The present disclosure relates to certain amides and heterocyclic compounds and uses of these amides and heterocyclic compounds to inhibit Rho-associated protein kinases and treat diseases including autoimmune disorders, graft versus host disease (GVHD), inflammation, cardiovascular disorders, central nervous system disorders, and neoplastic disorders.

An important large family of enzymes is the protein kinase enzyme family. Currently, there are about 500 different known protein kinases. Protein kinases serve to catalyze the phosphorylation of an amino acid side chain in various proteins by the transfer of the γ-phosphate of the ATP-Mg2+ complex to said amino acid side chain. These enzymes control the majority of the signaling processes inside the cells, thereby governing cell function, growth, differentiation, and destruction (apoptosis) through reversible phosphorylation of the hydroxyl groups of serine, threonine and tyrosine residues in proteins. Studies have shown that protein kinases are key regulators of many cell functions, including signal transduction, transcriptional regulation, cell motility, and cell division. Several oncogenes have also been shown to encode protein kinases, suggesting that kinases play a role in oncogenesis. These processes are highly regulated, often by complex intermeshed pathways where each kinase will itself be regulated by one or more kinases. Consequently, aberrant or inappropriate protein kinase activity can contribute to the rise of disease states associated with such aberrant kinase activity. Due to their physiological relevance, variety, and ubiquitousness, protein kinases have become one of the most important and widely studied families of enzymes in biochemical and medical research.
The protein kinase family of enzymes is typically classified into two main subfamilies: Protein Tyrosine Kinases and Protein Serine/Threonine Kinases, based on the amino acid residue they phosphorylate. The serine/threonine kinases (PSTK), include cyclic AMP- and cyclic GMP-dependent protein kinases, calcium- and phospholipid-dependent protein kinases, calcium- and calmodulin-dependent protein kinases, casein kinases, cell division cycle protein kinases, and others. These kinases are usually cytoplasmic or associated with the particulate fractions of cells, possibly by anchoring proteins. Aberrant protein serine/threonine kinase activity has been implicated or is suspected in a number of pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers, and other proliferative diseases. Accordingly, serine/threonine kinases and the signal transduction pathways which they are part of are important targets for drug design. The tyrosine kinases phosphorylate tyrosine residues. Tyrosine kinases play an equally important role in cell regulation. These kinases include several receptors for molecules such as growth factors and hormones, including epidermal growth factor receptor, insulin receptor, platelet derived growth factor receptor, and others. Studies have indicated that many tyrosine kinases are transmembrane proteins with their receptor domains located on the outside of the cell and their kinase domains on the inside. Much work is also under progress to identify modulators of tyrosine kinases as well.
A major signal transduction systems utilized by cells is the RhoA-signaling pathways. RhoA is a small GTP binding protein that can be activated by several extracellular stimuli such as growth factor, hormones, mechanic stress, osmotic change, as well as high concentration of metabolite like glucose. RhoA activation involves GTP binding, conformation alteration, post-translational modification (geranylgeranyllization and famesylation), and activation of its intrinsic GTPase activity. Activated RhoA is capable of interacting with several effector proteins including ROCKs and transmit signals into cellular cytoplasm and the nucleus.
Rho-associated protein kinases, ROCK1 and ROCK2, constitute a family of kinases that can be activated by RhoA-GTP complex via physical association. Activated ROCKs phosphorylate a number of substrates and play important roles in pivotal cellular functions. The substrates for ROCKs include the myosin binding subunit of myosin light chain phosphatase (MBS, also named MYPT1), adducin, moesin, myosin light chain (MLC), LIM kinase, as well as transcription factor FHL. The phosphorylation of these substrates modulates the biological activity of the proteins and thus provides a means to alter a cell's response to external stimuli. ROCK1 and ROCK2 are differentially expressed and regulated in specific tissues. For example, ROCK1 is ubiquitously expressed at relatively high levels, whereas ROCK2 is preferentially expressed in cardiac and brain and skeletal muscle. The isoforms are also expressed in some tissues and in a developmental stage specific manner. ROCK1 is a substrate for cleavage by caspase-3 during apoptosis, whereas ROCK2 is not. Smooth muscle specific basic calponin is phosphorylated only by ROCK2.
One well-documented example is the participation of ROCK in smooth muscle contraction. Upon stimulation by phenylephrine, the vascular smooth muscle contracts. Studies have shown that phenylephrine stimulates alpha-adrenergic receptors and leads to the activation of RhoA. Activated RhoA in turn stimulates kinase activity of ROCK1 that in turn phosphorylates MBS. Such phosphorylation inhibits the enzyme activity of myosin light chain phosphatase and increases the phosphorylation of myosin light chain itself by a calcium-dependent myosin light chain kinase (MLCK) and consequently increases the contractility of the myosin-actin bundle, leading to smooth muscle contraction. This phenomenon is sometimes called calcium sensitization. In addition to smooth muscle contraction, ROCKs have also been shown to be involved in cellular functions including apoptosis, cell migration, transcriptional activation, fibrosis, cytokinesis, inflammation, and cell proliferation. Moreover, in neurons, ROCK plays a critical role in the inhibition of axonal growth by myelin-associated inhibitory factors such as myelin-associated glycoprotein (MAG). ROCK-activity also mediates the collapse of growth cones in developing neurons. Both processes are thought to be mediated by ROCK-induced phosphorylation of substrates such as LIM kinase and myosin light chain phosphatase, resulting in increased contractility of the neuronal actin-myosin system.
Inhibitors of ROCKs have been suggested for use in the treatments of a variety of diseases. They include cardiovascular diseases such as hypertension, chronic and congestive heart failure, cardiac hypertrophy, restenosis, chronic renal failure, and atherosclerosis. In addition, because of its muscle relaxing properties, it is also suitable for asthma, male erectile dysfunctions, female sexual dysfunction, and over-active bladder syndrome. ROCK inhibitors have been shown to possess anti-inflammatory properties. Thus, they can be used as a treatment for neuroinflammatory diseases such as stroke, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and inflammatory pain, as well as other inflammatory diseases such as rheumatoid arthritis, irritable bowel syndrome, and inflammatory bowel disease. In addition, based on their neurite outgrowth inducing effects, ROCK inhibitors could be useful drugs for neuronal regeneration, inducing new axonal growth and axonal rewiring across lesions within the CNS. ROCK inhibitors are therefore likely to be useful for regenerative (recovery) treatment of CNS disorders such as spinal cord injury, acute neuronal injury (stroke, traumatic brain injury), Parkinson's disease, Alzheimer's disease, and other neurodegenerative disorders. Since ROCK inhibitors reduce cell proliferation and cell migration, they could be useful in treating cancer and tumor metastasis. Furthermore, there is evidence suggesting that ROCK inhibitors suppress cytoskeletal rearrangement upon virus invasion, thus they also have potential therapeutic value in antiviral and anti-bacterial applications. ROCK inhibitors may also be useful for the treatment of insulin resistance and diabetes.
Pulmonary Arterial Hypertension (PAH) is a condition in which the pressure in the lung circulation increases, eventually causing heart failure and death. Although many causes and conditions are found to be associated with PAH, many of them share in common several fundamental pathophysiological features. One important feature among these processes is dysfunction of the endothelium, the internal cellular layer of all vessel walls, which is normally responsible for the production and metabolism of a large array of substances that regulate vessel tone and repair and inhibit clot formation. In the setting of PAH, endothelial dysfunction can lead to excessive production of deleterious substances and impaired production of protective substances. Whether this is the primary event in the development of PAH or part of a downstream cascade remains unknown, but in either case, it is an important factor in the progressive vasoconstriction and vascular proliferation that characterize the disease. Recent in vivo studies showed that the Rho GTPase/RhoA pathway and its downstream effectors, the Rho-kinases (ROCK-1 and ROCK-2), have an important role in PAH, due to their lasting effects on vasoconstriction and pulmonary cell proliferation leading to vascular remodeling (See, for example, Wang et al., Inhibition of RhoA/ROCK signaling pathway ameliorates hypoxic pulmonary hypertension via HIF-1α-dependent functional TRPC channels, Toxicol Appl Pharmacol. 369: 60-72 (2019); Cantoni et al., Pharmacological characterization of a highly selective Rho kinase (ROCK) inhibitor and its therapeutic effects in experimental pulmonary hypertension, Eur J Pharmacol. 850:126-34; Zhuang et al., Fasudil preserves lung endothelial function and reduces pulmonary vascular remodeling in a rat model of end-stage pulmonary hypertension with left heart disease, Int J Mol Med. 42(3):1341-52 (2018)).
Given the extent of involved cellular processes and diseases, compounds that selectively inhibit one rho kinase, or inhibit ROCK1 and ROCK2 are desired. The present inventors have discovered novel heterocyclic compounds, which are inhibitors of ROCK activities. Such derivatives are useful in the treatment of disorders associated with inappropriate or dysregulated ROCK activities.

Amide compounds as kinase inhibitors, compositions and methods of treatment


The invention includes compositions and methods for promoting internalization and degradation of urokinase-type plasminogen activator.

