Method and agent for reducing water production from oil and gas wells. The agent comprises polymer, cross-linked particles which are stable in water-free solvents. The particles are manufactured in an oil-in-oil emulsion and are cross-linked with at least one water-stable cross-linker and at least one water-labile cross-linker. The water-labile cross-linker is chosen so that when it is opened or broken in a reaction with water a hydrophilic seat is formed which increases the particle's ability to swell in water. The particles furthermore comprise a controlled amount of an immobilized chemical compound which by means of the reaction between water and reactive groups in the polymer skeleton, become able to form chemical bonds to another particle, to another reactive seat in the same particle or to another compounds thereby increasing the agent's stability in the formation.

In oil and gas wells, over time, there is usually also a certain production of water. The water production typically increases with time and may after a while become so large that further production of hydrocarbons is no longer remunerative. The water can be naturally present in the reservoir. It can also be water injected from another well to maintain the production and the pressure in the reservoir. The produced water includes chemical compounds some of which may be harmful for the environment and must be removed before the water eventually may be discharged to the sea.
Some of the chemicals are dissolved in the water from nature's side while others are added and dissolved as production chemicals. Production chemicals are thus included in the produced water and constitute an environmental problem.
Produced water is thus not only an economic disadvantage for the oil companies but also a significant environmental challenge. In many cases produced water is reinjected to maintain the pressure. This also involves costs. The best technical and economical solution would be to shut off the water selectively in the reservoir which is the object of the present agent and method.
The prior art technology in this area covers a broad range of suggestions of use of water swellable polymers to block the flow of water through permeable zones.
There are water swellable polymers based on positively or negatively charged (ion active) monomers and polymers based on non ion active monomers. Some polymers are particulate during injection but are stretched out to linear polymers when swelled in water. Some of these can again have functional groups like PO4, which are intended to form some kind of bond (hydrogen bond or ion bond) or adhesion to the surface of the formation.
In general it is positive for the ability of the polymer to take up water that it is not strongly cross-linked but able to be converted to a substantially linear polymer when swelled in water. This way many water molecules may be associated to the polymer chain. On the other hand the same property (low degree of cross-linking) is negative for the stability of the polymer both with respect to remaining in position within the formation and with respect to maintaining the desired properties, such as viscosity and general chemical stability with respect to chemical influences from the environment.
With regard to polymers of negatively charged ions these have a significant disadvantage in the form of insufficient swellability in environments where salts or acids are present. The same may be said, though to a somewhat less extent, about polymers based on positively charged monomers. Neutral systems are influenced least by salt concentrations.
U.S. Pat. No. 5,701,955 (Framton, 1997) teaches a method and a dispersion for use to reduce water permeability in subterranean formations. The dispersion is comprised by water swellable polymer particles being produced by emulsifying polymerization of inverted (reverse) phase (water-in-oil), in which at least 90% of the particles have a size less than 10 μm. Cross-linkers are not given any particular attention in this patent. The water swellable polymer particles of this patent exhibit excellent swelling ability but the particles loose most of their stability during swelling as there are few water-stable bonds present and there is no occurrence of additional cross-linking in the swollen condition to stabilize the particles.
U.S. Pat. No. 6,454,003 B1 and the US patent applications NOs. 2003/0116317 A1, 2003/0149212 A1 and 2003/0155122 A1 (Chang et al.) teach the production of water swellable polymer particles produced in a reverse-phase emulsion polymerization. The particle swelling occurs upon breakage of labile cross-linking bonds initiated by pH change and increased temperature in an aqueous phase. Two types of cross-linkers ensure that swelling does not occur until the particles have reached the desired location in the formation but do not influence or increase the stability of the system as swelled. Furthermore the method described by Chang (water-in-oil) can not be used to capsulate solid, water soluble components with the object of later formation of a stable system, since the water soluble components would be dissolved in the discontinuous phase (water) during the particle formation involving chemical reactions already during the particle production. The desired reactions should only take place subsequent the placement in the subterranean formation and such systems can only be produced in oil-in-oil emulsion systems. A main object of the present invention is the formation of a stable, particle based system enduring high pressures and temperatures and in which the resulting water swelled system is held in place and remains pressure and temperature stable while blocking water (minimizing water permeability) by chemical reactions taking place subsequent to the system having been placed in the formation and has come into contact with formation water.
PCT patent application with publication No. WO A1 02/40828 describes a system which is based on cross-linked hydrophilic particles manufactured in a water-in-oil based emulsion process with subsequent polymerization to solid particles. The particles comprise water soluble scale inhibitors (dissolved in the discontinuous phase, water, during manufacture) and the particles are evenly distributed in a sand screen around the production well. When water is produced, the scale inhibitor is released from the particles in contact with water. The particles have a high degree of cross-linking and portion matrix as the particles are not to be deformed when the inhibitors have been released but maintain their form ad location as part of the sand screen. No gelling or water blocking is described or mentioned as desired according to this publication. The particles constitute an amount of only 10% of the volume of sand screen and the permeability is maintained. WO A1 02/40828 describes chelating (complex forming) chemicals like AMPS, vinyl phosphoric acid derivatives etc. since these molecules have scale inhibiting properties. It is these properties that are used according to this publication.
PCT patent application WO A1 02/14453 describes a method for stabilizing porous sand formations for a limited period of time to allow drilling and subsequent casing with a steel casing in the well without well cave-in (collapse). The method according to this publication makes use of chemicals to glue together sand grains in the formation but the process is not supposed to reduce the permeability of the formation. The chemicals used shall provide adhesion between sand particles present without blocking pores. WO A1 02/14453 does not describe an agent or a method for reducing or eliminating permeability. It is therefore not suitable for water blocking or the like. WO A1 02/14453 furthermore describes a system which over time is supposed to degrade and in which the components from the degradation process or substances added during the "placing process" are supposed to control reservoir phenomena like wax, scale, hydrates and moisture properties.
U.S. Pat. No. 6,169,058 B1 concretely concerns fracturing of subterranean formations using liquids of high viscosity. The viscosity of the liquids is controlled by addition of a per se known viscosity increasing agent. Furthermore the water swellable, hydrophilic polymer particles used are cross-linked and therefore not water soluble. The patent is not directed towards the particles as such. The primary object of the polymer particles is to reduce loss of fluids such as circulating drilling fluids in the formation.
PCT patent application with publication No. WO 98/06929 describes a method and a composition for reducing water permeability in subterranean formations. The composition is based on at least a vinyl amide monomer of a certain formula, a monomer comprising ammonium or quaternary ammonium units as well as a cross-linking monomer. The method involves injecting the particles into the formation in question by means of a carrier fluid and an inverting surfactant, the particle size being assumed to be of a magnitude less than the pore size of the formation. Zwitterionic monomers are not mentioned. It is clearly emphasized in this publication and the examples that the swellable particles are manufactured in an inverted (water-in-oil) polymerization process.
Even though many agents and methods have been described in the literature to shut off water in permeable zones in subterranean formations, there is still a need for new systems which are improved in the sense that they are better suited for all types of environments, not dependent upon depth, temperature, the rock species, acid or salt concentrations and which are able to meet any requirements of delaying the swelling process and in which the particle size during production can be adapted to the pore size or the permeability of the formation in question.

Method and chemical agent for reduction of water production from oil and gas containing wells


The disclosed techniques provide systems and methods for anonymizing various portions of information, action logs, end-user information, and/or other data sets that are stored in non-indexed storage systems. More specifically, various anonymization procedures are described for redacting UII and/or replacing UII in raw data with randomly generated information (RGI). The anonymization process is performed on a rolling basis as raw data is received. An anonymization mapping table maps (or associates) the replaced UII in the anonymized data to the RGI, and eventually all raw data can be deleted.

Companies can store a tremendous amount of end-user data. For example, end-user data can include, but is not limited to, address information, credit card information, photographs, e-mails, healthcare records, financial records, electronic documents, messages, associations with other end-users, and other types of information. Not only do the end-users have an expectation of privacy, but in many cases there can be legal requirements on the dissemination and use of the data. As a result, unauthorized access and/or use of the end-user's data can result in dissatisfied customers and potential legal liability.
Furthermore, when an end-user requests to delete an account, a company may be under ethical and/or legal obligations to expeditiously remove information associated with the deleted accounts. For example, in most cases, at least some of the information associated with the deleted account contains user identifiable information (UII). The term "user identifiable information" or "UII" includes any information that can be directly identified or linked to a specific individual or end-user, with or without his or her knowledge. Additionally, it is often the case that the UII related to a deleted account must be scrubbed or otherwise deleted from a company's storage systems within a specified time frame.
Traditionally, companies that store vast amounts of end-user data have both front-end systems and back-end systems (e.g., data warehouse(s)) for data storage purposes. However, because of the nature and volume of data stored in a back-end systems, at least some of the data in the back-end system may not be indexed (i.e., index lookups are not available). One such example of a system is Hive. Hive is a data warehouse system for Hadoop Distributed File System (HDFS) that facilitates easy data summarization, ad-hoc queries, and the analysis of large datasets stored in Hadoop compatible file systems.
Unfortunately, data in Hadoop is stored as files rather than as a database structure and thus, specific portions of information cannot be looked up via index lookups without reading the entire file. That is, an indexing issue exists in some storage systems in which some or all of the data, such as user log information, is not indexed. Consequently, to remove UII from the user log information, a system must scan each file in the data warehouse for UII and subsequently rewrite the entire file. This infrastructure becomes particularly troublesome when a company attempts to comply with a user's request to delete his/her account. This is because the system has to scan each file in the data warehouse for UII and subsequently rewrite the entire file each day that any user in the system deletes an account—essentially every day for a social networking company.
Companies may want to comply with a user's request to delete his/her account and remove UII. However, scanning and rewriting each file in a data warehouse is an arduous process that is both time consuming and processor intensive. Furthermore, if a company has petabytes of user data, this process can quickly become unmanageable.
Overall, the examples herein of some prior or related systems and their associated limitations are intended to be illustrative and not exclusive. Upon reading the following, other limitations of existing or prior systems will become apparent to those of skill in the art

Anonymizing user identifiable information


A power steering system includes a pair of valve members (42, 46) which are interconnected by a torsion-tension spring (52). During a steering maneuver, torque is applied to the torsion-tension spring (52) to effect increasing torsional deformation of the torsion-tension spring. Tensile force is also applied to the torsion-tension spring (52) to effect increasing axial deformation of the torsion-tension spring. The tensile force is applied to the torsion-tension spring (52) by interaction between rollers (110) of a thrust bearing (80) and annular arrays (84, 92) of cam surfaces (86, 94) which engage opposite sides of the rollers. The cam surfaces (86, 94) are connected with opposite ends of the torsion-tension spring (52) by rigid bodies(42, 62, 102, 76) so that any increase in the distance between the cam surfaces results in a corresponding elongation of the torsion-tension spring. The cam surfaces (86, 94) have a configuration such that the extent of axial deformation of the torsion-tension spring (52) during each increment of relative rotation decreases. This results in a decrease in the force required to effect each succeeding increment of axial deformation of the torsion-tension spring (52).

