A formulation comprising:

This application has been filed under 35 USC 371 as the National stoge of International application PCT/IB95/00001, filed Jan. 3, 1995.
The present invention relates to a wettable powder formulation of solid herbicides on a solid carrier material and large amounts of a nonionic surfactant which is a reaction product of an alcohol with longer chain length and identical or different alkylene oxides, and whose end groups may additionally be alkylated.
Pesticides are usually marketed as formulated concentrates. In addition to water-dispersible powders, it is also possible to use suspension concentrates, emulsifiable concentrates or other physical forms, as described, inter alia, in EP-B-0 190 995. Emulsifiable concentrates consist essentially of a concentrated solution of the active ingredient in a suitable organic solvent, typically a mineral oil or xylene, which can be emulsified in water by adding suitable surfactants. They usually have very good biological activity and are easily to handle when formulating the spray mixture. One disadvantage is the use of an organic solvent.
Water-dispersible and wettable powders typically consist of inert carrier materials, one or more active ingedients, and surface active compounds that ensure easily wettability with water. Organic solvents are not required. It is frequently observed that these powders have a markedly lower biological activity than emulsifiable concentrates, so that this type of formulation is impracticable, i.e. it must be used in too high concentration.
Nonionic surfactants derived from fatty alcohol ethoxylates may also be used for formulating wettable powders. Usually, however, only minor amounts of surfactant are used, as the powders are required to be readily flowable and must remain storage-stable over a considerable period of time. On contact with water, no lumps shall form and the powder must form a fine dispersion as rapidly as possible when stirred in water.
C. L. McGiness, P. J. Porpiglia and G. R. Gillespie report in Abstr. Meet. Weed Sci. Soc. Am. (32, 13, 1992) on greater biological control when using primisulfuron in admixture with ethoxylated fatty alcohols. The fatty alcohol ethoxylate preferably consists of a 70% ethoxylated C12-C14fatty alcohol. The fatty alcohol ethoxylate is mixed direct with the herbicide, the mixture is diluted with water and then applied in a greenhouse.
A wettable powder useful in practice having a high content of fatty alcohol ethoxylate and very good biological properties has so far not been disclosed.
It has now been found that storage-stable wettable powders of high biological activity can be obtained by applying herbicidally active compounds together with large amounts of an alkylene-oxylated alcohol with longer chain length as nonionic surfactant on a solid porous carrier material, even if said nonionic surfactant carries alkylated end groups. Accordingly, in one of its aspects the invention relates to a formulation comprising
a) at least one herbicide,
b) at least one porous solid carrier material, and
c) a nonionic surfactant,
which formulation contains 30 to 60% by weight, based on the total formulation, of at least one nonionic surfactant of formula I
R1xe2x80x94(Oxe2x80x94R2xe2x80x94)nOxe2x80x94R3xe2x80x83xe2x80x83(I)
wherein R1 is C8-C16alkyl or C8-C16alkenyl, R2 is identical or different C2-C4alkylene, R3 is hydrogen or C1-C4alkyl, and n is an integer from 5-10.
Suitable herbicides are known per se and described, inter alia, in R. Wegler, Chemie der Pflanzenschutz-und Schxc3xa4dlingsbekxc3xa4mpfungsmittel (Chemistry of Plant Protection Agents and Pesticides), Volume 2, Springer Verlag 1970, pp. 196-390.
Preferred herbicides are those selected from the groups consisting of the urea derivatives, imidazolinones, sulfonylureas, uracils, cyclohexanediones, chloroacetanilides, oxime ethers, triazines and phenoxypropionic acid derivatives.
Particularly preferred herbicides are those of the group of phenoxypropionic acid derivatives disclosed, inter alia, in EP 0 083 556. They are particularly useful active ingredients for the wettable powders of this invention.
Another preferred group of herbicides is that of the group of the sulfonylureas disclosed, inter alia, in EP-A-0 044 807 or in EP-A-0 120 814.
The novel formulations may additionally comprise safeners, typically those of the group of the quinoline derivatives. Particularly preferred safener-herbicide combinations are disclosed, inter alia, in EP-A-0 191 736 or in EP-A-0 094 349.
Particularly preferred herbicides are compounds of formula II which may be in the form of the R enantiomer or the racemate
wherein Q is a radical of formula
wherein R4 is hydrogen, F, Cl or Br;
R5 is CF3, CN, Cl, Br or I;
R7 and R8 are each independently of the other F, Cl, Br, I, CF3 or CN,
X is oxygen or sulfur, and n is 0 or an integer from 1 to 3;
Z is a radical of formula
wherein R6 is hydrogen, C1-C8alkyl, C3-C8alkenyl, C3-C8alkynyl, C1-C8haloalkyl, C3-C8haloalkenyl, C3-C8haloalkynyl, or C1-C6alkyl which is substituted by CN, NO2, C1-C4alkoxy, C1-C4alkyl-SOxe2x80x94, C1-C4alkyl-SO2xe2x80x94, C1-C8alkoxycarbonyl, C3-C8alkenyloxycarbonyl, C3-C8alkynyloxycarbonyl, C1-C4alkylidene-aminooxy or N(R10)(R11), or is C3-C8alkenyl;
R9 alkyl, haloalkyl, CN or C1-C4alkoxycarbonyl;
and R10 and R11 are each independently of the other C1-C8alkyl, C3-C8alkenyl, C3-C8alkynyl, phenyl, benzyl or phenyl or benzyl, each substituted by halogen, NO2, CN, OCH3, or CF3, or R10 and R11, together with the linking nitrogen atom, form a 5-7-membered saturated heterocycle.
Alkyl in R6, R9, R10 and R11 may be linear or branched and, in the significance of C1-C8alkyl, is typically ethyl, the different isomers of propyl, butyl, pentyl, hexyl, heptyl or octyl.
Alkenyl in R6, R10 and R11 may be linear or branched and in the significance of C3-C8alkenyl is typically the different isomers of propenyl, butenyl, pentenyl, hexenyl, heptenyl or octenyl. Alkenyl is preferably C2-C7alkenyl-CH2xe2x80x94.
Alkynyl may be linear or branched and in the significance of C3-C8alkynyl is typically the different isomers of propynyl, butynyl, pentynyl, hexynyl, heptynyl or octynyl. Alkynyl is preferably C2-C7alkynyl-CH2xe2x80x94,
C1-C4Alkoxy is typically methoxy, ethoxy, propoxy or butoxy. C1-C4Alkylthio may be methylthio, ethylthio, propylthio or butylthio.
The 3-8-membered N-heterocycle is preferably morpholino or piperidino.
Very particularly preferred herbicides are compounds of formula III or IV
especially in the R-configuration.
Further preferred compounds are those of formula V, VI or VII.
Suitable safeners are a number of the quinoline derivatives disclosed in the references cited hereinabove. A compound of formula
is particularly suitable.
The aforementioned compounds of Formulae III-VIII have the following common names in the art:
III clodinafop-propargyl
IV propaquizafop
V fluazifop-butyl
VI fenoxaprop-ethyl
VII quizalofop-ethyl
VIII cloquintocet-mexyl.
The herbicides can be used in an amount of 1 to 30% by weight, preferably of 5 to 15%, based on the entire formulation.
If a safener is concurrently used, the ratio of safener to herbicide is 1:5 to 5:1, preferably 1:4 to 1:1.
Herbicide and safener usually have an average particle size of 1:100, preferably of 1:50 and, most. preferably, of 1 to 25 xcexcm.
The solid carriers are porous and preferably have an inner surface area of at least 10 m2/g, preferably 20 to 400 m2/g and, most preferably, 20 to 200 m2/g. Solid carriers for wettable powders are usually natural mineral fillers such as calcite, talcum, kaolin, diatomaceous earth, montmorillonite or attapulgite. In order to improve the physical properties it is also possible to add highly dispersed silicic acid, synthetic highly absorbent silicic acid, or porous polymers such as urea/formaldehyde condensate (Pergopak). Suitable granulated adsorptive carriers are porous types such as pumice, broken brick, sepiolite or bentonite; and suitable nonsorbent carriers are materials such as calcite or sand. In addition, a great number of pregranulated materials of inorganic or organic nature can be used, e.g. especially dolomite or pulverised plant residues. The carrier material usually has an average particle size of 1 to 200 xcexcm, preferably 1 to 100 xcexcm and, most preferably, 1 to 25 xcexcm. The particle size of plant residues is usually larger and can be up to 500 xcexcm.