Plasminogen activators convert the inactive zymogen plasminogen into the broad-spectrum proteolytic enzyme, plasmin (Higgins et al., 1990, Annu. Rev. Pharmacol. Toxicol. 30:91-121; Holden, 1990, Radiology 174:993-1001; Mayer, 1990, Clin. Biochem. 23:197-211). One type of plasminogen activator, designated urokinase-type plasminogen activator (uPA), is a component of the circulatory system and other fluid compartments of the mammalian body.
uPA is the principal cell-associated plasminogen activator and has been implicated in several biological processes including angiogenesis, organogenesis, ovulation, inflammation, cancer, tumor cell invasion and metastasis, atherosclerosis, and other biological and pathological processes characterized by cell migration through physiological barriers such as fibrin and basement membranes (Gyetko et al., 1994, J. Clin. Invest. 93:1380-1387; Gyetko et al., 1996, J. Clin. Invest. 97:1818-1826; Shapiro et al., 1997, Am. J. Pathol. 150:359-369; Dado et al., 1994, Fibrinolysis 8 (Suppl. 1):189-203).
uPA is synthesized as a single chain zymogen, designated single chain uPA (scuPA), which exhibits little urokinase activity (Ellis et al., 1987, J. Biol. Chem. 262:14998-15003; Petersen et al., 1988, J. Biol. Chem. 263:11189-11195; Husain, 1991, Biochemistry 30:5707-5805; Colleen et al., 1986, J. Biol. Chem. 261:1259-1266). Activation of scuPA occurs by enzymatic cleavage of scuPA, yielding two-chain uPA (tcuPA). Physiological formation of tcuPA from scuPA is catalyzed primarily by plasmin (Robbins et al., 1967, J. Biol. Chem. 242:2333-2342). scuPA may also be activated by binding of scuPA to the cell-surface receptor, uPAR. In the case of scuPA binding to uPAR, scuPA remains a single chain molecule, but is active (Higazi et al., 1995, J. Biol. Chem. 270:17375-17380).
The activity of uPA is regulated, in part, by plasminogen activator inhibitor-1 (PAI-1), which is a member of the serine protease inhibitor (SERPIN) family of proteins (Kruithof, 1988, Enzyme 40:113-121; Potempa et al., 1994, J. Biol. Chem. 269:15957-15960; Lijnen et al., 1994, Eur. J. Biochem. 224:567-574). PAI-1 is thought to be the most relevant inhibitor of uPA activity in the fluid phase, due to its high second order rate constant of inhibition, 1.7×10−8 M−1·s−1, which is higher than any other protease inhibitor (Hekman et al., 1988, Arch. Biochem. Biophys. 262:199-210).
A soluble recombinant form of uPAR, designated suPAR, is known and differs from uPAR by lacking the portion of uPAR that links the receptor to the cell surface. suPAR possesses the same properties as uPAR with respect to binding and activating scuPA and promoting the adhesivity of the uPA-uPAR complex (Higazi et al., 1995, J. Biol. Chem. 270:17375-17380; Higazi et al., 1996, Blood 87:3545-3549).
Binding of scuPA to uPAR enhances urokinase activity of scuPA (Higazi et al., 1995, J. Biol. Chem. 270:17375-17380). Formation of the scuPA-uPAR complex also dampens the capacity of PAI-1 to inhibit scuPA activity, relative to the capacity of PAI-1 to inhibit tcuPA activity (Higazi et al., 1996, Blood 87:3545-3549). Formation of a complex between scuPA and uPAR also alters the regulation of scuPA enzymatic activity by peptide substrates of plasmin and promotes binding of scuPA to vitronectin (Higazi et al., 1996, Thromb. Res. 84:243-252; Higazi et al., 1996, Blood 88:542-551; Wei et al., 1994, J. Biol. Chem. 269:32380-32388; Wei et al., 1996, Science 273:1551-1555; Deng et al., 1996, J. Cell Biol. 134:1563-1571; Stefansson et al., 1996, Nature 383:441-443; O'Reilly et al., 1996, Nature Med. 2:689-692).
A region of uPA, comprising the protein sequence RHRGGS (SEQ ID NO: 1) at amino acid positions 179-184, is required for inhibition of uPA activity by PAI-1 (Madison et al., 1990, J. Biol. Chem. 265:21423-21426). Conservation of this sequence among mammalian uPA proteins has been demonstrated (Adams et al., 1981, J. Biol. Chem. 266:8476-8482). Working with a different plasminogen activator protein, namely tissue-type plasminogen activator (tPA), Madison et al. have identified a region of PAI-1 which is involved in inhibition of tPA by PAI-1 (1990, J. Biol. Chem. 265:21423-21426). This region of PAI-1 comprises the sequence RMAPEEIIMDR (SEQ ID NO: 2) at amino acids 346-356. It has been postulated that electrostatic interactions between this region of PAI-1 and tPA play a role in stabilizing a tPA-PAI-1 complex. Similarly, it has been postulated that electrostatic interactions between a region of PAI-1 and uPA may contribute to formation of a PAI-1-uPA complex. It has been observed, however, that the scuPA-uPAR complex is less susceptible to inhibition by PAI-1 (Higazi et al., 1996, Blood 87:3545-3549) than is tcuPA or uPAR-bound tcuPA (Higazi et al., 1996, Blood 87:3545-3549; Ellis et al., 1990, J. Biol. Chem. 265:9904-9908).
In addition to inhibiting urokinase activity of uPA, PAI-1 also promotes the internalization and lysosomal degradation of uPA, which involves the α2-macroglobulin receptor/low density lipoprotein-related receptor protein (α2MR/LRP; Nykjaer et al., 1994, J. Biol. Chem. 269:25668-25676). The complex formed between PAI-1 and tcuPA binds to α2MR/LRP with considerably higher affinity than does either component alone. Although it has been demonstrated that the increased affinity of the complex results from an independent contribution of epitopes present in each ligand, a possible conformation-altering effect of PAI-1 upon uPA has not been excluded (Nykjaer et al., 1994, J. Biol. Chem. 269:25668-25676).
When scuPA is bound to uPAR, scuPA is protected from inactivation by PAI-1. Furthermore, binding of scuPA to uPAR inhibits binding of scuPA to α2MR/LRP and internalization of scuPA caused by such binding (Nykjaer et al., 1994, J. Biol. Chem. 269:25668-25676; Higazi et al., 1996, Blood 87:3545-3549). Two mechanisms have been postulated for the reduced affinity of uPAR-bound scuPA for α2MR/LRP. Nykjaer et al. (supra) proposed that the site at which scuPA contacts α2MR/LRP is shielded by uPAR. An alternative mechanism is that binding of scuPA to uPAR induces a conformational change that both promotes scuPA binding to integrin ligands and leads to a loss of the scuPA epitope recognized by α2MR/LRP (Higazi et al., 1996, Blood 88:542-551). The latter proposed mechanism is consistent with the observation that soluble scuPA has a higher affinity for α2MR/LRP than does tcuPA and with the observation that tcuPA loses affinity for α2MR/LRP when the active site of tcuPA is occupied by diisofluoryl phosphate (Nykjaer et al., 1994, J. Biol. Chem. 269:25668-25676).
scuPA bound to uPAR is active, protected from inactivation by PAI-1, and protected from clearance from the cell surface mediated by binding of scuPA to α2MR/LRP and subsequent degradation. Furthermore, scuPA that dissociates from uPAR reverts to an inactive conformation and becomes essentially insusceptible to inactivation by PAI-1. Thus, unbound scuPA retains the capacity to rebind to uPAR and revert once again to its active conformation.
There are abundant epidemiological data which indicate that the expression or uPA and uPAR in human tissue correlates with the conversion of cells from a benign to a neoplastic state. Furthermore, expression of uPA and uPAR is associated with a wide variety of common malignancies, and is predictive of future development of those malignancies. Interference with uPA activity by binding an antibody to uPA, by expression of an antisense oligonucleotide complementary to mRNA encoding uPA, or by overexpression of catalytically inactive forms of uPA impede tumor progression in several experimental murine models of human cancers (Ossowski, 1988, J. Cell Biol. 107:2437-2445; Ossowski et al., 1991, Canc. Res. 51:275-281; Kook et al., 1994, EMBO J. 13:3983-3991; Crowley et al., 1993, Proc. Natl. Acad. Sci. USA 90:5021-5025; Jankun et al., 1997, Canc. Res. 57:559-563).
The capacity to regulate uPA activity would enable the practitioner to regulate a number of important human diseases and symptoms thereof. There remains a significant unmet need for compositions useful for modulating the activity of uPA in a mammal, particularly in a human, and for methods of using those compositions to treat pathological conditions attributable to undesirable uPA activity in the mammal. Particularly needed are compositions and methods for promoting internalization and degradation of scuPA which act independently of activation of scuPA by plasmin, independently of binding of scuPA to uPAR, and independently of inactivation of soluble or uPAR-bound scuPA by PAI-1.

Compositions and methods for promoting internalization and degradation of urokinase-type plasminogen activator

The Trustees of the University of Pennsylvania


A method and system are provided for the constant path-length translation of a laser beam. At least one pair of mirrors disposed at an angle (e.g., 90.degree.) to one another and fixed in relation to one another are disposed in the path of the (incoming) laser beam. The mirrors are positioned such that the incoming laser beam impinges on the first mirror, is reflected to the second mirror, and iii) is reflected from the second mirror as an (outgoing) laser beam parallel to the incoming laser beam. A positioner is coupled to the mirrors for simultaneously moving them in a direction that is parallel to the target plane and in a plane defined by the incoming and outgoing laser beams.

Lateral movement of a laser beam is typically accomplished in one of two fashions. In one approach, a laser beam is steered by a mirror capable of angular movement. For example, in FIG. 1, a laser source 10 is fixed in its position to direct laser beam 12 towards a galvo-mirror driver 14. As is known in the art, driver 14 is a motor-like device with a mirror affixed to its shaft. The shaft can make small angular movements to either side of a given center position. Thus, driver 14 operates to change the angular position of laser beam 12 relative to a workpiece 16. However, the angular movement of driver 14 must be controlled very precisely in order to achieve specific lateral displacement (e.g., in the x and/or y directions) on the surface of workpiece 16. In addition, each time the angle of laser beam 12 relative to workpiece 16 changes, so does the path length of the beam. This can present problems in laser machining operations (e.g., custom corneal ablation) where the laser beam may have been optimized for a particular path length. Thus, a change in path length means that the laser beam is no longer optimized when it strikes the workpiece. This can result in either too little or too much "machining" at the surface of the workpiece.
The second approach, shown schematically in FIG. 2, involves the use of a mirror 20 and a linear positioner 22 coupled to the mirror. A laser source 24 is fixed in its position and mirror 20 is placed in the path of the generated laser beam 26 at angle .theta. (e-g., 45.degree.) therewith. Linear positioner 22 is used to move mirror 20 linearly towards or away from laser source 24 as represented by two-headed arrow 28. Such movement of mirror 20 causes a 1:1 corresponding amount of lateral displacement of beam 26 at the surface of workpiece 30. While precise amounts of movement can be achieved with linear positioners, the path length of beam 26 from laser source 24 to workpiece 30 changes each time mirror 20 is moved. In addition, since beam displacement is in 1:1 correspondence with mirror displacement, response time in terms of beam displacement is dictated by the speed of the linear positioner.