The present invention relates to a new and improved hydraulic control valve for a hydraulic power steering system and more specifically to a hydraulic control valve having a torsion-tension spring that resists relative rotation between a pair of valve members.
In a known power steering system, a torsion bar is utilized to interconnect a pair of relatively rotatable hydraulic valve members. When a steering maneuver is made, the torsion bar is subjected to torsional, elastic deformation. As the torsion bar is elastically deformed, the valve members are rotated relative to each other. Relative rotation between the valve members allows pressurized hydraulic fluid flow from a pump to a hydraulic power steering motor connected between the frame of the vehicle and the steerable wheels to effect operation of the power steering motor and steering of the vehicle. Power steering systems in which a torsion bar is subjected to torsional deformation, are disclosed in U.S. Pat. Nos. 3,709,099; 4,557,342 and 4,598,787.
During operation of a vehicle, it is desirable to have a force which biases the hydraulic valve of a steering system to a neutral, non-steering condition when operator input steering torque is low or nonexistent. It is also desirable to have the amount of manual input torque required to turn the steerable vehicle wheels to be comparable whether a parking maneuver is made when the vehicle is stationary or operating at very low speeds or in a lane change maneuver at 55 miles per hour. However, the amount of torque which a driver of a vehicle must input to the steering system is approximately 240% greater during steering in a parking maneuver than during a lane change maneuver when a vehicle is moving at 55 miles per hour. Torsion bar springs have essentially linear spring rates, and provide a torque biasing the hydraulic control valve toward an on center condition which is the product of angular displacement multiplied times the spring rate. It is desirable to provide a preload to prevent angular displacement of the torsion bar until the input torque reaches a predetermined minimum level.


A lighting apparatus includes a lighting unit, a converting circuit, a sensing circuit, and a current control circuit. The lighting unit includes at least one light emitting diode and a switching device connected with each other in series. The converting circuit has an output end electrically connected to the lighting unit for driving it. The sensing circuit includes a sensing element capable of indirectly detecting the current flowing through the light emitting diode and outputting a feedback signal. The current control circuit receives a reference current, the feedback signal and a dimming command, and sends a dimming control signal to the lighting unit and a current control signal to the converting circuit, capable of controlling the amplitude of the current flowing through the light emitting diode.

1. Field of Invention
The present invention relates to a lighting apparatus and a control method thereof.
2. Related Art
The light emitting diode (LED) can be driven by a suitable current to emit desired light, and the brightness of the light emitted from the LED can be adjusted by controlling the current flowing therethrough. In general, the brightness of the LED can be adjusted by the way of continuous current dimming or pulse width modulation (PWM) dimming. Comparing these two dimming methods, the PWM dimming has the advantages of lower dimming depth and less color change, so it is widely used now. However, due to the variations in the both characteristics of LED and the output of power supply, it maybe results in the variation in the amplitude of LED at PWM dimming operation. Therefore, it is an important subject to provide a current with stable amplitude to the LED when using the PWM dimming method.

Lighting apparatus and control method thereof


A confocal microscope including a first condenser optical system that condenses light from a light source onto a sample; a pinhole member having a pinhole; a second condenser optical system that condenses light from the sample into the pinhole; a polygon mirror having a plurality of mirror surfaces achieving angles relative to a rotational axis different from one another and formed so as to surround the rotational axis in a full circle, which is disposed between the first condenser optical system and the pinhole; and a first optical system that separates the light from the light source and the light from the sample and guides the light from the sample departing the polygon mirror to the pinhole.

1. Field of the Invention
The present invention relates to a confocal microscope.
2. Description of Related Art
A light scanner for confocal system adopting a disk rotation system that utilizes a pinhole member having a plurality of pinholes formed therein is used in conjunction with a confocal microscope in the related art (see Japanese Patent Gazette No. 2663780). In addition, there is a polygon mirror apparatus known in the related art that allows laser light to be used directly for raster scanning with the single polygon mirror (see Japanese Laid Open Patent Publication No. H5-45600).


The disclosed embodiments provide for methods and systems for selecting sectors for handoff in a communication system. According to one aspect, the method includes monitoring an indicia of transmit power on a plurality of RL control channels directed to a plurality of sectors, and selecting one of the sectors as a candidate for a RL handoff. The disclosed embodiments also provide for methods and systems for indicating a selected serving sector for handoff in a communication system. According to one aspect, the method includes sending a first signal to a first sector to indicate the first sector as a serving sector for a forward-link handoff, and sending a second signal to a second sector to indicate the second sector as a serving sector for a reverse-link handoff.

I. Field
The present invention relates generally to communications, and more specifically to techniques for handoffs in a communication system.
II. Background
Communication systems are widely deployed to provide various communication services such as voice, packet data, and so on. These systems may be time, frequency, and/or code division multiple-access systems capable of supporting communication with multiple users simultaneously by sharing the available system resources. Examples of such multiple-access systems include Code Division Multiple Access (CDMA) systems, Multiple-Carrier CDMA (MC-CDMA), Wideband CDMA (W-CDMA), High-Speed Downlink Packet Access (HSDPA), Time Division Multiple Access (TDMA) systems, Frequency Division Multiple Access (FDMA) systems, and Orthogonal Frequency Division Multiple Access (OFDMA) systems.
A communication system may employ a handoff scheme to allow a moving access terminal to stay in communication with serving access points or sectors. There is therefore a need in the art for techniques to efficiently select reverse-link (RL) and/or forward-link (FL) serving sectors and indicate such choices for RL and/or FL handoffs in a communication system.

Methods and apparatus for flexible forward-link and reverse-link handoffs


A HUD apparatus, that can achieve favorable AR display by reducing display shift between a real and virtual image, includes: an image input unit that receives an image from a camera and extracts a predetermined object; an information acquiring unit that acquires object information containing the object's position and distance information containing the object's distance in space; an AR image creating unit that creates an AR image for superimposing on the object; a display position converter uses the acquired information to correct a position of an AR display area that is a range where the AR image is displayable in a visual recognition area and a display position of the AR image inside the AR display area; an AR display that controls superimposing of the AR image on the visual recognition area from data after the correction; and a display that displays the AR image on the visual recognition area.

As AR display apparatuses each having an AR function and systems of the AR display apparatuses, a HUD apparatus mounted on a car or others is cited. In the HUD apparatus (called AR-HUD in some cases), by projection of image light, a virtual image is superimposed on a transparent real image in a visual recognition area (screen) of a windshield, a combiner or others in a field of view of a user such as a driver. The virtual image will be described as an AR image below in some cases. As the virtual image, for example, image information for driving support, etc., related to the real image including a road and a car ahead of the subject car, etc., is exemplified. As a specific example, an image of vehicle information such as a car speed, an arrow image such as navigation system indicating a car-running direction, a frame image for use in attention seeking that indicates approach of an oncoming car, a pedestrian, a bicycle or others and for use in emphasis of a road sign or others are exemplified. As source data for use in creation of the virtual image, information of on-vehicle sensor, engine controller, navigation system and others are usable.
The HUD apparatus includes, for example, a display element, an optical source, and an optical system such as a lens or a mirror for use in guiding image light to the visual recognition area. The image light from the display element is projected on an area (referred to as an AR display area, a HUD display range, etc., below in some cases) inside the visual recognition area of the windshield, the combiner or others through the mirror or others. The light reflected on the area inside the screen enters the driver's eyes, and forms an image on a retina, so that the driver visually recognizes the image as the virtual image.
As related-art examples related to the on-vehicle HUD apparatus, Japanese Patent Application Laid-Open Publication No. 2010-70066 (Patent Document 1) is cited. The Patent Document 1 describes that shift of a projection position of the image from a line of sight of either one of eyes due to vibration of the vehicle or change of a driver's posture is reduced in the head up display to enhance visual recognition of the display information.

Head up display apparatus and display control method thereof


There is disclosed method and apparatus for retaining a reservoir for a therapeutic agent between the scalp and cranium of a subject, including providing a deformable pouch or rigid cylinder for dispensing the therapeutic agent from the reservoir to a location in the body of the subject. In one embodiment, a pump is used to pump the agent from the reservoir to the location in the subject""s body. In another example embodiment, there is provided method and apparatus for forming at least one cavity in the cranium of the subject, and placing at least a portion of the pump in the cavity. Power is applied to the pump in a variety of ways.

This invention relates generally to the field of medicine, and more particularly to implantable devices for delivering therapeutic agents to a body.
Localized drug therapy has been shown to be successful for chronic pain treatment and chemotherapy for spinal disorders using less drugs and without the potential adverse effects of a systemic dosage. Pumps for abdominal implant have been designed to dispense drugs as either continual dosage through a constant pressure, non-electrical means or as programmable, periodic dispensing through the use of an electrically driven pump and constant pressure reservoir.
More recently, the value of localized drug therapy for neurological disorders has been identified. Existing pumps, while potentially providing the therapeutic advantages of implantable infusion pumps, are large and are implanted abdominally. Such pumps if used will require a catheter tunneled from the abdominal implant site, through the neck to an entry site in the head, and then to the localized treatment site.
Present electrically powered pumps use primary (non-rechargeable) batteries as their power source. When the battery is depleted in these devices, the complete assembly must be removed and replaced. Rechargeable batteries have been used in previous implant devices including earlier pacemakers and present day artificial hearts and left ventricular assist devices (LVAD""s). Artificial hearts and LVAD""s require the use of an external power source due to the high power demand of the pumping system that would deplete an internal battery quickly. They also use a rechargeable battery to provide power for a patient when external power is not appropriate, such as when taking a shower or bath. Earlier pacemakers used a nickel cadmium rechargeable battery system that relied on the patient to recharge transcutaneously on a periodic basis.
According to one aspect, the present invention provides method and apparatus for retaining a reservoir for a therapeutic agent between the scalp and cranium of a subject. According to another aspect, there is provided method and apparatus for dispensing the therapeutic agent from the reservoir to a location in the body of the subject. According to yet another aspect, there is provided method and apparatus for pumping the agent to the location in the subject""s body with a pump. According to still another aspect, there is provided method and apparatus for forming at least one cavity in the cranium of the subject, and placing at least a portion of the pump in the cavity. According to still other aspects of the method and apparatus, power is supplied to the pump. These and other aspects of the invention are described below.

