The cosmetic topical formulation of this invention is directed toward diminishing skin wrinkling, fine line, improving skin tone, and combinations thereof. Preferably, the topical formulation contains a matrix metalloproteinase inhibitor, MMPI, and advantageously includes a natural estrogen, e.g., a true estrogen compound, such as 17-beta estradiol, or an estrogen-like steroid, (such as various phytoestrogens found in herbal preparations), as opposed to a synthetic estrogen. Other forms of the cosmetic topical formulation of this invention include combinations of synthetic estrogen and MMP inhibitor. Exemplary synthetic estrogens include, but are not limited to, ethinyl estradiol and clomiphine citrate. The cosmetic topical formulation is safe and effective diminishing wrinkling, and improving skin tone. Certain compositions of this invention are useful for minimizing photodamage to skin, while in other embodiments, the composition according to this invention is useful to prevent or minimize the adverse effects on skin induced by cigarette smoking.

This invention provides a composition and method for reducing or preventing wrinkling and damage of skin upon topical application.
As women go through menopause and men age, both experience increased skin wrinkling and decreased skin thickness. Until recently, the molecular mechanism responsible for these skin changes was not well understood. In post-menopausal women, the decreasing levels of plasma estrogen obviously plays a role in the process, but estrogen""s influence on the molecular pathways that lead to skin wrinkling and skin thinning was not recognized until recently. Ascroft et al. reported that oral estrogen replacement therapy reversed the delay in healing of skin biopsy wounds observed between pre-menopausal women and healthy post-menopausal women. (See G. S. Ascroft et al, xe2x80x9cEstrogen Accelerates Cutaneous Wound Healing Associated with an Increase in TGF-xcex21,xe2x80x9d Nature Medicine 3:1209-1215, 1997; Ascroft et al., xe2x80x9cHuman Ageing Impairs Injury-induced in Vivo Expression of Tissue Inhibitors of Matrix Metalloproteinases (TIMP-1 and -2 Proteins and mRNA,xe2x80x9d J. Pathol. 183:169-176, 1997; Ascroft et al., xe2x80x9cAge-Related Changes in the Temporal and Spatial Regulation of Matrix Metalloproteinases (MMP) Protein and mRNA Profiles in Normal Skin and Acute Cutaneous Wounds of Healthy Humans,xe2x80x9d Cell tissue Res. 290:581-591, 1997). In addition, they reported that systemic estrogen replacement therapy increased the level of transforming growth factor protein and decreased the levels of matrix metalloproteinases in wound sites. This discovery led Ascroft, et al., to hypothesize that systemic estrogen replacement therapy stimulated production of TGF-xcex21, which is known to stimulate synthesis of extracellular matrix proteins including collagen and simultaneously decreases the production of matrix metalloproteinase. The result of these combined effects of estrogen was to promote healing of the full-thickness punch wounds in the skin of post-menopausal women.
In a subsequent paper, Ascroft et al., investigated the effects of topical estrogen treatment in aged humans. (Ascroft et al., xe2x80x9cTopical Estrogen Accelerates Cutaneous Wound Healing in Aged Humans Associated with an Altered Inflammatory Response,xe2x80x9d Am. J. Pathol. 155:1137-1146, 1999). The skin punch biopsy model was utilized as before, but instead of placing the patients on oral estrogen replacement therapy or not, aged men (average age of 70 years old), and women (average age of 74 years old) were randomized to receive either estrogen (25 micrograms estradiol per 24 hours) delivered topically by a skin patch placed over the wound or placebo. Compared to placebo, topical estrogen treatment increased the extent of wound healing in both males and females with a decrease in wound size at day 7, increased collagen levels at both days 7 and 80, and increased fibronectin levels at day 7.
Taken together, these studies indicate that systemic or topical estrogen may improve healing of full-thickness skin wounds in aged men and women, by increasing the levels of TGF-xcex21 which in turn increases synthesis of collagen and simultaneously decreases levels of matrix metalloproteinases.
In U.S. Pat. No. 6,130,254, methods for inhibiting photoaging of skin are disclosed. The method disclosed includes the use of UVA and UVB blockers in combination with an MMP inhibitor, such as a retinoid. In one composition, a composition comprising a retinoid in combination with a flavone or isoflavone compound was disclosed and claimed for application to the skin at least eight hours prior to exposure to the sun.
None of the art identified by the present inventors includes the combination of a MMPI, and an estrogen or phytoestrogen for long-term, daily application to reduce the effects of aging on skin (wrinkling, fine lines, loss of tone, and the like). The present invention provides a solution that meets this need. In addition, in specific compositions according to this invention, combinations of non-retinoid MMP inhibitors, and non-flavone or isoflavone phytoestrogens are used in combination with known UVA and UVB blockers to treat, including to reverse, reduce, prevent or avoid aging photoaging of skin, including fine lines and wrinkles in skin.
The cosmetic topical formulation of this invention is directed toward diminishing skin wrinkling, improving skin tone, or both. Preferably, the topical formulation contains a matrix metalloproteinase inhibitor, MMPI, and advantageously includes a natural estrogen, e.g., a true estrogen compound, such as 17-beta estradiol, or an estrogen-like steroid, (such as various phytoestrogens found in herbal preparations), as opposed to a synthetic estrogen. Other forms of the cosmetic topical formulation of this invention include combinations of synthetic estrogen and MMP inhibitor. Exemplary synthetic estrogens include, but are not limited to, ethinyl estradiol and clomiphine citrate. The cosmetic topical formulation is safe and effective in diminishing wrinkling, and improving skin tone. In specific formulations, the composition of this invention may furthermore be used to reduce or reverse photoaging or cigarette smoking induced wrinkling or fine lines that occurs in living human skin.
In one exemplary embodiment of the present invention, a combination of a natural or synthetic estrogen with an MMP inhibitor, such as Ilomostat, is provided in a topical formulation for use as a cosmetic anti-wrinkle cream. The combination of the estrogen and the MMP inhibitor synergistically promotes deposition of new extracellular matrix and reduces its turnover, resulting in the reduction in wrinkling and thinning associated with normal skin aging. In addition, the method and composition according to this invention is useful in limiting the degree of skin wrinkling, fine lines and aging associated with cigarette smoking, cigar smoking, second hand smoke exposure, and the like, bum victims, fire-fighters, and others exposed to smoke.
The matrix metalloproteinase inhibitors (MMPIs) for use according to this invention include, but are not limited to, those MMPI compounds disclosed and claimed in U.S. Pat. Nos. 5,892,112; 5,773,438; 5,696,147, all of which are hereby incorporated herein by reference. Ilomostat is one preferred MMPI.
Collagen molecules provide the major tensile strength of the skin. As a person ages, protein components in the extracellular matrix of the dermis, such as collagen molecules, become degraded. As a result, the skin begins to sag, wrinkle, and thin. The second component of the present topical formulation, the MMP inhibitor, addresses this problem. A preferred MMP-inhibitor is Ilomostat, which is a small, modified dipeptide and an extremely potent inhibitor of the major classes of MMPs present in the skin including collagenases, gelatinases, and stromelysins. Ilomostat also has the desirable property of being amphipathic, which means that it has both hydrophobic and hydrophilic properties. Therefore, Ilomostat can diffuse through the hydrophobic keratinized layers of the epidermal layer of the skin, and also interact with the proteases that are present in the water-filled extracellular matrix of the dermis. Although the topical formulation includes Ilomostat, other MMP inhibitors (natural or synthetic or both) may be used in other embodiments of the topical formulation, such as tissue inhibitors of metalloproteinases (TIMP), Galardin, Batimastat, Marimastat or any hydroxamate-based synthetic inhibitors.
As discussed above, the topical formulation is a cosmetic composition, as opposed to a prescription drug. The cosmetic topical formulation of this invention is directed toward diminishing skin wrinkling, skin tone, or both. Preferably, the topical formulation includes an MMPI, and also advantageously includes a natural estrogen, e.g., a true estrogen compound, such as 17-beta estradiol, or an estrogen-like steroid, (such as various phytoestrogens found in herbal preparations), as opposed to a synthetic estrogen. Other forms of the cosmetic topical formulation of this invention include combinations of synthetic estrogen and MMP inhibitor. Exemplary synthetic estrogens include, but are not limited to, ethinyl estradiol and clomiphine citrate. In preferred compositions according to this invention, an extract of a plant rich in plant compounds having estrogen or estrogen-like activity is combined with the MMPI. Thus, in one specific embodiment of this invention, the plant extract is an extract of black cohosh, (Cimicifuga racemosa), which has been shown to contain a variety of triterpene glycosides (see, for example, Shao, et al., J. Nat. Prod., 2000, 63, 905-910, herein incorporated by reference for this purpose). In the present invention disclosure, we demonstrate that a composition comprising triterpene glycosides, a known class of phytoestrogens, in combination with a known MMPI results in dramatic reduction in skin wrinkling.
