The invention concerns a method and a composition against parasites and particularly ectoparasites and, preferably also endoparasites of small mammals and in particular dogs and cats. The composition contains a compound (A) of formula (I) and a compound (B) consisting of an endectoparasiticide of the macrocylic lactone type.

The present invention relates to an improvement to methods for combating animal parasites, namely parasites of small mammals and of birds and in particular ectoparasitical insects and endoparasites, in particular filariae and worms.
It also relates to a new composition for this use, on the basis of a combination in which already known parasiticides are synergically combined. Finally, it relates to the use of such already known parasiticides in the preparation of a composition for combating parasites and in particular the abovementioned combinations of parasites.
A new family of insecticides based on 1-N-phenylpyrazoles has been described in Patents EP-A-295,217 and EP-A-352,944. The compounds of the families defined in these patents are extremely active and one of these compounds, 1-[2,6-Cl2-4-CF3phenyl]-3-CN-4-[SO-CF3]-5-NH2pyrazole, the common name of which is fipronil, has proved to be particularly effective, not only against crop parasites but also against ectoparasites of mammals and in particular, but not exclusively, fleas and ticks.
Endectocidal compounds exhibiting a degree of activity against endoparasites and comprising avermectins and their derivatives and related products, such as ivermectin, are also known. Such substances are, for example, described in U.S. Pat. Nos. 3,950,360 and 4,199,569.
Provision has often been made to combine parasiticides with the aim of broadening the antiparasitical spectrum and the combination of the abovementioned 1-N-phenylpyrazole derivatives with avermectins, ivermectins and milbemycin had already been mentioned, among many others, without, all the same, determining the specific advantage which such a combination might have, taking into account the numerous and complex host-parasite interactions.
Patent Application AU-A-16 427/95 mentions the combination of a substituted 1-N-pyrazole derivative of this type with avermectins, ivermectin or moxidectin, among a very large number of insecticides or parasiticides of various types, including fipronil moreover, without, however, giving information on a composition comprising such a combination and without establishing a distinction regarding the targets susceptible to being targeted by specific combinations, among the innumerable parasites which can potentially be attacked.
Apart from a very general teaching, the prior art thus does not make it possible to distinguish, in each specific case, the animals and the parasites for which a specific combination might be useful or the form of a composition containing such a combination.
Moreover, the prior art is silent with respect to the presentations, dosages, posologies and administration routes of combinations of these parasiticides, the sites, methods of effect, duration of effect and targets of which are very different.
The invention intends in particular to improve methods for combating parasites of small mammals, and in particular cats and dogs, with the aim of ridding these animals of all the parasites commonly encountered.
The invention intends in particular to provide for effective and lasting destruction of ectoparasites, such as fleas and ticks and possibly itch mites and lice, and of endoparasites, such as filariae, in particular dirofilariae, and roundworms of the digestive tract, in cats and dogs.
The following are in particular targeted among roundworms or nematodes: ascarids (in particular Toxocara canis), ancylostoma species (in particular Ancylostoma caninum) and Echinococcus and Trichuris species, in particular Trichuris vulpis.
A particular object of the invention is to use already known parasiticides to prepare a composition which is extremely active against fleas and, if appropriate, against ticks.
Another object of the invention is to produce such compositions which make it possible, inter alia, effectively to combat certain endoparasites and in particular filariae and/or roundworms.
The very high effectiveness of the method and of the composition according to the invention implies not only high instantaneous effectiveness but also an effectiveness of very long duration after the treatment of the animal.
Flea within the meaning of the present invention is understood to mean in particular the Ctenocephalides species, in particular felis and canis.
Filaria is understood to mean in particular Dirofilaria immitis.
Toxocara canis, Ancylostoma caninum and Trichuris vulpis are understood in particular among the other nematodes.
The subject of the invention is a method for combating parasites and in particular ectoparasites and, preferably, also endoparasites of small mammals and in particular dogs and cats, characterized in that the animal is treated, preventively or curatively, by administration in effectively parasiticidal doses and proportions, on the one hand, of at least one compound (A) belonging to the formula (I)
in which:
R1 is a halogen atom, CN or methyl;
R2 is S(O)nR3 or 4,5-dicyanoimidazol-2-yl or haloalkyl;
R3 is alkyl or haloalkyl;
R4 represents a hydrogen or halogen atom or an NR5R6, S(O)mR7, C(O)R7 or C(O)OR7, alkyl, haloalkyl or OR8 radical or an xe2x80x94Nxe2x95x90C (R9) (R10) radical;
R5 and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, S(O)rCF3 or alkoxycarbonyl radical or R5 and R6 can together form a divalent alkylene radical which can be interrupted by one or two divalent heteroatoms, such as oxygen or sulphur;
R7 represents an alkyl or haloalkyl radical;
R8 represents an alkyl or haloalkyl radical or a hydrogen atom;
R9 represents an alkyl radical or a hydrogen atom;
R10 represents a phenyl or heteroaryl group optionally substituted by one or more halogen atoms or groups such as OH, xe2x80x94O-alkyl, xe2x80x94S-alkyl, cyano or alkyl;
R11 and R12 represent, independently of one another, a hydrogen or halogen atom and optionally CN or NO2, but H or halogen being preferred;
R13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF5 group;
m, n, q and r represent, independently of one another, an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a C-R12 radical, the three other valencies of the carbon atom forming part of the aromatic ring;
with the proviso that, when R1 is methyl, then either R3 is haloalkyl, R4 is NH2, R11 is Cl, R13 is CF3 and X is N or else R2 is 4,5-dicyanoimidazol-2-yl, R4 is Cl, R11 is Cl, R13 is CF3 and X is Cxe2x80x94Cl
and, on the other hand, of at least one compound (B) formed of an endectocidal parasiticide of macrocyclic lactone type.
The parasiticide (B) is preferably selected from the group formed by avermectins, ivermectin, abamectin, doramectin, moxidectin, milbemycins and the derivatives of these compounds.
The structure, the characteristics and the processes for the manufacture of the compounds of type (B) are well known to a person skilled in the art and reference can be made to the widely available technical and commercial literature. For avermectins, ivermectin and abamectin, reference may be made, for example, to the work xe2x80x9cIvermectin and Abamectinxe2x80x9d, 1989, by M. H. Fischer and H. Mrozik, William C. Campbell, published by Springer Verlag., or Albers-Schonberg et al. (1981), xe2x80x9cAvermectins Structure Determinationxe2x80x9d, J. Am. Chem. Soc., 103, 4216-4221. For doramectin, xe2x80x9cVeterinary Parasitologyxe2x80x9d, vol. 49, No. 1, July 1993, 5-15 may in particular be consulted. For milbemycins, reference may be made, inter alia, to Davies H. G. et al., 1986, xe2x80x9cAvermectins and Milbemycinsxe2x80x9d, Nat. Prod. Rep., 3, 87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett., 24, 5333-5336, and U.S. Pat. No. 4,134,973.
Compounds (B) can be either natural products or are semi-synthetic derivatives thereof. The structure of at least certain compounds (B) are closely related, e.g., by sharing a complex 16-membered macrocyclic lactone ring. The natural product avermectins are disclosed in U.S. Pat. No. 4,310,519 to Albers-Schonberg, et al., and the 22, 23-dihydro avermectin compounds are disclosed in Chabala, et al., U.S. Pat. No. 4,199,569. Mention is also made of Kitano, U.S. Pat. No. 4,468,390, Beuvry et al., U.S. Pat. No. 5,824,653, European Patent Application 0 007 812 A1, published Jun. 2, 1980, U.K. Patent Specification 1 390 336, published Apr. 9, 1975, European Patent Application 0 002 916 A2, and Ancare New Zealand Patent No. 237 086, inter alia. Naturally occurring milbemycins are described in Aoki et al., U.S. Pat. No. 3,950,360 as well as in the various references cited in xe2x80x9cThe Merck Indexxe2x80x9d 12th ed., S. Budavari, Ed., Merck and Co., Inc. Whitehouse Station, New Jersey (1996). Semisynthetic derivatives of these classes of compounds are well known in the art and are described, for example, in U.S. Pat. Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317, 4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,199,569, 5,055,596, 4,973,711, 4,978,677, 4,920,148.
The alkyl radicals of the definition of the compounds (A) of the formula (I) generally comprise from 1 to 6 carbon atoms. The ring formed by the divalent alkylene radical representing R5 and R6 and the nitrogen atom to which R5 and R6 are attached is generally a 5-, 6- or 7-membered ring.
A preferred class of compounds (A) of formula (I) comprises the compounds such that R1 is CN, R3 is haloalkyl, R4 is NH2, R11 and R12 are, independently of one another, a halogen atom and R13 is haloalkyl. Preferably still, X is Cxe2x80x94R12.
