetate, 3-triethoxysilylpropyl thioacetate, 3-trimethoxysilylpropyl thiopropionate, 3-triethoxysilylpropyl thiobenzoate; 3-triethoxysilylethyl thioacetate, 3-triethoxysilylmethyl thioacetate, 3-triethoxysilylpropyl thiooctanoate, and the like. Corresponding compounds in which silylalkoxy groups are replaced by silyloxyacetyl groups may also be used.
Moreover, in the condensation, dialkoxysiloxy units may be inserted into the oligomer to affect the cross-linking, surface active and viscoelastic properties of the oligomer. This may be done by using tetraalkoxysilanes, such as tetramethoxysilane or tetraethoxysilane.
The condensation of the alkoxy silane monomers is suitably performed in the presence of a carboxylic acid (e.g., acetic or formic acid) or water. Alternatively, a strong condensation catalyst may be used, e.g., a strong acid or an acidic ion exchange resin such as AMBERLYST resin from Rohm and Haas Co. The other reaction conditions of the condensation will depend on the monomeric silanes; however, temperature ordinarily will be in the range of 20 to 60xc2x0 C.
The oligomers of the invention are useful as crosslinkers, coupling agents, adhesion promoters, as intermediates for the preparation of other oligomers and as filler treating agents. Illustrative compositions into which the oligomers may be incorporated include curable polymer/filler compositions used for wire and cable insulation and the like; silicate hard coats; adhesion promoting primers for paints or adhesives; masonry sealants; UV or EB cured acrylic coatings; (meth)acrylate ester based adhesives and sealants, such as anaerobic adhesives and polymer-in-monomer syrup adhesives; polyester resin systems used to form reinforced composites with fiberglass, carbon or kevlar reinforcements; and RTV silicones.
The oligomers may also be converted to hydrolyzates, in which the OR2 groups are replaced by OH, and used in that form in aqueous dispersions, as adhesion promoting or sealing primers, as additives to polymer emulsions, as filler treating agents and in curable silicone formulations.
Curable Polymer/Filler Compositions
Curable polymer/filler compositions of the present invention may comprise: (1) a free-radically curable organic polymer, (2) an inorganic filler and (3) an oligomer of the invention. The composition may also include a free-radical catalyst or generator. Typical organic polymers to which the present invention applies are curable elastomers such as any of the synthetic or natural rubbers with which fillers are conventionally employed. Examples include natural rubber, synthetic rubbers such as styrene-butadiene rubber, ethylene-propylene copolymers, polyethylene, ethylene-vinyl acetate copolymers, ethylene-propylene terpolymer rubbers in which the third monomeric component is ethylidene norbornene or 1,4-hexadiene, urethane rubbers, polyisobutadiene rubbers, and any other vulcanizable or crosslinkable elastomeric material.
The inorganic fillers which may be used in the curable compositions are known to those skilled in the art and include any suitable finely divided or particulate inorganic substance. At the time of incorporation into the curable composition most fillers may be in the form of finely divided particles. They may be approximately isometric, having a maximum diameter, i.e., a maximum linear dimension of ten xcexcm, preferably five xcexcm; or they may be in the form of plates or needles (fibers) having a thickness or diameter of twenty pm or less, preferably five pm or less. Compositions containing larger particles may be usefully formulated, but they tend to give poor properties. The minimum size of the filler particles is not critical, any of the conventionally used fillers being suitable in this respect. Among the specific fillers which may be used in the present invention are asbestos, ground glass, kaolin and other clay minerals, silica, calcium silicate, calcium carbonate (whiting), magnesium oxide, barium carbonate, barium sulfate (barytes), metal fibers and powders, glass fibers, refractory fibers, titanium dioxide, mica, talc, chopped glass, alumina, aluminatrihydrate, quartz, wollastonite (calcium silicate), and inorganic coloring pigments. Kaolin clay is a filler of choice in the wire and cable industry and therefore is preferred.
A heat activated free-radical catalyst or generator will typically be incorporated into the curable compositions of the invention. However, in some cases such a catalyst may not be required, for instance when the oligomer contains disulfide or polysulfide groups, or when other sources of free radicals are used such as UV radiation. When a free-radical catalyst is employed it may be any known catalyst or vulcanizing agent compound, of which organic peroxides, azonitrile compounds (e.g. AIBN) and sulfur are examples. Metal drier compounds, such as fatty acid, octoate or naphthoate salts of zinc, calcium, cobalt, copper, molybdenum, manganese, chromium or nickel, may also be used as cure catalysts. Preferred catalysts are organic peroxides. Any of the peroxides described or listed in Martens"" U.S. Pat. No. 3,148,169 can be employed. The catalyst is one which is heat activated so that when a mixture of the organic elastomer and catalyst is heated to a given temperature or temperature range the crosslinking reaction takes place.
Any other additives conventionally employed in free-radically curable polymer/filler to the curable composition can be used. For example, stabilizers and antioxidants, cure boosters, cure activators, cure accelerators, crosslinkers, waxes, oils, wet electrical stabilizers, and plasticizers can be added. Additional pigmentation can be provided and any other additive for providing or modifying other properties can be used. Other silane crosslinkers, such as vinyltrimethoxysilane or (meth)acryloxytrimethoxysilane, may also be included in the composition, or such silanes may incorporated into the organic polymer backbone by copolymerization.