The porous carrier material is preferably used in an amount of 30 to 60% by weight, most preferably 35 to 50% by weight, based on the total formulation. The percentages in connection with the formulation make up 100%.
R1 in formula I is preferably C10-C15alkyl and, most preferably, C12-C14alkyl. Alkyl may be linear or branched and is preferably linear. Alkyl may be mixtures of alkyl radicals with different chain lengths. Typical examples are octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl and hexadecyl.
n in formula I is preferably an integer from 6 to 8. The compounds of formula I are preferably technical mixtures that contain oligomers in which n=5-10, preferably n=6-8.
R2 is typically ethylene, 1,2-propylene or 1,2-butylene. If R2 denotes different alkylene radicals, the compounds may be random or block oligomers.
R2 is typically a mixture of C2alkylene and C4alkylene and R3 is hydrogen or methyl.
Most preferably R1 is C10-C15alky1, R2 is C2alkylene, R3 is hydrogen and n is an integer from 6 to 8.
The novel formulations may additionally comprise other surface-active compounds, conveniently in an amount of 1 to 15% by weight, preferably 1 to 10% by weight, based on the total formulation.
Depending on the type of active ingredient or combination of active ingredients to be formulated, suitable surface-active compounds are nonionic, cationic and/or anionic surfactants having good emulsifying, dispersing and wetting properties. Surfactants will also be understood as comprising mixtures of surfactants.
Suitable anionic surfactants may be water-soluble soaps as well as water-soluble synthetic surface-active compounds.
Suitable soaps are the alkali metal salts, alkaline earth metal salts, ammonium salts or substituted ammonium salts of higher fatty acids (C10-C22), e.g. the sodium or potassium salts of oleic or stearic acid, or of mixtures of natural fatty acids which can be obtained, inter alia, from coconut oil or tall oil. Further suitable soaps are also the fatty acid methyl taurin salts.
More often, however, so-called synthetic surfactants are used, especially fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylarylsulfonates.
The fatty alcohol sulfonates or sulfates are usually in the form of alkali metal salts, alkaline earth metal salts, ammonium salts or substituted ammonium salts, and they contain a C8-C22alkyl radical which also includes the alkyl moiety of acyl radicals, e.g. the sodium or calcium salt of ligninsulfonic acid, of dodecylsulfate, or of a mixture of fatty alcohol sulfates obtained from natural fatty acids. These compounds also comprise the salts of sulfated and sulfonated fatty alcohol/ethylene oxide adducts. The sulfonated benzimidazole derivatives preferably contain two sulfonic acid groups and one fatty acid radical containing 8 to 22 carbon atoms. Illustrative examples of alkylarylsulfonates are the sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnaphthalenesulfonic acid, or of a condensate of naphthalenesulfonic acid and formaldehyde. Corresponding phosphates, typically salts of the phosphoric acid ester of an adduct of p-nonylphenol with 4 to 14 mol of ethylene oxide, or phospholipids, are also suitable.
Further suitable nonionic surfactants are preferably polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols or of saturated or unsaturated fatty acids and alkylphenols, said derivatives containing 3 to 30 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenols. Further suitable nonionic surfactants are the water-soluble polyadducts of polyethylene oxide with polypropylene glycol, ethylenediaminopolypropylene glycol and alkylpolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which polyadducts contain 20 to 250 ethylene glycol ether groups and 10 to 100 propylene glycol ether groups. These compounds usually contain 1 to 5 ethylene glycol units per propylene glycol unit.
Illustrative examples of nonionic surfactants are nonylphenol polyethoxylates, polyethoxylated castor oil, polyadducts of polypropylene and polyethylene oxide, tributylphenol polyethoxylate, polyethylene glycol and octylphenol polyethoxylate. Fatty acid esters of polyoxyethylene sorbitan are also suitable nonionic surfactants, typically polyoxyethylene sorbitan trioleate.
Cationic surfactants are preferably quaternary ammonium salts carrying, as N-substituent, at least one C8-C22alkyl radical and, as further substituents, unsubstituted or halogenated lower alkyl, benzyl or hydroxy-lower alkyl radicals. The salts are preferably in the form of halides, methyl sulfates or ethyl sulfates, for example stearyl trimethylammonium chloride or benzyl bis(2-chloroethyl)ethylammonium bromide.
The surfactants customarily employed in the art of formulation are described, inter alia, in xe2x80x9cMc Cutcheon""s Detergents and Emulsifiers Annualxe2x80x9d, MC Publishing Corp., Glen Rock, N.J., 1981, H. Stache, xe2x80x9cTensid-Taschenbuchxe2x80x9d (Handbook of Surfactants), Carl Hanser Verlag, Munich/Vienna 1981, and M. and J. Ash. xe2x80x9cEncyclopedia of Surfactantsxe2x80x9d, Vol. I-III, Chemical Publishing Co., New York, 1980-1981.
The compositions are prepared in known manner, e.g. by homogeneously mixing and/or grinding the active ingredients with extenders, typically with solvents, solid carriers and, in some cases, surface-active compounds (surfactants).
Mixing can be carried out in ordinary commercial mixers. If the active ingredients have a low melting point, it is expedient to premix a portion of the carrier material with the total amount of herbicide and the safener, if used, and to grind the mixture, then to add the rest of the carrier material and, finally, to add the surfactant useful in the practice of this invention and other optional adjuvants.
It is usually often possible to mix the carrier loaded with the surfactant with the herbicide and afterwards to grind the mixture.
If the active ingredients have higher melting points, components (a) and (b) are conveniently mixed in the finely ground state or ground together and component (c) is then added.
The end user will normally use the active ingredient concentrates or wettable powders in the form of dilute compositions. This is done by dispersing a biologically active amount of the formulation in water.
The invention therefore also relates to a composition for controlling weeds and grasses in crops of cultivated plants, which composition contains a biologically effective amount of the novel formulation in water.
The amount of formulation added to water to prepare a spray mixture will depend on the type of application. Usually a 0.1 to 10% by weight aqueous dispersion is prepared.
Suitable cultivated plants are preferably those which are important in the food or textile sector, typically sugar cane and, in particular, millet, maize, rice and cereals (wheat, rye, barley, oats). The use of the novel composition in crops of cereals is very particularly preferred.
The weeds to be controlled can be both monocot as well as dicot weeds.
The concentration of herbicide will usually be from 0.001 to 1 kg/ha, but preferably from 0.01 to 0.5 kg a.i./ha. In postemergence treatment of the weeds, a reduction of 80 to 98% of biomass is usually achieved.
Application of these compositions may be spraying, atomising, coating or drenching.
The invention also relates to a method of selectively controlling weeds, which comprises treating crops of cultivated plants, the seeds or the crop area thereof with an effective amount, usually from 0.01 to 0.5 kg/ha, of a herbicidal composition contains the herbicidal formulation of this invention, preferably using water as diluent.
The invention further relates to the use of nonionic surfactants of formula I for the preparation of wettable powder formulations for use as herbicidal compositions.