A compound (A) of formula (I) which is very particularly preferred in the invention is 1-[2,6-Cl2-4-CF3phenyl]-3-CN-4-[SOxe2x80x94CF3]-5-NH2pyrazole, hereinafter known as compound A, the common name of which is fipronil.
More generally, compounds (A) are pyrazoles such as phenylpyrazoles and N-arylpyrazoles, and reference is made to, for example, U.S. Pat. No. 5,567,429, U.S. Pat. No. 5,122,530, EP 295,117, and EP 846686 A1 (or Banks GB 9625045, filed Nov. 30, 1996 also believed to be equivalent to U.S. Ser. No. 309,229, filed Nov. 17, 1997). (e.g., 1-pyridyl imidazole compounds, an N-aryldiazole compounds, and a phenylpyrazole compounds).
Compounds (A) of formula (I) can be prepared according to one or other of the processes described in Patent Applications WO 87/3781, 93/6089 and 94/21606 or European Patent Application 295,117 or any other process coming within the competence of a person skilled in the art who is an expert in chemical synthesis. For the chemical preparation of the products of the invention, a person skilled in the art is regarded as having at his disposal, inter alia, the entire contents of xe2x80x9cChemical Abstractsxe2x80x9d and of the documents which are cited therein.
The two types of compounds can be administered concomitantly and preferably simultaneously in the form of a single composition.
Administration can be intermittent in time and, in this case, it is preferable for the treatment according to the invention to be carried out monthly on dogs and on cats.
Frequencies of less than a monthly frequency are also possible, for example bimonthly or quarterly or even more. In other words, a method for permanently combating in an environment in which the animal is subjected to strong parasitic pressure is characterized by an administration at a frequency far below a daily administration.
However, administration can also be continuous using means, known in themselves, which make possible slow liberation or release of the compounds combined in the treatment. Mention may in particular be made of microspheres based on polylactic acid polymer or on polylactic-glycolic acid copolymer.
In this case, it will be preferable to administer to the animal, by a route providing good systemic distribution, a mixture of two controlled-release formulations, one containing the compound (A) and the other the compound (B).
The compounds for the treatment can be administered by a systemic route, for example an oral or parenteral route.
Administration is preferably carried out topically, on the skin or the coat of the animal.
Preferably, in the case of topical administration, a single composition containing the compounds (A) and (B) in a substantially liquid vehicle and in a form which makes possible a single application, or an application repeated a small number of times, will be administered to the animal over a highly localized region of the animal, preferably between the two shoulders (formulation of spot-on type). It has been possible to observe, remarkably, that such a formulation makes it possible to obtain high effectiveness in the companion animal both against the targeted ectoparasites and the targeted endoparasites.
The treatment is preferably carried out so as to administer to the animal, on a single occasion, a dose containing between 0.001 and 100 mg/kg of derivative (A) and containing between 0.1 and 1000 xcexcg/kg of compound of type (B), in particular in the case of a direct topical administration.
The amount of compound (A) for animals which are small in size is preferably greater than 0.01 mg and in a particularly preferred way between 1 and 50 mg/kg of weight of animal.
For administration by the oral or parenteral route, the doses can comprise the compounds (A) and (B) in the same ranges mentioned above.
In the case where the compounds of the treatment according to the invention are administered continuously, for example from systemic-distribution release means, it is preferable for the release rate to be of the order of 0.001 to 0.5 mg, preferably of 0.05 to 0.1 mg/kg per day for the compound (A) and of 0.1 to 200 xcexcg/kg per day for the compound (B).
In the case of administration by an oral or parenteral systemic route, it is preferable for the dose to result in a blood concentration greater than or equal to 1 ng, for example 1 to 50 ng/ml for the compound (A).
To this end, it may be preferable to use controlled-release formulations. However, due to the persistence of the activity of fipronil and of the derivatives of type (B), it may be preferable for reasons of simplicity to carry out systemic administration using conventional vehicles.
The object of this method is non-therapeutic and relates in particular to the cleaning of the coats and of the skin of animals by removal of the parasites which are present and of their waste and excreta. The animals treated thus exhibit a coat which is more pleasing to the eye and more pleasant to the touch.
The invention also relates to such a method with a therapeutic aim intended for the treatment and prevention of parasitoses having pathogenic consequences.
Another subject of the invention is a composition, in particular for combating fleas in small mammals, in particular dogs and cats, characterized in that it contains, on the one hand, at least one compound (A) of formula (I). as defined above and, on the other hand, at least one endectocidal compound (B), in amounts and proportions having a parasiticidal effectiveness for fleas and worms, in a vehicle acceptable for the animal.
The preferred class of compounds of formula (I) is that which has been defined above.
A compound of formula (I) which is very particularly preferred in the invention is 1-[2,6-Cl2-4-CF3phenyl]-3-CN-4-[SOxe2x80x94CF3]-5-NH2pyrazole.
Among the compounds of type (B), for small animals, a compound selected from the group formed by ivermectin and milbemycin is preferred.
The effective amount in a dose is, for the compound (A), preferably between 0.001, preferentially 0.1, and 100 mg and in a particularly preferred way from 1 to 50 mg/kg of weight of animal, the higher amounts being provided for very prolonged release in or on the body of the animal.
The effective amount of compounds (B) in a dose is preferably between 0.1 xcexcg, preferentially 1 xcexcg, and 1 mg and in a particularly preferred way from 5 to 200 xcexcg/kg of weight of animal.
The proportions, by weight, of compounds of formula (I) and of compounds (B) are preferably between 5/1 and 10,000/1.
The vehicle can be simple or complex and it is suited to the route and to the method of administration chosen.
Thus, the composition according to the invention can be provided in the topical form, in particular in the form of a solution, suspension, microemulsion or emulsion to be poured or spread over the animal (solution of pour-on type), of a more concentrated solution, suspension, microemulsion or emulsion for intermittent application to a spot-on the animal, generally between the two shoulders (solution of spot-on type), or of an oil, cream, ointment or any other fluid formulation for topical administration.
The formulation which is particularly preferred, and which exhibits a particularly surprising effectiveness, in particular with respect to dogs and cats and small mammals generally, is the concentrated suspension or solution for intermittent application (solution of so-called spot-on type).
Such a preparation exhibits, in a particularly preferred way, the compounds (A) and (B) in a vehicle for cutaneous application containing an organic solvent and, preferably, an organic cosolvent and/or a crystallization inhibitor.
The compound (A) of formula (I) can advantageously be present in this formulation in a proportion of 1 to 20%, preferably of 5 to 15% (percentages as weight by volume =W/V).
The crystallization inhibitor can in particular be present in a proportion of 1 to 20% (W/V), preferably of 5 to 15%, this inhibitor preferably corresponding to the test according to which: 0.3 ml of a solution comprising 10% (W/V) of the compound of formula (I) in the solvent defined under c) below, as well as 10% of this inhibitor, are deposited on a glass slide at 20xc2x0 C. for 24 hours, following which few or no crystals, in particular less than 10 crystals, preferably 0 crystals, are observed with the naked eye on the glass slide.
The organic solvent will preferably have a dielectric constant of between 10 and 35, preferably between 20 and 30, the content of this solvent in the overall composition preferably representing the remainder to 100% of the composition.
The organic cosolvent will preferably have a boiling point of less than 100xc2x0 C., preferably of less than 80xc2x0 C., and will have a dielectric constant of between 10 and 40, preferably between 20 and 30; this cosolvent can advantageously be present in the composition according to a weight/weight (W/W) ratio with respect to the solvent of between 1/15 and 1/2; the cosolvent is volatile in order to act in particular as drying promoter and is miscible with water and/or with the solvent.
Although this is not preferred, the composition can optionally comprise water, in particular in a proportion of 0 to 30% (volume by volume V/V), in particular of 0 to 5%.
The composition can also comprise an antioxidizing agent intended to inhibit oxidation in air, this agent being in particular present in a proportion of 0.005 to 1% (W/V), preferably of 0.01 to 0.05%.
Use can in particular be made, as organic solvents, of the following: acetone, ethyl acetate, methanol, ethanol, isopropanol, dimethylformamide, dichloromethane or diethylene glycol monoethyl ether (Transcutol). These solvents can be supplemented by various excipients according to the nature of the desired phases, such as C9-C10 caprylic/capric triglyceride (Estasan or Miglyol 812), oleic acid or propylene glycol.
An organic solvent can be selected from the group consisting of acetone, benzyl alcohol, butyl diglycol, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, dipropylene glycol monomethyl ether, propylene glycol, diethylene glycol monoethyl ether, ethylene glycol, and a mixture of at least two of these solvents.