The proportions of components in the curable composition are not narrowly critical and conventionally are based on weight parts per 100 wt. parts of organic elastomer. On this basis the inorganic filler can be varied from 25 to 200, preferably 50 to 150, wt. parts per 100 wt. parts of elastomer. The coupling composition can be present in an amount ranging from 0.1 to 10, preferably from 0.5 to 3 weight parts per 100 wt. parts of filler and the peroxide or other radical catalyst can be used in amounts of 0.5 to 10 wt. parts, preferably 2 to 5 wt. parts per 100 wt. parts of elastomer.
The curable compositions, except for the catalyst component are conventionally prepared in a BANBURY mixer (Farrel Co.) or any other intensive mixer. Accepted rubber industry compounding techniques may be used. The catalyst, if employed, may be added in the BANBURY mixer or by transferring the resulting compound to a roll mill wherein it is rolled and the peroxide is added and mixed into the compound. Either way, the result is a curable composition which then can be used to coat electrical conductors for the purpose of insulating same after curing. These compositions can also be used for a variety of other applications where low water pickup is desirable, for instance encapsulating of electrical components and other electrical insulation applications, gaskets, seals, pump diaphragms, automotive ignition wires, sulfur cured rubbers, etc. Wire and cable insulations are preferred uses for the filled compositions of the invention.
In order to cure the curable compositions it is only necessary to apply heat above the temperature at which the catalyst becomes activated. Preferably a peroxide is chosen for use having a decomposition temperature in excess of 200xc2x0 F. (93xc2x0 C.), preferably in excess of 250xc2x0 F. (121xc2x0 C.). In producing insulated wire cable the curable composition, in heated readily deformable condition (but below the decomposition temperature of the catalyst), is applied through an extruder to a conductor to form an insulating coating around the conductor. After extrusion onto the conductor the combined conductor and coating of curable composition is passed into an oven or autoclave where the temperature is raised to a point above the decomposition temperature of the peroxide upon which the curable composition crosslinks to form a tough cured thermoset insulating coating around the conductor.
Other Curable Compositions
These oligomers of formula (1) above, are also useful in coatings or adhesive formulations, as crosslinkers, adhesion promoters, to provide a dual radical/moisture cure mechanism, and/or to provide moisture resistance in the cured coating. The oligomers may be used as reactive diluents, in that they have little volatility, provide little or no contribution to volatile organic compounds (VOCs) and have an adjustable viscosity to match an application, or to dilute another composition to make the entire composition spreadable or sprayable. For such applications oligomers in which R3 comprises an acrylate or methacrylate group are preferred.
The oligomers may be used in masonry waterproofing, paints, corrosion protection systems, and on substrates such as cement, metal, polymers (PVC, PVS, EPDM, PE, PP, ABS, EPR, BR, silicone, polycarbonate, etc.), wood, a paint layer (as a primer) or rubber. Moreover, oligomers may be used in silicate hardcoats.
The oligomers may also be employed in curable compositions comprising ethylenically unsaturated monomers or prepolymers and a free-radical catalyst. Such compositions include UV or EB curable adhesives and coatings, resins and gel-coats formulated from unsaturated polyesters, anaerobically curable adhesives, acrylic engineering adhesives based on polymer-in-monomer syrups, and the like. For such applications the oligomer preferably comprises a free-radically curable group, for instance one or more R3 groups, or vulcanizable group, such as a blocked mercaptan or polysulfide. More preferably the oligomer comprises at least one vinyl, acryl or methacryl group. The oligomer may be employed at levels of from about 0.5 to about 99% of such compositions, preferably about 1 to about 50%, depending on the properties desired to be obtained or modified in the cured formulations.
The adhesive and coating compositions of the invention also will typically include a free-radical catalyst, although this is not always necessary, for instance in formulations designed for EB curing or where the oligomer contains a polysulfide group in the bridge group B or in an R4 group. The free radical catalyst may be any of the heat activatable catalysts described above or a free radical photoinitiator. Examples of free-radical photoinitiators include benzophenone, acetophenone, chlorinated acetophenone, dialkoxyacetophenones, dialkylhydroxyacetophenones, dialkylhydroxyacetophenone esters, benzoin, benzoin acetate, benzoin alkyl ethers, dimethoxybenzoin, dibenzylketone, benzoylcyclohexanol and other aromatic ketones, acyloxime esters, acylphosphine oxides, acylphosphosphonates, ketosulfides, dibenzoyldisulphides, diphenyldithiocarbonate and diphenyl(2,4,6-trimethylbenzoyl) phosphine oxide. Typically the photoinitiator will be employed in an amount of 0.1 to 10%, preferably 0.5 to 5% by weight of the composition.
The adhesive or coating compositions of the invention may also include any other component conventional for the type of formulation into which the oligomer is incorporated.
The invention is illustrated by the following examples.

Silicone oligomers with higher alkoxy groups

Abstract: An oligomer of the formula:

Abstract: [R3SiOxc2xd]m[Oxc2xdSi(R2)Oxc2xd]n[SiO{fraction (3/2)}R]o[SiO{fraction (4/2)}]pxe2x80x83xe2x80x83(I)

Abstract: wherein

Abstract: each R is selected individually from the group consisting of R1, xe2x80x94OR2 and xe2x80x94OR3; each R1 is independently a substituted or unsubstituted hydrocarbon group; each R2 is a C1-C6 alkyl group or an acyl group; and each R3 is a independently an alkyl or alkenyl group having at least 8 carbon atoms;

Abstract: with the provisos that

Abstract: The oligomer is a useful component of in insulation formulations for wire and cable used in underground locations.