Wettable powder formulations of herbicides

Abstract: A formulation comprising:

Abstract: a) a herbicide,

Abstract: b) a porous solid carrier, and

Abstract: c) 30-60% by weight of a nonionic surfactant of formula I:

Abstract: The herbicides may be selected from the group consisting of urea herbicides, imidazolinones, sulfonylureas, uracils, cyclohexanediones, chloroacetanilides, oxime ethers, triazines, or phenoxypropionic acid herbicides, in particular, the phenoxypropionic acid derivatives:

Abstract: (III) clodinafop-propargyl

Abstract: (IV) propaquizafop

Abstract: (V) fluazifop-butyl

Abstract: (VI) fenoxaprop-ethyl

Abstract: (VII) quizalofop-ethyl

Abstract: optionally in combination with the safener (VIII) cloquintocet-mexyl.


A transfer case is provided with a range unit, an interaxle differential, a clutch assembly and a power-operated actuation mechanism. The range unit includes a planetary gearset driven by an input shaft, and a synchronized dog clutch assembly for releasably coupling one of the input shaft or an output component of the planetary gearset to an input member of the interaxle differential. The interaxle differential further includes a first output member driving a first output shaft, a second output member operably driving a second output shaft. The clutch assembly is a multi-plate friction clutch operably disposed between the first and second output shafts. The power-operated actuation mechanism includes a range actuator assembly, a ball-ramp clutch actuator assembly and a motor assembly operable to control actuation of the range actuator assembly and the clutch actuator assembly.

The present invention is generally related to transfer cases for use in four-wheel drive vehicles and, more particularly, to an improved two-speed on-demand transfer case equipped with a ball-ramp clutch assembly.
In view of increased consumer popularity in four-wheel drive vehicles, a plethora of power transfer systems are currently being utilized in vehicular driveline applications for selectively directing power (i.e., drive torque) from the powertrain to all four wheels of the vehicle. In many power transfer systems, a transfer case is incorporated into the driveline and is operable in a four-wheel drive mode for delivering drive torque from the powertrain to both the front and rear wheels. Many conventional transfer cases are equipped with a mode shift mechanism that can be selectively actuated to shift between a two-wheel drive mode and a four-wheel drive mode. In addition, many transfer cases also include a range shift mechanism which can be selectively actuated by the vehicle operator for shifting between four-wheel high-range and low-range drive modes.
It is also known to use xe2x80x9con-demandxe2x80x9d power transfer systems for automatically biasing power between the front and rear wheels, without any input or action on the part of the vehicle operator, when traction is lost at either the front or rear wheels. Modernly, it is known to incorporate the xe2x80x9con-demandxe2x80x9d feature into a transfer case by replacing the mechanically-actuated mode shift mechanism with a clutch assembly that is interactively associated with an electronic control system and a sensor arrangement. During normal road conditions, the clutch assembly is typically maintained in a non-actuated condition such that drive torque is only delivered to the rear wheels. However, when the sensors detect a low traction condition, the clutch assembly is automatically actuated to deliver torque xe2x80x9con-demandxe2x80x9d to the front wheels. Moreover, the amount of drive torque transferred through the clutch assembly to the non-slipping wheels can be varied as a function of specific vehicle dynamics, as detected by the sensor arrangement. This on-demand clutch control system can also be used in full-time transfer cases to automatically bias the torque ratio across an interaxle differential.
In some two-speed on-demand transfer cases the range shift mechanism and the clutch assembly are independently controlled by separate power-operated actuators. For example, U.S. Pat. No. 5,407,024 discloses a two-speed range shift mechanism actuated by an electric motor and a clutch assembly actuated by an electromagnetic coil. In an effort to reduce cost and complexity, some transfer cases are equipped with a single power-operated actuator that is operable to coordinate actuation of both the range shift mechanism and the clutch assembly. In particular, U.S. Pat. Nos. 5,363,938 and 5,655,986 each illustrate a transfer case equipped with a motor-driven sector with cam surfaces adapted to coordinate actuation of the range shift mechanism and the clutch assembly for establishing a plurality of distinct two-wheel and four-wheel drive modes. While transfer cases equipped with such coordinated actuation systems have been commercially successful, a need exists to develop alternative systems which further reduce the lost and complexity of two-speed on-demand transfer cases.
Accordingly, it is an object of the present invention to provide a transfer case equipped with a two-speed range unit, a clutch assembly, and a power-operated actuation mechanism for controlling coordinated actuation of the range unit and the clutch assembly.
It is another object of this invention that the transfer case be interactively associated with a control system for controlling operation of the power-operated actuation mechanism to establish various four-wheel high-range and low-range drive modes.
It is further object of the present invention to locate the clutch assembly across an interaxle differential to provide automatic torque biasing in a full-time four-wheel drive mode.
As a related object, the clutch assembly can be operably disposed between the front and rear output shafts to provide automatic torque transfer in an on-demand four-wheel drive mode.
Another object is to provide a synchronized range unit for permitting on-the-move shifting between high-range and low-range drive modes.
According to a preferred embodiment, a transfer case is provided with a range unit, an interaxle differential, a clutch assembly, a power-operated actuation mechanism, and a control system. The range unit includes a planetary gearset driven by an input shaft, and a synchronized dog clutch assembly for releasably coupling one of the input shaft or an output component of the planetary gearset to an input member of the interaxle differential. The interaxle differential further includes a first output member driving a first output shaft, a second output member operably driving a second output shaft, and a gearset transferring drive torque from the input member to the first and second output members. The clutch assembly is a multi-plate friction clutch operably disposed between the first and second output shafts. The power-operated actuation mechanism includes an electric motor assembly, a drive shaft driven by the motor assembly, a range actuator assembly and a clutch actuator assembly. The range actuator assembly includes a cam rotatively driven by the drive shaft, and a shift fork having a follower segment retained in a groove formed in the cam and a fork segment retained in a groove formed in a shift collar associated with the synchronzied dog clutch assembly. Rotation of the cam results in movement of the shift collar between high-range (H), neutral (N) and low-range (L) positions. The clutch actuator assembly includes a ball-ramp unit and a gear assembly. The ball-ramp unit includes a first plate, a second plate, and balls retained in ramped grooves formed between the first and second plates. The gear assembly includes a first gear driven by the drive shaft, a second gear fixed to the first plate of the ball-ramp unit, and a third gear meshed with the first and second gears. The control system is adapted to control the magnitude and direction of rotary motion of the drive shaft through controlled energization of the motor assembly.
The power-operated actuation system of the present invention is arranged to permit sufficient bi-directional rotation of the drive shaft to move the shift collar between its H and L positions without causing the ball-ramp unit to engage the multi-plate clutch. However, once the shift collar is positively located in either of the H or L positions, continued rotation of the drive shaft causes actuation of the ball-ramp unit for exerting a clutch engagement force on the multi-plate friction clutch.