Mention may in particular be made, as crystallization inhibitor which can be used in the invention, of:
polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and of vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates and others,
anionic surfactants, such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; sodium abietate; alkyl sulphates, in particular sodium lauryl sulphate and sodium cetyl sulphate; sodium dodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fatty acids, in particular those derived from coconut oil,
cationic surfactants, such as water-soluble quaternary ammonium salts of formula N+Rxe2x80x2Rxe2x80x3Rxe2x80x2xe2x80x3Rxe2x80x3xe2x80x3 Yxe2x88x92, in which the R radicals are optionally hydroxylated hydrocarbon radicals and Yxe2x88x92 is an anion of a strong acid, such as halide, sulphate and sulphonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants which can be used,
amine salts of formula N30 Rxe2x80x2Rxe2x80x3Rxe2x80x2xe2x80x3, in which the R radicals are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one of the cationic surfactants which can be used,
non-ionic surfactants, such as optionally polyoxyethylenated esters of sorbitan, in particular Polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxide and of propylene oxide,
amphoteric surfactants, such as substituted lauryl compounds of betaine,
or preferably a mixture of at least two of them.
In a particularly preferred way, use will be made of a crystallization inhibitor pair, namely the combination of a film-forming agent of polymeric type and of a surface-active agent. These agents will be selected in particular from the compounds mentioned above as crystallization inhibitor.
Mention may be made, among the particularly advantageous film-forming agents of polymeric type, of:
the various grades of polyvinylpyrrolidone,
polyvinyl alcohols, and
copolymers of vinyl acetate and of vinylpyrrolidone.
For the surface-active agents, mention will very particularly be made of non-ionic surfactants, preferably polyoxyethylenated esters of sorbitan and in particular the various grades of Polysorbate, for example Polysorbate 80.
The film-forming agent and the surface-active agent can in particular be incorporated in similar or identical amounts within the limit of the total amounts of crystallization inhibitor mentioned elsewhere.
The pair thus constituted secures, in a noteworthy way, the objectives of absence of crystallization on the coat and of maintenance of the cosmetic appearance of the fur, that is to say without a tendency towards sticking or towards a sticky appearance, despite the high concentration of active material.
Mention may in particular be made, as cosolvent which is a promoter of drying, of: absolute ethanol, isopropanol (2-propanol) or methanol.
Use is in particular made, as antioxidizing agent, of conventional agents, such as: butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulphite, propyl gallate, sodium thiosulphate or a mixture of not more than two of them.
These concentrated compositions are generally prepared by simple mixing of the constituents as defined above; advantageously, the starting point is to mix the active material in the main solvent and then the other ingredients or adjuvants are added.
The volume applied can be of the order of 0.3 to 1 ml, preferably of the order of 0.5 ml, for cats and of the order of 0.3 to 3 ml for dogs, depending on the weight of the animal.
Microemulsions are also well suited to intermittent topical application.
Microemulsions are quaternary systems comprising an aqueous phase, an oily phase, a surfactant and a cosurfactant. They are translucent and isotropic liquids.
They are composed of stable dispersions of microdroplets of the aqueous phase in the oily phase or conversely of microdroplets of the oily phase in the aqueous phase. The size of these microdroplets is less than 200 nm (1000 to 100,000 nm for emulsions). The interfacial film is composed of an alternation of surface-active (SA) and co-surface-active (Co-SA) molecules which, by lowering the interfacial tension, allows the microemulsion to be formed spontaneously.
The oily phase can in particular be formed from mineral or vegetable oils, from unsaturated polyglycosylated glycerides or from triglycerides, or alternatively from mixtures of such compounds. It will preferably concern triglycerides and more particularly medium-chain triglycerides, for example C8-C10 caprylic/capric triglyceride. The oily phase will represent in particular from 2 to 15%, more particularly from 7 to 10%, preferably from 8 to 9%, V/V of the microemulsion.
The aqueous phase can in particular be selected from water or glycol derivatives in general, such as propylene glycol, glycol ethers, polyethylene glycols or glycerol. Preference will be given to propylene glycol, diethylene glycol monoethyl ether and dipropylene glycol monoethyl ether.
It will amount to a proportion in particular of 1 to 4% V/V in the microemulsion.
The surfactant will preferably be selected from diethylene glycol monoethyl ether, dipropylene glycol monomethyl ether, polyglycolysed C8-C10 glycerides or polyglyceryl-6 dioleate.
The cosurfactant will preferably be selected from short-chain alcohols, such as ethanol and propanol. It can also be one of the compounds mentioned as surfactant.
Some compounds are common to the three components: aqueous phase, surfactant and cosurfactant. However, it will be arranged to use different compounds for each component of the same formulation.
The cosurfactant to surfactant ratio will preferably be from 1/7 to 1/2. There will preferably be from 25 to 75% V/V of surfactant and from 10 to 55% V/V of cosurfactant in the microemulsion.
One or more crystallization inhibitors defined above can advantageously be added to the microemulsion. It will preferably be a crystallization inhibitor pair as described above, in particular Polysorbate 80 and polyvidone (polyvinylpyrrolidone), such as Kollidon 17 PF from BASF, Germany. The amounts will be the same as for the cutaneous spot-on solution, for example approximately 5% N/V of each of the compounds of the crystallization inhibitor pair.
The active compounds (A) and (B) can be present in the proportions shown for the cutaneous solution of spot-on type.
For administration by the oral route, use can be made of all the usual formulations, such as solutions, microemulsions, emulsions or suspensions, to be mixed with foods, or appetent formulations, such as pellets or tablets, powders, hard gelatin capsules or others.
The preferred compound (A) is, in the case of a composition for oral absorption, the derivative of formula (II):
For parenteral administration, preference will be given to a formulation in solution injectable, preferably, by the subcutaneous route, preferably with an oily adjuvant, for example a mixture of organic solvents and of vegetable oils.
The composition for parenteral administration can also be produced in particulate form, in particular in the form of nanoparticles and nanocapsules, microparticles, microcapsules or liposomes or alternatively in the form of implants. These particles can be produced, in particular, from polylactic or polylactic-glycolic acid polymer, for example in water or in a vegetable oil or a medium-chain triglyceride.
The compositions according to the invention have proved to be extremely effective in the very long lasting treatment of fleas of mammals and in particular of small mammals such as dogs and cats.
They also exhibit a degree of effectiveness against other parasitic insects and in particular ticks and flies and it is understood that it is possible to extend the application of the composition according to the invention to the treatment of ectoparasites, indeed of endoparasites, for which parasites the composition proves to exhibit a true usefulness capable of being obtained in practice, according to the criteria of the veterinary art, in particular against major endoparasites, in particular the dirofilariasis parasite and/or roundworms.
Thus, for example, a composition based on fipronil and on milbemectin can also be used, in particular against filariae and roundworms.
Another subject of the invention is the use of at least one compound of formula (I) and of at least one compound of type (B), as defined above, in the preparation of a composition as defined above.
Other advantages and characteristics of the invention will become apparent on reading the following description, given by way of non-limiting example.


To reduce the energy needed to unload and reload ladders from and onto the roof of utility vehicles, a ladder rack assembly has been devised which minimizes the movement of the center of gravity of the ladder load when going between a first position atop the vehicle to a second position along a vertical side of the vehicle. To achieve this advantage, the rear and front four-bar linkages are driven by a rotatable drive shaft such that a ladder support member of the front four-bar linkage is at a higher elevation than the ladder support member of the rear four-bar linkage when the two are aligned with the side of the vehicle.

I. Field of the Invention
This invention relates generally to vehicle mounted roof racks for transporting loads, and more particularly to a movable ladder rack that can be used to readily raise and lower a ladder onto and from the roof of a motor vehicle, such as a truck or van.
II. Discussion of the Prior Art
In my earlier U.S. Pat. Nos. 5,297,912, 6,092,972, 6,099,231 and in my currently pending application Ser. No. 09/758,729, filed Jan. 11, 2001, the teachings of which are hereby incorporated by reference, there are described different designs of truck or van-mounted ladder racks that facilitate the loading and unloading of one or more ladders with respect to the vehicle""s roof. These devices comprise front and rear four-bar linkage assemblies that include a stationary member which is adapted to rigidly affixed to the vehicle""s roof or to cross-members that clamp to the vehicle""s roof, and a ladder support member pivotally joined to the stationary member by a pair of transversely spaced links. A drive shaft is journaled for rotation in the stationary members of the front and rear four-bar linkage assemblies and is rigidly affixed to one of the pair of links of the front and rear four-bar linkage assemblies. Thus, when the drive shaft is rotated, either manually with a crank or automatically by means of a motor, ladders resting on the front and rear ladder support members are lifted and rotated from a position parallel to the vehicle""s roof to a position parallel to the vehicle""s side during an unloading maneuver. When reloading ladders onto the vehicle, the drive shaft is rotated in an opposite direction to raise and rotate the ladder load onto the vehicle""s roof.