Constant path-length beam translating system and method


A motorcycle tire is provided with crown main oblique grooves disposed on alternating sides of the tire equator and each extending from its axially inner end to its axially outer end, without cutting across the tire equator, while inclining to one circumferential direction, wherein the axially outer end is located outside an upstanding tire's ground contact annular zone. When measured in the annular zone, the circumferential distance between the circumferentially adjacent crown main oblique grooves existing on the same side of the tire equator is in a range of not more than 0.5 times an upstanding tire's ground contact length. In the annular zone, the crown main oblique grooves on one side of the tire equator is partially overlaps those on the other side. When measured in the annular zone, the circumferential length of the crown main oblique groove is less than the upstanding tire's ground contact length.

The present invention relates to a pneumatic tire for motorcycle, more particularly to a tread pattern for street use capable of improving transient characteristic and ride comfort while securing wet performance.
A motorcycle tire is required to have stable handling characteristic on dry roads from the upstanding state during straight running to a leaning state during cornering and vice versa. Especially required are appropriate suppleness (ride comfort) and transient characteristic which is uniform even if the leaning angle of the tire is changed. On wet roads, on the other hand, a high aquaplaning resistance is required. It is effectual for improving the aquaplaning resistance to provide grooves whose inclination angle is small with respect to the tire circumferential direction. However, such grooves have a tendency to decrease the generation of lateral force (such as cornering force and camber thrust) necessary for providing a good cornering performance on dry roads.
Japanese Patent Application Publication No. 06-55909 discloses a motorcycle tire, wherein in order to improve wet performance and cornering performance, a circumferentially continuously extending groove is disposed on the tire equator, and oblique grooves whose angle with respect to the tire circumferential direction is gradually increased toward the axially outside of the tire are disposed on each side of the tire equator.
In such a tread pattern, however, it is difficult to uniform the transient characteristic from the upstanding state during straight running to a leaning state during cornering and vice versa, therefore, there is still room for improvement in the cornering performance.


Passive entry sensor systems and associated sensors are disclosed. The system sensor is locatable in the handle of a door or like structure and can provide an electromagnetic radiation beam transmitted either along the length of the handle between opposite ends thereof or between the handle and the door such that the sensor can detect at least a partial interruption of the beam by a user actuating the handle. The system can include an independent optical locking switch for actuation by a user to lock the door which locking switch comprises a shutter for intercepting the beam so as to flag the sensor. The system can include a power-up switch for actuation by a user to power-up the system, back-up switches for detecting a pull on the handle, indicators for indicating system status to the user, and backlight and ground light lighting.

It is important, for many reasons, to control access to premises, vehicles and personal property so that only authorized users are allowed access. Typically this is done using keys which fit a lock to allow the user of the key to open the lock and gain entry. One problem with the existing key and lock arrangements is that loss or damage to the key can render access impossible. In addition, if the key lock itself is blocked or damaged this can also prevent access. One other problem is that the use of a key requires a specific action such as unlocking a latch with the key from the authorized person before an action of opening the door. This specific action is very often not easy to do, not ergonomic and is time-consuming.
A number of ways have been proposed to try to overcome these disadvantages. With security devices for cars, it is well known that a keyless fob can be used, such that actuation of a button on the fob generates an infrared (IR) or radio frequency (RF) signal which is detected by a sensor in the vehicle which unlocks the doors. A key is still required by the user in order to operate the ignition system. The fob also contains a lock button which generates a similar IR or RF signal to lock the vehicle. Such vehicle keyless access systems have been known for a number of years. Such systems operate on the basis that when the IR or RF "open" signal is generated by the fob, the signal is used to actuate a mechanism which unlocks the car door so that when the user pulls on the handle, the door is already unlocked. Similar arrangements may be used for building entry.
One problem with this arrangement is that the user still has to initiate a specific action such as, in the case of a fob, taking the fob in his hand and pressing on the fob button, or in the case of a magnetic card or the like, inserting the card in a slot or to present it in front of a card reader/detector or the like, in order to unlock the door and have access to the vehicle, these specific actions being time-consuming and not ergonomic.
One other problem with this arrangement is that if the user decides not to enter the vehicle but forgets to actuate the "lock" signal, the car and/or building remains open and is thus vulnerable. In addition, with existing keyless locking systems, particularly for vehicles, a conventional locking mechanism is used which is susceptible to interference by thieves to gain access to the car. For buildings, conventional locks are actuated in the same way and are susceptible to the same procedures by intruders to gain access to the premises.
A passive entry sensor system for use in a keyless access system used in automotive applications transmits a beam of light from a sensor that is bracket-mounted and spaced behind the door skin. The beam of light strikes a lens protector mounted on the door skin, where the beam is deflected towards a mirror mounted on the door handle. On striking the mirror, the beam is reflected back to the lens protector where it is deflected into the sensor and detected. Alternatively, the bracket-mounted sensor can be configured to provide a beam from one end of the handle to the other by optically coupling the bracket-mounted sensor to the handle using light guides.
Such passive entry sensor systems are expensive to implement, particularly in automotive applications, as a result of high piece part count and assembly time. Furthermore, in order to use such systems, extensive modification of the door skin of the vehicle is necessary. Also, the functionality of such sensors is limited.
There is a need to provide a more cost effective passive entry sensor system. There is also a need to provide a multi-functional passive entry sensor system. Additionally, more efficient passive entry sensors and systems are necessary which can be used to open doors, access panels or the like in a range of applications.


The present invention provides a wholly aromatic liquid-crystalline polyester consisting of the repeating units represented by formulae (I), (II), (III) and (IV):

In modern societies, multimedia in daily life is rapidly developing and ITS (Intelligent Transport Systems) such as ETC device used in toll roads and GPS becomes widely used. In order to treat the extraordinary increase of information and telecommunications technologies, the frequency of signals used for the transmission is becoming higher.
As material used for the information communication devices employing such a high frequency, engineering plastics which exhibit excellent dielectric properties in high frequency regions (especially in gigahertz bands) attract attention. The engineering plastics also exhibit good productivities and lightweight properties and therefore, they are expected to be applied for chassis and package of communication devices and electronic devices as well as for dielectric body and the like.
Among the engineering plastics, thermotropic liquid-crystalline polyester resin (which is called as liquid-crystalline polyester resin or LCP hereinafter) has the following excellent properties and is especially expected to be suitable for manufacturing devices which use high frequency signals:    (1) excellent dielectric properties: the relative permittivity (∈r) is constant in the frequency regions employed and dielectric loss tangent (tan δ) is small,    (2) good physicalities: mechanical properties including low-expansion property (dimensional stability), heat resistance, flame retardancy and rigidity are good, and    (3) good molding flowability: which allows processing of molded articles having down-sizing and thinner parts.
Among the liquid-crystalline polyester resins, wholly aromatic liquid-crystalline polyesters comprising 6-oxy-2-naphthoyl repeating unit, 4,4′-dioxybiphenyl repeating unit and aromatic dicarbonyl repeating unit in certain proportions are recently proposed because they exhibit good dielectric properties, heat resistance and molding processability (see US Patent Application Publication No. 2004-152865 and US Patent Application Publication No. 2004-164282).
The liquid-crystalline polyesters disclosed in the above two references and Japanese Patent Application laid open No. 2007-154169 include a great amount of 6-oxy-2-naphthoyl repeating unit. Though such liquid-crystalline polyesters exhibit excellent dielectric properties, their mechanical properties such as impact strength are relatively poor.
Accordingly, a wholly aromatic liquid-crystalline polyester resin which exhibits excellent dielectric properties as well as good mechanical properties such as impact strength is desired.

Wholly aromatic liquid-crystalline polyester

Abstract: wherein:                the molar proportion of the repeating unit represented by formula (I) based on the total repeating units constituting the wholly aromatic liquid-crystalline polyester is 40-80 mol %;        the molar ratio of the total amount of the repeating units represented by formulae (II) and (III) to the repeating unit represented by formula (IV) is from 90/100 to 100/90;        the molar proportion of the repeating unit represented by formula (II) based on the total amount of the repeating units represented by formulae (II) and (III) is 80-99.9 mol%; and        the two “—O—” attached to the benzene ring in formula (III) are positioned meta or para to each other and “Ar” in formula (IV) represents a bivalent aromatic group.The wholly aromatic liquid-crystalline polyester of the present invention exhibits excellent dielectric properties in high frequency regions as well as good mechanical properties such as impact strength.


An integratable sensor for an airfoil of an aircraft such as an airplane and a helicopter comprises a sensor capsule, in whose inner chamber a measuring element for measuring an environmental parameter is situated. A capsule carrier is implemented to accommodate and removably attach the sensor capsule and is integratable in an airfoil of an airplane or a helicopter. Elastic contact elements are used for secure electrical connection of the sensor capsule to the capsule carrier. The sensor capsule is replaceable, while the capsule carrier is permanently integrated in the airfoil, in particular in a rotor blade. The measuring element is, for example, a pressure sensor.