The cosmetic topical formulation is safe and effective for diminishing wrinkling, and improving skin tone. Known carriers for the skin are various creams, gels and solutions, many of which are adapted for facilitating transdermal penetration of the biologically effective agent included in the applied composition.
Compositions according to this invention, in addition to the foregoing compositions, which are intended for daily usage, without regard to exposure to the sun, may include compositions for diminishing, avoiding, or preventing photoaging of skin. As noted, in U.S. Pat. No. 6,130,254, certain compositions and methods of use thereof, were disclosed, comprising retinoids for reducing the degree of MMP expression in response to exposure to sunlight, in combination with flavone or isoflavone compounds. In addition, the composition contained UVA and UVB blockers. The disclosure of the U.S. Pat. No. 6,130,254 patent is hereby incorporated by reference for the purpose of providing known compositions comprising UVA and UVB blockers. However, compositions of the present invention that are adapted for application to the skin prior to exposure to the sun include direct inhibitors of matrix metalloproteinases, as described above, rather than indirect suppressors of matrix metalloproteinase expression. As a result, the present composition may be applied to the skin in a time frame much more proximate to the anticipated exposure to sun than the eight hours disclosed as being optimal according to the U.S. Pat. No. 6,130,254 patent. In addition, compositions of this invention which are adapted for reducing photoaging of the skin comprise estrogen, synthetic estrogen, phytoestrogens other than flavones or isoflavones, such as the triterpene glycosides present in plant extracts, such as black cohosh.
As disclosed herein, testing of the cosmetic topical formulation of this invention has been conducted on volunteers and the effects of the composition on wrinkling was scored. Embodiments of the present invention are found to dramatically increase the tone and reduce wrinkling of skin by either visual inspection or photomicrograhic analysis.
In a further exemplary embodiment of this invention, a prescription topical formulation is prepared, based on similar principles to those described above, except in higher dosages than for the cosmetic formulation described above. The prescription formulation, like the cosmetic formulation, includes an MMP inhibitor in combination with at least one natural or synthetic estrogen or both.
Those skilled in the art will appreciate that a wide variety of cosmetic vehicles may be employed according to the present invention. For example, the vehicle may be a simple combination of a buffered solution of propylene glycol, and an acrylate gelation agent, or any of a wide variety of known or commercially available cream or gel formulations. In a further composition according to this invention, a carrier is included which itself has been shown to have beneficial effects for wrinkle reduction. Thus, for example, the carrier may be that disclosed according to U.S. Pat. No. 5,885,596, hereby incorporated by reference. According to that patent, a composition comprising about 40% by weight of water; up to about 35% by weight, of a permeation enhancing compound selected from the group consisting of dibutyl adipate, isopropyl myristate and combinations thereof; up to about 15% by weight of a fatty alcohol; and one or more emollients or moisturizing humectants. As disclosed in the ""596 patent, such a carrier, containing no active agents, has a significant anti-wrinkle effect. According to the present invention, in one embodiment, the carrier disclosed according to the ""596 patent, or an equivalent thereof, is combined with the active agents as disclosed herein, namely an MMPI and an estrogen, or phytoestrogen. Furthermore, UVA and UVB blocking agents, such as those disclosed according to the U.S. Pat. No. 6,130,254 patent, may be included to provide a composition effective at preventing, minimizing or avoiding photoaging.
For each component, an effective amount is that amount correlative with the amount of matrix metalloproteinase, and estrogen, phytoestrogens or both, consistent with reduction in wrinkling required in a given time period. The ratio of MMPI to estrogen/phytoestrogen in the composition might be in the range of about 1000:1 to about 1:1000 on a molar basis, so long as at least an additive effect is noted as compared to use of the MMPI alone or the estrogenic compound alone. Other desirable ratios include, but are not limited to 100:1 to about 1:100, 10:1 to about 1:10, and about 1:1 ratios, all of which may be verified by routine experimentation based on the present disclosure. Concentrations of about 10 ng/mL to about 100 mg/mL of the MMPI are preferred. Preferably, the estrogen or phytoestrogen is present in the composition at a concentration of about 10 ng/mL to about 100 mg/mL, depending on such routinely defined parameters as solubility and dose response requirements for prevention or reduction of skin wrinkling.
In light of the general disclosure provided herein above, with respect to the manner of practicing this invention, and the manner of making the composition according to this invention, those skilled in the art will appreciate that this invention enables the practice of the invention as defined in the attached claims. However, the following experimental details are provided to ensure a complete written description of this invention, including of the best mode thereof. However, it will be appreciated that the scope of this invention should not be construed in terms of the specific examples provided. Rather, the scope of this invention is to be apprehended with reference to the claims appended hereto, in light of the complete description of this invention constituted by this entire invention disclosure.

University of Florida Research Foundation, Inc.


Compounds having the following formula (I), or a stereoisomer or pharmaceutically-acceptable salt thereof, where R1, R2, R3, R4, and R5 are as defined herein, are useful in the modulation of IL-12, IL-23 and/or IFNα, by acting on Tyk-2 to cause signal transduction inhibition.

The heterodimeric cytokines interleukin (IL)-12 and IL-23, which share a common p40 subunit, are produced by activated antigen-presenting cells and are critical in the differentiation and proliferation of Th1 and Th17 cells, two effector T cell lineages which play key roles in autoimmunity. IL-23 is composed of the p40 subunit along with a unique p19 subunit. IL-23, acting through a heterodimeric receptor composed of IL-23R and IL-12Rβ1, is essential for the survival and expansion of Th17 cells which produce pro-inflammatory cytokines such as IL-17A, IL-17F, IL-6 and TNF-α (McGeachy, M. J. et al., "The link between IL-23 and Th17 cell-mediated immune pathologies", Semin. Immunol., 19:372-376 (2007)). These cytokines are critical in mediating the pathobiology of a number of autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and lupus. IL-12, in addition to the p40 subunit in common with IL-23, contains a p35 subunit and acts through a heterodimeric receptor composed of IL-12Rβ1 and IL-12Rβ2. IL-12 is essential for Th1 cell development and secretion of IFNγ, a cytokine which plays a critical role in immunity by stimulating MHC expression, class switching of B cells to IgG subclasses, and the activation of macrophages (Gracie, J. A. et al., "Interleukin-12 induces interferon-gamma-dependent switching of IgG alloantibody subclass", Eur. J. Immunol., 26:1217-1221 (1996); Schroder, K. et al., "Interferon-gamma: an overview of signals, mechanisms and functions", J. Leukoc. Biol., 75(2):163-189 (2004)).
The importance of the p40-containing cytokines in autoimmunity is demonstrated by the discovery that mice deficient in either p40, p19, or IL-23R are protected from disease in models of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, lupus and psoriasis, among others (Kyttaris, V. C. et al., "Cutting edge: IL-23 receptor deficiency prevents the development of lupus nephritis in C57BL/6-lpr/lpr mice", J. Immunol., 184:4605-4609 (2010); Hong, K. et al., "IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis like skin disorder", J. Immunol., 162:7480-7491 (1999); Hue, S. et al., "Interleukin-23 drives innate and T cell-mediated intestinal inflammation", J. Exp. Med., 203:2473-2483 (2006); Cua, D. J. et al., "Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain", Nature, 421:744-748 (2003); Murphy, C. A. et al., "Divergent pro- and anti-inflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation", J. Exp. Med., 198:1951-1957 (2003)).
In human disease, high expression of p40 and p19 has been measured in psoriatic lesions, and Th17 cells have been identified in active lesions in the brain from MS patients and in the gut mucosa of patients with active Crohn's disease (Lee, E. et al., "Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris", J. Exp. Med., 199:125-130 (2004); Tzartos, J. S. et al., "Interleukin-17 production in central nervous system infiltrating T cells and glial cells is associated with active disease in multiple sclerosis", Am. J. Pathol., 172:146-155 (2008)). The mRNA levels of p19, p40, and p35 in active SLE patients were also shown to be significantly higher compared with those in inactive SLE patients (Huang, X. et al., "Dysregulated expression of interleukin-23 and interleukin-12 subunits in systemic lupus erythematosus patients", Mod. Rheumatol., 17:220-223 (2007)), and T cells from lupus patients have a predominant Th1 phenotype (Tucci, M. et al., "Overexpression of interleukin-12 and T helper 1 predominance in lupus nephritis", Clin. Exp. Immunol., 154:247-254 (2008)).