Implantable reservoir and system for delivery of a therapeutic agent


A thermocouple connector arrangement that has a first connector configured to have a thermocouple probe lead extending therefrom and a second connector configured to have an electrical connection lead extending therefrom. Each connector has an interior configured to receive a terminus of the respective lead. The connectors include electrically conductive mating parts that, when mated, provide an electrical conduction path. At least one of the first and second connectors includes housing parts that mate in a snap-lock arrangement without the use of a threaded fastener to secure the housing parts together and to enclose the respective interior, one of the housing parts engages the respective terminus and secures the respective terminus against removal by shrouding an end of the respective conductive mating part and pressing the respective terminus into electrical contact with the respective conductive mating part during the mating of the housing parts.

1. Field of the Invention
The present invention relates to thermocouple connectors, and more particularly to a connector arrangement having enhanced connectivity features.
2. Description of Prior Art
Connectors are utilized to interconnect a thermocouple probe or sensor or splice member within a thermocouple system. One portion of the connection arrangement is interconnected with a probe member. A second portion of the connection arrangement is connected to a wire that may extend to a strip panel. In turn, the strip panel may be operatively connected via cable or the like to one or more instruments.
It is known to use screws to connect wire leads and screws that secure a cover onto a body of at least one portion of the connector arrangement. It is labor intensive to provide such connections. Also, such construction may not provide for ease of variation of component parts.

Thermocouple connector and connector arrangement with enhanced connectivity features


The present disclosure provides veterinary formulations comprising a therapeutically effective amount of a voriconazole and a polymer. The disclosure also provides methods, and kits for the treatment of disease, such as for treating a fungal infection in an animal utilizing the veterinary formulations.