In my earlier designs described in the aforereferenced patents, the four-bar linkages have been designed such that the top and foot of the ladders remain generally horizontal throughout their range of motion as the drive shaft is rotated. This design featured significant lowering of the ladder""s center of gravity, thus requiring still significant forces.
While the earlier designs reflected in the above-listed patents greatly simplify the loading and unloading of heavy extension ladders onto and from transport vehicles, it is deemed advantageous to provide a rotatable ladder rack assembly for a motor vehicle that requires less force to be applied during the unloading and reloading operations.
In accordance with the present invention, I have redesigned the frontmost four-bar linkage assembly so that as a ladder load is transferred from the vehicle""s roof to its position alongside the vehicle, the front or top end of the ladder is at an increased elevation relative to its foot such that the ladder is inclined relative to the horizontal. The height drop from a roof top position to the lowered disposition is reduced and, therefore, requires less force to operate. With the inclined position, the ladder feet are lowered further and the user is then better able to grasp the ladder at its foot end while the top or front end thereof is still engaged and supported by the front ladder support member. The foot of the ladder can be lifted free of the rear ladder support member and lowered to the ground. Because the top end of the ladder is still being supported by the front ladder support member, less force is required to accomplish the maneuver.
The user may then move to a location along the side of the vehicle to the approximate center of mass of the ladder, whereupon the front portion of the ladder is lifted to disengage it from the front ladder support member and the ladder can be carried to the worksite.


Methods and apparatuses for reduction of Read Disturb errors in a NAND FLASH memory system comprise a controller configured to organize FLASH memory devices into blocks, each block having a plurality of pages, and each page defining an individually addressable physical memory location. The controller is further configured to accumulate a Block READ Count corresponding to the number of times any pages in a first block of pages have been read since the first block was last erased. Once the READ count reaches a predetermined number, the controller responds to subsequent READ requests for pages within the first block by moving data associated with a requested page to a page in a second, different block without moving data associated with other pages in the first block, and modifying a logical-to-physical translation table to associate the moved data with the physical address of the page in the second block.

1. Field of the Invention:
This disclosure relates generally to methods and apparatus for reducing or eliminating certain data errors associated with FLASH memory devices utilizing a NAND architecture.
2. Description of the Related Art:
In general, a FLASH memory device is one type of memory device that can retain stored digital data, even when no power is being provided to the device.
Typical FLASH memory devices are formed from a number of individual storage elements, where each storage element comprises a memory cell that includes a transistor and a charge storage area. In many FLASH devices, the charge storage area comprises either a floating gate or a charge-trapping region. The presence or absence of an electric charge in the charge storage area of a cell can be used to store a logic "1" or a logic "0" in the cell.
For many FLASH memory devices, the presence of a relatively large electrical charge on the cell corresponds to a logic "1" and the absence of such a charge corresponds to a logic "0." It should be noted, however, that this assignment of a logic "1" to the condition where charge is present is somewhat arbitrary and the presence of a charge could be used to indicate a logic "0" and the absence of charge as a logic "1." For purposes of this disclosure, however, it will be presumed that the presence of charge corresponds to a logic "1" condition and the absence of charge to a logic "0."
The previous discussion of flash memory suggested the ability to store one of two logical states within a flash memory cell, a logical "0" or a logical "1." While this is true of SLC (single-level cell) flash memory, MLC (multi-level cell) flash memory provides the capability to store more than two logical states. MLC devices currently available at the time of this writing can store up to eight distinct logical states, corresponding to various different quantities of charge residing in a cell's charge storage area. While much of the discussion herein is centered on SLC flash memory, the read disturbance phenomenon and the mechanisms leading to it apply to all NAND FLASH memory, MLC as well as SLC. For simplicity, this discussion focuses primarily on SLC memory.
The presence or absence of the charge in the associated storage cell may be stored and/or detected in a variety of ways. Certain FLASH memory devices utilize a NAND architecture ("NAND FLASH memory devices") to store and read the digital data stored within the memory cells of the device. A NAND architecture is one in which several FLASH memory cells are connected to one another in series.
FIG. 1 generally illustrates a highly simplified NAND FLASH memory 100. FIG. 1 will be used to describe certain relevant aspects of the general operation of a NAND FLASH memory device.
In the example of FIG. 1, the NAND FLASH memory 100 includes nine memory cells 110a-110i, arranged in a three-by-three array.
For purposes of illustration, cells using a floating gate construction are used. In a floating gate transistor cell, it is common to identify a floating gate and a control gate, although other names may be used to describe these elements. The floating gate is generally electrically isolated from other transistor structures and is used to store electrical charge injected into it through a programming operation. The control gate is use to control the reading, writing (programming) and erasing of cells. Throughout this document, the term "gate," without any modifiers, is understood to refer to the control gate.
From top to bottom, the cells are coupled together in series to form what is sometimes called a bit line. As one example, cells 110a, 110d and 110g are coupled together in series to form a bit line. In the simplified illustrated example, a pull-up resistor is provided for each bit line. In an actual embodiment addressing circuitry, control transistors and other structures would be included. These elements are not illustrated in FIG. 1, which provides a highly simplified representation of a NAND FLASH memory.
Across the structure, the gates of cells sharing the same relative location are connected to one another. Thus, the gates of cells 110d, 110e, and 110f are coupled to one another. The coupling of these gates of the cell is such that all of the cells sharing a common gate line are typically read from or written to at the same time.
Typically, the memory cells within a NAND FLASH memory device are arranged into "Pages" and "Blocks." A Page is a group of data bits that are accessed, internal to the memory, generally in a parallel manner at the same time. Thus, in the example of FIG. 1, the cells 110d, 110e, and 110f could be considered to be a Page, in the sense that the gates of the three cells are coupled to one another such that the data within the three cells can be accessed at the same time. Like FIG. 1, most NAND FLASH memory devices perform read or write operations on a Page-by-Page basis.
While some flash memory devices support operations on "partial pages," these partial page operations are generally less efficient than their complete page counterparts. The underlying physical mechanisms associated with these partial page operations are roughly identical to their complete page counterparts, except for the fact that they operate on a subset of the overall FLASH memory page. As such, even though such pages may be referred to in some situations as "partial pages" because they are accessed in a parallel manner at the same time, they are considered "pages" for purposes of this disclosure. As noted above, as used herein a "Page" refers to a group of data bits within a given memory device that are accessed at the same time.
In a NAND FLASH memory, the Pages of data within the memory may be arranged so that they are associated with one another in one or more "Blocks" of data, typically as a result of the physical layout of the specific FLASH device at issue. In the example of FIG. 1, the grouping of the nine depicted memory cells 110a-110i could be considered to be a "Block" of data.
The exemplary device of FIG. 1 is highly simplified for purposes of discussion. Most actual FLASH memory devices will contain a substantially larger number of Pages and memory cells. For example, in current FLASH memory devices, the sizes of the Pages can vary from 512, 2,048, 4,096, or 8,192 bytes and the Blocks for a given FLASH device can vary in size, for example, from 32 Pages of 512 Bytes per Page for a 16 KB Block size; to 64 Pages of 2,048 bytes for a 128 KB Block size; to 64 Pages of 4,096 bytes for a 256 KB Block size; to 128 Pages of 4,096 bytes for a 512 KB Block size. The invention described herein does not presume a particular page size or architecture, beyond the architectural features leading to the read disturbance phenomenon described below.
In general, there are a number of operations that are performed within FLASH memory devices. The most common such operations are the ERASE, PROGRAM, and READ operations. During an ERASE operation, the logical bit stored in a given memory cell is set to a logical "0," which—in the example of discussion—corresponds to the absence of a substantial electric charge in the memory cell's charge storage area. The ERASE operation is typically performed by taking the voltage of the gates for the various storage devices within a Block, and other voltages that impact the amount of charge in the charge storage regions of the storage cells, to such levels that the electrical charge stored on the floating gates of the devices (or the charge trapping area) is reduced to zero or a low amount.
Because of the physical nature of most NAND FLASH memory devices, the ERASE operation is performed on a "Block" basis. Thus, anytime one desires to erase the data in a given memory cell within a given Block, one will also erase the data in all other memory cells within that Block.