Moreover, genome-wide association studies have identified a number of loci associated with chronic inflammatory and autoimmune diseases that encode factors that function in the IL-23 and IL-12 pathways. These genes include IL23A, IL12A, IL12B, IL12RB1, IL12RB2, IL23R, JAK2, TYK2, STAT3, and STAT4 (Lees, C. W. et al., "New IBD genetics: common pathways with other diseases", Gut, 60:1739-1753 (2011); Tao, J. H. et al., "Meta-analysis of TYK2 gene polymorphisms association with susceptibility to autoimmune and inflammatory diseases", Mol. Biol. Rep., 38:4663-4672 (2011); Cho, J. H. et al., "Recent insights into the genetics of inflammatory bowel disease", Gastroenterology, 140:1704-1712 (2011)).
Indeed, anti-p40 treatment, which inhibits both IL-12 and IL-23, as well as IL-23-specific anti-p19 therapies have been shown to be efficacious in the treatment of autoimmunity in diseases including psoriasis, Crohn's Disease and psoriatic arthritis (Leonardi, C. L. et al., "PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1)", Lancet, 371:1665-1674 (2008); Sandborn, W. J. et al., "Ustekinumab Crohn's Disease Study Group. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease", Gastroenterology, 135:1130-1141 (2008); Gottlieb, A. et al., "Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomized, double-blind, placebo-controlled, crossover trial", Lancet, 373:633-640 (2009)). Therefore, agents which inhibit the action of IL-12 and IL-23 may be expected to have therapeutic benefit in human autoimmune disorders.
The Type I group of interferons (IFNs), which include the IFNα members as well as IFNβ, IFNε, IFNκ and IFNω, act through a heterodimer IFNα/β receptor (IFNAR). Type I IFNs have multiple effects in both the innate and adaptive immune systems including activation of both the cellular and humoral immune responses as well as enhancing the expression and release of autoantigens (Hall, J. C. et al., "Type I interferons: crucial participants in disease amplification in autoimmunity", Nat. Rev. Rheumatol., 6:40-49 (2010)).
In patients with systemic lupus erythematosus (SLE), a potentially fatal autoimmune disease, increased serum levels of interferon (IFN)-α (a type I interferon) or increased expression of type I IFN-regulated genes (a so-called IFNα signature) in peripheral blood mononuclear cells and in affected organs has been demonstrated in a majority of patients (Bennett, L. et al., "Interferon and granulopoiesis signatures in systemic lupus erythematosus blood", J. Exp. Med., 197:711-723 (2003); Peterson, K. S. et al., "Characterization of heterogeneity in the molecular pathogenesis of lupus nephritis from transcriptional profiles of laser-captured glomeruli", J. Clin. Invest., 113:1722-1733 (2004)), and several studies have shown that serum IFNα levels correlate with both disease activity and severity (Bengtsson, A. A. et al., "Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies", Lupus, 9:664-671 (2000)). A direct role for IFNα in the pathobiology of lupus is evidenced by the observation that the administration of IFNα to patients with malignant or viral diseases can induce a lupus-like syndrome. Moreover, the deletion of the IFNAR in lupus-prone mice provides high protection from autoimmunity, disease severity and mortality (Santiago-Raber, M. L. et al., "Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice", J. Exp. Med., 197:777-788 (2003)), and genome-wide association studies have identified loci associated with lupus that encode factors that function in the type I interferon pathway, including IRF5, IKBKE, TYK2, and STAT4 (Deng, Y. et al., "Genetic susceptibility to systemic lupus erythematosus in the genomic era", Nat. Rev. Rheumatol., 6:683-692 (2010); Sandling, J. K. et al., "A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE", Eur. J. Hum. Genet., 19:479-484 (2011)). In addition to lupus, there is evidence that aberrant activation of type I interferon-mediated pathways are important in the pathobiology of other autoimmune diseases such as Sjögren's syndrome and scleroderma (Båve, U. et al., "Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism", Arthritis Rheum., 52:1185-1195 (2005); Kim, D. et al., "Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase I: association of higher interferon-alpha activity with lung fibrosis", Arthritis Rheum., 58:2163-2173 (2008)). Therefore, agents which inhibit the action of type I interferon responses may be expected to have therapeutic benefit in human autoimmune disorders.
Tyrosine kinase 2 (Tyk2) is a member of the Janus kinase (JAK) family of nonreceptor tyrosine kinases and has been shown to be critical in regulating the signal transduction cascade downstream of receptors for IL-12, IL-23 and type I interferons in both mice (Ishizaki, M. et al., "Involvement of Tyrosine Kinase-2 in Both the IL-12/Th1 and IL-23/Th17 Axes In Vivo" J. Immunol., 187:181-189 (2011); Prchal-Murphy, M. et al., "TYK2 kinase activity is required for functional type I interferon responses in vivo" PLoS One, 7:e39141 (2012)) and humans (Minegishi, Y. et al., "Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity" Immunity, 25:745-755 (2006)). Tyk2 mediates the receptor-induced phosphorylation of members of the STAT family of transcription factors, an essential signal that leads to the dimerization of STAT proteins and the transcription of STAT-dependent pro-inflammatory genes. Tyk2-deficient mice are resistant to experimental models of colitis, psoriasis and multiple sclerosis, demonstrating the importance of Tyk2-mediated signaling in autoimmunity and related disorders (Ishizaki, M. et al., "Involvement of Tyrosine Kinase-2 in Both the IL-12/Th1 and IL-23/Th17 Axes In Vivo" J. Immunol., 187:181-189 (2011); Oyamada, A. et al., "Tyrosine kinase 2 plays critical roles in the pathogenic CD4 T cell responses for the development of experimental autoimmune encephalomyelitis" J. Immunol. 183:7539-7546 (2009)).
In humans, individuals expressing an inactive variant of Tyk2 are protected from multiple sclerosis and possibly other autoimmune disorders (Couturier, N. et al., "Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility" Brain 134:693-703 (2011)). Genome-wide association studies have shown other variants of Tyk2 to be associated with autoimmune disorders such as Crohn's Disease, psoriasis, systemic lupus erythematosus, and rheumatoid arthritis, further demonstrating the importance of Tyk2 in autoimmunity (Ellinghaus, D. et al., "Combined Analysis of Genome-wide Association Studies for Crohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci" Am. J. Hum. Genet. 90:636-647 (2012); Graham, D. et al. "Association of polymorphisms across the tyrosine kinase gene, TYK2 in UK SLE families" Rheumatology (Oxford) 46:927-930 (2007); Eyre, S. et al. "High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis" Nat. Genet. 44:1336-1340 (2012)).
In view of the conditions that may benefit by treatment involving the modulation of cytokines and/or interferons, new compounds capable of modulating cytokines and/or interferons, such as IL-12, IL-23 and/or IFNα, and methods of using these compounds may provide substantial therapeutic benefits to a wide variety of patients in need thereof.

Imidazopyridazine compounds useful as modulators of IL-12, IL-23 and/or IFN-α responses


The invention relates to thermoplastic nanocomposites comprising

This application is a 371 of PCT/EP00/00967 filed Feb. 7, 2000.
The invention relates to thermoplastic nanocomposites with an advantageously balanced mechanical property profile.
Composite materials made from organic polymers, such as polyamides, and from phyllosilicates are known. These materials have high stiffness. However, while addition of the phyllosilicates improves stiffness, it reduces toughness.
It is usual for a stable mixture of the organic material with the inorganic material to be achieved by using an upstream step to modify the inorganic material.
WO 93/04117 relates to composite materials which have a polymer matrix and, dispersed therein, lamellar particles, preferably phyllosilicates. The particles are associated with onium compounds of the formulae
+NH3R1, +NH2R2R3, +PR4R5R6R7,
thus being hydrophobicized. The hydrophobicization step carried out is upstream of the mixing with the polymer.
DE-A 43 21 247 relates to polyamide resin compositions which comprise a polyamide component and an inorganic filler. Known silane coupling agents may be applied to the inorganic fillers in an upstream step in order to give stable mixing of the polyamide and the inorganic fillers.
It is an object of the present invention to provide thermoplastic nanocomposites with a balanced and advantageous mechanical property profile, dispensing with any modification of the inorganic material by way of an upstream step, such as hydrophobicization of the phyllosilicates used.
We have found that this object is achieved by way of thermoplastic nanocomposites comprising
a) a thermoplastic (A), in which from 0.1 to 10% by weight of the monomer units present in component (A) bear ionic groups, and
b) at least one phyllosilicate (B), uniformly dispersed in component (A).