Two-speed transfer case with ball-ramp clutch and single motor activator/shift system


The invention provides intrafallopian devices and non-surgical methods for their placement to prevent conception. The efficacy of the device is enhanced by forming the structure at least in part from copper or a copper alloy. The device is anchored within the fallopian tube by a lumen-traversing region of the resilient structure which has a helical outer surface, together with a portion of the resilient structure which is biased to form a bent secondary shape, the secondary shape having a larger cross-section than the fallopian tube. The resilient structure is restrained in a straight configuration and transcervically inserted within the fallopian tube, where it is released. Optionally, permanent sterilization is effected by passing a current through the resilient structure to the tubal walls.

1. Field of the Invention
The present invention relates generally to contraception, and more particularly to intrafallopian contraceptive devices and nonsurgical methods for their delivery.
Worldwide demand exists for safe, effective methods of both contraception and permanent sterilization. Although a variety of contraception and sterilization methods are available, all of the existing methods have limitations and disadvantages. Thus, the need for additional safe, low cost, reliable methods of contraception and permanent sterilization, both in developed and less developed countries, is widely recognized.
Many presently available contraception methods require significant user involvement, and user non-compliance results in quite high rates of failure. While the theoretical effectiveness of existing contraceptives, including barrier methods and hormonal therapies, is well established, overcoming user noncompliance to improve overall efficacy has proven difficult.
One form of contraception which is less susceptible to user noncompliance is the intrauterine device (IUD). IUDs have been found to have higher rates of reliability, and are effective for a longer period of time, than most other commercially available contraceptives. Unfortunately, IUDs are also associated with serious infectious complications. For this reason, the use of IUDs within the United States has decreased dramatically. Additionally, IUDs are subject to unplanned expulsion, and must be removed due to excessive pain or bleeding in a percentage of cases, further reducing the acceptance of the IUD as a contraceptive method. Interestingly, the efficacy of copper IUDs appears to be higher than that of non-metallic IUDs. The reason for this has not been fully explained.
Commercially available options for permanent sterilization include fallopian tube ligation and vasectomy. These methods are surgical, are difficult to reverse, and are not available to many people in the world. It is common knowledge that fertilization occurs in the fallopian tubes where the sperm and ovum meet. Tubal ligation avoids this by complete occlusion of the fallopian tubes.
It has previously been proposed to reversibly occlude the fallopian tubes, for example, by in vitro formation of an elastomeric plug, or otherwise anchoring a device on either side of the narrowest region of fallopian tube, called the xe2x80x9cisthmus.xe2x80x9d Such fallopian tube occlusion methods appear promising; however, an unacceptably high percentage of the non-surgical devices proposed to date have become dislodged during previous studies. Even where non-surgical intrafallopian devices have remained in place, they have been found to be only moderately effective at preventing conception.
For these reasons, it would be desirable to provide effective, reliable intrafallopian devices for contraception and sterilization. It would be particularly desirable to provide highly effective intrafallopian devices which did not require surgery for placement. It would be especially desirable if such devices and methods allowed easy placement of the device, but were less susceptible to being dislodged than previously proposed non-surgical intrafallopian devices.
2. Description of the Related Art
The experimental use of a stainless steel intrafallopian device is described in Transcatheter Tubal Sterilization in Rabbits, Penny L. Ross, RT 29 xe2x80x9cInvestigative Radiologyxe2x80x9d, pp. 570-573 (1994). The experimental use of an electrolytically pure copper wire as a surgical contraceptive intrafallopian device in rats was described in xe2x80x9cAntifertility Effect of an Intrafallopian Tubal Copper Devicexe2x80x9d, D. N. Gupta, 14 Indian Journal of Experimental Biology, pp. 316-319 (May 1976).
U.K. Patent Application Pub. No. 2,211,095 describes a uterine screw plug for blocking the fallopian tube. European Patent Application Pub. No. 0,010,812 describes a device for placement in the oviducts having enlargements at either end for anchoring the device. The same device appears to be described in Netherlands Patent No. 7,810,696.
The use of tubal occlusion devices is described in xe2x80x9cHysteroscopic Oviduct Blocking With Formed-in-Place Silicone Rubber Plugsxe2x80x9d, Robert A. Erb, Ph.D., et al., The Journal of Reproductive Medicine, pp. 65-68 (August 1979). A formed-in-place elastomeric tubal occlusion device is described in U.S. Pat. No. 3,805,767, issued to Erb. U.S. Pat. No. 5,065,751, issued to Wolf, describes a method and apparatus for reversibly occluding a biological tube. U.S. Pat. No. 4,612,924, issued to Cimber, describes an intrauterine contraceptive device which seals the mouths of the fallopian tubes.
German Patent No. 28 03 685, issued to Brundin, describes a device for plugging a body duct with a device which swells when in contact with a body fluid.
Alternative contraceptive devices are disclosed in co-pending U.S. patent application Ser. No. 08/474,779, the full disclosure of which is herein incorporated by reference.
The present invention provides intrafallopian devices and methods for their placement to prevent conception. The intrafallopian devices of the present invention are transcervically delivered and mechanically anchored within the fallopian tube to provide long term contraception, or alternatively permanent sterilization, without the need for surgical procedures or the risks of increased bleeding, pain, and infection associated with intrauterine devices (IUDs).
The intrafallopian devices of the present invention will often comprise a structure having a lumen-traversing region with a helical outer surface. The helical surface is mechanically anchored by a resilient portion of the structure which is biased to form an enlarged secondary shape, preferably forming distal and proximal anchoring loops. The anchoring loops help prevent the helical outer surface from rotating out of position, and also directly deter axial motion within the fallopian tube. In alternative embodiments, anchoring may be provided by a straight coil which is resiliently deflected by the axial curvature of the tortuous fallopian tube, and a radially expandable braid, malecott, or some other tubular structure may help affix the device within the fallopian tube.
The use of copper in the intrafallopian device of the present invention improves its efficacy as a contraceptive method. Devices formed from plastically deformable materials, however, are less readily restrained in the fallopian tube. Apparently, the large variation in the actual shape and dimensions of fallopian tubes does not provide reliable anchoring for a pre-formed deformable intrafallopian device. The intrafallopian device of the present invention therefore often comprises a resilient structure, usually a metallic coil, which includes a copper alloy or plating, ideally comprising an alloy including at least 75% copper. The coil material typically includes beryllium, zinc, stainless steel, platinum, a shape memory alloy, such as Nitinol(copyright), or the like. Preferably, the coil is composed of an alloy of beryllium and copper
Although the present device will generally result in occlusion, it need not completely occlude the fallopian tube to prevent the meeting of the sperm and ovum. Instead, in some embodiments, the presence of the copper on the resilient structure is sufficient to provide effective contraception. Hence, contraception can be provided by disrupting the normal architecture and/or function of the fallopian tube, despite the presence of an open lumen. This concept is referred to herein as xe2x80x9cfunctional occlusionxe2x80x9d. As used herein, functional occlusion means that the device, when implanted in the fallopian tube, disrupts the normal architecture and/or functioning of the fallopian tube so as to inhibit fertilization and/or conception.
Conveniently, the present invention further comprises non-surgical placement of such intrafallopian devices by transcervical introduction. The resilient structure is restrainable in a straight configuration, e.g., by use of a corewire, greatly facilitating and reducing the risks of introduction. Thus, the cost and dangers associated with existing surgical contraceptive and sterilization procedures are avoided. The resilient structure will often comprise a coil. In some embodiments, an element is disposed along the coil, and is adapted to incite a tissue reaction in the tubal tissues which inhibits conception. A distal anchor of the coil may be inserted into the ampulla, distal of the isthmus, while a proximal anchor is located in the ostium. These anchors prevent rotation of the device, and also help avoid axial movement. Alternatively, at least one of the anchors may be positioned anywhere past the ostium and within the fallopian tube, while the other extends into the uterus, depending on their length and configuration. Preferably, at least some anchoring is provided along the intramural to isthmic region of the fallopian tube. In some embodiments, electrosurgical attachment of an intraluminal device to a surrounding lumenal wall may provide effective anchoring even without loops and other anchoring structures. Electrical current may also be used to decouple the intrafallopian device from the delivery system, typically by electrolytically dissolving a solder bond. Current may also actuate an anchor, such as by releasing a resilient radially expandable tubular structure within the fallopian tube.
The present invention also provides improved contraceptive devices which incite a tissue reaction within the fallopian tube to prevent conception. This group of intrafallopian devices will often make use of a highly flexible coil structure to avoid damaging or penetrating through the delicate tubal tissues. The desired tissue reaction may be the result of the material of intrafallopian device, or may be incited by a coating, a surface treatment, a mechanical interaction between the device and the surrounding tubal wall, or the like. The tissue will often help impede conception by occluding the fallopian tube, by interrupting the transport mechanisms of the tubal tissues, and/or by restraining the intrafallopian tubal device within the tube. Specific tissue reactions which may provide these intended results include tissue ingrowth into the contraceptive device and/or the tubal lumen, scar tissue formation, sclerosing of the tubal tissues, and the like.