After a Block of FLASH memory is erased, the individual data within the device can be programmed. The PROGRAM operation involves the writing of data into a memory cell that has been previously ERASED. When one desires to write a logical "1" into a previously erased FLASH memory cell—which would have no or low stored charge and therefore be at a logic "0" level—one may use the PROGRAM operation to inject charge onto the floating gates of the erased cells (or into their charge trapping regions) at levels sufficient to alter their threshold voltages. The threshold voltage reflects, in a general sense, the value of control gate voltage required to turn the transistor on (conducting) or off (non-conducting). The PROGRAM operation is typically performed by driving the control gate voltage level of the cell to be programmed to a sufficiently high level, while maintaining the voltage levels for the other terminals of the transistor in the cell at levels sufficient for charge injection to occur. When one desires to write a logical "0" into a previously erased FLASH memory cell, the PROGRAM operation involves the maintenance of the state of the cell established during the ERASE operation. The PROGRAM operation is performed in such a way that all of the bits being programmed (typically all of the bits within a single Page) will be programmed to have the desired "1" or "0" levels at the same time.
Once Pages of a FLASH memory device are programmed, they can be read. In general, the READ operation involves the reading of the logical data stored in the memory cells of a Page of FLASH data. Referring to FIG. 1, the READ operation would involve the application of a first voltage level (such as a high voltage level) to the top portion of each bit line within the Block, the application of a second voltage level (such as a low voltage level or zero) to the bottom of each bit line within the Block, the application of a third voltage to the control gates of all of the memory cells within the Block that reside in Pages that are not being read, and the application of a fourth voltage to the control gates of all of the memory cells within the Block that reside in the Page that is being read. The voltage applied to the gates of the unread cells is sufficient in magnitude to render the corresponding transistors conductive, regardless of their programming state, yet smaller in magnitude than the voltage supplied to a control gate in order to program a cell. The voltage applied to the gates of the cells being read is such that their transistors will be rendered either conductive or non-conductive, depending upon their programming state. Since all unread cells within a bit line are rendered conductive, while the cells being read may be conductive or non-conductive, the voltage at the top of each bit line may be pulled low (conductive) or remain high (non-conductive). The voltage level at the top of a bit line, therefore, gives an indication of the status (programmed or unprogrammed) of the one cell being read within that bit line.
For typical NAND flash memory devices in use at the time of this writing, the accumulated charge in a programmed cell will mandate a higher control gate voltage for the corresponding transistor to become conductive. Hence, a programmed cell will be non-conductive during a read operation and the top of the corresponding bit line will remain at a sufficiently high voltage to detect the fact that the cell being read has been programmed. Correspondingly, an unprogrammed cell will be conductive during a read operation and the top of the corresponding bit line will be pulled to a sufficiently low voltage to detect the fact that the cell being read has not been programmed. Taken as a whole, the voltage values at the top of the bit lines yield the programming status of all cells within a page being read.
As the above shows, for the exemplary NAND FLASH memory devices, the performance of a READ operation on one or more storage cell tends to impose elevated voltage stresses on the other unread cells within the same Block. This stress arises from the application of an elevated voltage to the control gates of the unread cells, sufficient in magnitude to render the unread cells conductive, regardless of their programming states. Over time, repeated application of this higher magnitude voltage to the gates of a given cell in a FLASH memory can result in charge migrating onto the floating gate of the cell or into its charge-trapping region. Over time, this charge can accumulate to the point that the amount of charge on a cell that was previously reflective of a logic "0" (or low or no charge state) can rise to a level where the cell is weakly programmed and, when subject to a READ operation, will erroneously produce a reading reflecting the storage of a logic "1" (higher charge state). This weak programming resulting from the READ operation cannot always be predicted accurately and can result in a number of bits in memory cells not associated with the cells being read becoming corrupted such that one could no longer determine whether the originally stored data bit was a "1" or a "0." Because the errors described above are induced by the disturbances created by the READ operation, they are known as "Read Disturb" errors.
While the preceding paragraphs describe operations and mechanisms generally encountered with SLC NAND FLASH memory, similar operations and mechanisms also pertain to MLC NAND FLASH memory. In such NAND FLASH memory devices, the control gates of unread cells are driven with a voltage that is guaranteed to render the unread cells conductive and that also leads to read disturbance in the unread cells. In such devices, the control gates of cells being read are driven with a different voltage, one that is such that the conductivity of the cell being read will differ based upon the quantity of charge stored in the cells' charge storage area or areas. MLC NAND FLASH memory is generally much more susceptible to read disturb errors than its SLC counterpart.
Read Disturb errors are a recognized condition of NAND FLASH memories. The most common approach for addressing the issue of Read Disturb errors in NAND FLASH memories is to utilize one or more error correction and checking ("ECC") techniques. While there are a number of different ECC techniques, ECC generally involves the utilization of one or more code bits (in addition to the original stored data bits) to allow one to determine and, in some instances correct, errors that may occur in data associated with the specific ECC code bit(s). ECC is typically implemented on a Page level and typically with respect to Pages that include one or more storage elements and, therefore, store data items comprising multiple bits. Alternatively, the quantity of data associated with a group of ECC code bits may be a subset of the overall Page, allowing multiple data sets within the same Page to be checked and/or corrected independently of one another. If one of the data bits associated with a particular group of ECC code bits becomes corrupted, the ECC bits can be used to detect the corrupted bit and possibly reconstruct it.
There are limitations associated with the use of ECC to address Read Disturb errors in NAND FLASH memory. For example, most ECC techniques are capable of identifying and addressing errors resulting from a disturbance of only one, or a small number of, the bits in the data item to which the ECC is applied. If more than one of the bits in the data item is disturbed, most ECC techniques will not be able to reconstruct the original data item. Moreover, if a large number of bits in a data item are errantly disturbed, certain ECC techniques will be incapable of identifying the existence of an error. Compounding this issue is the fact that Read Disturb errors occur in Pages that are not being read, while data and ECC bits must be read to perform checking and correction. Hence, the number of errors in a disturbed page can grow from a correctable number to an uncorrectable number without any warning that the seriousness of the induced errors is increasing. Thus, while ECC techniques may be widely utilized, they are not always effective.
Another approach used to address Read Disturb errors in NAND FLASH memory devices is to maintain a count of the number of times a given Block is accessed after an ERASE operation has occurred and to move the data in the Block to a new location and then perform an ERASE operation on the original Block if the READ count for the Block exceeds a pre-established number. While this approach can potentially avoid certain Read Disturb errors, it can limit the performance of a device or system utilizing this technique since the movement of the Block of data imposes burdens on the device or system in terms of overhead, speed, efficiency, power and other aspects that can degrade the overall performance of the device or system. Not only does it take an appreciable amount of overhead in terms of processing power and time to move the entire Block of data, the ERASE operation for the original Block can be time consuming. For systems where high speed read operations are desired, such burdens are undesirable and inefficient.
Another issue associated with the approach of maintaining a count and moving and erasing a data Block when the READ count for the Block is exceeded is that it imposes upon the system a relatively large number of ERASE operations. In particular, because the entire contents of a Block are moved and erased each time the predetermined count for that Block is exceeded, the processing of the data in a given Block that includes multiple, frequently accessed Pages, will require a large number of ERASE operations over the lifetime of the product. Because FLASH memory devices do not have unlimited lifetimes and because a given FLASH memory cell is subject to failure upon the occurrence of a given number of ERASE operations that will vary from manufacturer to manufacturer and from device to device, the described system tends to shorten the overall useful life of the devices within a FLASH memory system.
Accordingly, what is needed is a more effective and efficient way to reduce Read Disturb errors in NAND FLASH memories.

Efficient reduction of read disturb errors in NAND FLASH memory


The present invention relates to a specific phenylboronic acid compound having anti-cancer, anti-inflammatory, and anti-microbial activity, in addition to a pharmaceutical composition comprising the same. The present invention also discloses a process for preparing said compound. The compound is represented by the formula (I):

Cancer is one of the main causes of death in the world. Although significant efforts have been made to find new approaches for treating cancer, the primary treatment options remain surgery, chemotherapy and radiation therapy, either alone or in combination. Surgery and radiation therapy, however, are generally useful only for defined types of cancer. Chemotherapy is the method that is generally useful in treating patients with metastatic cancer or diffuse cancers, such as leukemias. Although chemotherapy can provide a therapeutic benefit, it often fails to result in cure of the disease due to the patient's cancer cells becoming resistant to the chemotherapeutic agent. Due, in part, to the likelihood of cancer cells becoming resistant to a chemotherapeutic agent, such agents are commonly used in combination to treat patients.
Similarly, infectious diseases caused by microorganisms are becoming increasingly difficult to treat and cure. Particularly, more and more microorganisms are developing resistance to current antimicrobial agents.