The proportion of the monomer units present in component (A) which bear ionic groups is preferably from 2 to 8% by weight, particularly preferably from 4 to 6% by weight.
Injection moldings made from the thermoplastic nanocomposites of the invention have higher heat resistance, higher strength, and higher stiffness than those produced from known thermoplastic nanocomposites.
In comparison with glass-fiber-reinforced thermoplastics, an improvement is achieved in the surface of moldings produced from the thermoplastic nanocomposites, with comparable mechanical properties, with a lower filler content.
The thermoplastic nanocomposites of the invention preferably comprise
a) from 30 to 99.99% by weight, preferably from 30 to 79% by weight, particularly preferably from 30 to 68% by weight, of component (A),
b) from 0.01 to 20% by weight, preferably from 1 to 15% by weight, particularly preferably from 4 to 10% by weight, of component (B),
c) from 0 to 50% by weight, preferably from 10 to 30% by weight, particularly preferably from 15 to 20% by weight, of other fillers (C), and
d) from 0 to 50% by weight, preferably from 10 to 30% by weight, particularly preferably from 15 to 20% by weight, of other additives (D),
where all of the components together give 100% by weight.
The thermoplastics are preferably those selected from polyamides, vinyl polymers, polyesters, polycarbonates, polyaldehydes and polyketones. Polyamides are particularly preferred.
Possible polyamide-forming monomers are lactams, such as xcex5-caprolactam, enantholactam, capryllolactam and laurolactam, and also mixtures of these, preferably xcex5-caprolactam. Examples of other polyamide-forming monomers which may be used are dicarboxylic acids, for example alkanedicarboxylic acids having from 6 to 12 carbon atoms, in particular from 6 to 10 carbon atoms, such as adipic acid, pimelic acid, suberic acid, azelaic acid or sebacic acid, or else terephthalic acid or isophthalic acid, diamines, for example C4-C12-alkyldiamines, in particular having from 4 to 8 carbon atoms, such as hexamethylenediamine, tetramethylenediamine, or octamethylenediamine, or else m-xylylenediamine, bis(4-aminophenyl)methane, 2,2-bis(4-aminophenyl)propane, or bis(4-aminocyclohexyl)methane, or else mixtures of dicarboxylic acids and diamines in any desired combination within each group, but preferably in an equivalent ratio each to the other, for example hexamethylenediammonium adipate, hexamethylenediammonium terephthalate or tetramethylenediammonium adipate, preferably hexamethylenediammonium adipate or hexamethylenediammonium terephthalate. Particular industrial importance is attached to polycaprolactam, to polyamides composed of hexamethylenediamine and adipic acid, to polyamides composed of xcex5-caprolactam, hexamethylenediamine, isophthalic acid and/or terephthalic acid, in particular nylon-6 (from xcex5-caprolactam) and nylon-6,6 (from hexamethylenediamine/adipic acid).
Monomers suitable for preparing vinyl polymers are ethylene, propylene, butadiene, isoprene, chloroprene, vinyl chloride, vinylidene chloride, vinyl fluoride, vinylidene fluoride, styrene, xcex1-methylstyrene, divinylbenzene, acrylic acid, methyl acrylate, ethyl acrylate, n-propyl acrylate, isopropyl acrylate, n-butyl acrylate, isobutyl acrylate, tert-butyl acrylate, methacrylic acid, methyl methacrylate, ethyl methacrylate, n-propyl methacrylate, isopropyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, tert-butyl methacrylate, acrylamide, methacrylamide, ethylacrylamide, n-propylacrylamide, isopropylacrylamide, acrylonitrile, vinyl alcohol, norbornadiene, N-vinylcarbazole, vinylpyridine, 1-butene, isobutene, vinylidene cyanide, 4-methyl-1-pentene vinyl acetate, vinyl isobutyl ether, methyl vinyl ketone, vinyl vinyl ketone, methyl vinyl ether, vinyl vinyl ether, vinyl vinyl sulfide, and acrolein. These monomers may be used alone or in combination with one another. Preferred vinyl polymers are polystyrene, in particular syndiotactic polystyrene, polyethylene, polypropylene, and polyvinyl chloride.
Polyesters are also suitable thermoplastics, preferably those based on terephthalic acid and diols, particularly preferably polyethylene terephthalate and polybutylene terephthalate.
Other suitable thermoplastics are polycarbonates, polyketones, and polyaldehydes, such as polyoxymethylene.
According to the invention, from 0.1 to 10% by weight, preferably from 2 to 8% by weight, particularly preferably from 4 to 6% by weight, of the monomer units present in component (A) bear ionic groups.
This achieves stable mixing of the inorganic material with the thermoplastic without any need for modification of the inorganic material in an upstream step.
Preferred ionic groups are anionic groups, such as carboxylates, sulfonates, and phosphates, as long as it is possible to prepare the appropriate monomers suitable for polymerization. The ionic groups in the monomer units are particularly preferably carboxylates or sulfonates. The sodium salt of sulfoisophthalic acid is very particularly preferred.
Examples of suitable appropriate monomers are tri- and tetracarboxylic acids, and also carboxylic dianhydrides, and salts of tri- or tetrasulfonic acids.
Examples of tricarboxylic acids are benzene-1,2,3-tricarboxylic acid, 2-methylbenzene-1,3,5-tricarboxylic acid, trimellitic acid (benzene-1,2,4-tricarboxylic acid), and cis,cis-1,3,5-trimethyl-cyclohexane-1,3,5-tricarboxylic acid.
Examples of tetracarboxylic acids are cyclopentane-1,2,3,4-tetracarboxylic acid, cyclobutane-1,2,3,4-tetracarboxylic acid, and 2,2-dimethylcyclo-butane-1,1,3,3-tetracarboxylic acid.
Examples of suitable carboxylic dianhydrides are pyromellitic dianhydride, naphthalene-1,4,5,8-tetracarboxylic dianhydride, and 3,3,4,4-biphenyltetracarboxylic dianhydride.
Examples of suitable salts of tri- or tetrasulfonic acids are the trisodium salt of naphthalene-1,3,6-trisulfonic acid, the trisodium salt of 8-tetradecyloxypyrene-1,3,6-trisulfonic acid, and the tetrasodium salt of pyrene-1,3,6,8-tetrasulfonic acid.
It is preferable to use carboxylic dianhydrides, and particular preference is given to pyromellitic dianhydride.
In the aqueous polymerization solution, the monomers mentioned are present in the form of their corresponding anions.
Phyllosilicates are generally understood to be silicates in which the SiO4 tetrahedra have been bonded in infinite two-dimensional networks. (The empirical formula for the anion is (Si2O52xe2x88x92n)). The individual layers have bonding to one another via the cations lying between them, and the cations mostly present in the phyllosilicates which occur naturally are Na, K, Mg, Al and/or Ca.
Examples which should be mentioned of synthetic or naturally occurring phyllosilicates are montmorillonite, smectite, illite, sepiolite, palygorskite, muscovite, allevardite, amesite, hectorite, fluorohectorite, saponite, beidellite, talc, nontronite, stevensite, bentonite, mica, vermiculite, fluorovermiculite, halloysite, and fluorine-containing synthetic grades of talc. Particular preference is given to montmorillonite.
The layer thicknesses of the phyllosilicates are usually from 5 to 100 xc3x85, very particularly preferably from 8 to 25 xc3x85 (distance from the upper boundary of one layer to the upper boundary of the next layer).
The distance between the layers here may then be increased by using polyamide monomers to convert (swell) the phyllosilicates, e.g. at from 25 to 300xc2x0 C., preferably from 80 to 280xc2x0 C., and in particular from 80 to 260xc2x0 C., using a residence time which is generally from 5 to 120 min, preferably from 10 to 60 min. Depending on the length of the residence time and the nature of the monomer selected, the distance between the layers becomes enlarged by from 10 to 150 xc3x85, preferably by from 10 to 50 xc3x85. The length of the lamellae is usually up to 2,000 xc3x85, preferably up to 1,500 xc3x85. Any prepolymers present or formed generally also contribute to the swelling of the phyllosilicates.
Suitable fillers are particulate or fibrous fillers. Suitable particulate fillers are carbonates, such as magnesium carbonate or chalk. Preference is given to the use of fibrous fillers. Examples of suitable fibrous fillers are carbon fibers, potassium titanate whiskers, aramid fibers, and glass fibers. It is particularly preferable to use glass fibers. If glass fibers are used, these may have been provided with a size and with a coupling agent to improve compatibility with the matrix material. The diameter of the carbon fibers or glass fibers used is generally in the range from 6 to 16 xcexcm. The glass fibers incorporated may either be in the form of short glass fibers or else in the form of continuous-filament fibers (rovings). Carbon fibers or glass fibers may also be used in the form of wovens, mats, or glass silk rovings.