In one aspect, the invention provides a tissue reaction contraceptive device for use in a fallopian tube. The contraceptive device comprises a coil having a proximal end and a distal end and defining an axis therebetween. The coil is axially flexible and has a cross-section suitable for insertion into the fallopian tube. An element disposed along the coil is adapted to incite a tissue reaction in the tubal tissues adjacent the coil so as to inhibit conception.
In some embodiments, the element may promote ingrowth of the tubal tissues into the contraceptive device. For example, the element may include a braided or woven polyester, a micro-porous material or surface treatment, or the like. Alternatively, a sharp edged helical ribbon or other mechanical interaction element may incite the formation of scar tissue, or a surface coating of the coil may sclerose the tubal tissues, exciting formation of tough fibrous connective tissues which interfere with conceptive transport. In many embodiments, the presence of the contraceptive device in combination with the tissue reaction can provide effective contraception without having to rely on total occlusion of the fallopian tube.
In another aspect, the present invention provides a tissue ingrowth contraceptive device for use in a fallopian tube. The contraceptive device comprises a tubular retention structure having a proximal end, a distal end and an axis therebetween. The retention structure is axially flexible, and is insertable within the fallopian tube. A material which can incite ingrowth of the tubal tissue is attached to, and exposed radially from, the retention structure.
In the exemplary embodiment, the retention structure comprises a helical coil in which the ingrowth material is disposed. Such helical coils may optionally be radially expansible within the fallopian tube, thereby allowing the device to accommodate a wide variety of tubal physiologies. The ingrowth material may be in the form of braided or woven fibers of polyester, P.T.F.E., or the like.
In another aspect, the present invention provides a tissue ingrowth contraceptive device for use in a fallopian tube. The contraceptive device comprises a resilient elongate body having a proximal end and a distal end and defining an axis therebetween. A retention structure is disposed along the resilient body. The retention structure is adapted to restrain the resilient body within the fallopian tube. A bond affixes the retention structure to the resilient body. At least one of the resilient body, the retention structure, and the bond comprises a micro-porous material which promotes tissue ingrowth therein.
In another aspect, the present invention provides a contraceptive method comprising transcervically inserting a contraceptive device within a fallopian tube. The device is inserting by resiliently deflecting a distal body of the contraceptive device against a tubal wall, so that the distal body guides the contraceptive device axially along the fallopian tube. A tissue reaction is incited with an element of the contraceptive device in the tubal tissues. This tissue reaction affixes the contraceptive device within the fallopian tube.
The present invention also provides improved contraceptive devices, systems, and methods adapted for use in the widely varying geometry of the fallopian tube. In recognition of the wide variations in tubal physiology, the contraceptive structures of the present invention are radially expandable within the fallopian tube to engage the tubal wall. Surprisingly, the contraceptive devices of the present invention will often make use of tubular structures such as resilient helical coils. Such tubular devices will often effect contraception by disrupting the architecture and/or transport mechanisms of the tubal tissues, rather than relying entirely on total blockage of the tube. The passages through the tubular contraceptive devices of the present invention may optionally be occluded by promoting tissue ingrowth within the device, for example, by including woven or braided polyester fibers within a helical coil. Regardless, such tubular retention structures are capable of radially expanding against tubal walls throughout a wide range of tubal sizes to safely anchor the contraceptive device, without having to resort to protruding barbs or the like.
In one aspect, the present invention provides a contraceptive device for use in fallopian tube having a tubal wall. The contraceptive device comprises a tubular retention structure having a proximal end, a distal end, and an axis therebetween. The retention structure is radially expandable in situ from a narrow configuration (in which the retention structure has a first diameter which is suitable for axial insertion into the fallopian tube) so as to define a second, enlarged diameter. The expanded retention structure is adapted to engage the surrounding tubal wall and retain the contraceptive device within the fallopian tube.
In another aspect, the present invention provides a contraceptive device for use in a fallopian tube having a tubal wall. The contraceptive device comprises a conception inhibiting body which defines an axis. A helical coil is disposed about the body. A portion of the helical coil is movable relative to the body so that the helical coil can expand resiliently throughout a range of tubal cross-sectional sizes. Hence, the coil can radially engage the surrounding tubal wall and safely affix the contraceptive device within the fallopian tube.
The present invention also provides intrafallopian contraceptive devices having elongate coils which are substantially straight. Surprisingly, when such straight coils are positioned axially within the tortuous fallopian tubes, the bends imposed on the coil by the fallopian tube can result in resilient anchoring of the coil. Such straight coils are also highly advantageous when advancing the contraceptive device into (and within) the fallopian tube. Straight resilient coils can act as an integral guidewire during transcervical deployment of the device within the fallopian tube, thereby avoiding the delay associated with the sequential use of guidewires, tubal axis catheters, and the like.
The present invention provides an intrafallopian contraceptive device for use in a fallopian tube. The contraceptive device comprises an elongate coil having a proximal end, a distal end, and an axis therebetween. The axis is substantially straight when the coil is at rest, and the coil is axially resilient to facilitate insertion of the body axially into the tube. The device is adapted to be retained within the fallopian tube so as to inhibit conception.
In another aspect, the present invention provides an intrafallopian contraceptive device for use in a fallopian tube. The tube has a tubal wall with a tubal cross-section and an axial curvature. The contraceptive device comprises an elongate body having a proximal end and a distal end and defining an axis therebetween. The body has a cross-section suitable for axial insertion within the tubal cross-section. At least a portion of the body is straighter than the axial curvature of the fallopian tube. The body is sufficiently flexible to deflect against the tubal wall without injuring the tubal wall. The body is also sufficiently resilient to impose an anchoring force against the tubal wall when the straight portion flexes along the axial curvature of the fallopian tube.
In another aspect, the present invention provides a contraceptive device for use in a fallopian tube having an axis. The contraceptive device comprises a structure having a proximal end, a distal end, and an axis therebetween. The structure is adapted to provide effective tubal occlusion when disposed substantially coaxially within the fallopian tube. An elongate member is affixed to the occlusion structure. The member extends distally of the occlusion structure and is sufficiently flexible and axially resilient to help guide distal advancement of the occlusion structure within the fallopian tube.
In a contraceptive method provided by the present invention, an elongate resilient body is transcervically inserted into an axially curving fallopian tube so that the fallopian tube imposes an axial bend on the body. The bent body imposes an anchoring force which helps anchor the bent body within the fallopian tube. The body is anchored within the fallopian tube so that the affixed resilient body inhibits conception.
In another aspect, the present invention provides a contraceptive method comprising transcervically inserting an intrafallopian contraceptive device along the fallopian tube by guiding the contraceptive device with a distal guidewire-like structure of the contraceptive device. The device, including at least a portion of the guidewire-like structure, is retained within the fallopian tube so that the device inhibits conception.
In another aspect, the present invention provides a contraceptive kit. The kit comprises an intrafallopian contraceptive device and instructions for its use. The instructions describe and/or set forth the method steps of transcervically introducing the contraceptive device into a fallopian tube and affixing the contraceptive device within the tube. Optionally, a variety of delivery structures may also be provided in the kit, including guidewires, corewires, delivery catheters, and the like.
In yet another aspect, the invention provides an intrafallopian contraceptive system comprising an elongate delivery body having a proximal end and a distal end. A first energy conduit extends therebetween, and an intrafallopian structure near the distal end has a first cross-section. An energy source is coupled to the structure by the first conduit. Energy from the energy source reconfigures the structure to a second cross-section to restrain the structure within a fallopian tube and inhibit conception.
In a final aspect, the invention provides an elongate delivery body having proximal and distal ends with first and second conductors extending therebetween. An intrafallopian contraceptive structure is near the distal end of the delivery body. An electrical power supply can be coupled to the structure by the first and second conductors. This advantageous bipolar arrangement can, for example, allow actuation of a shape-memory alloy structure by transmitting current through at least a portion of the structure from a hand-held battery.