Furthermore, a growing number of diseases are classified as inflammatory diseases. Such diseases include conditions such as asthma. These diseases continue to affect larger and larger numbers of people worldwide, despite new therapies and medical advances.
Proteasome inhibitors (PIs) are a proven class of therapeutic agents in the treatment of cancers including multiple myeloma (MM), Waldenstr öm macroglobulinemia, and mantle cell lymphoma. These proteasome inhibitors have also showed promise in treating autoimmune diseases in animal models. For example, studies in mice bearing human skin grafts found a reduction in the size of lesions from psoriasis after treatment with a proteasome inhibitor. These inhibitors also showed positive effects in rodent models of asthma. In addition proteasorne inhibitors have shown promising results in treating microbial infections.
Proteasome inhibitors (PIs) are chemically classified into boronates, beta-lactams, epoxyketones, and peptide amides. Boronic acid and ester compounds hold particular promise as inhibitors of the proteasome and display a variety of pharmaceutically useful biological activities.


A liquid crystal display device displaying a three-dimensional image using a left-eye image and a right-eye image includes a liquid crystal panel including first and second substrates that are spaced apart from each other; a patterned retarder disposed over the liquid crystal panel; and an optical member disposed under the liquid crystal panel, wherein the optical member includes at least one inclined plane corresponding to each pixel region of the liquid crystal panel.

1. Field of the Invention
The disclosure relates to a liquid crystal display device, and more particularly, to a liquid crystal display device including a patterned retarder layer.
2. Discussion of the Related Art
Recently, with the rapid development of information technologies, various display devices for displaying images have been proposed. Liquid crystal display devices, which are able to display not only two-dimensional images but also three-dimensional images, have been developed.
Human beings perceive depth and a three-dimensional effect due to psychological and memorial factors in addition to a binocular disparity from a separation distance of eyes.
As one of the methods for displaying three-dimensional images using these factors, a stereoscopic type uses a physiological factor of both eyes to perceive the three-dimensional effect.
The stereoscopic type uses stereography in which, when two-dimensional linking images including parallax information are provided to left- and right-eyes spaced apart from each other with a distance of about 65 mm, the brain produces space information about the front and the rear of the screen during merging them and thus perceives the three-dimensional effect.
The stereoscopic type may be classified into a glasses type, where the user wears specific glasses, and a glasses-free type, where a parallax barrier or a lens array such as lenticular or integral is used at a display side, depending on a position in which a substantial three-dimensional effect is produced.
The glasses type has wider viewing angles and causes less dizziness than the glasses-free type. In addition, the glasses type can be manufactured with relatively low costs.
The glasses type may be classified into a shutter glasses-type and a polarization glasses-type.
In the shutter glasses-type, left- and right-eye images are alternately displayed in a screen, sequential opening and closing timing of a left shutter and a right-shutter of the shutter glasses is accorded with alternation time of the left- and right-eye images, and the respective images are separately perceived by the left eye and the right eye, thereby producing the three-dimensional effect.
In the shutter glasses-type, the alternation timing of the images may not be controlled to be completely accorded. Thus, flicker may occur, and this may cause fatigue such as dizziness while watching the images.
In the polarization glasses-type, pixels of a screen are divided into two parts by columns, rows or pixels, left- and right-eye images are displayed in different polarization directions, the left-glass and the right-glass of the polarization glasses have different polarization directions, and the respective images are separately perceived by the left eye and the right eye, thereby producing the three-dimensional effect.
The polarization glasses-type does not have factors of causing flicker, and fatigue is less caused while watching the images.
In addition, since the polarization glasses-type can use a polarization dividing optical means, which is patterned and is able to divide polarized light, such as a patterned retarder, for example, on a front surface of a display panel, the viewer can wear polarization glasses, which are very cheaper than the shutter glasses, to watch it. Accordingly, costs of the polarization glasses-type are relatively low.
Hereinafter, a polarization glasses-type liquid crystal display (LCD) device of the related art will be described with reference to accompanying drawings.
FIG. 1 is a cross-sectional view of schematically illustrating a polarization glasses-type LCD device according to the related art and explains a three dimensional (3D) crosstalk, FIG. 2 is a cross-sectional view of schematically illustrating a polarization glasses-type LCD device including a black stripe to remove a 3D crosstalk according to the related art.
In FIG. 1, the polarization glasses-type LCD device 1 according to the related art includes a first substrate 10, a second substrate 20 and a third substrate 50. Gate lines (not shown), data lines (not shown) and thin film transistors (not shown) are formed on the first substrate. The second substrate 20 includes left-eye horizontal pixel lines HI, right-eye horizontal pixel lines Hr and black matrix BM. A patterned retarder 52 is formed on the third substrate 50 by applying reactive mesogen.
A liquid crystal panel 30 is formed by attaching the first substrate 10 and the second substrate 20 and produces images.
A first polarizer (not shown) is attached at a lower surface of the first substrate 10, and a second polarizer 40 is attached at an upper surface of the second substrate 20.
Here, the first polarizer (not shown) and the second polarizer 40 transmit linearly polarized light, which is parallel to respective transmission axes. The transmission axis of the first polarizer (not shown) is perpendicular to the transmission axis of the second polarizer 40.
The patterned retarder 52 is attached at an upper surface of second polarizer 40. The patterned retarder 52 includes left-eye retarders RI and right-eye retarders Rr.
At up and down viewing angles of the polarization glasses-type LCD device, as shown in a portion A, some of the left-eye image II′ displayed by the left-eye horizontal pixel lines HI passes through the right-eye retarder Rr of the patterned retarder 52 and is right-circularly polarized differently from front or left and right viewing angles.
Then, the some of the left-eye image II′ circularly polarized passes through the right-eye lens of the polarization glasses 70 together with the right-eye image Ir circularly polarized and is transmitted to the right-eye of the viewer.
Therefore, 3D crosstalk occurs due to the interference between the right-eye image Ir and the some of the left-eye image II′, and the up and down viewing angles in the 3D mode are decreased.
Here, the 3D crosstalk means that recognition of the clear 3D image is disturbed by providing the left-eye image II to the right-eye or providing the right-eye image Ir to the left-eye. The resolution of the 3D image increases and tiredness of the eyes decreases as the 3D crosstalk gets small.
To prevent occurrence of the 3D crosstalk, as shown in FIG. 2, the polarization glasses-type liquid crystal display device 11 of the related art includes a black stripe BS over the patterned retarder 52. The black stripe BS is disposed between the left-eye retarder RI and the right-eye retarder Rr.
The some of the left-eye image II′, which passes through the left-eye horizontal pixel line HI of the liquid crystal panel 30 and goes into the right-eye retarder Rr of the patterned retarder, is blocked by the black stripe BS.
As a result, only the right-eye image Ir is circularly polarized and is transmitted to the right-eye of the viewer through the right-eye lens of the polarization glasses 70. The 3D crosstalk due to the interference between the right-eye image Ir and the some of the left-eye image II′ is prevented.
However, the non-display area of the liquid crystal panel 30 is increased due to the black stripe BS. The aperture ratio and the brightness are decreased.
In addition, the polarization glasses-type liquid crystal display device 1 or 11 uses a glass substrate for the third substrate 50 on which the patterned retarder 52 is formed.
The glass substrate has advantages of superior surface flatness, high transparency, and uniform optical properties without birefringence. Moreover, an alignment layer or reactive mesogens can be formed on the glass substrate with a uniform thickness by a spin coating method.
On the other hand, the glass substrate is expensive, is fragile during processes and causes low yields and productivity due to long manufacturing time.

Liquid crystal display device having particular optical member


A mail processing system in which an estimated group of mail pieces is sorted in a mailroom area and delivered to a preset number of mailboxes is provided. The mail processing system includes a memory for storing information related to sorting and delivery and a processor that uses the sorting and delivery related information to determine, (i) an amount of time required to sort the estimated group of mail pieces, and (ii) an amount of time required to deliver the estimated group of mail pieces to the mail boxes. Operation of the mailroom may be evaluated by comparing a sum of the amount of time required to sort the estimated group of mail pieces and the amount of time required to deliver the estimated group of mail pieces to the preset number of mail boxes with an amount of time available for both sorting the estimated group of mail pieces and delivering the mail pieces to the preset number of mail boxes.

The disclosed embodiments relate to a mail processing system in which the functionality of a mailroom is assessed to evaluate whether an estimated group of mail pieces can be delivered to a preset number of mailboxes in a timely manner.