Keratomycosis is a vision-threatening disease caused by fungal infection of the cornea. Fungal keratitis is an emerging cause of corneal disease in horses, with the reported incidence in North America rising from 13% of keratitis cases in the 40 years preceding 2006 to approximately 25% in 2013. Keratomycosis is particularly prevalent in tropical or subtropical environments, such as the southern United States. For example, in the state of Alabama, keratomycosis accounted for 40% of the equine corneal disease caseload presenting to the Auburn University Large Animal Teaching Hospital (AULATH) during the 2012-2013 academic year.
Equines, in particular horses, are believed to be prone to fungal ocular infections due to their large globe size, unique orbital shape and resultant globe exposure, suspected tear film instability and living environment. Fungi are ubiquitous in the equine environment (e.g. in hay, soil and bedding) and are also part of the normal ocular surface microbiota of the horse. More than 30 genera of fungi have been implicated in equine keratomycosis, with the most common being the filamentous fungi Aspergillus, Fusarium and Penicillium and the yeast Candida.
Development of keratomycosis requires disruption of the normal defense mechanisms of the equine cornea and conjunctiva such as the intact corneal epithelium, normal bacterial microbiota, flushing of commensal organisms through tear flow and eyelid movement, and tear film macrophages, lysozymes and immunoglobulins. Following disruption of one or more of these defense mechanisms, commensal or introduced (environmental) fungi are able to adhere to the cornea, proliferate and invade the conical stroma. Fungal organisms, damaged keratocytes and inflammatory cells attracted to the area by the fungi then release proteases which facilitate vertical movement of fungi through the conical stroma and Descemet's membrane. This may ultimately result in fungal migration into the anterior chamber, lens and iris, with subsequent development of severe endophthalmitis.
Clinical manifestations of equine keratomycosis include corneal ulceration (with or without keratomalacia), conical microerosions, superficial punctate keratitis, stromal abscessation, stromal plaque formation, and conical perforation with iris prolapse. Of these, stromal ulcerative keratomycosis is the most common manifestation, comprising 50.80% of reported cases of equine keratomycosis.
Furthermore, equine keratomycosis is a source of severe morbidity in horses Fungal organisms and infiltrating immune cells are capable of initiating both vigorous inflammatory responses and protease overproduction in the cornea. In turn, this may lead to the development of acute complications in affected eyes including rapid keratomalacia (melting of the cornea), unresolving ulceration, abscess formation, uncontrolled anterior uveitis, endophthalmitis and corneal perforation. Long term sequelae may include corneal scarring, cataract or synechiae formation, phthisis bulbi and vision loss. In various case studies reporting outcomes in horses affected with equine keratomycosis, success rates (as defined by restoration of functional vision and/or ocular survival) in these equine populations varied from 50% to greater than 90%, with the majority of case series reporting retention of functional vision in <70% of cases. In light of the severity of potential sequelae of keratomycosis described above, these success rates are undesirable.
Equine keratomycosis treatment is challenging, prolonged and expensive and requires compliance from both horses and their handlers. The average duration of treatment varies from 48 to 72 days, and up to 192 days of treatment has been described. The average time required in the hospital varies from 15 to 21 days, which represents an investment of thousands of dollars and a source of considerable stress for the horse and has been defined as a risk factor for development of colic.
Fungal keratitis can be treated with either medical therapy alone or a combination of medical and surgical therapy. Although surgical procedures are immediately indicated in animals with acute corneal perforation or in those with imminent or pre-existing rupture of a stromal abscess into the anterior chamber, medical treatment with antifungal agents is a major therapeutic option in most cases, whereby success depends on the agent's ability to penetrate the conical epithelium and achieve therapeutic concentrations in the anterior segment of the eye. In order to reach therapeutic concentrations in the cornea and anterior chamber, treatment typically involves application of topical medication every 1-2 hours in acute disease, decreasing ultimately to every 6-12 hours, with potential concurrent administration of oral antifungals, anti-inflammatory agents, and antibiotics.
Voriconazole is a second generation triazole antifungal drug and is a relatively new antifungal agent in equine and human ophthalmology. Despite the excellent corneal penetration of voriconazole, several additional barriers exist in the eye which must be overcome in order to obtain higher or more sustained therapeutic voriconazole concentrations in the cornea and anterior chamber following topical delivery. Upon topical administration, pre-corneal factors and anatomical barriers negatively affect the bioavailability of topical formulations. Anatomical drug transport barriers include corneal and conjunctival epithelial tight junctions and clearance from the vasculature in the conjunctiva. Furthermore, despite effective corneal penetration, sustained drug delivery is still severely limited by ocular barriers and this effect is short lived, with studies is rabbits demonstrating the need for administration of voriconazole every 30 minutes in order to achieve a sustained high level of voriconazole in the anterior chamber.
Therefore, there exists a need for new compositions and formulations that provide therapeutic options for treating keratomycosis. Accordingly, the present disclosure provides veterinary formulations comprising a therapeutically effective amount of voriconazole, as well as kits, and also methods of using the formulations and kits, which exhibit desirable properties and provide related advantages for improvement in administration and treatment of keratomycosis.
The present disclosure provides veterinary formulations comprising a therapeutically effective amount of voriconazole and a polymer. The disclosure also provides kits comprising voriconazole and a polymer, as well as methods of treating a fungal infection in an animal, said method comprising the step of administering a veterinary formulation comprising a therapeutically effective amount of voriconazole and a polymer to the animal utilizing the veterinary formulations and kits of the present disclosure.
The veterinary formulations, kits, and methods according to the present disclosure provide several advantages compared to other formulations and methods known in the art. First, a sustained-release veterinary formulation comprising voriconazole has great potential to improve comfort and ultimate outcome for animals suffering from keratomycosis, especially horses. Second, such a formulation can provide a treatment which would be available to all affected animals, regardless of budget, as it could be administered in the field. Third, the formulation, given via subconjunctival injection, would negate the need for frequent topical application of voriconazole to animals. This would result in minimizing stress in patients and improving compliance by decreasing the volume, frequency, and cost of medication required for treatment. Fourth, utilization of thermogel polymers (e.g., thermosensitive biodegradable hydrogels or 'thermogels') can advantageously be administered as a liquid, followed by conversion to a gel deposit upon reaching the appropriate temperature. As a result, the thermogel polymers can maintain a sustained release of drug at the site of administration in the animal, for example over weeks to months. The sustained release of voriconazole to an animal suffering from keratomycosis would increase the local bioavailability of the medication, decrease systemic side effects, and improve client compliance.
The following numbered embodiments are contemplated and are non-limiting:
1. A veterinary formulation comprising i) a therapeutically effective amount of voriconazole and ii) a polymer.
2. The veterinary formulation of clause 1, wherein the veterinary formulation further comprises an alcohol.
3. The veterinary formulation of clause 2, wherein the alcohol is ethanol.
4. The veterinary formulation of any one of clauses 1 to 3, wherein the veterinary formulation further comprises a second therapeutic agent.
5. The veterinary formulation of clause 4, wherein the second therapeutic agent is selected from the group consisting of an oral antifungal agent, an anti-inflammatory agent, and an antibiotic.
6. The veterinary formulation of any one of clauses 1 to 5, wherein the polymer is a thermogel polymer.
7. The veterinary formulation of clause 6, wherein the thermogel polymer is selected from the group consisting of poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), poly (N-isopropyl acrylamide) (PNIPAAm), poly(N,N-diethyl acrylamide) (PDEAM), poly(N-ethyl methacrylamide) (PNEMAM), poly(methyl vinyl ether) (PMVE), poly(2-ethoxyethyl vinyl ether) (PEOVE), poly(N-vinyl isobutyramide) (PNVIBAM), poly(N-vinyl n-butyramide) (PNVBAM), poly(N-vinyl caprolactam) (PNVCa), and poly (hydroxypropyl methacrylamide) (HPMA), poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA-PEG-PLGA), poly(DL-lactide)-b-Poly(ethylene glycol)-b-Poly(DL-lactide) (P(DL)LA-PEG-P(DL)LA), and poly(lactide-co-caprolactone)-b-Poly(ethylene glycol)-b-Poly(lactide-co-caprolactone) (PLCL-PEG-PLCL).
8. The veterinary formulation of clause 6, wherein the thermogel polymer is a combination of two or more thermogel polymers selected from the group consisting of poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), poly (N-isopropyl acrylamide) (PNIPAAm), poly(N,N-diethyl acrylamide) (PDEAM), poly(N-ethyl methacrylamide) (PNEMAM), poly(methyl vinyl ether) (PMVE), poly(2-ethoxyethyl vinyl ether) (PEOVE), poly(N-vinyl isobutyramide) (PNVIBAM), poly(N-vinyl n-butyramide) (PNVBAM), poly(N-vinyl caprolactam) (PNVCa), and poly (hydroxypropyl methacrylamide) (HPMA), poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA-PEG-PLGA), poly(DL-lactide)-b-Poly(ethylene glycol)-b-Poly(DL-lactide) (P(DL)LA-PEG-P(DL)LA), and poly(lactide-co-caprolactone)-b-Poly(ethylene glycol)-b-Poly(lactide-co-caprolactone) (PLCL-PEG-PLCL).
9. The veterinary formulation of clause 6, wherein the thermogel polymer is PLGA-PEG-PLGA.
10. The veterinary formulation of clause 9, wherein the PLGA-PEG-PLGA has a molecular weight of 1100:1000:1100 Da.
11. The veterinary formulation of clause 9, wherein the PLGA-PEG-PLGA has a molecular weight of 1500:1500:1500 Da.
12. The veterinary formulation of clause 9, wherein the PLGA-PEG-PLGA has a molecular weight of 1600:1500:1600 Da.
13. The veterinary formulation of clause 9, wherein the PLGA-PEG-PLGA has a molecular weight of 1700-1500-1700 Da.
14. The veterinary formulation of clause 9, wherein the PLGA-PEG-PLGA is a combination of two different PLGA-PEG-PLGA compositions, wherein the first PLGA-PEG-PLGA composition and the second PLGA-PEG-PLGA composition are selected from the group consisting of a PLGA-PEG-PLGA with a molecular weight of 1100:1000:1100 Da, a PLGA-PEG-PLGA with a molecular weight of 1500:1500:1500 Da, a PLGA-PEG-PLGA with a molecular weight of 1600:1500:1600 Da, and a PLGA-PEG-PLGA with a molecular weight of 1700-1500-1700 Da.
15. The veterinary formulation of clause 9, wherein the PLGA-PEG-PLGA is a combination of two different PLGA-PEG-PLGA compositions, wherein the first PLGA-PEG-PLGA composition has a molecular weight of 1100:1000:1100 and the second PLGA-PEG-PLGA composition has a molecular weight of 1500:1500:1500.
16. The veterinary formulation of clause 15, wherein the ratio of the first PLGA-PEG-PLGA composition and the second PLGA-PEG-PLGA composition is about 1:1.
17. The veterinary formulation of clause 15, wherein the ratio of the first PLGA-PEG-PLGA composition and the second PLGA-PEG-PLGA composition is about 2:1.
18. The veterinary formulation of clause 15, wherein the ratio of the first PLGA-PEG-PLGA composition and the second PLGA-PEG-PLGA composition is about 3:1.
19. The veterinary formulation of clause 9, wherein the PLGA-PEG-PLGA is at a ratio of 1:1 (lactide:glycolide).
20. The veterinary formulation of clause 9, wherein the PLGA-PEG-PLGA is at a ratio of 2:1 (lactide:glycolide).
21. The veterinary formulation of clause 9, wherein the PLGA-PEG-PLGA is at a ratio of 3:1 (lactide:glycolide).
22. The veterinary formulation of clause 9, wherein the PLGA-PEG-PLGA is at a ratio of 15:1 (lactide:glycolide).
23. The veterinary formulation of clause 6, wherein the thermogel polymer is P(DL)LA-PEG-P(DL)LA.
24. The veterinary formulation of clause 23, wherein the P(DL)LA-PEG-P(DL)LA has a molecular weight of 1700-1500-1700 Da.
25. The veterinary formulation of clause 6, wherein the thermogel polymer is PLCL-PEG-PLCL.
26. The veterinary formulation of clause 25, wherein the PLCL-PEG-PLCL has a molecular weight of 1700-1500-1700 Da.
27. The veterinary formulation of clause 25, wherein the PLGA-PEG-PLGA is at a ratio of 60:40 CL:LA.
28. The veterinary formulation of clause 6, wherein the thermogel polymer has a gelation set point at a temperature of about 30° C. to about 40° C.
29. The veterinary formulation of clause 6, wherein the thermogel polymer has a gelation set point at a temperature of about 33° C. to about 44° C.
30. The veterinary formulation of clause 6, wherein the thermogel polymer has a gelation set point at a temperature of about 33° C. to about 36° C.
31. The veterinary formulation of clause 6, wherein the thermogel polymer has a gelation set point at a temperature of about 31° C. to about 42° C.
32. The veterinary formulation of clause 6, wherein the thermogel polymer has a gelation set point at a temperature of about 27° C. to about 45° C.
33. The veterinary formulation of any one of clauses 1 to 32, wherein the veterinary formulation further comprises one or more dissolution additives.
34. The veterinary formulation of clause 33, wherein the one or more dissolution additives is selected from the group consisting of N-methylpyrolidinone (NMP), mannitol, and mPEG-P (DL) La.
35. The veterinary formulation of clause 34, wherein the mPEG-P (DL) La is mPEG-P (DL) La (2000-2200 Da).
36. The veterinary formulation of any one of clauses 1 to 35, wherein the veterinary formulation is single-use formulation.
37. The veterinary formulation of any one of clauses 1 to 35, wherein the veterinary formulation is a multi-use formulation.
38. The veterinary formulation of any one of clauses 1 to 37, wherein the veterinary formulation is a controlled release formulation.
39. The veterinary formulation of clause 38, wherein the controlled release formulation releases voriconazole from veterinary formulation for about 7 days.
40. The veterinary formulation of clause 38, wherein the controlled release formulation releases voriconazole from veterinary formulation for about 10 days.
41. The veterinary formulation of clause 38, wherein the controlled release formulation releases voriconazole from veterinary formulation for about 14 days.
42. The veterinary formulation of clause 38, wherein the controlled release formulation releases voriconazole from veterinary formulation for about 21 days.
43. The veterinary formulation of clause 38, wherein the controlled release formulation releases voriconazole from veterinary formulation for about 28 days.
44. The veterinary formulation of any one of clauses 1 to 44, wherein the veterinary formulation is an injectable formulation.
45. The veterinary formulation of clause 44, wherein the injectable formulation is configured for injection in a subconjunctival space (SCS).
46. The veterinary formulation of clause 45, wherein the SCS is a dorsal bulbar SCS.
47. The veterinary formulation of clause 45, wherein the SCS is a ventral bulbar SCS.
48. A kit comprising i) voriconazole and ii) a polymer.
49. The kit of clause 48, wherein the kit further comprises an alcohol.
50. The kit of clause 49, wherein the alcohol is ethanol.
51. The kit of any one of clauses 48 to 50, wherein the polymer is a thermogel polymer.
52. The kit of clause 51, wherein the thermogel polymer is selected from the group consisting of poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), poly (N-isopropyl acrylamide) (PNIPAAm), poly(N,N-diethyl acrylamide) (PDEAM), poly(N-ethyl methacrylamide) (PNEMAM), poly(methyl vinyl ether) (PMVE), poly(2-ethoxyethyl vinyl ether) (PEOVE), poly(N-vinyl isobutyramide) (PNVIBAM), poly(N-vinyl n-butyramide) (PNVBAM), poly(N-vinyl caprolactam) (PNVCa), and poly (hydroxypropyl methacrylamide) (HPMA), PLGA-PEG-PLGA, P(DL)LA-PEG-P(DL)LA, and PLCL-PEG-PLCL.
53. The kit of clause 51, wherein the thermogel polymer is a combination of two or more thermogel polymers selected from the group consisting of poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), poly (N-isopropyl acrylamide) (PNIPAAm), poly(N,N-diethyl acrylamide) (PDEAM), poly(N-ethyl methacrylamide) (PNEMAM), poly(methyl vinyl ether) (PMVE), poly(2-ethoxyethyl vinyl ether) (PEOVE), poly(N-vinyl isobutyramide) (PNVIBAM), poly(N-vinyl n-butyramide) (PNVBAM), poly(N-vinyl caprolactam) (PNVCa), and poly (hydroxypropyl methacrylamide) (HPMA), PLGA-PEG-PLGA, P(DL)LA-PEG-P(DL)LA, and PLCL-PEG-PLCL.
54. The kit of clause 51, wherein the thermogel polymer is PLGA-PEG-PLGA.
55. The kit of clause 54, wherein the PLGA-PEG-PLGA has a molecular weight of 1100:1000:1100 Da.
56. The kit of clause 54, wherein the PLGA-PEG-PLGA has a molecular weight of 1500:1500:1500 Da.
57. The kit of clause 54, wherein the PLGA-PEG-PLGA has a molecular weight of 1600:1500:1600 Da.
58. The kit of clause 54, wherein the PLGA-PEG-PLGA has a molecular weight of 1700-1500-1700 Da.
59. The kit of clause 54, wherein the PLGA-PEG-PLGA is a combination of two different PLGA-PEG-PLGA compositions, wherein the first PLGA-PEG-PLGA composition has a molecular weight of 1100:1000:1100 and the second PLGA-PEG-PLGA composition has a molecular weight of 1500:1500:1500.
60. The kit of clause 59, wherein the ratio of the first PLGA-PEG-PLGA composition and the second PLGA-PEG-PLGA composition is about 1:1.
61. The kit of clause 59, wherein the ratio of the first PLGA-PEG-PLGA composition and the second PLGA-PEG-PLGA composition is about 2:1.
62. The kit of clause 59, wherein the ratio of the first PLGA-PEG-PLGA composition and the second PLGA-PEG-PLGA composition is about 3:1.
63. The kit of clause 54, wherein the PLGA-PEG-PLGA is at a ratio of 1:1 (lactide:glycolide).
64. The kit of clause 54, wherein the PLGA-PEG-PLGA is at a ratio of 2:1 (lactide:glycolide).
65. The kit of clause 54, wherein the PLGA-PEG-PLGA is at a ratio of 3:1 (lactide:glycolide).
66. The kit of clause 54, wherein the PLGA-PEG-PLGA is at a ratio of 15:1 (lactide:glycolide).
67. The kit of clause 51, wherein the thermogel polymer is P(DL)LA-PEG-P(DL)LA.
68. The kit of clause 67, wherein the P(DL)LA-PEG-P(DL)LA has a molecular weight of 1700-1500-1700 Da.
69. The kit of clause 51, wherein the thermogel polymer is PLCL-PEG-PLCL.
70. The kit of clause 69, wherein the PLCL-PEG-PLCL has a molecular weight of 1700-1500-1700 Da.
71. The kit of clause 69, wherein the PLGA-PEG-PLGA is at a ratio of 60:40 CL:LA.
72. The kit of clause 51, wherein the thermogel polymer has a gelation set point at a temperature of about 30° C. to about 40° C.
73. The kit of clause 51, wherein the thermogel polymer has a gelation set point at a temperature of about 33° C. to about 44° C.
74. The kit of clause 51, wherein the thermogel polymer has a gelation set point at a temperature of about 33° C. to about 36° C.
75. The kit of clause 51, wherein the thermogel polymer has a gelation set point at a temperature of about 31° C. to about 42° C.
76. The kit of clause 51, wherein the thermogel polymer has a gelation set point at a temperature of about 27° C. to about 45° C.
77. The kit of any one of clauses 48 to 76, wherein the kit further comprises one or more dissolution additives.
78. The kit of clause 77, wherein the one or more dissolution additives is selected from the group consisting of N-methylpyrolidinone (NMP), mannitol, and mPEG-P (DL) La.
79. The kit of clause 78, wherein the mPEG-P (DL) La is mPEG-P (DL) La (2000-2200 Da).
80. The kit of any one of clauses 48 to 79, wherein the polymer is a liquid.
81. The kit of clause 80, wherein the liquid polymer is configured to form a gel deposit upon administration to an animal.
82. The kit of clause 81, wherein the gel deposit is formed at a temperature of about 30° C. to about 40° C.
83. The kit of clause 81, wherein the gel deposit is formed at a temperature of about 33° C. to about 44° C.
84. The kit of clause 81, wherein the gel deposit is formed at a temperature of about 33° C. to about 36° C.
85. The kit of clause 81, wherein the gel deposit is formed at a temperature of about 31° C. to about 42° C.
86. The kit of clause 81, wherein the gel deposit is formed at a temperature of about 27° C. to about 45° C.
87. The kit of any one of clauses 48 to 86, wherein the kit further comprises instructions for combination of the voriconazole and the polymer.
88. A method of treating a fungal infection in an animal, said method comprising the step of administering a veterinary formulation comprising i) a therapeutically effective amount of voriconazole and ii) a polymer to the animal.
89. The method of clause 88, wherein the veterinary formulation is the veterinary formulation of any one of clauses 1-47.
90. The method of clause 88, wherein the veterinary formulation is formed from the kit of any one of clauses 48-87.
91. The method of any one of clauses 88-90, wherein the fungal infection is caused by an Aspergillus species.
92. The method of any one of clauses 88-90, wherein the fungal infection is caused by a Fusarium species.
93. The method of any one of clauses 88-90, wherein the fungal infection is caused by a Penicillium species.
94. The method of any one of clauses 88-90, wherein the fungal infection is caused by a Candida species.
95. The method of any one of clauses 88-94, wherein the fungal infection is an ocular infection.
96. The method of any one of clauses 88-95, wherein the fungal infection causes keratomycosis in the animal.
97. The method of any one of clauses 88-96, wherein the animal is an equine.
98. The method of clause 97, wherein the equine is a horse.
99. The method of clause 97, wherein the equine is a donkey.
100. The method of clause 97, wherein the equine is a zebra.
101. The method of any one of clauses 88-90, wherein the animal is a feline.
102. The method of any one of clauses 88-90, wherein the animal is a canine.
103. The method of any one of clauses 88-90, wherein the animal is a camelid.
104. The method of clause 103, wherein the camelid is selected from the group consisting of dromedary camels, Bactrian camels, wild Bactrian camels, llamas, alpacas, vicuñas, and guanacos.
105. The method of clause 103, wherein the camelid is a llama.
106. The method of clause 103, wherein the camelid is an alpaca.
107. The method of any one of clauses 88-106, wherein the administration is an injection.
108. The method of clause 107, wherein upon the injection to the animal, the polymer of the veterinary formulation is a liquid.
109. The method of clause 108, wherein the liquid polymer forms a gel deposit in the animal subsequent to the injection.
110. The method of clause 109, wherein the gel deposit is formed at a temperature of about 30° C. to about 40° C.
111. The method of clause 109, wherein the gel deposit is formed at a temperature of about 33° C. to about 44° C.
112. The method of clause 109, wherein the gel deposit is formed at a temperature of about 33° C. to about 36° C.
113. The method of clause 109, wherein the gel deposit is formed at a temperature of about 31° C. to about 42° C.
114. The method of clause 109, wherein the gel deposit is formed at a temperature of about 27° C. to about 45° C.
115. The method of any one of clauses 107 to 114, wherein the injection is in a subconjunctival space (SCS).
116. The method of clause 115, wherein the SCS is a dorsal bulbar SCS.
117. The method of clause 115, wherein the SCS is a ventral bulbar SCS.
118. The method of any one of clauses 88 to 117, wherein the voriconazole diffuses through a cornea of the animal.
119. The method of any one of clauses 88 to 118, wherein the voriconazole diffuses through a sclera of the animal.
120. The method of any one of clauses 88 to 119, wherein the administration provides a concentration of voriconazole greater than the target minimum inhibitory concentration for about 7 days.
121. The method of any one of clauses 88 to 119, wherein the administration provides a concentration of voriconazole greater than the target minimum inhibitory concentration for about 10 days.
122. The method of any one of clauses 88 to 119, wherein the administration provides a concentration of voriconazole greater than the target minimum inhibitory concentration for about 14 days.
123. The method of any one of clauses 88 to 119, wherein the administration provides a concentration of voriconazole greater than the target minimum inhibitory concentration for about 16 days.
124. The method of any one of clauses 88 to 119, wherein the administration provides a concentration of voriconazole greater than the target minimum inhibitory concentration for about 21 days.
125. The method of any one of clauses 88 to 119, wherein the administration provides a concentration of voriconazole greater than the target minimum inhibitory concentration for about 28 days.
126. The method of any one of clauses 88 to 125, wherein the veterinary formulation is administered as a single unit dose.
127. The method of any one of clauses 88 to 125, wherein the veterinary formulation is administered as a multiple dose regimen.
128. The method of any one of clauses 88 to 127, wherein the method further comprises administration of a second therapeutic agent.
129. The method of clause 128, wherein the second therapeutic agent is selected from the group consisting of an oral antifungal agent, an anti-inflammatory agent, and an antibiotic.
130. The method of any one of clauses 88 to 129, wherein the method of treating is performed without co-administration of a topical antifungal to the animal.
131. The method of any one of clauses 88 to 130, wherein the therapeutically effective amount of the voriconazole is at a dose of about 1 mg.
132. The method of any one of clauses 88 to 130, wherein the therapeutically effective amount of the voriconazole is at a dose of about 2 mg.
133. The method of any one of clauses 88 to 130, wherein the therapeutically effective amount of the voriconazole is at a dose of about 2.5 mg.
134. The method of any one of clauses 88 to 130, wherein the therapeutically effective amount of the voriconazole is at a dose of about 3 mg.
135. The method of any one of clauses 88 to 130, wherein the therapeutically effective amount of the voriconazole is at a dose of about 4 mg.
136. The method of any one of clauses 88 to 130, wherein the therapeutically effective amount of the voriconazole is at a dose of about 5 mg.
137. The method of any one of clauses 88 to 130, wherein the therapeutically effective amount of the voriconazole is at a dose of about 7.5 mg.
138. The method of any one of clauses 88 to 130, wherein the therapeutically effective amount of the voriconazole is at a dose of about 10 mg.
139. The method of any one of clauses 88 to 130, wherein the therapeutically effective amount of the voriconazole is at a dose of about 0.001 to about 1 mg/kg of weight of the animal.
140. The method of any one of clauses 88 to 130, wherein the therapeutically effective amount of the voriconazole is at a dose of about 0.01 to about 0.1 mg/kg of weight of the animal.
141. The method of any one of clauses 88 to 130, wherein the voriconazole is released from the polymer at a rate between about 100 μg/day to about 10,000 μg/day.
Various embodiments of the invention are described herein as follows. In one embodiment described herein, a veterinary formulation is provided. The veterinary formulation comprises i) a therapeutically effective amount of voriconazole and ii) a polymer.
In another embodiment, a kit is provided. The kit comprises i) voriconazole and ii) a polymer.
In yet another embodiment, a method of treating fungal infection in an animal is provided. The method comprises the step of administering a veterinary formulation comprising i) a therapeutically effective amount of voriconazole and ii) a polymer to the animal.
In various embodiments, the veterinary formulation comprises a therapeutically effective amount of voriconazole. Voriconazole is generally known in the art as an azole antifungal agent and can be used to treat a number of fungal infections, including, for example, aspergillosis, candidiasis, coccidioidomycosis, histoplasmosis, penicilliosis, and infections caused by Scedosporium and Fusarium.
As used herein, the term "voriconazole" refers to voriconazole base, pharmaceutically acceptable salts of voriconazole, other salts of voriconazole, metabolites of voriconazole, and prodrugs of voriconazole. The term "pharmaceutically acceptable salt" refers to an addition salt that exists in conjunction with the acidic or basic portion of voriconazole. Such salts include the pharmaceutically acceptable salts listed in HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, P. H. Stahl and C. G. Wermuth (Eds.), Wiley-VCH, New York, 2002 which are known to the skilled artisan. Pharmaceutically acceptable salts of an acid addition nature are formed when voriconazole and any of its intermediates containing a basic functionality are reacted with a pharmaceutically acceptable acid. Pharmaceutically acceptable acids commonly employed to form such acid addition salts include inorganic and organic acids. Pharmaceutically acceptable salts of a base addition nature are formed when voriconazole and any of its intermediates containing an acidic functionality are reacted with a pharmaceutically acceptable base. Pharmaceutically acceptable bases commonly employed to form base addition salts include organic and inorganic bases.
In addition to pharmaceutically acceptable salts, other salts are included in the present invention. They may serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically-acceptable salts, or are useful for identification, characterization or purification.
The chemical structure of voriconazole is:

In the various embodiments, the voriconazole is present in the veterinary formulation at a therapeutically effective amount. As used herein, the term "therapeutically effective amount" refers to an amount which gives the desired benefit to an animal and includes both treatment and prophylactic administration. The amount will vary from one animal to another and will depend upon a number of factors, including the overall physical condition of the animal. The amount of voriconazole used for the therapeutically effective amount gives an acceptable effect and maintains desired response at a beneficial level. A therapeutically effective amount of the composition used in the methods of the present disclosure may be readily ascertained by one of ordinary skill in the art using publicly available materials and procedures.
In certain embodiments, the veterinary formulation further comprises an alcohol. In some embodiments, the alcohol is ethanol.
In various embodiments, the veterinary formulation comprises one or more second therapeutic agents. In some embodiments, second therapeutic agent is selected from the group consisting of an oral antifungal agent, an anti-inflammatory agent, and an antibiotic.
In various embodiments, the polymer is a thermogel polymer. Thermogel polymers (aka "thermogels") are generally known in the art as polymers that exist in liquid phase when refrigerated and exist in solid phase when at room temperature. Typically, the steric hindrance of thermogel polymers combined with a low molecular weight prevents crystallization, and therefore provides their thermosensitivity. Thermogel polymers, when mixed together, provide various ranges in degradation time.
In some embodiments, the thermogel polymer is selected from the group consisting of poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), poly (N-isopropyl acrylamide) (PNIPAAm), poly(N,N-diethyl acrylamide) (PDEAM), poly(N-ethyl methacrylamide) (PNEMAM), poly(methyl vinyl ether) (PMVE), poly(2-ethoxyethyl vinyl ether) (PEOVE), poly(N-vinyl isobutyramide) (PNVIBAM), poly(N-vinyl n-butyramide) (PNVBAM), poly(N-vinyl caprolactam) (PNVCa), and poly (hydroxypropyl methacrylamide) (HPMA), poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA-PEG-PLGA), poly(DL-lactide)-b-Poly(ethylene glycol)-b-Poly(DL-lactide) (P(DL)LA-PEG-P(DL)LA), and poly(lactide-co-caprolactone)-b-Poly(ethylene glycol)-b-Poly(lactide-co-caprolactone) (PLCL-PEG-PLCL).
In other embodiments, the thermogel polymer is a combination of two or more thermogel polymers selected from the group consisting of poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), poly (N-isopropyl acrylamide) (PNIPAAm), poly(N,N-diethyl acrylamide) (PDEAM), poly(N-ethyl methacrylamide) (PNEMAM), poly(methyl vinyl ether) (PMVE), poly(2-ethoxyethyl vinyl ether) (PEOVE), poly(N-vinyl isobutyramide) (PNVIBAM), poly(N-vinyl n-butyramide) (PNVBAM), poly(N-vinyl caprolactam) (PNVCa), and poly (hydroxypropyl methacrylamide) (HPMA), poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PLGA-PEG-PLGA), poly(DL-lactide)-b-Poly(ethylene glycol)-b-Poly(DL-lactide) (P(DL)LA-PEG-P(DL)LA), and poly(lactide-co-caprolactone)-b-Poly(ethylene glycol)-b-Poly(lactide-co-caprolactone) (PLCL-PEG-PLCL).
In certain embodiments, the thermogel polymer is poly(lactide-co-glycolide)-b-poly(ethylene glycol)-b-poly(lactide-co-glycolide) (aka "PLGA-PEG-PLGA"). The structure of PLGA-PEG-PLGA is as follows:

In some embodiments, the PLGA-PEG-PLGA has a molecular weight of 1100:1000:1100. For example, a PLGA-PEG-PLGA with a molecular weight of 1100:1000:1100 can be referred to as PolyVivo AK24 (i.e., Poly(lactic-co-glycolic acid)-b-Poly(ethylene glycol)-b-Poly(lactic-co-glycolic acid) copolymers, with a molecular weight of components at a ratio of 1100:1000:1100 Da and 3:1 lactide:glycolide; Akina, Inc., West Lafayette, Ind.).
In other embodiments, the PLGA-PEG-PLGA has a molecular weight of 1500:1500:1500. For example, a PLGA-PEG-PLGA with a molecular weight of 1500:1500:1500 can be referred to as PolyVivo AK19 (i.e., Poly(lactic-co-glycolic acid)-b-Poly(ethylene glycol)-b-Poly(lactic-co-glycolic acid) copolymers, with a molecular weight of components at a ratio of 1500:1500:1500 Da and 1:1 lactide:glycolide; Akina, Inc., West Lafayette, Ind.).
In yet other embodiments, the PLGA-PEG-PLGA has a molecular weight of 1600:1500:1600 Da. For example, a PLGA-PEG-PLGA with a molecular weight of 1600:1500:1600 can be referred to as PolyVivo AK088 (i.e., Poly(lactic-co-glycolic acid)-b-Poly(ethylene glycol)-b-Poly(lactic-co-glycolic acid) copolymers, with a molecular weight of components at a ratio of 1600:1500:1600 Da and LG 75:25; Akina, Inc., West Lafayette, Ind.).
In other embodiments, the PLGA-PEG-PLGA has a molecular weight of 1700-1500-1700 Da. For example, a PLGA-PEG-PLGA with a molecular weight of 1700-1500-1700 can be referred to as PolyVivo AK097 (i.e., Poly(lactic-co-glycolic acid)-b-Poly(ethylene glycol)-b-Poly(lactic-co-glycolic acid) copolymers, with a molecular weight of components at a ratio of 1700-1500-1700 Da and LA:GA 15:1; Akina, Inc., West Lafayette, Ind.).
In some embodiments, the PLGA-PEG-PLGA is a combination of two different PLGA-PEG-PLGA compositions, wherein the first PLGA-PEG-PLGA composition and the second PLGA-PEG-PLGA composition are selected from the group consisting of a PLGA-PEG-PLGA with a molecular weight of 1100:1000:1100 Da, a PLGA-PEG-PLGA with a molecular weight of 1500:1500:1500 Da, a PLGA-PEG-PLGA with a molecular weight of 1600:1500:1600 Da, and a PLGA-PEG-PLGA with a molecular weight of 1700-1500-1700 Da.
In other embodiments, the PLGA-PEG-PLGA is a combination of two different PLGA-PEG-PLGA compositions, wherein the first PLGA-PEG-PLGA composition has a molecular weight of 1100:1000:1100 and the second PLGA-PEG-PLGA composition has a molecular weight of 1500:1500:1500. In certain aspects, the ratio of the first PLGA-PEG-PLGA composition and the second PLGA-PEG-PLGA composition is about 1:1. In other aspects, the ratio of the first PLGA-PEG-PLGA composition and the second PLGA-PEG-PLGA composition is about 2:1. In other aspects, the ratio of the first PLGA-PEG-PLGA composition and the second PLGA-PEG-PLGA composition is about 3:1.
In yet other embodiments, the PLGA-PEG-PLGA is at a ratio of 1:1 (lactide:glycolide). In some embodiments, the PLGA-PEG-PLGA is at a ratio of 2:1 (lactide:glycolide). In other embodiments, the PLGA-PEG-PLGA is at a ratio of 3:1 (lactide:glycolide). In yet other embodiments, the PLGA-PEG-PLGA is at a ratio of 15:1 (lactide:glycolide).
In certain embodiments, the thermogel polymer is poly(DL-lactide)-b-Poly(ethylene glycol)-b-Poly(DL-lactide) (aka "P(DL)LA-PEG-P(DL)LA"). The structure of P(DL)LA-PEG-P(DL)LA is as follows:

In some embodiments, the P(DL)LA-PEG-P(DL)LA has a molecular weight of 1700-1500-1700. For example, a P(DL)LA-PEG-P(DL)LA with a molecular weight of 1700-1500-1700 can be referred to as PolyVivo AK100 (i.e., Poly(DL-lactide)-b-Poly(ethylene glycol)-b-Poly(DL-lactide) triblock copolymers, with a molecular weight of components at a ratio of 1700-1500-1700 Da; Akina, Inc., West Lafayette, Ind.).
In certain embodiments, the thermogel polymer is poly(lactide-co-caprolactone)-b-Poly(ethylene glycol)-b-Poly(lactide-co-caprolactone) (aka "PLCL-PEG-PLCL"). The structure of PLCL-PEG-PLCL is as follows:

In some embodiments, the PLCL-PEG-PLCL has a molecular weight of 1700-1500-1700. For example, a PLCL-PEG-PLCL with a molecular weight of 1700-1500-1700 can be referred to as PolyVivo AK109 (i.e., Poly(lactide-co-caprolactone)-b-Poly(ethylene glycol)-b-Poly(lactide-co-caprolactone), with a molecular weight of components at a ratio of 1700-1500-1700 Da and 60:40 CL:LA; Akina, Inc., West Lafayette, Ind.).
In various aspects, the thermogel polymer has a gelation set point at a temperature of about 30° C. to about 40° C. As used herein, the gelation set point refers to a temperature or a temperature range at which conversion of a thermogel from its liquid state to its solid state occurs. In other aspects, the thermogel polymer has a gelation set point at a temperature of about 33° C. to about 44° C. In certain aspects, the thermogel polymer has a gelation set point at a temperature of about 33° C. to about 36° C. In other aspects, the thermogel polymer has a gelation set point at a temperature of about 31° C. to about 42° C. In yet other aspects, the thermogel polymer has a gelation set point at a temperature of about 27° C. to about 45° C.
In various embodiments, the veterinary formulation further comprises one or more dissolution additives. Generally, a dissolution additive may be added to the veterinary formulation in order to modify the dissolution speed of the thermogel polymer(s) in the formulation. In some embodiments, the one or more dissolution additives is selected from the group consisting of N-methylpyrolidinone (NMP), mannitol, and mPEG-P (DL) La. In one embodiment, the mPEG-P (DL) La is mPEG-P (DL) La (2000-2200 Da).
In some embodiments, the veterinary formulation is single-use formulation that is intended to be given to an animal in a single administration. In other embodiments, the veterinary formulation is multi-use formulation that is capable of being given to an animal in a single administration or in multiple administrations. Two or more polymers may be combined to achieve the correct temperature for the most efficacious product or for the desired immediate and/or extended release times.
In some embodiments, the veterinary formulation is a controlled release formulation. A controlled release formulation is intended to more slowly release the voriconazole of the veterinary formulation to the animal. In some aspects, the controlled release formulation releases voriconazole from veterinary formulation for about 7 days. In other aspects, the controlled release formulation releases voriconazole from veterinary formulation for about 10 days. In yet other aspects, the controlled release formulation releases voriconazole from veterinary formulation for about 14 days. In some aspects, the controlled release formulation releases voriconazole from veterinary formulation for about 21 days. In yet other aspects, the controlled release formulation releases voriconazole from veterinary formulation for about 28 days.
In some embodiments, the veterinary formulation is an injectable formulation. As used herein, an injectable formulation refers to a formulation with the ability to be introduced under pressure at a site of an animal (as by introduction using a syringe). "Syringe" refers to any device that may be used to inject or withdraw compositions of the present disclosure. In some aspects, the injectable formulation is configured for injection in a subconjunctival space (SCS) of an animal. As used herein, the subconjunctival space generally refers to the area in an eye of the animal that is located between the conjunctiva and the sclera. In some embodiments, the SCS is a dorsal bulbar SCS. In other embodiments, the SCS is a ventral bulbar SCS.
In another embodiment, a kit is provided. The kit comprises i) voriconazole and ii) a polymer. The previously described embodiments of the veterinary formulation are applicable to the kit described herein.
In various embodiments, the kit further comprises one or more dissolution additives. In some embodiments, the one or more dissolution additives is selected from the group consisting of N-methylpyrolidinone (NMP), mannitol, and mPEG-P (DL) La. In one embodiment, the mPEG-P (DL) La is mPEG-P (DL) La (2000-2200 Da).
In certain aspects, the polymer, for example the polymer provided in the kit, is a liquid. In various embodiments, the liquid polymer is configured to form a gel deposit upon administration to an animal. For example, when the liquid polymer is a thermogel polymer, the liquid polymer undergoes conversion to a gel deposit upon reaching an appropriate temperature.
In some embodiments, the gel deposit is formed at a temperature of about 30° C. to about 40° C. In other embodiments, the gel deposit is formed at a temperature of about 33° C. to about 44° C. In yet other embodiments, the gel deposit is formed at a temperature of about 33° C. to about 36° C. In other embodiments, the gel deposit is formed at a temperature of about 31° C. to about 42° C. In yet other embodiments, the gel deposit is formed at a temperature of about 27° C. to about 45° C.
In certain aspects, the kit further comprises instructions for combination of the voriconazole, the polymer, and any other element as described herein.
In another embodiment, a method of treating a fungal infection in an animal is provided. The method comprises the step of administering a veterinary formulation comprising i) a therapeutically effective amount of voriconazole and ii) a polymer to the animal. The previously described embodiments of the veterinary formulation and of the kit are applicable to the method of treating a fungal infection in an animal described herein. In certain aspects, the veterinary formulation is formed from the kit as described herein.
In various embodiments, the fungal infection is caused by an Aspergillus species. In other embodiments, the fungal infection is caused by a Fusarium species. In yet other embodiments, the fungal infection is caused by a Penicillium species. In some embodiments, the fungal infection is caused by a Candida species.
In certain aspects, the fungal infection is an ocular infection. In some embodiments, the fungal infection is causes keratomycosis in the animal. Keratomycosis, sometimes referred to as fungal keratitis, is generally known as a fungal infection of the cornea (i.e., the anterior part of the eye which covers the pupil).
In various embodiments, the animal is an equine. In some embodiments, the equine is a horse. In other embodiments, the equine is a donkey. In yet other embodiments, the equine is a zebra.
In some aspects, the animal is a feline. In other aspects, the animal is a canine. In yet other aspects, the animal is a camelid. In some embodiments, the camelid is selected from the group consisting of dromedary camels, Bactrian camels, wild Bactrian camels, llamas, alpacas, vicuñas, and guanacos. In other embodiments, the camelid is a llama. In yet other embodiments, the camelid is an alpaca.
In certain aspects, the administration to the animal is an injection. In some aspects, upon the injection to the animal, the polymer of the veterinary formulation is a liquid. In various aspects, the liquid polymer forms a gel deposit in the animal subsequent to the injection. In some embodiments, the gel deposit is formed at a temperature of about 30° C. to about 40° C. In other embodiments, the gel deposit is formed at a temperature of about 33° C. to about 44° C. In yet other embodiments, the gel deposit is formed at a temperature of about 33° C. to about 36° C. In other embodiments, the gel deposit is formed at a temperature of about 31° C. to about 42° C. In yet other embodiments, the gel deposit is formed at a temperature of about 27° C. to about 45° C.
In some embodiments, the injection is in a subconjunctival space (SCS). In various embodiments, the SCS is a dorsal bulbar SCS. In other embodiments, the SCS is a ventral bulbar SCS.
In certain aspects, the voriconazole diffuses through a cornea of the animal. In other aspects, the voriconazole diffuses through a sclera of the animal.
In some embodiments, the administration provides a concentration of voriconazole greater than the target minimum inhibitory concentration for about 7 days. In other embodiments, the administration provides a concentration of voriconazole greater than the target minimum inhibitory concentration for about 10 days. In yet other embodiments, the administration provides a concentration of voriconazole greater than the target minimum inhibitory concentration for about 14 days. In some embodiments, the administration provides a concentration of voriconazole greater than the target minimum inhibitory concentration for about 16 days. In other embodiments, the administration provides a concentration of voriconazole greater than the target minimum inhibitory concentration for about 21 days. In yet other embodiments, the administration provides a concentration of voriconazole greater than the target minimum inhibitory concentration for about 28 days.
In certain aspects, the veterinary formulation is administered as a single unit dose. In other aspects, the veterinary formulation is administered as a multiple dose regimen. In yet other aspects, the method further comprises administration of a second therapeutic agent. In some embodiments, the second therapeutic agent is selected from the group consisting of an oral antifungal agent, an anti-inflammatory agent, and an antibiotic. In various aspects, the method of treating is performed without co-administration of a topical antifungal to the animal.
In certain embodiments, the therapeutically effective amount of the voriconazole is at a dose of about 1 mg. In some embodiments, the therapeutically effective amount of the voriconazole is at a dose of about 2 mg. In other embodiments, the therapeutically effective amount of the voriconazole is at a dose of about 2.5 mg. In yet other embodiments, the therapeutically effective amount of the voriconazole is at a dose of about 3 mg. In some embodiments, the therapeutically effective amount of the voriconazole is at a dose of about 4 mg. In other embodiments, the therapeutically effective amount of the voriconazole is at a dose of about 5 mg. In yet other embodiments, the therapeutically effective amount of the voriconazole is at a dose of about 7.5 mg. In some embodiments, the therapeutically effective amount of the voriconazole is at a dose of about 10 mg. In other embodiments, the therapeutically effective amount of the voriconazole is at a dose of about 0.001 to about 1 mg/kg of weight of the animal. In yet other embodiments, the therapeutically effective amount of the voriconazole is at a dose of about 0.01 to about 0.1 mg/kg of weight of the animal. In other embodiments, the voriconazole is released from the polymer at a rate between about 100 μg/day to about 10,000 μg/day.

Sustained-release voriconazole-containing thermogel and uses thereof


A magnesium alloy comprising up to about six weight percent zinc and up to about one weight percent cerium may be hot worked to produce an intermediate or final alloy workpiece that exhibits enhanced ductility and strength at room temperature. The addition of zinc and a small amount of cerium may affect the magnesium alloy by increasing strength and ductility, and improving the work hardening behavior.

Magnesium is the lightest structural metal. In engineering applications it is alloyed with one or more elements, for example, aluminum, manganese, rare earth metals, lithium, zinc, and silver. Magnesium usually constitutes eighty-five percent by weight or more of these alloys.
The cost of magnesium has decreased dramatically in recent years and magnesium and its alloys have become attractive structural materials for a wide range of applications due in part to desirable physical properties such as light weight, high specific strength and stiffness, machinability, and the ability to be easily recycled. However, the use of magnesium in wrought products like sheets and extrusions has been limited due to the poor workability of magnesium castings and the lower formability and ductility of magnesium in the primary fabricated stage. At room temperature, pure magnesium is generally characterized by limited ductility as a result of its hexagonal close-packed crystal structure and resulting limited number of active slip systems. This inherent limitation often discourages widespread use of magnesium in wrought products made from sheets and extrusions because it is difficult and expensive to process the poorly workable metal into useable finished shapes.
It has been shown that the ductility of Mg-0.2 wt % Ce alloy extrusions is higher than that of magnesium and other known magnesium alloys. However, the yield and tensile strengths of the Mg-0.2 wt % Ce alloy remain low. The addition of aluminum to the Mg-0.2 wt % Ce alloy improves its strength, but significantly decreases its ductility.
Thus, there is a general need to provide magnesium alloys in a primary fabrication stage having improved ductility and strength for fabrication into wrought magnesium metal products.

High ductility/strength magnesium alloys


A timepiece apparatus (10) comprising: a rotatable shaft (30) operatively connected to a magnet (40); a magnetic detection device (50) to detect a magnetic field of the magnet (40) when proximal to the magnetic detection device (50); wherein if a predetermined sequence of magnetic fields is detected by the magnetic detection device (50), a predetermined operation is performed.