This application claims the priority of German patent document 10 2005 052 929.1-22, filed Nov. 3, 2005, the disclosure of which is expressly incorporated by reference herein.
The present invention relates to an integratable sensor for airfoils of aircraft such as airplanes and helicopters, a rotor blade, and an airplane wing.
Sensors are increasingly integrated in wings of airplanes and in rotor blades of helicopters to measure environmental parameters, such as pressure, temperature, flow, etc. Sensors of this type are subjected to especially rough environmental conditions in operation. For example, the sensors may be damaged by incident particles or contaminants, such as dust and insects.
Especially during use in airfoils and/or rotor blades, the sensors are also subjected to extreme weather influences, such as frost, varying temperatures, and varying air pressure.
In the event of contamination or a defect of the sensors, they must be replaced, which requires great effort and correspondingly high maintenance costs of the airplane or helicopter.
One object of the present invention is to reduce the maintenance costs of helicopters and airplanes equipped with sensors.
Another object of the invention is to provide an integratable sensor which may be put into service more easily and rapidly.
These and other objects and advantages are achieved by the integratable sensor for airfoils of aircraft and helicopters according to the present invention, which comprises a sensor capsule with a measuring element situated therein for measuring an environmental parameter. A capsule carrier, which is integratable in an airfoil of an aircraft, is equipped to accommodate and removably attach the sensor capsule; and contact elements are provided for electrically connecting the sensor capsule to the capsule carrier.
According to the present invention, in the event of a sensor defect or contamination, the defective part of the sensor may be replaced easily, without having to remove the entire sensor from the airfoil or the rotor blade. That is, replaceable sensor capsules may be used, which may be exchanged easily in the event of a defect. Electrical connections, cables, etc. do not have to be dismounted and subsequently mounted again; rather they may remain in location. The removal of the rotor blade and integration of a new rotor blade including the required cabling is no longer necessary in the event of a defective sensor, for example. By integrating the measuring element in the sensor capsule and accommodating the latter in the capsule carrier, an especially reliable and robust sensor having an increased service life also results. The maintenance costs of helicopters and airplanes are significantly reduced.
The contact elements are preferably elastic, providing an especially reliable electrical connection between sensor capsule and capsule carrier, which may be produced easily and disconnected again rapidly. There is no danger that the contacts will break or be damaged by penetrating water, as would be the case with contact pins, for example.
The measuring element is advantageously a pressure sensor element, and the integratable sensor may thus be a pressure sensor. However, it is also possible to use other measuring elements, such as for measuring flow, temperature, humidity, acceleration, or other physical parameters.
The capsule carrier is advantageously integrated permanently in a rotor blade or an aircraft airfoil.
The inner chamber of the sensor capsule is preferably enclosed by a capsule wall, whose external shape is tailored to the interior of the capsule carrier. The measuring element is thus protected in the inner chamber of the sensor capsule; in addition, the sensor capsule may be accommodated completely in the capsule carrier and held securely there.
The sensor capsule is preferably provided with a protective cover, which has at least one through opening as an air passage. In this manner, especially good protection of the measuring element in the inner chamber of the sensor capsule results, while the ambient air nonetheless is able to reach the measuring element in the inner chamber.
The surface of the protective cover of the sensor capsule advantageously runs in a plane with the surface of the airfoil in the integrated state. The flow on the airfoil thus remains largely uninfluenced by the sensor.
The continuous opening in the protective cover advantageously runs at least partially diagonally or transversely to the surface of the protective cover. Direct impact of particles on the measuring element in the inner chamber of the sensor capsule is prevented by the structuring of the protective cover because of the geometry of the through openings.
In particular, the sensor element may comprise at least two wafers which are bonded to one another, and are shaped in such a way that they form a cavity sealed by a diaphragm. An especially reliable pressure sensor is thus provided, which is producible cost-effectively and provides precise measurement results. In addition, it has a very long service life.
The sensor capsule is preferably held in the capsule carrier by a magnetic force, which results in a still further reduction of the effort when mounting and/or replacing the sensor capsule. The sensor capsule is nonetheless held securely by the magnetic force in the capsule carrier, so that it withstands high accelerations. The magnetic force is generated, for example, by a permanent magnet or by electromagnets in the capsule carrier, for example. An electromagnet has the special advantage that it exerts an even stronger force for retaining the sensor capsule and may be turned off to replace the sensor capsule. In contrast, a permanent magnet has the advantage of simpler and/or less costly construction of the sensor.
The permanent magnet may, for example, be situated in the capsule carrier, while ferromagnetic metal such as iron is situated in the sensor capsule. Alternatively, it is also possible to situate the permanent magnet in the capsule and ferromagnetic metal in the capsule carrier. The latter arrangement has the advantage that, when the capsule carrier is laminated into the carbon-fiber reinforced plastic material of the rotor blade or the airfoil, damage to the permanent magnet because of the heat developed and possibly exceeding the Curie temperature of the permanent magnet are avoided. Furthermore, it is also possible to situate a permanent magnet in both the sensor capsule and the capsule carrier.
The capsule carrier preferably has planar electrical contacts for contacting the elastic contact elements of the sensor capsule, which achieves a very secure and reliable electrical connection between capsule carrier and sensor capsule, due to the planar surface of the capsule carrier, which is easily disconnectable and is protected against damage such as buckling, breaking, or due to penetration of water.
The capsule carrier advantageously has a wall whose interior is tailored to the external form of the sensor capsule. Thus, for example, a formfitting integration of the sensor capsule into the capsule carrier may be performed. In addition, the sensor capsule is secured against strong radial forces, such as occur in the rotating rotor blade, for example, by the guide in the capsule carrier.
The capsule carrier and the sensor capsule are preferably mutually engaged using a notch and a corresponding projection, in order to prevent relative twisting. In this manner, the sensor capsule can be introduced in a defined way into the capsule carrier, so that the contact elements of the sensor capsule each rest precisely on the planar contacts of the capsule carrier. Mutual twisting of sensor capsule and capsule carrier is prevented by the notch and the corresponding projection.
The sensor element advantageously comprises a cavity which is hermetically sealed by a flexible diaphragm, and the interior of the cavity diametrically opposite the diaphragm is tailored to the contour of the diaphragm in the deflected state. The diaphragm is protected better from damage in this manner, since the diaphragm itself rests flat on the contoured interior of the cavity in the event of inhomogeneous eccentric load. Moreover, an overload protection at excessive pressure results, due to the delimitation of the deflection of the diaphragm, by which tearing of the diaphragm is prevented.
According to one aspect of the present invention, a rotor blade for helicopters is provided, in which a sensor according to the present invention is integrated.
According to a further aspect of the present invention, an airplane airfoil is provided, in which a sensor according to the present invention is integrated.
Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings.

Integrated sensor for airfoils of aircraft, particularly of airplanes and helicopters, as well as rotor blades and airplane airfoil


The present invention provides antiretroviral methods using the compounds of formula (I) EQU X-X1-P1-Val-Z-Leu-P2-Y. wherein:. Z is Statine or ACHPA; PA1 X is H-Pro-paF, H-Pro-His, Ac-Tyr, Ac-NA, Ac-Trp, Ac-YOM, Ac-Phe, Ac-paF, H-His, Ac-His or Ac-Gly-Tyr-YOM, PA1 X1 is Pro Ser or Ac, PA1 P1 is Phe, paF or YOM, PA1 P2 is Phe or Leu, and PA1 Y is NH.sub.2, paF--NH.sub.2, His--NH.sub.2, Phe--NH.sub.2 or Tyr-Lue--NH.sub.2, PA1 X is H-Pro-His, H-Pro-paF, Ac-paF or Ac-His, PA1 P1 is Phe, PA1 P2 is Phe, and PA1 Y is paF--NH.sub.2 and His--NH.sub.2.. and when Z is Statine,. provided that when X1 is Ac then there is no X residue;. and when Z is ACHPA,. The invention further provides methods for determining the retroviral protease inhibitory activity of compounds using viral polypeptides made using recombinant DNA techniques.

Diseases caused by retroviruses are becoming alarmingly prevalent. Sexually transmitted retroviral infections and those transmitted by blood transfusion have been the focus of intensive research efforts over the past several years. The tools of modern molecular biology have yielded many of the secrets of retroviral infection, maturation and replication. The present invention concerns the discovery that certain short peptides are useful in treating retroviral infections because the peptides can inhibit the action of the retroviral proteases. The invention also relates to methods for discovering other compounds which display retroviral protease inhibitory activity.

Methods for treating retroviral infection


Approaches are described for providing quality of experience (QoE) driven in-transport communications services. For example, in-transit communications services are provided over a network to content consumption devices on one or more transport craft. During a measurement window, delivery of the in-transit communications services can be measured to obtain network-level delivery (NLD) measurements, and consumption of the in-transit communications services by one or more of the content consumption devices can be measured to obtain customer-level consumption (CLC) measurements. The NLD and CLC measurements can be used to compute a QoE score that indicates a delivered quality of service as perceived by one or more passengers of the one or more transport craft. The QoE score can be used to update stored service level data. The update can cause generation of one or more service level triggers, which can trigger automatic remedial action to address QoE-related conditions.

Residential or business customers of communications and content services typically enter into relatively long-term (e.g., monthly, yearly, etc.) contractual relationships with providers of those services, such as with Internet service providers, television service providers, over-the-top media service providers, and others. Those customers generally expect a certain contracted level of service; and when those customers experience an undesirable level of service, they are often motivated to contact the service provider to report the undesirable level of service. For example, frustrated customers can be likely to contact their Internet service provider whenever there is a service outage, an appreciable slow-down, configuration issues, etc. To help ensure a desirable experience for their customers, such service providers typically encourage their customers to report issues and work to address those issues in a timely fashion.
It is becoming more common for users to desire to consume communications resources (e.g., for streaming media, email, Internet, etc.) while in transit on a transport craft. For example, passengers may bring mobile phones, laptop computers, tablet computers, integrated media terminals, and/or other in-transport terminals while travelling by car, airplane, bus, train, cruise ship, or other transport craft. In many cases, some or all of the communications services are provided to the passengers via a remote network (e.g., Internet) in communication with the transport craft. In such cases, there is often contractual relationship between a communications provider and the transportation provider that operates the transport craft. To help ensure a particular level of service is being provided by the communications provider, some such providers tend periodically to check that their services are available for a percentage of time and/or are satisfying some contracted data rate threshold.
While there is often a relatively long-term contractual relationship between the communications provider and the transportation provider, there may only be a relatively short-term relationship between the communications provider and the passengers. For example, a passenger of an airline may only use that airline's Internet service for part of the duration of a single flight. During that time, though the service may be technically available and providing at least a minimum data rate to the airplane, the passenger may still experience poor, or no, service for a number of reasons. As such, both the transportation providers and the communications providers may have an incomplete understanding of end users' experiences, which can tend to frustrate the ability of those providers to become aware of, and to properly address, issues arising with regard to those end users' experiences.