A typical business entity, such as a corporation, may process its hardcopy mail by way of a two tiered process which mail pieces are sorted in accordance with a selected criterion, and then delivered to a plurality of mail sites, with each site or "stop," including one or more mailboxes. For many conventional mailroom operations, the United States Postal Service (USPS) provides the largest volume of incoming mail to be processed. Typical tasks may include receiving one or more mail tubs containing unsorted mail, performing a rough sort followed by a fine sort. Pursuant to the sorting process, mail may be put into alphabetical order (by name) to facilitate its delivery to the above-mentioned mail stops or similar delivery area.
In operation, a typical mailroom will assign associates or mail operators to perform the process of sorting and delivering regular USPS mail (such as first class and third class mail). In one known approach of operation, the sorting and delivery are performed serially. In a serial approach, one or more tubs of mail are delivered to a sorting area of the mailroom at a fixed time, such as 9:00 AM. A first group of one or more associates then performs a rough sort, in accordance with the selected criteria (e.g., by mail class and/or alphabetical order) to suitably group the mail for delivery. A second group of one or more associates (which may be the same as the first group of associates) then transports the sorted mail to one or more mail stops for placement of the same into individual slots or mailboxes. In turn, mail lacking sufficient information, such as an address, is returned to a sorting area.
It is understood that many mailrooms, by agreement, are obligated to have the USPS mail delivered by a selected time, e.g., have the USPS mail in the relevant mailboxes by 2:00 PM. Assuming the amount of incoming USPS mail received is constant on a day-by-day basis, then the above-described serial approach may be well suited for its intended purpose. Referring to FIGS. 1A and 1B, representing, in combination, an Individual and Moving Range chart showing fluctuating demand of incoming regular USPS mail in an exemplary mailroom is provided. As illustrated by the chart, over a period of over 20 days, the amount of incoming mail can vary considerably relative to a mean.
For the situation illustrated by FIG. 1, when volume is relatively high, late delivery can occur unless, for instance, either (a) more than the usual number of associates supports the sorting process in the serial approach, or (b) some delivery occurs in parallel with sorting. In either (a) or (b), substantial additional labor cost may be incurred. Moreover, considerable waste can be incurred in (b) unless the sorting process is suitably synchronized with the delivery process. For instance, if the allocation of associates to one of the processes is improper, then labor cost will inevitably be higher than necessary. It would be desirable to provide an improved mail processing system permitting proper structuring of the delivery and sorting processes.
In accordance with one aspect of the disclosed embodiments, there is provided a mail processing system in which an estimated group of mail pieces is sorted in a mailroom area and delivered to a preset number of mailboxes. The mail processing system includes: (a) a memory for storing information related to sorting and delivery, the sorting and delivery related information including (i) an estimate of a total quantity of mail pieces to be received at the mailroom, (ii) a sorting rate, (iii) an estimate of individual quantities of mail pieces to be delivered respectively to of the preset number of mail boxes, (iv) a rate of placement of the mail pieces in the preset number of mail boxes, and (v) a time required to travel between the mailroom and the preset number of mail boxes; (b) a processor, said processor using the sorting and delivery related information to determine, (i) an amount of time required to sort the estimated group of mail pieces, and (ii) an amount of time required to deliver the estimated group of mail pieces to the mail boxes; and (c) wherein operation of the mailroom is evaluated by comparing a sum of the amount of time required to sort the estimated group of mail pieces and the amount of time required to deliver the estimated group of mail pieces to the preset number of mail boxes with an amount of time available for both sorting the estimated group of mail pieces and delivering the mail pieces to the preset number of mail boxes.
In accordance with another aspect of the disclosed embodiments, there is provided a mail processing system in which an estimated group of mail pieces is sorted and delivered to a preset number of mailboxes. The mail processing system includes as well as a mailroom evaluation application running on the processor. The mailroom evaluation application includes a time control evaluation for determining a total time required to both sort the estimated group of mail pieces and deliver the estimated group of mail pieces to the preset number of mailboxes, said time control evaluation including a set of sorting and delivery related variables. In response to assigning respective values to the set of sorting and delivery variables, the processor compares the total time determined with the mailroom evaluation application with a pre-selected time availability value to determine whether the estimated group of mail pieces can be delivered to the preset number of mailboxes in a timely manner.
In accordance with yet another aspect of the disclosed embodiments, there is provided a method for processing mail in which an estimated group of mail pieces is sorted and delivered to a preset number of mailboxes. The method includes: (a) storing sets of time-related information in a memory, the sets of time related information including, (i) a first set of information relating to an amount of time required to sort the estimated group of mail pieces, and (ii) a second set of information relating to an amount of time required to deliver the estimated group of mail pieces to the mail stops; (b) storing in a memory a value corresponding with an amount of time available for both sorting the estimated group of mail pieces and delivering the estimated group of mail pieces to the preset number mailboxes; and (c) using a processor to, (i) determine, with the first set of information, a total mail piece sorting time, (ii) determine, with the second set of information, a total mail piece delivery time, and (iii) compare a sum of the total mail piece sorting time and the total mail piece delivery time with the value corresponding with the amount of time available to determine whether operation of the mail room is within the acceptable time range.
Referring now to FIG. 2, an exemplary mail sorting/delivery system (hereinafter referred to simply as "mail system") in which the disclosed embodiments may be practiced is designated by the numeral 10. The mail system 10 includes a mailroom, designated by the numeral 12, and a plurality of mailboxes 14-i, where I=1,n. As shown, the mailboxes (each of which is represented in the form of "MBi"), are arranged in n mailbox areas. As will be appreciated, the subsystems 12 and 14-i can be separated by relatively little or considerable distance. In one example, the mailroom is in one discrete area of a corporate "campus," while the mailboxes are distributed about the campus in what are sometimes referred to as "mail stops." The mail system 10 communicates with a conventional hardcopy mail (referred to hereinafter simply as "mail") source 16 such as a local branch of the United States Postal Service, from which the mail may delivered at selected times (e.g., each morning at a selected time) by conventional means to the sorting subsystem 12. In practice, the mail is sorted in the mailroom 12 and delivered (with the aid of "associates") to the mailbox areas.
In a general approach of mail delivery, Ttotal, the total amount of time required to sort and deliver Qarr mail pieces (i.e., the number of mail pieces arriving at the mailroom at a selected time), may vary as a function of sorting time (Tsort), the total time required to place Qarr mail pieces in n mail boxes (Tpm), and the time required to travel from the mailroom to the n mailboxes pursuant to delivering the mail pieces to the mailboxes (Ttrav).
To determine Tsort, it may be assumed that Qarr can be sorted at a rate of rs mail pieces per hour. Qarr may be estimated by one of several approaches. In one example, incoming mail pieces would be provided to the mailroom 12 (FIG. 2) in tubs, with each tub being about the same size. Based on historical knowledge, the estimate of Qarr would be obtained through multiplying the typical number of mail pieces in each tub by the number of tubs.
To determine Tpm, the rate of putting sorted mail pieces into n mailboxes is denoted by a rate of rm. Additionally, the individual quantity of mail pieces delivered to each ith mailbox is denoted as qi. Accordingly, the value of Tpm can be obtained by summing the term qi/rm over the interval of 1 to n.
FIG. 3 comprises a block diagram illustrating an exemplary layout of a serial transportation network of a series of mail-stops to which batches of mail-pieces are delivered. It should be understood that each mailbox area or mail stop might include one or more mailboxes 14-i. As shown in FIG. 3, tdi (where i=1,n) is the time required to deliver the mail pieces to n number of mailboxes. Depending on the distance from the nth mailbox to the mailroom, the value of tdn+1 may or may not be trivial. In the presently described general approach, travel time is obtained by summing tdn+1 over the interval of 1 to n.
In the general approach, Ttotal may be solved with the following formula (1):
                              T          total                =                              T            sort                    +                                    ∑                              i                =                1                            n                                                                  q                i                                            r                m                                              +                                    ∑                              i                =                1                            n                                                  t                              d                                                                                i                                                                        (        1        )
The general approach can be solved with suitable software (such as an Excel application ("Excel" a trademark used by Microsoft Corp.)) running on a suitable processing platform, and can be very effective in determining if the Qarr mail pieces can be sorted and delivered within a given time constraint. In one example, a constraint would include Ttotal<Tavail where Tavail=the amount of time allotted for both sorting and delivery of the Qarr mail pieces. As is known, Tavail may be provided by a service level agreement (SLA), the SLA setting the latest time at which the mail pieces are to be placed in the n mailboxes. For those instances in which Ttotal≧Tavail, however, it has been found that modifying equation (1), to accommodate for several other variables, can be very helpful in resolving how to meet the given time constraint.