In digital wrist worn timepieces such as watches, chronometers and personal electronic products, data is typically entered or retrieved from the timepiece by manually and repeatedly pushing at least one button to follow a sequence of steps. However, this is a slow process if there are many options to choose from or a lot of information is to be scanned through.
It is important to consider the availability of internal space within the timepiece, and water resistance of the timepiece to protect the internal electrical and mechanical components of the timepiece.
Accordingly, there is a desire for a timepiece that allows entry, retrieval and scanning of data relatively quickly which ensures reliability, water resistance and is relatively simple to manufacture.


Fibrous cellulosic products incorporating both conventional cellulosic fibers and laterally expanded cellulose fibers exhibit exceptional porosity, bulk, absorbency and resiliency properties. Typical products include absorbent tissue products, absorbent fluff products and flat papers. The laterally expanded cellulose fibers exhibit: (i) a broadened X-Ray diffraction peak for the most prominent reflection having a width at half-height, (W1/2h)A, of at least about 3.0° 2Θ, (ii) broad overlapping maxima in their Raman spectrum between 285 and 500 cm−1, the height of the two tallest of said maxima in said spectrum between 285 and 500 cm−1 being between 35 and 50% of the height of the peak near 1098 cm−1 and (iii) a blue stain when treated with Graff C-stain, the stain exhibiting less red than the stains exhibited with bleached hardwood kraft fibers and bleached softwood kraft fibers.

The treatment process for preparation of LEC is described in WO2009124240, Highly Disordered Cellulose, (Atalla I), the entirety of which is incorporated herein by reference. In Atalla I, cellulose is treated with an alkali and an alcohol/water co-solvent system. Cellulose so treated shows dramatically less crystallinity than normal Kraft pulp, which makes this treatment ideal for subsequent enzymatic treatment to convert the cellulose to glucose. Cellulose chains in the fibers appear to be much more accessible after this treatment. Given this increased accessibility, it was hypothesized that this fiber might exhibit much less bonding and more bulk than an untreated fiber. However, fibers treated according to Atalla I still retain substantial crystallinity particularly along the length of the cellulosic chains, it appears that the primary effect of treatment according to Atalla I is to relax the bonds between adjacent chains thereby making the cellulose therein more accessible while greatly weakening the bonds between adjacent cellulosic chains. Fiber so treated is neither amorphous nor mercerized nor completely disordered but is, rather, nanoporous or laterally expanded. FIGS. 42A and 42B are schematic illustrations to help in visualizing the hypothesized differences in structure thought to result from the Atalla I treatment. In particular, FIG. 42A and FIG. 42B each illustrate 4 roughly parallel chains C of cellulose inside a single cellulose fiber. In FIG. 42A, representing untreated cellulose, chains C are largely parallel and are interconnected by inter-chain bonds IB, where the portions of bonds IB, hidden behind an adjacent cellulose chain C, are indicated in finer (0.25 point) broken lines. In FIG. 42B, representing treated cellulose, inter-chain bonds IB have been disrupted so that the spacing between them has grown and chains C are no longer as parallel. It is hypothesized that a disruption of this nature leads to the spreading and shifts observed in the X-Ray diffraction peaks of the treated fibers.
LEC fibers can be incorporated into tissue sheets made by any known process, including conventional wet pressing ("CWP"), through-air drying using a Yankee dryer ("TAD"), through air drying in which the sheet is dried on the fabric rather than being creped from a Yankee ("UCTAD") as well as methods in which a web at between about 30% and about 60% consistency is creped from a transfer cylinder using either a woven creping fabric or a perforate polymeric belt and thereafter dried in any convenient manner. Other new papermaking techniques recently developed for manufacture of tissue products can be used as well. The LEC fiber can be incorporated into the sheet homogeneously or layered into the exterior layers as would any other papermaking fiber. In cases where the anfractuous nature of the fibers conflicts with obtaining the desired degree of formation, well known foam forming techniques can be used to considerable advantage. Alternatively, well known associative thickener technology can be used as well to address formation issues thought to be attributable to the anfractuous nature of the fibers. Conventional papermaking chemicals can be used as well known by those having skill in the art. Conventional converting procedures can be used for transforming basesheets into finished salable products.
Conventional cellulosic fibers include any fiber typically used for papermaking having cellulose as a major constituent except those fibers described herein as laterally expanded cellulosic fibers or nanoporous cellulose. Conventional cellulosic fibers thus include cellulosic fibers prepared from virgin pulps or recycle (secondary) cellulosic fibers. Conventional cellulosic fibers include: nonwood fibers, such as cotton fibers, cotton linters, or cotton derivatives, abaca, kenaf, sabai grass, flax, esparto grass, straw, jute hemp, bagasse, milkweed floss fibers, corn stover, rice straw and pineapple leaf fibers; and wood fibers such as those obtained from deciduous and coniferous trees, including softwood fibers, such as northern and southern softwood kraft fibers; hardwood fibers, such as eucalyptus, maple, birch, aspen, or the like. Conventional cellulosic fibers can be liberated from their source material by any one of a number of chemical pulping processes familiar to one experienced in the art including sulfate, sulfite, polysulfide, soda pulping, etc and may be bleached, if desired, by chemical means including the use of chlorine, chlorine dioxide, oxygen, alkaline peroxide and so forth. Conventional fibers (whether derived from virgin pulp or recycle sources) also include mechanical or high yield fibers including groundwood, fibers prepared from thermomechanical pulp (TMP), chemithermomechanical pulp (CTMP) pressure/pressure thermomechanical pulp (PTMP), and alkaline peroxide mechanical pulp (APMP), neutral semi-chemical sulfite pulp (NSCS), high coarseness lignin-rich fibers, such as bleached chemical thermomechanical pulp (BCTMP), may, for example, be derived from a plant selected from the group consisting of: wood, cotton, flax, sisal, abaca, hemp, hesperaloe, jute, bamboo, bagasse, kudzu, corn, sorghum, gourd, agave, loofah and mixtures thereof. Conventional cellulosic fibers included wood pulp fibers which may be short (typical of hardwood fibers) or long (typical of softwood fibers). Nonlimiting examples of short fibers include fibers derived from a fiber source selected from the group consisting of Acacia, Eucalyptus, Maple, Oak, Aspen, Birch, Cottonwood, Alder, Ash, Chemy, Elm, Hickory, Poplar, Gum, Walnut, Locust, Sycamore, Beech, Catalpa, Sassafras, Gmelina, Albizia, Anthocephalus, and Magnolia. Nonlimiting examples of long fibers include fibers derived from Pine, Spruce, Fir, Tamarack, Hemlock, Cypress, and Cedar. Softwood fibers derived from the kraft process and originating from more-northern climates may be preferred. These are often referred to as northern softwood kraft (NSK) pulps. For the purposes of this application, mercerized fibers prepared from any of the preceding sources should also be considered conventional cellulosic fibers.
We found that addition of LEC fibers to otherwise conventional papermaking blends makes it possible for the papermaker to obtain great improvements in bulk, porosity, and opacity as well as novel tactile properties. It can be appreciated that not only do LEC fibers impart remarkable improvements in properties to standard TAPPI handsheets, they also respond more favorably to refining as demonstrated by TAPPI standard Valley Beater curves.
To demonstrate these points, a Northern Softwood Kraft (NSWK) was chosen as a premium fiber used in all types of papermaking, including tissue and towel production. The findings of this work can be summarized as follows:                Adding LEC fibers to a blend, whether refined or not, generally reduces tensile, burst, tear and stretch while increasing caliper, bulk, and porosity over the entire range of blending ratios.        Properties like caliper, bulk, burst, tensile, tear and stretch respond linearly with addition rates of unrefined blends while porosity is increased greatly.        LEC fibers respond to refining but consistently respond more slowly and end up with higher freeness and lower strengths than untreated NSWK fibers.        Proper mixing of the treated and untreated fibers is important to limit variability.
More specifically, results set forth herein indicate that:                The Atalla I treatment produces a highly desirable papermaking fiber where higher caliper, lower tensile and increased porosity is desired. This is especially true for tissue and towel grades, and is applicable to both wet pressed and through air dried base sheets.        In wet press processes, the relative insensitivity of these fibers to wet pressing can be exploited to increase the degree of wet pressing applied, thereby increasing productivity and/or reducing drying energy costs without necessarily unduly increasing the density of the sheets. This is especially applicable to grades where shoe presses are used.        The increased freeness realized with the addition of LEC fibers will allow for greater amounts of pressing at each section without the resultant crushing that often occurs with comparable conventional fibers. More efficient pressing in flat paper grades can result in substantial drying energy savings.        The very substantial increase in air flow through pressed sheets dramatically increases the potential to use typically very slow draining furnishes for through air dried products.        Treatment of recycled fibers with the Atalla I process offers the potential to dramatically improve the formation of typically slow draining furnishes by significantly raising their freeness, thereby improving productivity of the paper machine while reducing grade costs.
Currently, few high end premium consumer products are made with large amounts of recycled fiber. Applying the Atalla I treatment to form LEC fibers from recycle grades as described herein offers the potential to dramatically improve the tactile properties of recycled furnishes without the usual reduction in yield typically resulting from conventional processing of the raw waste paper to improve the quality thereof.
Non-woody fibers are often suggested for papermaking but tend to be slow draining furnishes that produce thin, noisy, sheets. Subjecting these fibers to the Atalla I process can significantly improve their properties for papermaking Rather than densifying the sheets, these treated non-woody fibers can open up the sheet and reduce the bonding potential.
The Atalla I process can be used to reduce the environmental impact of many agricultural operations. For example in many cases, rice straw is burned or buried to prepare the ground for the next crop. Instead, this straw could be used to produce a highly desirable papermaking fiber along with useful amounts of glucose if so desired. Similarly, fibers which are currently viewed as having very little value, such as those derived from corn stover, switchgrass, miscanthus, and lawn and tree maintenance byproducts can be utilized to produce glucose, papermaking fiber, glucose with papermaking fiber as a by-product or papermaking fiber with glucose as a by-product.
Since the Atalla I process apparently decreases the inter-chain bonding between the cellulosic chains in LEC fibers, it appears that, when LEC fibers are incorporated into blends of conventional papermaking fibers, these treated fibers create a debonding and bulk building effect on otherwise standard fiber blends, improving drying efficiency both through better air flow through the sheet as well as by starting with a dryer sheet, resulting in increased removal of water through mechanical pressing and in softer, thicker sheets.

Tissue products incorporating nanoporous cellulose fiber