The compositions may also comprise additives. Examples of these additives are processing aids, stabilizers, and oxidation retarders, heat stabilizers, UV stabilizers, lubricants, mold-release agents, flame retardants, dyes, pigments, and plasticizers.
The amounts generally present of pigments and dyes are from 0 to 4% by weight, preferably from 0.5 to 3.5% by weight, and particularly preferably from 0.5 to 3% by weight, based on the total weight of the compositions.
The pigments for coloration of thermoplastics are well known, see for example R. Gxc3xa4chter and H. Mxc3xcller, Taschenbuch der Kunststoffadditive, Carl Hanser Verlag, 1983, pp. 494 to 510. A first preferred group of pigments which should be mentioned is that of white pigments, such as zinc oxide, zinc sulfide, white lead (2 PbCO3xc2x7Pb(OH)2), lithopones, antimony white, and titanium dioxide. Of the two commonest crystalline forms of titanium dioxide (rutile and anatase), it is particularly the rutile form which is used for white coloration of the thermoplastic nanocomposites of the invention.
Black pigments which may be used according to the invention are iron oxide black (Fe3O4), spinel black (Cu(Cr,Fe)2O4), manganese black (a mixture of manganese dioxide, silicon dioxide, and iron oxide), cobalt black and antimony black, and also particularly preferably carbon black, the forms mostly used being furnace black and gas black (in this connection see G. Benzing, Pigmente fxc3xcr Anstrichmittel, Expert-Verlag (1988), pp. 78 et seq.).
According to the invention it is, of course, possible to set particular shades of color by using inorganic color pigments, such as chromium oxide green, or organic color pigments, such as azo pigments or phthalocyanines. Pigments of this type are generally commercially available.
It can also be advantageous to use a mixture of the pigments or dyes mentioned, e.g. carbon black with copper phthalocyanines, since this generally makes it easier to disperse the color in the thermoplastic.
Examples of oxidation retarders and heat stabilizers which according to the invention may be added to the thermoplastic materials are halides of metals of group I of the Periodic Table, e.g. sodium halides, potassium halides, and lithium halides, where appropriate combined with copper(I) halides, e.g. chlorides, bromides, or iodides. The halides, in particular of copper, may also contain electron-rich xcfx80-ligands. Examples which may be mentioned of copper complexes of this type are Cu-halide complexes with, for example, triphenylphosphine. It is also possible to use zinc fluoride and zinc chloride. Use may moreover be made of sterically hindered phenols, hydroquinones, substituted members of this group, secondary aromatic amines, where appropriate combined with phosphorus-containing acids or, respectively, with salts of these, or mixtures of these compounds, generally in concentrations of up to 1% by weight, based on the weight of the mixture.
Examples of UV stabilizers are various substituted resorcinols, salicylates, benzotriazoles, and benzophenones, usually used in amounts of up to 2% by weight.
Lubricants and mold-release agents, which are usually used in amounts of up to 1% by weight of the thermoplastic material, are stearic acid, stearyl alcohol, alkyl stearates and stearamides, and also esters of pentaerythritol with long-chain fatty acids. Stearates of calcium, of zinc, or of aluminum, or else dialkyl ketones, e.g. distearyl ketone, may also be used.
There are various ways of preparing the thermoplastic nanocomposites of the invention.
1. In-situ Method
In the in-situ method, the phyllosilicate (B) is mixed, in suspension or as a solid, with the monomers polymerizable to give the thermoplastic (A), from 0.1 to 10% by weight of the monomers bearing ionic groups. Swelling of the phyllosilicate by the monomers then takes place. The polymerization of the monomers which follows may be carried out in a usual manner. The resultant nanocomposites are then compounded, where appropriate, with the other components (C) and (D).
For the purposes of the present invention, compounding is the mixing of the components of which the nanocomposites are composed, for example in an extruder, to give the finished nanocomposite.
For this, the hydrophobicized phyllosilicates (B) are suspended in liquid monomers polymerizable to give component (A) (thermoplastics) and polymerized in the presence of generally from 0.1 to 8% by weight, preferably from 0.1 to 7% by weight, of water, based on the monomers. The polymerization is preferably carried out in the presence of more than 0.2% by weight of water, for example from 0.25 to 6% by weight of water.
The water may be added to the suspension. If these suspensions already comprise water, either no further water is added or the amount of water added is only that needed so that the total amount of water, based on the monomers, is within the range according to the invention.
To achieve very good and thorough mixing, the suspension is advantageously stirred, particularly preferably with high shear. Stirred tank reactors, for example, are suitable for this purpose. The water is then generally added all at once, little by little, or continuously, while the temperature of the suspension is generally from 70 to 100xc2x0 C., preferably from 75 to 95xc2x0 C. The temperature of the aqueous suspension is increased, either at the same time or subsequently, generally as far as from 180 to 330xc2x0 C., preferably from 220 to 320xc2x0 C. The suspension may either remain in the apparatus in which it has been prepared, or may be transferred into another reaction vessel, prior to or after the temperature increase, or prior to or after the addition of water. It is particularly advantageous to carry out the polymerization with simultaneous application of shear.
A variety of methods may be used for conducting the process to prepare the compositions of the invention. For example, they may be prepared by a batch process or a continuous process.
In the batch process, the aqueous suspension may be polymerized under the abovementioned conditions of temperature and shear, and under pressure. The pressure here is generally from 5 to 30 bar, preferably from 8 to 20 bar (absolute). The residence times here are substantially dependent on the temperature selected during the polymerization and are generally from 0.5 to 3 h. After equilibrium conversion has been reached, the water is generally evaporated and the pressure reduced to atmospheric pressure. Any water still present in the melt can cause further molecular weight increase, even at this pressure. The reaction mixture is then discharged, for example as shaped strips of melt, cooled, advantageously by passing through a water bath, and comminuted, preferably pelletized. The resultant polyamides generally have molar masses of up to 22,000 g/mol, preferably from 8,000 to 22,000 g/mol.
In one preferred embodiment, the continuous process is generally carried out by feeding the aqueous suspension, whose temperature is from 70 to 100xc2x0 C., preferably from 75 to 95xc2x0 C., continuously to a first reaction zone and polymerizing the same there under the abovementioned conditions of temperature and shear. In one particularly preferred embodiment, prepolymers of other monomers, or of the same monomers, may be fed, alongside the aqueous suspension, to the first reaction zone. These may derive from the extraction of pelletized product (see below), for example. The pressure in the first reaction zone is generally below 5 bar (absolute), for example from 1 to 3 bar (absolute).
The residence time, which substantially depends on the temperature, pressure, and water content of the reaction mixture, is generally selected to be from 2 to 5 h, preferably from 3 to 4 h. If prepolymers are fed into the first stage of the reaction, the residence times are generally below 2 h, preferably from 0.5 to 1 h. When caprolactam is used, polycondensation in the first reaction zone is usually to a molar mass of 3,000 g/mol or above, preferably from 5,000 to 7,000 g/mol. Examples of the total end group concentration here are from 200 to 600 mmol/kg, preferably from 300 to 400 mmol/kg.
The reaction mixture is passed from the first reaction zone into a second reaction zone. The reaction vessel of the second reaction zone may, for example, be tube-shaped, and it is preferably equipped with internals. These include ordered mixing elements, such as packings (e.g. Raschig rings, beads or Pall rings) so as preferably to ensure a minimum period of residence of the as yet unreacted monomers in the melt (in order to achieve a high degree of conversion) and to avoid to a very substantial extent the presence of any zones in which no, or only minimal, transport of the melt takes place (xe2x80x9cdead zonesxe2x80x9d), and also to avoid any back-mixing. The temperatures in the second reaction zone are generally within the same range as those in the first reaction zone. The residence time in the second reaction zone may vary within wide limits, depending on the type of monomer, the temperature, the pressure, and the nature of the reaction vessel. The residence time in the second reaction zone is generally longer if no prepolymer has been added in the first reaction zone. The polymer melt is generally discharged from the second reaction zone in the form of shaped strands of melt, cooled using a water bath, and comminuted, preferably pelletized. Examples of molar masses of polyamides obtained in this way are from 12,000 to 22,000 g/mol.