The following describes a detailed approach for determining Ttotal:
Referring to FIGS. 2 and 3, in the detailed approach, at least one mailroom associate sorts one batch of mail pieces (e.g., batch 2 (B2) while at least one other associate picks up another batch of mail pieces (e.g., batch 1 (B1) to start the delivery process. However since qi is known only after the entire sorting process is completed, it is difficult to estimate what batch size to split the overall sorting process into for simultaneous sorting and delivery. As a simplifying assumption in the detailed approach, historical data may be used to determine how a randomized batch volume is to be split or distributed across n mailboxes. The fractional allocation for the number of mail pieces typically received at an ith one of the mailboxes is denoted by βi. While, in reality, βi is stochastic random variable, it has been found that a meaningful value for Ttotal can be obtained by assuming that βi has a fixed value for each mailbox. It is understood that the value of βi for each ith mailbox can vary within a range and, for each ith mailbox, a conservative approach of setting βi at an upper spec limit is taken.
It is further assumed, in the detailed approach, that αi denotes the fraction of mail pieces that are distributed across each batch, and that the Qarr mail pieces are sorted into p batches. Also, the detailed approach accommodates for labor allocation by assuming that M_sj associates sort p batches while M_dj operators deliver sorted mail pieces to n mailboxes. If the detailed approach is to satisfy the available hours constraint (where Ttotal (also referred to as "makespan")<Tavail), it can be expressed by the following function or equation (2):
                                                        α              1                                                                  Q                arr                            /                              M_s                1                                                                r              2                                +                      Max            (                                                            ∑                                      j                    =                    2                                    p                                                                                α                    j                                                                                Q                      arr                                        /                                          M_s                      j                                                                                r                    s                                                              ,                                                ∑                                      j                    =                    1                                    p                                                                  (                                                                                ∑                                                  i                          =                          1                                                n                                                                                β                            i                                                                                (                                                                                α                                j                                                                                Q                                arr                                                                                )                                                                                M_d                            j                                                                                r                            m                                                                                +                                                                  ∑                                                  r                          =                          1                                                                          n                          +                          1                                                                                t                                                  d                                                                                i                                                                                )                                                      )                          <=                  T          avail                                    (        2        )
The following equations (3)-(8) serve as constraints with respect to the above equation (2):
                                          ∑                          j              =              1                        p                                          α            j                          =        1                            (        3        )            M—sj+M—dj≦M  (4)
where M is the maximum number of associates available for sorting/delivery0<p<pmax  (5)p=integer  (6)M_sj=integer  (7)M_dj=integer  (8)
In view of the desirability of minimizing the amount of labor required to perform sorting/delivery, and yet still satisfy the constraint of equation 2, the detailed approach contemplates use of the following labor hours function or labor requirement evaluation of equation (9):
                    H        =                                            ∑                              j                =                1                            p                                                                  α                j                                                                            Q                  arr                                /                                  r                  s                                                              +                                    ∑                              j                =                1                            p                                                  (                                                                    ∑                                          i                      =                      1                                        n                                                                                β                        i                                                                                (                                                                              α                            j                                                                                Q                            arr                                                                          )                                                                                r                      m                                                                      +                                                      M_d                    i                                                                                ∑                                              i                        =                        1                                                                    n                        +                        1                                                                                t                                              d                                                                                i                                                                                )                                                          (        9        )
Referring specifically to equation (9), the decision variables are, in one instance, the p coefficients, namely αj and the associate or operator allocation per batch, namely M_sj and M_dj. In total there will be 3p design variables subject to the constraint set (2)-(8). Pursuant to use of the detailed approach, decision variables that minimize Equation (9) can be found. Clearly, if no time constraint existed such as that specified by equation (2), then the solution that minimizes equation (9) would be p=1, α1=1 and M_d1=1. However, to satisfy the timeliness constraint of equation (2), the mail pieces or jobs are split into multiple batches and multiple operators are allocated. Solving equation (9), as proposed above, is a discrete nonlinear optimization problem. An exemplary approach for handling this type of problem follows:
Example:
Qarr=800 mail pieces
rs=800 pieces/h
rm=400 pieces/h
n=3 mail boxes
td1=td2=td3=0.1 h
td4=0.2 h
M=3 operators
β1=β2=β3=0.5
pmax=2 batches.
Tavail=2.5 h
The optimization problem is a mixed discrete integer-programming problem with integer and continuous decision variables. As contemplated in the detailed approach, the problem, as follows from the description below, may be solved in two phases.
Referring still to the Example above, the discrete operator allocation decision variable may be solved by enumeration. If there are M operators and pmax batches; then for every batch there are M(M−1) options of allocating labor to the sorting and delivery tasks. For pmax batches there are (M(M−1))p options of allocating labor. Assuming a maximum of 10 associates available for the task, and a maximum of 3 batches; then the number of options that would be enumerated are 903=729000. For each option, a linear programming problem in αj is solved to get the optimal value of αj. The value of αj that minimizes (9) is the one that can be selected.
For the Example, 36 ({(3)(2)}2) scenarios are enumerated. Some of these scenarios (with results obtained by solving equations (2)-(9)), and where a first batch is designated as B1 and a second batch is designated as B2) are listed below:
B1B2Scenario 1:M_s21M_d12H = 3.5 hMakespan = 1.719 hOptimal allocations:α1 = 0.1; α2 = 0.9Scenario 2:M_s11M_d11H = 3Makespan = 2.372Optimal allocations:α1 = 0.1; α2 = 0.9Each one of the above scenarios is feasible and capable of meeting customer requirements (where Ttotal or makespan<Tavail), but the second scenario is selected because it requires less labor. It will be appreciated that while only two scenarios were considered above, a computer could readily run through a relatively large number of scenarios (solving equations (2)-(9), as required) in a relatively short time interval. Additionally, the above description anticipates, through the use of a two step process of enumeration and linear programming, a tool for both evaluating the feasibility of a given labor allocation and of optimizing it.
Referring to the results provided immediately below, an implementation of the above-described algorithm (based on the conjunctive solution of equations (2)-(9)), using Excel solver ("Excel" is a trademark used by Microsoft Corp.) is shown. While the solver may not be particularly well suited for jointly optimizing the labor allocation and job allocation problem described above, the above approach of using enumeration coupled with a linear programming approach to solve the job allocation problem converges quickly.
ProblemvariablesQarr800rs800rm400n3tdi0.10.10.10.2M3βi0.330.330.34pmax2Tavail2.5DesignB1B2variablesαi0.10.9M_s11M_d11ConstraintsM_d + M_s <= M22Total Time < TavailSorting time0.10.9Mail stop0.0660.5940.612delivery timeper batch0.5940.5940.612Travel Time0.5Total2.372MakespanSorting labor10.10.9timeDelivery labor0.0660.0660.068time per batch0.5940.5940.612Total labor3time
The above-described solutions can be implemented in several ways to provide a tool that, among other things, allocates labor and performs scheduling policy in a mailroom environment. In one example, the tool might comprise a web-hosted solution running on a "fast" platform.
The above description relates to, several approaches for improving the operation of a mailroom, e.g., whether the time required to sort and deliver an estimated group of mail pieces (Ttotal) is less than or equal to an allotted or available time (Tavail). In one approach, information related to sorting and delivery is stored in memory and a suitable platform or processor is used to calculate (i) an amount of time required to sort the estimated group of mail pieces, and (ii) an amount of time required to deliver the estimated group of mail pieces to a preset number of mail boxes. In turn, evaluation can be achieved by comparing the sum of (i) and (ii) with Tavail.
Use of certain enhancements in determining if Ttotal<Tavail is contemplated. For instance, the estimated group of mail pieces can be sorted into p batches, and distribution information, indicating how the mail pieces are to be allocated across the p batches (αj) may be provided. Further distribution information (including βi) can be used to estimate a fractional allocation of mail delivery typically encountered at each mailbox.
The disclosed approaches accommodate for labor utilization by respectively corresponding integer values to a sorting group (M_sj) and a delivery group (M_dj). In one exemplary constraint, the sum of these integers is no greater than an integer value M.
In another approach, a timeliness function, including several applicable variables, is used to calculate Ttotal. The timeliness function can be solved in conjunction with a labor hours function to minimize the number of hours required to sort and deliver the estimated group of mail pieces. It has been found that this conjunctive solution can be advantageously implemented by enumeration coupled with a linear programming, and that such implementation can be readily achieved with "off-the-shelf" software.
In yet another approach a time control evaluation or function can be advantageously solved with a labor control evaluation or function to assess and/or optimize the amount of labor time required to both sort the estimated group of mail pieces and deliver the same to a preset number of mailboxes.
The claims, as originally presented and as they may be amended, encompass variations, alternatives, modifications, improvements, equivalents, and substantial equivalents of the embodiments and teachings disclosed herein, including those that are presently unforeseen or unappreciated, and that, for example, may arise from applicants/patentees and others.