Contraceptive transcervical fallopian tube occlusion devices and methods


Norepinephrine reuptake inhibitors are used to treat psoriasis.

The invention belongs to the fields of pharmaceutical chemistry and dermatological medicine, and provides a method of treatment of the dermatological disorder known as psoriasis.
Psoriasis is a chronic, painful skin disorder that affects more than 7 million Americans. With as many as 250,000 new cases occurring each year, psoriasis typically does not discriminate on the basis of the age or gender of its victims. The disorder occurs slightly more often in women than men, and it has been reported to present itself initially from birth to the age of 90 years. Psoriasis exacts a heavy societal burden in terms of both patient suffering and costs. Annual outpatient treatment of psoriasis was estimated in 1999 to be from $1.6 to $3.2 billion, with over 1.5 million patients seen annually for this disorder by U.S. physicians.
Treatment options currently available to patients suffering from psoriasis include a variety of topical medications, phototherapies, and internal medications. Topical treatments include steroids, coal tar, anthralin, vitamin D3 and analogs, retinoids, and sunshine. Side effects associated with the use of these topical treatments include skin thinning, stretch marks, burns, irritation, and photosensitivity. The use of steroids may also lead to resistance, rendering subsequent steroid treatment ineffective. Phototherapy encompasses the medically supervised administration of ultraviolet light B or psoralen in combination with ultraviolet light A. Long term use of phototherapies may prematurely age the skin and increase the incidence of skin cancers. Internal medications, typically reserved for the most serious cases of psoriasis, include the administration methotrexate, oral retinoids, and cyclosporine. The use of methotrexate requires careful monitoring to avoid liver damage. Use of oral retinoids must be carefully controlled in women because of the potential for severe birth defects. This risk extends for years after the use of the drug has been terminated. Cyclosporine, an immunosuppresant, is reserved for patients that have failed other internal treatments, or for whom the other internal treatments are contraindicated. Rotating between therapies, and combinations of topical medications with phototherapies, have also been found to be useful regimens in the treatment of psoriasis.
There is no cure for psoriasis, and not all patients respond to or tolerate currently available therapies. New treatment options for psoriasis, with improved efficacy, safety, and side effect profiles, are needed.
The present invention provides a method of treating psoriasis comprising the administration to a patient in need of such treatment of an effective amount of a norepinephrine reuptake inhibitor.
This invention also provides the use of a norepinephrine reuptake inhibitor for the manufacture of a medicament for the treatment of psoriasis. Additionally, this invention provides a pharmaceutical formulation adapted for the treatment of psoriasis containing a norepinephrine reuptake inhibitor.
Many compounds, including those discussed at length below, are norepinephrine reuptake inhibitors, and no doubt many more will be identified in the future. In the practice of the present invention, it is intended to include reuptake inhibitors which show 50% effective concentrations of about 1000 nM or less, in the protocol described by Wong et al., Drug Development Research, 6, 397 (1985). The norepinephrine reuptake inhibitors useful for the method of the present invention are characterized in being selective for the inhibition of neurotransmitter reuptake relative to their ability to act as direct agonists or antagonists at other receptors. Norepinephrine reuptake inhibitors useful for the method of the present invention include, but are not limited to:
Tomoxetine, (R)-(xe2x88x92)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine, is usually administered as the hydrochloride salt. Tomoxetine was first disclosed in U.S. Pat. No. 4,314,081. The word xe2x80x9ctomoxetinexe2x80x9d will be used here to refer to any acid addition salt or the free base of the molecule. See, for example, Gehlert, et al., Neuroscience Letters, 157, 203-206 (1993), for a discussion of tomoxetine""s activity as a norepinephrine reuptake inhibitor;
The compounds of formula I:
wherein X is C1-C4 alkylthio, and Y is C1-C2 alkyl or a pharmaceutically acceptable salt thereof. The compounds of formula I were described in U.S. Pat. No. 5,281,624, of Gehlert, Robertson, and Wong, and in Gehlert, et al., Life Sciences, 55(22), 1915-1920, (1995). The compounds are there taught to be inhibitors of norepinephrine reuptake in the brain. It is also explained that the compounds exist as stereoisomers, and that they accordingly include not only the racemates, but also the isolated individual isomers as well as mixtures of the individual isomers. For example, the compounds of formula I include the following exemplary species:
N-ethyl-3-phenyl-3-(2-methylthiophenoxy)propylamine benzoate;
(R)-N-methyl-3-phenyl-3-(2-propylthiophenoxy)-propylamine hydrochloride;
(S)-N-ethyl-3-phenyl-3-(2-butylthiophenoxy)propylamine;
N-methyl-3-phenyl-3-(2-ethylthiophenoxy)propylamine malonate;
(S)-N-methyl-3-phenyl-3-(2-tert-butylthiophenoxy)-propylamine naphthalene-2-sulfonate;
(R)-N-methyl-3-(2-methylthiophenoxy)-3-phenyl-propylamine;
Reboxetine (Edronax(trademark)), 2-[xcex1-(2-ethoxy)phenoxybenzyl]morpholine, is usually administered as the racemate. It was first taught by U.S. Pat. No. 4,229,449, which describes its utility for the treatment of depression. Reboxetine is a selective norepinephrine reuptake inhibitor. The term xe2x80x9creboxetinexe2x80x9d will be used here to refer to any acid addition salt or the free base of the molecule existing as the racemate or either enantiomer;
Duloxetine, N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, is usually administered as the hydrochloride salt and as the (+) enantiomer. It was first taught by U.S. Pat. No. 4,956,388, which shows its high potency. The word xe2x80x9cduloxetinexe2x80x9d will be used here to refer to any acid addition salt or the free base of the molecule. A preferred duloxetine enteric formulation is a pellet formulation comprising a) a core consisting of duloxetine and a pharmaceutically acceptable excipient; b) an optional separating layer; c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and a pharmaceutically acceptable excipient; d) an optional finishing layer. This formulation is taught in U.S. Pat. No. 5,508,074;
Venlafaxine is known in the literature, and its method of synthesis and its activity as an inhibitor of serotonin and norepinephrine uptake are taught by U.S. Pat. No. 4,761,501. Venlafaxine is identified as compound A in that patent; and
Milnacipran (N,N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide is taught by U.S. Pat. No. 4,478,836, which prepared milnacipran as its Example 4. The patent describes its compounds as antidepressants. Moret et al., Neuropharmacology 24, 1211-19 (1985), describe its pharmacological activities as an inhibitor of serotonin and norepinephrine reuptake.
All of the U.S. patents mentioned above in connection with compounds and formulations used in the present invention are incorporated herein by reference.