This patent is subject to a terminal disclaimer.

Systems and methods for quality of experience driven in-transport communications


A vacuum cleaner nozzle assembly having at least one auxiliary suction opening along an edge thereof for picking up dirt and debris as the nozzle is moved along a wall or other obstruction. The auxiliary suction openings may be on both sides of the nozzle assembly, located proximate the ends of the primary intake opening. Auxiliary suction ducts connect the auxiliary intake openings to an internal plenum that also supplies vacuum to the main intake opening. The primary and secondary airflows merge in the plenum for withdrawal and collection. The nozzle assembly may be a power nozzle having a roller brush and a drive motor, or may be an unpowered carpet nozzle.

a. Field of the Invention
The present invention relates generally to vacuum cleaners for use on carpeted and non-carpeted surfaces, and, more particularly, to a vacuum cleaner nozzle assembly having at least one suction duct with an intake opening located along an edge of the housing for enhanced cleaning close to a wall or other obstruction.
b. Related Art
The cleaning power of a vacuum cleaner is generated primarily by its suction motor, largely in the form of "airflow," a rapid movement of air that carries dust and dirt from the surface being cleaned to a dirt receptacle, such as a disposable paper bag or a removable bagless container.
Vacuum cleaners normally employ a nozzle to apply the airflow to the carpet or other surface being cleaned. Non-motorized "carpet nozzles" and motor-powered "power nozzles" are engineered to create an effective airflow pattern for cleaning carpeted surfaces, with power nozzles having the added benefit of a spinning, bristled "roller brush" which agitates the carpet and loosens embedded dirt.
A long-standing difficulty with conventional nozzle assemblies, whether of the carpet or the power type, is their inability to clean effectively in areas very close to a wall or other obstruction. For example, the edge of a carpeted area where this meets the wall often forms a crevice which tends to collect dirt and debris that conventional nozzle assemblies have difficulty removing.
Designers have attempted to deal with this problem, referred to as "edge-cleaning performance", by positioning the ends of the intake opening (and roller brush, in power nozzles) as close as possible to the lateral edges of the nozzle assembly. However, even when made as thin as possible the end wall of the opening and the end support for the roller brush always create a gap that prevents the cleaning action from reaching into the crevice. In some instances, designers have formed small channels that extend laterally from the main airflow opening and under the roller brush end supports in an effort to generate some suction along the edges of the nozzle assembly but in general these have only a marginal effect; in any event such channels must be quite limited in size or else they will compromise the ability of the assembly to generate an upwards suction force with sufficient airflow when moving over the floor in areas away from the wall.
In an effort to deal with these problems most vacuum cleaners are provided with a separate "crack tool" or "crevice tool", which is a flat, narrow nozzle that is mounted on the end of a suction hose. Although these tools usually work adequately, they add an irksome and tiring step to the edge-cleaning process, requiring the operator to frequently bend over, thereby straining the muscles of his/her back. As a result, traditional "crevice tools" do not provide a satisfactory solution, and are in fact simply not used by many operators.
Another factor impacting the design of a vacuum cleaner nozzle assembly is that the total weight of the assembly must be kept to a minimum for maneuverability and ease of use. Although a number of prior nozzle assemblies have incorporated new features for the purported convenience of the operator and/or better cleaning, the benefits of the features have frequently been negated by additional weight that has made the machines cumbersome and difficult to use.
Accordingly, there exists a need for a vacuum cleaner nozzle assembly that provides an effective cleaning action along both its lateral edges or at least one lateral edge thereof, so as to effectively remove dirt and debris along the junctures between the floor and walls or other obstructions. Furthermore, there exists a need for such a nozzle assembly that provides effective edge-cleaning without compromising the ability of the assembly to provide a vertical suction against floor surfaces when cleaning in areas away from the wall. Still further, there exists a need for such a nozzle assembly that provides effective edge-cleaning in a single pass, without requiring the use of separate tools or additional cleaning steps. Still further, there exists a need for such a nozzle assembly that provides enhanced edge-cleaning without adding significantly to the total weight of the assembly. Still further, there exists a need for such an assembly which is adaptable to use with existing forms of suction-generating motors, roller brushes, drives and other mechanisms associated with conventional vacuum cleaners and nozzle assemblies, so as to minimize the costs for tooling and development thereof. Still further, there exists a need for such a nozzle assembly that is structurally simple, economical to manufacture, and durable in use.
These and other features and advantages of the present invention will be apparent from a reading of the following detailed description with reference to the accompanying drawings.

Vacuum cleaner nozzle assembly having edge-cleaning ducts


A content acquisition device includes a processor that executes a procedure. The procedure includes: acquiring group data to identify a group that a user belongs to; and based on a period of time needed to acquire content from each of a first data processing device that holds content shared by the group indicated by the group data, and a second data processing device that is in the process of acquiring the content from the first data processing device, selecting a data processing device from which to acquire the content.

Recently, services, such as SNS, that share content between particular users are increasing. Moreover, as a result of it now being possible to generate high picture quality content due to the increasingly high functionality of terminals, the size of shared content is ballooning, with a tendency for the waiting times for uploading and downloading content to get longer.
Methods that employ cache servers are widely utilized as methods to shorten the waiting times for uploading and downloading content. For example, for content accessed by many unspecified users under a cache server, frequently-accessed content is distributed to that cache server. This enables the time taken to download content to be shortened for users under that cache server.
There has also been a proposal, when transmitting data, to select, from plural cache servers, a cache server that has a light load and a short delay when communicating with a client, and to distribute data from that cache server to the client.


Disclosed is a semiconductor device that reduces the area of a transistor in a ReRAM. A plurality of memory cells differ from each other in the combination of bit line and plate line. The potential of plate line PL2 is a forming voltage. By contrast, the potentials of the other plate lines are +Vi. The potential of bit line BL2 is 0 V (ground potential). By contrast, the potentials of the other bit lines are +Vi. The potential of is +Vgf. By contrast, the potentials of the other word lines are +Vi.

The present invention relates to a semiconductor device and a forming method. More specifically, the present invention relates to a technology that is applicable, for instance, to a resistance random access memory (ReRAM).
The ReRAM is currently developed as a nonvolatile memory. The ReRAM is a memory that uses a variable resistance element. In an initial state, the variable resistance element is an insulator. As described, for instance, in Japanese Unexamined Patent Application Publication No. 2010-218615, the variable resistance element decreases its resistance when subjected to forming. In forming, a high voltage (forming voltage) is applied to the variable resistance element. After forming, the variable resistance element is in either a high-resistance state or a low-resistance state. When a voltage is applied to the variable resistance element, the variable resistance element can switch from the high-resistance state to the low-resistance state or from the low-resistance state to the high-resistance state. The ReRAM retains either "0" or "1" as data depending on whether the variable resistance element is in the high-resistance state or the low-resistance state.
An example of the ReRAM is described in Japanese Unexamined Patent Application Publication No. 2005-25914. This ReRAM includes a plurality of memory cells, a plurality of plate lines, and a plurality of bit lines. Each memory cell includes a transistor and a variable resistance element. The drain of the transistor is coupled to a plate line through the variable resistance element. The source of the transistor is coupled to a bit line. A voltage between the plate line and the bit line causes the variable resistance element in each memory cell to switch from the high-resistance state to the low-resistance state or from the low-resistance state to the high-resistance state.


An apparatus for detecting motion of a wheel comprising tyre. The apparatus comprises a pressure sensor for measuring the tyre pressure and generating a signal corresponding to the measured tyre pressure, and means for detecting a component of said signal that corresponds to, or is generated by, vibrations of the tyre. Upon detection of the signal component, the apparatus determines that the wheel is in motion. The detecting means may arranged to detect an audio signal component or signal components having a frequency in the range 200 Hz to 300 Hz.

Tyre pressure monitoring systems are well known. European Patent Application EP 0 793 579, which is hereby incorporated herein by way of reference, discloses an example of a known tyre pressure monitoring system. Typically, the system includes a pressure sensor which is incorporated into a vehicle's pneumatic tyre in order to monitor the air pressure therein. A control module, typically comprising a microprocessor, is provided for processing the output of the pressure sensor. The system also includes a transmitter for signalling the measured tyre pressure to a remote console usually provided in the vehicle's cabin. Normally, a battery is provided for supplying electrical power to the control module, the transmitter and any associated circuitry.
Conservation of battery power is an important consideration in a tyre pressure monitoring system. To this end, the system may adopt a normal operating mode when the vehicle is moving (or at least moving above a pre-determined threshold speed) and a conservation mode when the vehicle is stationary (or moving slower than a threshold speed). In the conservation mode, the system is less active than when in normal mode—for example, the pressure monitoring/transmitting cycle may occur one every few minutes rather then once every few seconds—and so battery usage is reduced.
Conventional tyre pressure monitoring systems usually include a mechanical roll switch (which typically includes a ball and spring mechanism), an accelerometer, or an equivalent mechanism, for detecting when the vehicle is in motion, or when the vehicle exceeds a threshold speed. Not only do such mechanisms add to the overall size of the system, but they are also considered to be relatively expensive and unreliable.
It would be desirable, therefore, to provide a relatively inexpensive, robust and space-saving alternative to conventional roll switches and equivalent mechanisms.
Several studies [1], [2] have indicated that a tyre when fitted to a wheel rim exhibits a natural resonance when excited. The presence of this resonance can be demonstrated when a fitted tyre is struck with a tyre iron or other object. The vibration or resonance of the tyre results in the generation of an audio signal or tone. The frequency of the tone is dependant on the structure and size of the tyre and also on the pressure (typically air pressure) inside the tyre. Research indicates that, for a normal passenger car, the general range of the resonant frequency is between 200 and 300 Hz.