The compositions obtained from the batch process, and those obtained from the continuous process, may also comprise volatile constituents, such as the lactam used (for example in caprolactam polymerization), and other monomer units, and also steam-volatile oligomers. These are generally removed from the polymer granules by countercurrent extraction with water (see, for example, DD-A 206999). Another way to do this is gas-phase extraction (see EP-A 0 284 968) with simultaneous molecular weight increase, and superheated steam may be used to give simultaneous extraction and annealing in this extraction process. In one preferred embodiment, the volatile constituents are reintroduced quantitatively into the process, i.e. preferably into the first reaction zone. To this end, the concentration in the extraction water is preferably increased to an extract content of not more than 85% by weight, and the water content of the concentrate obtained is adjusted by adding fresh monomers in such a way that the polycondensation can be carried out in the presence of the amount of water according to the invention. If the polymerization is carried out in this way, at least one adiabatic release of pressure is generally brought about during the polymerization in order to reduce the water content (see Dxcex5-A-19 752 181).
The desired viscosity number of the final product may also be adjusted in a known manner by drying, or by polymerization during annealing in the solid phase.
The desired viscosity number of the final product here is generally in the range from 80 to 350 ml/g, preferably from 120 to 200 ml/g (measured on a 0.5% strength by weight solution in 95% strength by weight sulfuric acid, after removal of the insoluble constituents).
Where appropriate, usual methods are used to compound the resultant nanocomposites with other components (C) and (D), for example by compounding in an extruder.
2. Melt Intercalation
In another preferred embodiment, the thermoplastic nanocomposites of the invention may be obtained by mixing the thermoplastic (component A) having ionic groups with the phyllosilicate (component B), and also, where appropriate, components (C) and (D) by well-known processes, e.g. using extrusion at from 160 to 320xc2x0 C., particularly preferably at from 240 to 300xc2x0 C. A high-shear twin-screw extruder is particularly suitable for this, preferred shear stresses to DIN 11 443 being from 10 to 105 Pa, in particular from 102 to 104 Pa.
The resultant thermoplastic nanocomposites of the invention have, in particular, excellent toughness together with very good stiffness. They can be used to produce moldings, preferably by extrusion, thermoforming, or injection molding.
The present invention therefore also provides moldings obtainable using the nanocomposites of the invention.
The examples below give further description of the invention.

Abstract: The invention further relates to a process for preparing these nanocomposites, and also to their use.


In an apparatus for heat treating a material web that enters and exits the apparatus through respective gaps, an air cushion generating unit includes a slot nozzle through which a ventilator blows a laminar flow of air, which then flows laminarly along a convexly curved surface of the unit, to form a laminar air cushion which flows directly along the material web through one of the gaps, then expands outside of this gap, and is sucked back into the air cushion generating unit and recirculated through the slot nozzle. The laminar air cushion steadily holds and supports the material web so that the mechanical gap size can be reduced while reducing losses of hot process air and still avoiding physical contact with the material web.

This application is based on and claims the priority under 35 U.S.C. xc2xa7119 of German Patent Application 100 07 004.3, filed on Feb. 16, 2000, the entire disclosure of which is incorporated herein by reference.
The invention relates to a method for stably guiding and supporting a web of goods, and preferably a non-air-permeable or air-tight material web such as a thermoplastic web that can be stretched to form a film, between the inlet or entrance gap and the outlet or exit gap of a heat treating apparatus. The invention further relates to an arrangement that forms the entrance and exit gaps of a heat treating apparatus, so as to reduce air losses therethrough.
Various thermal treatment processes are known, in which a web of goods, such as a thermoplastic web that may be expanded or stretched to form a thermoplastic film, is guided through a heat treating apparatus. The-web enters the apparatus through an inlet or entrance gap, and leaves the apparatus through an outlet or exit gap. The inflow of cold outside air and the outflow of heated process air through the entrance gap and the exit gap cause undesirable energy losses from the apparatus and from the heat treating process. Additional energy must be supplied to the apparatus and the process in order to make up for the lost heat energy.
The extent of this energy loss is essentially dependent on the vertical size of the entrance gap and the exit gap, and the transport velocity with which the material web travels through the heat treating apparatus. The energy losses are further dependent on the prevailing pressure difference between the interior space of the heat treating apparatus and the atmospheric environment outside of the heat treating apparatus. In other words, the positive pressure that is typically developed inside the heat treating apparatus will constantly seek a compensating path to the lower atmospheric pressure outside of the heat treating apparatus, so that hot process air will constantly flow out of the apparatus through the entrance and exit gaps. It is further understandable that the energy losses increase with the size of the entrance and exit gaps, as well as with an increasing web transport speed. The crosswise width of the entrance and exit gaps is determined by the width of the material web to be processed or to be achieved, so that it is conceptually not possible to reduce or limit this width of the gaps, and the present specification will not further discuss the energy losses resulting therefrom.
The height or the vertical size of the entrance and exit gaps can be influenced or adjusted, and thereby the energy losses may be reduced, as is known from a variety of prior art solutions in this context. For example, it is known to carry out a corresponding control or regulation of the pressure within the heat treating apparatus. As an example, by maintaining a slight under-pressure or negative pressure inside the heat treating apparatus relative to its surrounding environment, energy losses arising from the above mentioned static pressure difference can be avoided. In such a case, however, it is disadvantageous that the surrounding atmospheric air, which is much colder than the temperature of the hot process air within the apparatus, is constantly sucked into the heat treating apparatus through the entrance and exit gaps due to the reduced pressure inside the apparatus.
The quantity of air that is sucked into the apparatus.must then correspondingly be removed from the apparatus in a precisely controlled manner, in order to maintain the intended reduced or negative pressure level within the heat treating apparatus. Simultaneously, additional energy must be introduced, in order to heat the in-flowing, relatively cold surrounding atmospheric air to a temperature level that is sufficiently high so as not to interfere with the heat treating process being carried out within the heat treating apparatus. At the typical high temperatures, for example approximately 240xc2x0 C. for treating a polyester film, the required continuous supply of additional energy can lead to a considerable energy consumption and increased cost of the process.
The dynamic energy losses that arise due to the quantities of air being carried or pulled along with the web of goods out of the heat treating apparatus at the transport speed of the web cannot be avoided by the above described measure of establishing a reduced or negative pressure within the treating chamber. Instead, other means are necessary to avoid or reduce this type of as energy loss. One possibility is to make the entrance and exit gaps as narrow as possible. To achieve this, for example, partitions or bulkhead members are arranged above and below the material web across the entire width of the heat treating apparatus, along the upper and lower portions of the entrance and exit gaps. Such partition or bulkhead members can be embodied as hanging metal plates or flap doors with a great variety of configurations. In any event, these partition or bulkhead members reduce the vertical height of the open gap.
Such measures are only effective, however, as long as the material web remains stably supported on the intended web transport plane. In this regard, very wide webs and particularly such webs of heavy, limp or slack materials, will hang and bow downward. On the other hand, webs of very thin or delicate materials, which cannot be adequately tensioned, will flutter or billow up and thus away from the intended web transport plane. Webs of material with such characteristics thus come into direct contact with the above described partition or bulkhead members along the entrance or exit gaps. This direct physical contact can cause damage or even tearing of the material web. Thereupon, such a damaged or torn material web leads to a stop or interruption of the heat treating process, which in turn triggers various undesired results, and particularly a slow down or loss of production output, and increased costs.
Another possibility of reducing energy losses is the use of an air curtain or air sluice. In this context, a vigorous air stream is directed in the form of an air curtain substantially perpendicularly against the material web, above and below the material web at the entrance gap and the outlet gap, in order to thereby form a barrier that is intended to block the inflow or outflow of air past or through this air curtain. A disadvantage of such air curtains is that the additional quantities of air that are used for forming the blocking air curtains must again be removed from the heat treating apparatus, insofar as they are sucked into the apparatus. Also, the air curtains directed substantially perpendicularly against the material web do not support the web, but instead are rather difficult to control in order to avoid a billowing or fluttering of the material web.
For the above reasons, there must be a sufficiently large spacing distance between the material web and the nozzles that are necessary for establishing the air curtain. A physical contact between the material web and the nozzles must absolutely be avoided. This in turn requires a sufficiently high air flow velocity and a sufficiently high air flow volume in order to form an effective air curtain spanning this relatively large spacing distance and still achieving an effective blocking or separation of an airflow through the respective gap. As a result, disadvantageous turbulences arise directly in or along the web plane, which can lead to fluttering or billowing of the material web. Such an unsteady travel of the material web is especially disadvantageous for the process reliability when rather sensitive material webs are being treated.
In view of the above, it is an object of the invention to provide appropriate measures at the entrance and exit gaps of a material web heat treating apparatus, to minimize the loss of energy in the form of hot air out through the entrance and exit gaps, while essentially completely avoiding physical contact between the material web and the mechanical gap-closing components. The invention aims to avoid mechanical rolls for supporting and guiding the material web near the entrance and exit gaps. The invention further aims to avoid or overcome the disadvantages of the prior art, and to achieve additional advantages, as apparent from the present specification.