While all compounds exhibiting norepinephrine reuptake inhibition are useful for the method of the present invention, certain are preferred. It is preferred that the norepinephrine reuptake inhibitor is selective for norepinephrine over other neurotransmitters. It is also preferred that the norepinephrine reuptake inhibitor is selected from tomoxetine, reboxetine, or a compound of formula I. It is especially preferred that the norepinephrine reuptake inhibitor be selected from tomoxetine, reboxetine, or (R)-N-methyl-3-(2-methylthiophenoxy)-3-phenylpropylamine. The use of tomoxetine hydrochloride for the treatment of psoriasis is the most preferred embodiment of the present invention.
It will be understood by the skilled reader that most or all of the compounds used in the present invention are capable of forming salts, and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free bases. In all cases, the use of the pharmaceuticals described above as salts is contemplated in the description herein, and often is preferred, and the pharmaceutically acceptable salts of all of the compounds are included in the names of them.
Many of the compounds used in this invention are amines, and accordingly react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Since some of the free amines of the compounds of this invention are typically oils at room temperature, it is preferable to convert the free amines to their pharmaceutically acceptable acid addition salts for ease of handling and administration, since the latter are routinely solid at room temperature. Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, b-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable salts are those formed with hydrochloric acid.
Administration
The dosages of the drugs used in the present invention must, in the final analysis, be set by the physician in charge of the case using knowledge of the drugs, the properties of the drugs in combination as determined in clinical trials, and the characteristics of the patient including diseases other than that for which the physician is treating the patient. General outlines of the dosages, and some preferred dosages, can and will be provided here.
Tomoxetine: from about 5 mg/day to about 200 mg/day; preferably in the range from about 60 to about 150 mg/day; more preferably from about 60 to about 130 mg/day; and still more preferably from about 60 to about 120 mg/day;
Compounds of formula I: from about 0.01 mg/kg to about 20 mg/kg; preferred daily doses will be from about 0.05 mg/kg to 10 mg/kg; ideally from about 0.1 mg/kg to about 5 mg/kg;
Reboxetine: from about 1 to about 30 mg, once to four times/day; preferred, from about 5 to about 30 mg once/day;
Duloxetine: from about 1 to about 30 mg once/day; preferred, from about 5 to about 20 mg once/day;
Venlafaxine: from about 10 to about 150 mg once-thrice/day; preferred, from about 25 to about 125 mg thrice/day; and
Milnacipran: from about 10 to about 100 mg once-twice/day; preferred, from about 25 to about 50 mg twice/day.
All of the compounds concerned are orally available and are normally administered orally, and so oral administration is preferred. However, oral administration is not the only route or even the only preferred route. For example, transdermal administration may be very desirable for patients who are forgetful or petulant about taking oral medicine. The drugs may also be administered by the percutaneous, intravenous, intramuscular, intranasal or intrarectal route, in particular circumstances. The route of administration may be varied in any way, limited by the physical properties of the drugs and the convenience of the patient and the caregiver. The following examples illustrate formulations useful for the administration of norepinephrine reuptake inhibitors, and are not intended to limit the scope of the present invention in any way.
The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
The components are blended and compressed to form tablets, each weighing 240 mg.
The active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50xc2x0 C.-60xc2x0 C. and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
The glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90xc2x0 C. When the polymers have gone into solution, the solution is cooled to about 50-55xc2x0 C. and the active ingredient is slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
Psoriasis is a chronic skin disorder of unknown causation, characterized by inflamed skin lesions. A number of different types of psoriasis have been identified, and are described in the following paragraphs.
Erythrodermic psoriasis is an inflamed lesion of the skin with fine scales, and is frequently accompanied by severe pain, itching, and possibly swelling.
Guttate psoriasis is characterized by the appearance of small red dots of psoriasis, typically occurring on the arms, legs, and trunk of the patient.
Inverse psoriasis is inflamed lesions without scales, typically appearing at the armpit, groan, under the breast, and other skin folds.
Plaque psoriasis, the most commonly observed variety, is characterized by inflamed lesions covered with a silvery white scale. Although plaque psoriasis may occur on any skin surface, it is most commonly found on the knees, elbows, scalp, and trunk.
Pustular psoriasis is characterized by the appearance of blister-like lesions of non-infectious pus. The lesions may be localized or widespread over the skin.
Psoriasis may also present itself as pits in toenails and fingernails. The pitting may be accompanied by discoloration and thickening of the nail, and the nail may detach from the nail bed.
Psoriasis is also categorized by degree based upon the prevalence of the lesions. Patients with lesions over less than 2% of their body are considered to have mild psoriasis. Patients with lesions occurring on from 2%-10% of their bodies are considered to have moderate psoriasis, while patients with lesions covering over 10% of their bodies are considered to have severe psoriasis.
The method of the present invention is useful for the treatment of all forms and degrees of psoriasis.
Inhibition or Norepinephrine Reuptake
The ability of compounds to inhibit the reuptake of norepinephrine may be measured by the general procedure of Wong, et al., supra.
Male Sprague-Dawley rats weighing 150-250 gm are decapitated and brains are immediately removed. Cerebral cortices are homogenized in 9 volumes of a medium containing 0.32 M sucrose and 10 mM glucose. Crude synaptosomal preparations are isolated after differential centrifugation at 1000xc3x97g for 10 minutes and 17,000xc3x97g for 28 minutes. The final pellets are suspended in the same medium and kept in ice until use within the same day.
Synaptosomal uptake of 3H-norepinephrine is determined as follows. Cortical synaptosomes (equvalent to 1 mg of protein) are incubated at 37xc2x0 C. for 5 minutes in 1 mL Krebs-bicarbonate medium containing also 10 mM glucose, 0.1 mM iproniazide, 1 mM ascorbic acid, 0.17 mM EDTA and 50 nM 3H-norepinephrine. The reaction mixture is immediately diluted with 2 mL of ice-chilled Krebs-bicarbonate buffer and filtered under vacuum with a cell harvester (Brandel, Gaithersburg, Md.). Filters are rinsed twice with approximately 5 mL of ice-chilled 0.9% saline and the uptake of 3H-norepinephrine assessed by liquid scintillation counting. Accumulation of 3H-norepinephrine at 4xc2x0 C. is considered to be background and is subtracted from all measurements. The concentration of the test compound required to inhibit 50% of the 3H-norepinephrine accumulation (IC50 values) are determined by linear regression analysis.