Method and apparatus for detecting wheel motion in a tire pressure monitoring system


This invention is directed to a method for the in vitro application of bioregulator compounds. When applied to intact plants in bioregulatory amounts, the compounds enhance important plant properties such as sugar content, essential oils, vitamins, proteins, and an overall increase in total biomass. The treated plants exhibit accelerated growth, accelerated fruit ripening, improved color scores of juice products and an accelerated maturation. The bioregulator compounds which comprise the invention enhance these plant properties when applied individually to plants. It has also been discovered that the application of mixtures of such compounds effect a greater than additive result and enhance the aforementioned plant properties to an unpredicted and unexpected degree when compared to known bioregulator agents. The present application discloses the usage of plant bioregulator agents in an in vitro environment.

This application is a continuation-in-part of presently pending U.S. application Ser. No. 860,413 filed on Mar. 30, 1992 and a continuation in part of copending application Ser. No. 954,725 filed on Sep. 30, 1992. The disclosures of both of these applications are incorporated herein by reference.
Developments in agriculture have produced chemical compounds and methods for their application which function as plant bioregulators and thus serve to enhance one or more properties of the treated plant. For example, U.S. Pat. No. 3,671,219 discloses a quartenary ammonium compound which when applied to plants enhances the sugar content of sugar cane. U.S. Pat. No. 4,204,859 discloses that the addition of certain phenoxytrialkylamines enhance the hydrocarbon production of rubber in plants. U.S. Pat. No. 4,159,903 discloses a method for increase of polyisoprene production in rubber producing plants such as Guayule. U.S. Pat. No. 3,833,350 discloses that carotenoid accumulation in plants can be increased according to a method comprised by applying compounds including (halogenated phenoxy) trialkylamines. U.S. Pat. Nos. 3,864,501, 3,911,148, and 3,911,152 disclose a method for increasing-the carotenoid pigments of fruits and vegetables which comprises the application of compounds including (methyl phenoxy) trialkylamines.
U.S. Pat. No. 4,797,153 discloses a method for increasing total plant biomass and individual plant constituents such as sugar, protein, lipid, and essential oils which comprises the application of certain substituted phenoxytrialkylamines and substituted phenylthiotrialkyl amines, or dialkylmorpholium halides. The compounds are applied in bioregulatory amounts to plant seeds, plant seedlings, or plant buds at the early stage of plant development, or to trees during a week before or after flower bud swell. It has since been shown that the application of the compounds of this reference in bioregulatory amounts affect the photosynthetic pathway in green plants in a manner which facilitates the assimilation of carbon dioxide in the photosynthetic pathway, thereby increasing the carbon atoms available for synthesis of total biomass and individual plant constituents.
U.S. Pat. No. 4,363,188 discloses a method for the stimulation of the in vitro propagation of Guayule. A substituted trialkyl amine bioinducing agent is introduced into a nutrient medium containing Guayule tissue. Selective or differentiated propagation of shoots or callus is obtained by varying the amounts of substituted trialkyl amine present in the nutrient medium. The Guayule growth, which is described as being luxuriant, can be processed for its polyisoprene content or may be transferred to a rooting medium for production of whole plants that are identical clones of the original tissue. Suitable bioinducing agents are disclosed at columns 5, 6, and 7 of the specification, and include the bioregulator agents disclosed in U.S. Pat. No. 4,797,153. The compounds disclosed in method of the present invention are not disclosed in the '188 patent.
The growth of plants in vitro offers several distinctive advantages over plants grown in their natural environment. Since the in vitro environments are created by individuals the various parameters which constitute the environments such as heat, light, moisture, nutrient content, pH, etc, can be selected so as to best facilitate plant growth. Consequently, the ease in which the environmental parameters can be controlled facilitates research since clinical studies are easily developed and managed. It is a further consequence that certain plants not indigenous to a certain geographical locale can be made available in that region without the need to import them from elsewhere, or that plants can be made available out of season. Furthermore, plants exhibiting superior genetic tendencies can be cloned to produce plants exhibiting the same superior traits. The advantages offered by growth in vitro provide beneficial results to researchers and, commercial growers alike.

Method of in vitro application of bioregulator compounds

The United States of America as represented by the Secretary of Agriculture


An articulated railcar has several well car units for carrying shipping containers, highways trailers, or a combination of the two. The well car units permit the nose of a highway trailer to overhang the articulated connection between two adjacent cars. A brake valve is located in a relief formed in the main bolster of one of the articulated units, out of the way of the overhanging trailer. Each well car unit has a side beam having a roll formed top chord reinforced by a top chord plate, a downwardly extending web, and a lower sill formed of a thick angle. The service, or auxiliary, and emergency brake reservoirs are mounted in a saddle bag configuration to the outside face of the webs of the opposite side beams of the articulated unit, tucked underneath the reinforced roll formed top chord.