The above objects have been achieved according to the invention in a method of stably guiding a material web, such as a thermoplastic material web that can be expanded or stretched to form a thermoplastic film, which is subjected to a heat treatment in a heat treating apparatus. According to the invention, the material web is transported into the heat treating apparatus through an entrance gap, is heat treated in the apparatus, and is then transported out of the apparatus through an exit gap. Proximate to at least one of the gaps, the invention further applies a force to the material web within the heat treating chamber, so as to positively hold the material web in a defined horizontal plane over at least a prescribed length or range ahead of and behind the respective gap.
Especially according to the invention, the above mentioned force is provided by a laminar air flow that forms an air cushion which holds or supports the material web directly in the respective gap, and then expands outside of the respective gap, where the resulting expanded air is sucked back into the heat treating apparatus, or particularly a special air cushion generator unit within the heat treating apparatus. The most important feature of the method according to the invention is that a laminar air flow is generated at least between the bottom surface of the material web and the lower gap boundary of at least the entry gap or the exit gap in the heat treating apparatus. This laminar air flow develops an air cushion between the material web and the device that guides or generates the laminar air flow. This resulting air cushion is maintained over at least a prescribed length or distance range before and after the respective gap of the heat treating apparatus. Preferably, such air cushions are provided at both the entrance gap and the exit gap. The air cushion then expands outside of the respective gap, i.e. down-stream of the exit gap or upstream of the entrance gap, and the resulting expanded air is sucked back into the heat treating chamber or especially into a suitable air cushion generating unit within the heat treating apparatus.
According to further embodiment details of the inventive method, the air flow that forms the air cushion is directed to flow at a prescribed acute angle, e.g. not greater than 30xc2x0 and preferably not greater than 20xc2x0, and especially parallel and tangential relative to the material web plane. The air cushion is formed continuously crosswise relative to the transport direction and entirely across the width of the material web. The phrase xe2x80x9centirely across the widthxe2x80x9d of the material web or the gap is intended to also cover the situation in which the air cushion does not extend across 100% of the physical maximum width of the gap, but leaves an insignificant portion of the width of the gap, e.g. at the ends or edges of the air cushion, without having any significant influence on the functionality. As a further feature of the invention, the parameters determining the characteristics of the air cushion are continuously adjustable in a stepless manner and the thickness and height of the air cushion serves to minimize the opening size of the respective entrance or exit gap.
More particularly, the air cushion is formed by blowing the laminar air flow along the contoured profile surface of an air guide member located opposite and facing the material web, whereby this profile surface has an outwardly curved convex contour, similar to the contour of the upper surface of an aircraft lifting wing. This profile surface guides the air flow in such a manner so that it cannot deviate or separate from the side or surface facing the material web. Thus, this air flow causes a Coanda effect between the respective facing surface of the material web and the contoured surface of the profiled air guide member.
While the respective surface of the material web facing the air guide member is especially the bottom surface of the web, i.e. the air cushion is especially provided below the material web, it is additionally or alternatively possible to provide an air cushion according to the invention above the material web. In any event, due to the relatively high air flow velocity of the air flowing along the surface of the curved or contoured profile member, a negative or reduced pressure develops relative to the opposite facing surface of the material web, much like the negative pressure and lift developed on the upper surface of an aircraft wing. Due to this reduced pressure between the material web and the contoured profile surface, the material web is pulled in a direction toward this contoured surface. Thereby, the material web is steadily held and supported relative to the air blowing slot nozzle or particularly the curved contour of the profile member. This holding effect is achieved regardless whether the inventive air cushion is formed above or below the material web. The positive holding effect on the material web is particularly steady and well defined, because the material web must remain a sufficient spacing distance away from the nozzle arrangement and particularly the air guide surface thereof to allow the laminar cushion of air to exit between the material web and the air guide surface. In other words, on the one hand the material web is pulled or sucked toward the air guide surface, and on the other hand the material web is held away from the air guide surface by the interposed air cushion.
The above objects have further been achieved according to the invention in a heat treating apparatus for heat treating material webs, such as thermoplastic material webs that can be expanded or stretched to form thermoplastic films. The heat treating apparatus includes an entrance gap entering into a heat treating chamber enclosed in a housing of the apparatus, and an exit gap exiting out of the heat treating chamber. Respective gap covering components that are movably adjustable, are arranged above and below the web transport plane in both the entrance gap and the exit gap. According to the invention, at least one of the gap covering components, and preferably the gap covering component below the web transport plane, comprises a substantially box-like air cushion generating structural unit that extends entirely across the width of the material web. The term xe2x80x9csubstantially box-likexe2x80x9d is intended to define a shape that encloses an interior volume therein, and is especially (preferably) substantially rectangular, except for a surface thereof that lies across from or faces the material web plane, which surface has an outwardly curved convex contour, generally similar to the contour of the upper surface of an aircraft wing.
Furthermore, this air guide surface forms an air outlet slot in the manner of a slot nozzle that is directed generally transversely and particularly smoothly tangentially to the material web transport plane. This surface is curved and arranged in such a manner so that it gradually tapers the spacing distance between the material web transport plane and this surface in a direction toward the respective entrance or exit gap to a prescribed minimum gap distance. On the inflow side and the outflow side of the treating apparatus, this surface of the air cushion generator structural unit extends across the width of the entrance gap and the exit gap defined by the location of the upper gap covering or closing member. The air guide surface thus extends across and to both sides of the vertical gap plane at the narrowest portion of the respective entrance or exit gap.
It is significant in the inventive apparatus, that the laminar air flow is formed by guiding an air flow through an air outlet slot nozzle along the above mentioned air guide surface contour of the air cushion generating structural unit. This is achieved by the structural unit, in that the first air guide surface of a first air guide sheet or plate member of the structural unit is overlapped by a second air guide sheet or plate member of the structural unit, so as to form the above mentioned slot nozzle therebetween. With such an arrangement, the air flowing between the two air guide sheet or plate members and then exiting from the corresponding slot nozzle flows further along the surface of the first air guide surface and thereby forms an air cushion between this surface and the facing surface of the material web. A separation of the laminar air flow from the guide surface will not occur, because no obstructions exist between the flow surface of the structural unit and the facing surface of the web.
Depending on and responsive to the position of the air outlet slot nozzle and the first air guide plate member, as well as the flow velocity of the airflow being ejected from the airflow slot nozzle, the material web is advantageously held in a constant manner at a pre-defined spacing distance between the upper gap cover member and the first air guide surface of the structural unit, due to the balancing or counteracting effects of the prevailing negative pressure and the air cushion between the first air guide surface and the material web as described above. Thus, any fluttering, billowing, bulging, or sagging of the material web will be prevented in the area of the entrance gap and of the exit gap. As a result, it is advantageously possible according to the invention to position the upper gap covering member very close to the material web plane, without having to fear a contact and resulting damage of the material web.
According to further embodiment details of the invention, the structural unit is separated into a pressure chamber and a suction chamber, i.e. a positive pressure chamber and a negative pressure chamber. The outwardly directed wall of the negative pressure or suction chamber has a plurality of suction openings adjacent to the area in which the air cushion will expand outside of the respective gap. An air line, such as a hose, duct, conduit, pipe, air channel, or the like, is connected between the positive pressure chamber and the negative pressure or suction chamber, with a ventilator, such as a blower, fan, air pump, compressor or the like interposed therein, in order to move the air flow between the two chambers, so as to create the positive pressure in the pressure chamber and the negative pressure in the suction chamber. From the positive pressure chamber, the air then flows out through the above described slot nozzle. The air flow velocity and volume can be regulated by regulating the rotational speed of the above mentioned ventilator, in so far as a separate air supply or air circulation for the air cushion is provided, and insofar as the ventilator has an adjustable operating speed. If such a rotational speed regulation or control is not provided, then the air flow speed and volume can be adjusted by throttling the suction flow or the pressure flow of the ventilator using any conventionally known and suitable air flow regulating device, such as any type of air valve, and particularly a sliding gate valve, for example.
The structural unit is arranged and supported in the apparatus so as to be adjustable at least in a direction perpendicular to the material web plane. Thereby, the thickness of the air cushion can be defined or prescribed, and additionally, the entire structural unit can be moved away from the material web plane in the event of operation interruptions of the apparatus, in order to avoid damage of the material web caused by the structural unit itself. The structural position of the slot nozzle is freely selectable, and can be adjusted as needed to achieve the required air cushion effect in connection with the particular type of material web being treated.