This invention relates to improvements in the structure of well cars, and in particular to the braking system of those cars.
Railway well cars may be considered as upwardly opening U-shaped channels of a chosen length, simply supported on a pair of railcar trucks. Although single unit well cars are still common, there has been a trend in recent years toward articulated, multi-unit railcars which increase the number of containers per unit length of train. Further, articulated cars are cheaper to build and maintain per container slot.
Contemporary well cars may carry a number of alternative loads made up of containers in International Standards Association (ISO) sizes or domestic sizes, and of highway trailers. The ISO containers are 8xe2x80x2-0xe2x80x3 wide, 8xe2x80x2-6xe2x80x3 wide, and come in a 20xe2x80x2-0xe2x80x3 length weighing up to 52,900 lbs., or a 40xe2x80x2-0xe2x80x3 length weighing up to 67,200 lbs. Both stand-alone and articulated well cars can be all-purpose trailer on flat car (xe2x80x9cTOFCxe2x80x9d) or container on flat car (xe2x80x9cCOFCxe2x80x9d) railcars. This means that they can carry both containers and trailers or containers only. Domestic containers are 8xe2x80x2-6xe2x80x3 wide and 9xe2x80x2-6xe2x80x3 high. Their standard lengths are 45xe2x80x2, 48xe2x80x2 and 53xe2x80x2. All domestic containers have a maximum weight of 67,200 lbs. Recently 28xe2x80x2 long domestic containers have been introduced in North America. They are generally used for courier services which have lower lading densities. The 28xe2x80x2 containers have a maximum weight of 35,000 lbs.
Two common sizes of highway trailers are, first, the 28xe2x80x2 pup trailer weighing up to 40,000 lbs., and second, the 45xe2x80x2 to 53xe2x80x2 trailer weighing up to 60,000 lbs. for a two axle trailer or up to 90,000 lbs. for a three axle trailer. It is advantageous to provide well cars with TOFC and COFC hitches at both ends. This permits either a single 53xe2x80x2 three axle trailer or, or two back-to-back 28xe2x80x2 pup trailers to be loaded. The wheels of a trailer can rest in the well, with the front of the trailer overhanging decking at one end or the other of well car unit. A second trailer may rest in the well facing in the opposite direction. Altematively shipping containers, typically of 20 ft., 28 ft, or 40 ft lengths, may be placed in the well, with other shipping containers stacked on top. Further, well cars may carry mixed loads of containers and trailers.
When a long highway trailer rests in the well of one unit of a multiple unit articulated well car, the nose of the trailer is held in a king pin mount on the end structure of that same unit, and can overhang both the articulated connection and part of the end structure of the adjacent well car unit. Larger highway trailers usually imply larger loads. A deep side beam can generally carry a greater load than a shallow beam. Deep side beams generally yield a relatively deep well. A higher load capacity also tends to require the use of a larger, 38 inch wheel truck and a deeper end structure. The result is that the clearance from the top of the end structure of each well car unit to the underside of the nose of the highway trailer may be relatively small. For example, in the well car described herein, the design clearance is about 5.5 inches above the bolsters and running boards. The clearance above the shear plate is greater, approximately 13 inches plus a small amount. The versatility of a well car is improved if the well is designed to receive highway trailers of most common sizes. Similarly, the structure of the well car unit is generally designed not to foul a design envelope defined by the extent of the sizes of the overhanging noses of highway trailers whose wheels can be received in the well, whether in terms of height or width.
A standard AAR brake reservoir is a cylindrical steel tank approximately 16 inches in diameter and 34 inches long. The reservoir has an internal curved plate which divides the cylinder into two compartments. One compartment is an auxiliary compartment for containing compressed air used for service brake applications. The other compartment is an emergency compartment, also for containing compressed air, and is used in emergency brake applications when more rapid braking is required. Both the brake valve and the brake reservoir are too large to fit within the 5.5 inch height restriction of the well car described herein, beneath the nose of the overhanging trailers.
A compressed air trainline is formed when the cars of the train are coupled together. Compressed air from the locomotives is supplied through the trainline to charge the various reservoirs. The normal charge in the reservoirs is 90 p.s.i.g. When the locomotive engineer applies the brakes under normal service conditions, pressure is bled down from the train line, to 85, 80 or 75 p.s.i.g., for example. This causes the brake valve in each successive car to bleed pressure from the auxliary reservoir to the car""s brake cylinder or cylinders to match the lowered pressure in the trainline. The air bled from each auxiliary reservoir is bled to its respective brake cylinder, and causes the brakes to be applied, either gently or more firmly depending on the pressure level selected by the locomotive engineer. In normal operation it takes a significant length of time for the signal of the pressure drop in the train line to reach the last car in the train, and for the pressure to stabilize at the particular value selected by the train locomotive engineer.
The brake valve will only open the emergency reservoir when the pressure drop in the trainline is large and rapid. It is desirable that an emergency signal travel down the trainline more quickly than in normal operation. When emergency operation is selected to xe2x80x9cdumpxe2x80x9d the trainline, the brake valve not only causes both the auxiliary and emergency reservoirs to be opened to the brake cylinders, but also causes a valve to vent the trainline to ambient at that specific car, rather than having to drain all the way back to the locomotive. The rapidity of the emergency brake response is then a function of the distance between the valves that vent, or xe2x80x9cdumpxe2x80x9d, the trainline to ambient. The American Association of Railroads (AAR) standard S-401-92 requires that the length of brake pipe between any two adjacent control valves not exceed 175 feet, to give desired emergency brake performance. A more equal spacing of the brake valves leads to a more even time lapse between successive brake valve actualizations and hence a more uniform brake application from one car to the next. The term xe2x80x9cuniformxe2x80x9d means that there is less time delay in the brake application from one car to the next. This in turn results in less slack action in the train.
Traditionally, brake valves and brake reservoirs have been located on top of the end structure of the articulated well car units. The need to maintain clearance from the noses of the highway trailers, as noted above, requires a different placement. One alternative is to locate the brake valve in the space between the car units, above an articulation truck. However, the space available tends to be limited by the requirement that the cars be able to follow a 180xe2x80x2 bend radius.
In light of the foregoing, there is a need for a multiple unit articulated railcar that can satisfy the twin requirements that the brake valves and brake reservoirs not interfere with overhanging highway trailers that can fit in the very restrictive space between adjacent intermediate units and that they not be separated by more than 175 feet.
The U-shaped section of the car is generally made up of a pair of spaced apart left and right hand side beams, and structure between the side beams to hold up whatever load is placed in the well, and to carry shear between the beams under lateral loading conditions.
In earlier types of well car the side beams tended to be made in the form of a single, large beam. While simple in concept, they were often wasteful, having a large weight of material in locations where stress may have been low. It is advantageous to design a sill in the form of a hollow section, of relatively thin walls, and to provide local reinforcement where required. It is also advantageous that the hollow section be formed at the mill as a hollow tube or roll-formed section where possible, rather than welded. This often yields a saving in effort, may permit the use of a higher yield stress steal, and may also reduce the number of stress concentrations in the resulting structure. As the wall thickness decreases the prospect of buckling under buff loads increases, and measures to increase stiffness and hence to increase the buckling load would be advantageous. It would also be advantageous to provide protection for the sills to discourage damage to the sills due to clumsy loading of trailers or containers.
In the past one method of dealing with areas of higher flange stresses in the side construction stress concentration was to use a member of greater weight. As the thickness of structural members is reduced it would be advantageous to transfer loads from the railcar trucks to the bolsters, and thence to the side sills, more smoothly to discourage or reduce stress concentrations. One way to do this is to increase the depth of section at the bolster, with a consequent increase in height of the end decking.
In a first aspect of the present invention there is a main bolster for an articulation connection end of a railcar unit of an articulated railcar. The bolster is positionable to extend laterally to both sides of a central sill for mounting an articulation connector, and the bolster has a relief formed therein for accommodating a brake valve.
In an additional feature of that aspect of the invention the bolster has a distal end most distant from the center sill, and a foremost side for placement generally facing a main bolster of an adjacent railcar unit. The relief is formed in the foremost side adjacent the distal end. In a further additional feature bolster has a tapered portion is adjacent its tip.
In another aspect of the invention there is a railcar unit of an articulated railcar. The railcar unit has at least one articulation connection end. The railcar unit comprises a sill for mounting an articulated connector, and a main bolster having arms extending laterally from the sill. At least one of the arms has a relief formed therein for accommodating a brake valve.
In an additional feature of this aspect of the invention, the articulated end includes a shear plate mounted below the bolster, a lateral reinforcement mounted to the shear plate, and a pair of protruding load bearing arms extending longitudinally therefrom on either side of the sill. The relief is located outboard of one of the load bearing arms. In a further additional feature, the reinforcement is mounted above the bolster and the reinforcement has another relief corresponding to the relief of the bolster.
In a further additional feature of that aspect of the invention, the railcar unit is a well car unit. It has a well in which the wheels of a highway trailer can be placed with the nose of the highway trailer overhanging the articulation connection end in a space defined as a clearance envelope. The brake valve is mounted at least partially within the relief with all of the brake valve lying outside the envelope.
In a further additional feature of that aspect of the invention, the railcar unit further comprises a pair of longitudinal side walls. It has emergency and service reservoirs for its brakes. At least one of the service brake and emergency reservoirs is mounted to one of the side walls. In a further feature of that additional feature, the service reservoir is mounted to one of the side walls and the emergency reservoir is mounted to the other side wall.
In an alternative additional feature of that aspect of the invention, the railcar unit has a pair of end structures each for mounting to a railcar truck, and a pair of side beams extending between the end structures. Each of the beams has a top chord and a lower sill. A brake valve is mounted at least partially within the relief. Service and emergency brake reservoirs are connected to the brake valve and mounted to at least one of the beams.
In a further additional alternative feature of that aspect of the invention, each of the top chords is formed of a hollow section having an inboard portion and an outboard portion. Each beam has a web connected between the inboard portion and the lower sill. The web has an outboard face. At least one of the service and emergency reservoirs is mounted to one of the outboard faces and is at least partially overhung by the top chord.
In a further alternative additional feature of the invention the railcar unit is a well car unit having a well for receiving the wheels of a highway trailer, such that the nose of the highway trailer overhangs the articulation connection end to define a highway trailer clearance envelope. The railcar unit has a brake valve mounted to lie at least partially within the relief. All of the brake valve lies outside the envelope. The railcar unit has a service brake reservoir and an emergency brake reservoir mounted thereto outside the envelope.
In another alternative additional feature of that aspect of the invention, the railcar unit is a well car unit. It has a well for receiving the wheels of a highway trailer, such that the nose of that highway trailer overhangs said articulation connection to define a highway trailer clearance envelope. The well car unit has a pair of end structures each for mounting to a railcar truck. A pair of side beams extend between the end structures. Each of the beams has a top chord, a lower sill, and a web extending between the top chord and the lower sill. Each web has an outboard face. A brake valve is mounted to the railcar unit at least partially within the relief and completely outside the envelope. A service brake reservoir is connected to the brake valve and mounted to the outboard face of one of the webs. An emergency brake reservoir is connected to the brake valve and mounted to the outboard face of the other web. The top chord of one beam at least partially overhangs the service brake reservoir. The top chord of the other beam at least partially overhangs the emergency reservoir.
In another aspect of the invention, there is a well car unit of an articulated railcar. It comprises a pair of end structures, at least one of the end structures being an articulation connection end for connection to an articulation truck. It has a well capable of receiving the wheels of at least one size of highway trailer, the size of the noses of the sizes of highway trailer which the well is capable of receiving defining a nose overhang clearance envelope relative to said articulation connection end. The railcar includes a brake cylinder for actuating the brake of said well car unit. A brake valve is connected to control the brake cylinder and is mounted to the well car unit within half the length of the well car unit from the articulation connection end. A service brake reservoir is connected to the brake valve. An emergency brake reservoir is connected to the brake valve. The service and emergency brake reservoirs are mounted to the well car unit to lie outside the envelope.
In an additional, alternative feature of that aspect of the invention, the well car unit has a pair of side beams extending longitudinally between the end structures to define sides of the well. The service reservoir is mounted to one of the sides and the emergency reservoir is mounted to the other.
In a further alternative additional feature of that aspect of the invention, the well car unit has a pair of side beams extending longitudinally between the pair of end structures to define sides of the well. The beams have an outboard face. The service reservoir is mounted to the outboard face of one of the beams and the emergency reservoir is mounted to the outboard face of the other. In a further alternative feature of that additional feature, each of the beams has a top chord, a lower sill and a web joining the top chord and the lower sill. The top chord overhangs the one of the service and emergency reservoirs mounted to the beam.
In a further alternative additional feature of that aspect of the invention, the brake valve is mounted to one of the end structures and the reservoirs are mounted to the well car unit closer to the brake valve than to the other end structure.
In a still further aspect of the invention, there is an articulated railcar having at least two articulated railcar units sharing an articulation truck and each having an articulation connection end connected to the truck. At least one of the railcar units is a well car unit. It has a well, and a pair of end structures at opposite ends of thereof The well is capable of receiving the wheels of at least one size of highway trailer. The sizes of the noses of the sizes of highway trailer which the well is capable of receiving define a nose overhang clearance envelope relative to the articulation connection ends of the railcar units. At least one of the railcar units has a brake cylinder for operating a brake of the railcar. At least one of the railcar units has a brake valve connected to control operation of the brake cylinder. The brake cylinder valve is mounted to the one railcar unit less than half the length of that railcar unit from the articulation connection end. At least one of the railcar units has a service brake reservoir connected to the brake valve. At least one of the railcar units has an emergency brake reservoir connected to the brake valve. The brake valve, service brake reservoir and emergency brake reservoir are all mounted to the railcar in positions lying outside the envelope.
In an additional feature of that aspect of the invention, the railcar has another brake valve mounted thereto less than 175 feet from the other brake valve.
In a still further aspect of the invention, there is a railcar unit comprising a pair of ends mounted to railcar trucks, and intermediate structure connecting the. A service brake reservoir and an emergency brake reservoir are separately mounted to the railcar unit.
In an alternative, additional feature of that aspect of the invention, the intermediate structure includes a pair of side walls extending longitudinally between the ends. The service and emergency brake reservoirs are each mounted to one of the side walls. In a further, additional alternative feature, the service brake reservoir is mounted to one of the, sidewalls and the emergency brake reservoir is mounted to the other.
In yet another further aspect of the invention, there is an articulated railcar having at least two articulated railcar units. Each of the units has an articulation connection end. Each of the ends has a central sill and an articulated connector mounted therein. The railcar units share a railcar truck to which the articulated connectors are mounted. Each unit has a main bolster extending laterally of its respective central sill. At least one of the bolsters has a relief formed therein to accommodate a brake valve between the bolsters.

Railcar structure for accommodating a brake valve


Disclosed herein is a oral extended release dosage form comprising a plurality of granules of an effective amount of a pharmaceutically active compound, at least one amino acid, and an intragranular polymer in which the granule is dispersed within a hydrophilic extragranular polymer matrix which is more rapidly hydrating than the intragranular polymer. The amino acid is selected for hydropathy characteristics depending on solubility characteristics of the active compound.

In traditional sustained release matrix systems, the drug is incorporated into a matrix consisting of either hydrophobic or hydrophilic materials such as polymers. The predominant mechanism of drug release from such systems is diffusion, resulting in curved release profiles that can be described by square root of time kinetics. Such release profiles are characterized by initial rapid release followed by a gradual decline in the rate of release, resulting in a prolonged "tailing off" in the late time phase. This "tailing off" is often accompanied by incomplete dissolution. Furthermore, there is typically an initial rapid release described as a "burst effect" which is attributed to the initial rapid wetting and dissolution of drug on the surface of the dosage form. This type of curved release profile may be a disadvantage for drugs that are to be absorbed throughout the gastrointestinal tract over an extended period of time at a controlled or constant rate. More specifically, the amount of drug available for absorption, over a period of drug release, steadily decreases. This may necessitate more frequent dosing compared to a dosage form that has a more linear drug release profile over an extended period of time. However, even in formulations that have a near zero order release, burst effects are frequently seen. The burst effect can be expected to be especially problematic as drug load increases, because by implication the concentration of drug at the tablet surfaces increases.
A number of approaches have been adopted to counteract the natural diffusive processes which control mass transfer from compressed tablets into surrounding aqueous dissolution media and to limit the burst effect. In particular, several methods to achieve so-called "zero order" controlled release or constant rates of release and approximate linear release profiles have been developed. These approaches include geometric modifications of the tablet, resulting in control of the surface area available for drug diffusion. Other examples include the use of multiple layer tablets, osmotic pumps, and coated pie shaped and hemispherical tablets with strategically located un-coated portions of surface area.
Many of the above named systems are of great utility, however they suffer shortcomings in that they are relatively costly and complicated to manufacture, often requiring multiple manufacturing steps and specialized equipment.
In addition, osmotic pump systems and multiple layer systems tend to deliver the drug in linear fashion only to about 85% of the total drug loaded, with severe tailing off thereafter. In the case of oral osmotic systems, this effect may be ascribed to the exhaustion of the reservoir device and the loss of osmotic pressure. Also, the aforementioned devices are of limited usefulness for the controlled delivery of large doses of medicament, for example more than 600 mg., especially if the medicament is relatively water soluble. In such cases of high drug loading, the addition of an absolute minimum of rate controlling excipient is necessary to achieve a tablet size that can be comfortably swallowed. Additionally, the need to add relatively large amounts of osmoagent and/or hydrophilic rate controlling swelling polymer layers severely limits the maximum drug load achievable in such systems.
Thus there is a need for a simple monolithic matrix tablet that is capable of delivering a high drug load irrespective of drug solubility to approximate zero order release kinetics.
In recent years, the value of hydrophilic polymer based systems employing controlled release has been increasingly demonstrated with the publication of numerous patents and research papers. Infield et al., U.S. Pat. No. 5,393,765, describes a hydrophilic erodible monolithic tablet formulation capable of approximating zero order drug release based on hydroxypropylmethyl cellulose and various erosion enhancing excipients such as lactose and surfactants such as Pluronic®. These constituents are mixed with a drug to form a matrix, and subsequently tableted. When ingested, the Infield et al. matrix forms two layers, an outer layer of hydrated matrix and an inner layer of unchanged matrix.
While semi-synthetic cellulose derivatives have found wide use in controlled release formulations, a number of polysaccharide based excipients have also been employed in oral controlled release systems. Polysaccharides which have been used as controlled release excipients, and have been employed on their own or in combination with other excipients, include chitosan, alginic acid, carrageenan, scleroglucan, and modified starch products.
Xanthan gum, a semi-synthetic polysaccharide of bacterial origin, has also received frequent attention as a controlled release material. The potential of xanthan gum alone has been evaluated, and a number of studies of xanthan gum in combination with alginic acid or guar gum have also been published. Baichwal et al., U.S. Pat. Nos. 4,994,276, 5,128,143, and Staniforth et al., U.S. Pat. No. 5,135,757, disclose controlled release excipient systems utilizing xanthan gum and a synergistically interacting polysaccharide such as locust bean gum or guar gum, along with secondary and tertiary components such as saccharides or other hydrophilic polymers. In these patents, it is speculated that a synergistic interaction occurs between xanthan and the polysaccharide gum resulting in an increased viscosity and gel strength. Based on similar principles of a synergistic interaction between xanthan and a gum, Baichwal, et al., U.S. Pat. No. 5,455,046, discloses a sustained release dosage form suitable for insoluble drugs such as nifedipine by employing cross-linked heteropolysaccharides and polysaccharides.
Guar, a natural galactomannan, obtained from the seeds of Cyanopsis tetragonolobus has found use in the pharmaceutical industry as a disintegrating and binding agent for tablets, as well as a suspending, thickening, and stabilizing agent for liquid and semi solid products. Guar gum has also been used in some extended release formulations and combinations of xanthan gum and guar gum have been extensively studied. The studies indicate that in certain instances, large amounts of hydroxypropylmethyl cellulose had to be added to guar gum to achieve acceptable sustained release formulations. Altaf et al. (1998 ) and Yu et al. (1998) published articles on a guar gum based sustained release formulation containing diltiazem which was shown to be equivalent in vitro and in vivo to a commercial product (Dilacor XR®). However, neither of these two preparations achieved a predominantly zero order release profile. Khurts, in U.S. Pat. No. 5,292,518, discloses prolonged release formulations consisting of gel forming dietary fiber, such as guar gum, a drug, a mineral salt, which releases a physiologically acceptable gas on ingestion, disintegrants and binders. Optionally, organic acids such as maleic and citric acid can be included to further aid disintegration.
Furthermore, guar gum has been found to undergo efficient enzymatic degradation in the human large intestine and has therefore been used as a carrier for colon specific drug delivery. Modifying guar gum with borax or glutaraldehyde has been reported as an effective means of producing cross linked polymers with limited swelling potential and increased viscosity. The limited swelling and increased viscosity reportedly increases the potential for the polymer matrix to stay intact and release a minimum of drug until the colon is reached. Friend and Wong, U.S. Pat. No. 5,811,388, disclose a simple formulation consisting of a drug useful for treating colonic disorders or a peptide drug that can be absorbed from the colon, and a hydrocolloid gum obtainable from higher plants, preferably guar gum. The authors mention the possible inclusion of a host of substances that may serve to stabilize a peptide or protein drug, or aid in drug penetration of gastrointestinal membranes and absorption.
Amino acids such as glycine find frequent use as plasticizers in polymer film coatings, as buffering agents and excipients used in the stabilization and formulation of lyophilized products, injectables, nose drops and oral solutions. For example, DL-leucine has been used as a hydrophilic lubricant. Ibsen, U.S. Pat. No. 5,288,500, discloses the possible use of amino acids in combination with hydrophilic polymers to enhance rapid swelling in order to mask grittiness and taste in formulations of granules that are to be rapidly dispersed in water prior to ingestion. Adesunloye, U.S. Pat. No. 5,874,106, discloses that amino acids in combination with carboxylic acids such is as citric acid, prevent cross-linking in gelatin capsules. Finally, Thombre et al., U.S. Pat. No. 5,697,922, describe an osmotic device wherein solubility adjusting substances, which may simultaneously act as osmoagents, can be made into coated macro particles. These solubility adjusting substances may include ionizing substances, salts, surfactants or amino acids.
Though useful as dosage forms, the release profiles of many of the prior compositions are usually characterized by initial rapid release followed by a gradual decline in the rate of release, resulting in a "prolonged tailing off" in the late time phase. The "tailing off" often results in incomplete dissolution and failure to achieve 100% drug release. Furthermore, there is typically an initial "burst effect", causing a relatively large amount of drug to be released early in dissolution, which is attributed to the initial rapid wetting and dissolution of drug on the surface of the dosage form. Lastly, many such systems suffer practical shortcomings in that they are relatively costly and complicated to manufacture, often requiring multiple manufacturing steps and specialized equipment.
Kim et al., WO 99/21551, discloses a simple polymeric matrix tablet that is designed to deliver drugs over extended periods of time, while being relatively easy to manufacture. The drug is first granulated with a swellable polymer to form granules. The granules are then dispersed within a matrix of a more swellable, erodible polymer and compressed to form a monolithic matrix tablet which is readily manufactured on commercial high speed tabletting equipment. Kim et al. does not make use of amino acids to mediate polymer swelling and dissolution of the drug, and the solubility of the drug plays the greatest role in determining the release profile and release duration. Therefore, Kim et al. is limited in application to highly soluble drugs.
The present invention provides an extended release dosage form for simple monolithic matrix tablets capable of delivering a high drug load of pharmaceutically active substances according to zero order release kinetics over an extended period of time, preferably 12 to 24 hours, in which drug release is mediated by the inclusion of an amino acid.
Definitions
As used herein the following terms have the definitions set forth below.
"Hydropathy" refers to a scale of solubility characteristics combining hydrophobicity and hydrophilicity of amino acids. More particularly this term refers to a sliding scale, similar to a pH scale, which assigns relative values which represent the relative balance between hydrophobic and hydrophilic components of an amino acid. A typical scale is set forth in Pliska et al., J. Chromatog. 216, 79, 1981, entitled Relative Hydrophobic Character of Amino Acid Side Chains, wherein glycine has a value of 0, representing a relatively equal balance between hydrophobic and hydrophilic components and may be referred to as relatively 'neutral', 'balanced', 'slightly hydrophilic'; or 'weakly hydrophobic', iso-leucine has a positive value of 1.83 and is strongly hydrophobic, and on the opposite end of the scale, aspartic acid has a negative value of −2.15 and may be characterized as strongly hydrophilic. Such a scale and the hydropathy characteristics described herein are well known and understood by those skilled in the art. Representative values and hydropathy characteristics are set forth in Table 1.
"Monolithic" refers to tablets that do not require multiple layers, special shapes, osmotic compartments and/or specialized coatings, typically without joints or seams, and are capable of being tableted on modern high speed tableting equipment.

Amino acid modulated extended release dosage form