Due to the above described dynamic effects that are achieved when forming the air cushion according to the invention, it is possible to arrange the structural unit above as well as or instead of below the material web plane. Preferably, the structural unit is only arranged below the material web, because in such an arrangement the structural unit can easily be retracted away from the material web in the event of an operation interruption of the apparatus, without requiring significant additional external energy, i.e. simply due to the weight or gravitational mass of the unit.
The top of each gap, i.e. the area of the gap above the material web plane, can be substantially covered by a gap boundary or gap covering member in the form of a pivotable flap door, which simply hangs down into a stable equilibrium position, again due to its own weight, without requiring any additional positioning energy, in normal operation. In order to open this gap covering flap door, various mechanisms can be used, such as levers, tension cables, or the like, as would be recognized by a person of ordinary skill in the art, in order to achieve the required pivoting motion. The operation thereof can be achieved manually, hydraulically, electrically, etc. Preferably, the pivoting mechanism includes a free play range, especially in the direction of the web travel from the neutral downward position, so that the flap door may freely xe2x80x9cgivexe2x80x9d or yield by swinging in the web travel direction in the event of any arising shocks or impacts in this context.
In order not to interfere with or upset the air balance within the heat treating apparatus and possibly also the surrounding environment, while creating the required negative pressure and the air cushion as described above by flowing the required air volumes through the slot nozzle and along the curved contour of the structural unit, it is further provided that this air flow can again be sucked away in the rearward part of the treating apparatus, namely in the area after the air has exited from the gap between the material web and the deflector surface. In this manner, a substantially closed continuous loop air circulation is achieved, which is completely independent of the process air within the heat treating apparatus. The term xe2x80x9csubstantially closed continuous loopxe2x80x9d does not require 100% recirculation of the air cushion air. Instead, it is intended to define the air recirculation loop in which some of the air of the air cushion is lost outside of the apparatus, and some external environmental air is sucked in to replace the lost air cushion air. The key point is that no significant amount of the hot process air within the heat treating chamber is involved in forming the air cushion. The suction or sucking of the return air is carried out in such a manner so that it does not interfere with the actual function of the heat treating apparatus so that it is reliable and secure in its operation. Particularly, the air of the air cushion, after it expands outside of the gap, is sucked back into the air cushion generator unit through a perforated suction surface that is substantially perpendicular to the material web plane. With such an arrangement, the suction area cannot be plugged or blocked by relatively small particles of the material web or other contaminants or soiling which might rise, and which would otherwise interfere with the proper operation of the entire system.

Method and arrangement for supporting a web and avoiding air losses in a heat treating apparatus


A radar detector for exploration of subsurface embedded objects comprising an antenna array (1) for high-frequency electromagnetic waves, which is connected and individually switchable with at least one transmit/receive unit, a time-controlled signal processor, an evaluation device for SAR and a display device. The antenna array (1) exhibiting at least three antennas (sx, rx, sy, ry) scanning an area by their positioning.

The invention relates to a subsurface exploratory radar detector for a hand tool device such as a percussion drill or a chipping hammer.
The use of a hand tool device when working with masonry embedded with electrical wiring, plastic piping, etc. and steel reinforcement requires knowledge of the presence, the nature, and the location of such lines or steel or iron reinforcement relative to the tool. Such knowledge is important because such embedded objects could damage the tool. Further, such knowledge is important to properly carry out the work, i.e., placement of dowel fastener holes with minimum clearance from lines or steel reinforcements.
U.S. Pat. No. 5,541,605 discloses a subsurface radar detector for detection of reinforcement iron and steel in concrete, wherein the detector operates in the ultra-wideband range and is swept over the surface.
According to U.S. Pat. No. 5,051,748 discloses a portable ground penetrating radar detector operating in the microwave range for the detection of reinforcement iron and steel in concrete. The disclosed radar detector comprises an antenna array with wave guides arranged in intervals along a line, whose pin-hole antennae directly produce a line image which, with a movement of the antenna array diagonally to the direction of the array and in conjunction with a computer, produces a flat image of the buried object, whose image is then displayed on an image output device.
U.S. Pat. No. 5,900,833 discloses a portable radar detector equipped with a synthetic radar antenna (SAR xe2x80x9csynthetic aperture radarxe2x80x9d) whose signals are initially processed in signal processors. The radar detector can produce three-dimensional images of objects buried underground, such as reinforcement steel. Moreover, the images are represented on an image display device. The individual antennas, which need not necessarily be arranged linearly, are moved diagonally to the antenna array to produce a synthetic aperture with the radar detector.
U.S. Pat. No. 5,512,834 discloses a portable subsurface exploration radar detector that detects electrical lines, plastic pipelines, and reinforcement steel when creating bore holes. The radar detector sends and receives narrow band, periodically modulated electromagnetic waves into and from the subsurface area being explored for objects arranged in a near field area. The radar detector makes possible adjustment for depth and provides area resolution by evaluating the pulse forms and the geometry and intervals of the associated antennas of two complete detectors or the receiving antennas of a common transmitter. Depending on the results of the detection, a hand tool, such as a nail gun tool, to which the detector is attached, is controlled automatically via the nail dispenser. Objects that are closely adjacent to one another; for example, those arranged in grids, cannot be oriented with sufficient precision by the two spaced receiving antennas. Similarly, no information is received on the orientation or the depth of embedding of the buried objects.
The object of the present invention is to provide a subsurface exploration radar detector that is simple to use and can be mounted on the hand tool for the detection of embedded objects situated in close proximity to one another.
This object is achieved, in accordance with the invention, by a radar detector that explores subsurface embedded objects comprising an antenna array for high-frequency electromagnetic waves with at least three antennas having at least one transmit/receive unit. The at least one transmit/receive unit is connected to at least one timed signal processor for paired temporal correlation of the demodulated signals and the one time signal processor is connected in an information transferring manner with an evaluation unit for SAR for resolution of the demodulated signals and to a display device. Moreover, the at least three antennas by their positions together scan an area and wherein the at least three antennas are switchably connected with at least one transmit-receive device.
In essence, a subsurface exploratory radar detector, in accordance with the invention, exhibits at least three high-frequency electromagnetic wave antennas whose positions sweep an area together and which are individually connected with transmit and receive units. The demodulated signals of such antennas can be processed in paired temporal correlation and combined evaluation in a time-controlled signal processor, wherein the processor is in an evaluation unit for SAR and is connected to a display device.
The paired temporal correlation of two of the at least three antennas arranged on a surface and the combined evaluation thereof enables the position in space of buried or embedded objects to be determined without having to reposition the radar detector.
Advantageously, exactly two of the at least three antennas are temporally shifted by the control unit as a transmit-receive antenna pair switchably connected with the radar transmitter or the radar receiver, whereby only one radar transmitter and one radar receiver is required.
Also, at least two antennas are polarized differently relative to each other, whereby the orientation of an elongate object can be ascertained by paired temporal correlation and combined evaluation.
The antennas that arc polarized parallel relative to each other are linearly arranged and the two rows are arranged in the shape of an xe2x80x9cXxe2x80x9d (lit. cross shape). Along each row, the transmit and receive antenna pair that is switchably connected with the radar transmitter or with the radar receiver can be repositioned.
At least three antennas that are polarized parallel relative to one another are arranged in at least one row, whereby two transmit and receive antenna pairs can be switched to different spacing relative to each. In such an arrangement, the depth of embedded objects can be determined independent of the propagation velocity of the radar waves in the subsurface.
The antennas, arranged crosswise in two rows, are further arranged in central symmetry relative to each other, thereby simplifying evaluation.
Also, the arrangement of the antennas in the centrally-symmetrically cross shape forms an empty space at the central intersection, into which a tool can be inserted.
Advantageously, through the evaluation of the characteristic of the reflected radar waves between different materials, for example, plastic and iron, embedded objects can be distinguished and displayed, for example by light-emitting diodes (LED).
The evaluation unit is configured as a neural network, which represents the plurality of combined, paired temporal correlation to be interpreted as an input variable in a numerically limited number of classifications, that are divided into:
centrally punctuate/discrete
vertically elongate
transversely elongate
horizontally elongate
centrally crossed
and
no object
and the classifications are displayed, for example, using an LED.
Also, the depth of the embedded object is displayed on a discrete scale.
Further, all the information is displayed together on a small graphic display.
Moreover, a parameter, such as maximum drilling depth, is transferred from the hand tool and the parameter is taken into consideration in the interpretation.
The classification is transmitted by the evaluation unit as a control signal to the hand tool and utilized by the hand tool for blocking or releasing a work process, for example, drilling.

Subsurface exploratory radar detector for a hand tool device