The invention provides a method and system for correcting imbalance in in-phase and quadrature components of a modulated received signal. The method includes assuming a signal imbalance to exist in the received signal, the signal imbalance having an amplitude imbalance and a phase imbalance, generating an amplitude imbalance correction factor and a phase imbalance correction factor to lessen the signal imbalance, and re-evaluating the amplitude and phase imbalance correction factors over a set of readings of the in-phase and quadrature components until the signal imbalance is minimized.

1. Field of the Invention
The present invention relates to a method and system for detecting and correcting in-phase/quadrature imbalance in digital communication receivers. More particularly, the invention relates to a method for detecting and correcting amplitude and phase imbalance using simulation models.
2. The Background Art
A receiver is used to reprocess signal data received from a channel through undoing signal modifications made at the transmitter and the channel. Typically, the signal is distorted by the channel, as well as by internal and external causes. This distortion may be represented by a signal-to-noise ratio (SNR) defined as the ratio of the signal power to the noise power.
A modulated signal includes an in-phase component and a quadrature component. When the modulated signal is received, after conversion from an analog to a digital signal using an analog-to-digital converter, each bit is demodulated into the in-phase and quadrature signal components using sine and cosine functions. Typically, there is an amount of deviation in the proper alignment of the in-phase and quadrature components of the modulated received signal. This deviation may occur in both the amplitude and the phase of the in-phase and quadrature components of the signal. Moreover, imbalance is typically introduced by a tuner when the signal is received.
When a channel is changed or a channel is newly acquired, correction of signal imbalance is desirable. Typically, correction of the amplitude and phase imbalance is handled by hardware. For example, an equalizer may be used to correct interference present in the received signal. However, equalizers are expensive and not typically required to correct noise present in satellite receiving systems. A need exists for a method and system for first detecting and then correcting imbalance in the in-phase and quadrature signal components which may be implemented in software, significantly reducing the costs of such a system. Through the use of such a system, correction of imbalance may be performed off-line as the signal is being viewed.

Method and system for detecting and correcting in-phase/quadrature imbalance in digital communication receivers


In a method for executing software, a result produced from an execution of a copy of the software by a corresponding platform can be received from each of a plurality of platforms. A number of results of execution of the software can be determined. The extent to which the results match can be compared to a threshold. The matching results can be accepted as an agreed-upon output of the software when the extent to which the results match is equal to or greater than the threshold. The software can include an implementation of at least a portion of an act associated with an agreement between at least two entities.

Agreements between entities, such as persons and businesses, underpin a wide variety of transactions, particularly in commercial settings. Agreements that create legally enforceable obligations are known as contracts. A smart contract is a machine that facilitates implementation of at least a portion of an act associated with an agreement between entities. For example, a vending machine can be a realization of a smart contract between a purchaser and an owner of the merchandise inside the vending machine. A smart contract can also be realized using computer hardware, software, or a combination of both. Because portions of acts associated with agreements between entities can be automated by computerized systems, advocates of smart contracts believe that the transactional costs of smart contracts may be less than the transactional costs of traditional contracts.
Another example of a smart contract is a starter interrupt device, which allows a lender at a remote location to disable an automobile whose owner is late making a payment on a loan. More generally, aspects of smart contracts can be found in computer-implemented systems and software that provide quality of service mechanisms associated with service level agreements for packet switched computer networks, automated digital rights management for copyright licenses, cryptographic systems such as those that are often used for financial transactions, and automated enforcement mechanisms in peer-to-peer file sharing networks.

System and method for ensuring correct execution of software


Load balancing of client transactions, for the duration of a client session, in a Web site is implemented by a cluster of servers. An initial request in each client session is sent to the site load balancer, thus, greatly enhancing the capability of the site to accept new session requests. All subsequent requests from a client are forwarded directly to the server first selected so that the sessions cannot be later broken by the load balancer.

The present invention deals with the global Internet network and more particularly to those of the Internet Servers of World Wide Web (WWW)sites organized as a cluster or group of servers forming a single entity.
The Internet is the world""s largest network, and it has become essential in organizations such as government, academia and commercial enterprises. Transactions over the Internet are becoming more common, especially in the commercial arena. The information that organizations have on their traditional or legacy business applications may now be published and made accessible to a wide audience. This access may include a person checking a bank savings account, making a hotel reservation or buying tickets for a concert. Making this information or service available for their customers is a competitive advantage for any organization. However, regardless of the innovation and potential benefits provided by a company""s Internet solution, its value is greatly reduced if the information cannot be accessed in a reasonable response time. The load on an Internet site is unlikely to remain constant. The number of accesses on a Web server can increase for several reasons.
1. Most companies add their Web site""s address to television, radio and print advertising and to product catalogues and brochures. Therefore, awareness of the Web site grows.
2. As time passes, the Web site gains better coverage in the on-line search engines.
3. Assuming the site is providing useful information or a useful service to customers, repeat visitors should increase.
4. Most Web sites begin simply, with fairly modest content, mostly text, with some images. As the site designers grow in confidence, more resources are allocated, and as Web users in general increase their modem speeds, most sites move towards richer content. Thus, not only do hit rates increase, but the average data transfer per hit also rises.
5. Most sites begin as presence sites providing corporate visibility on the Internet and making information about the company available to potential customers. Most present sites use predominantly static Hyper Text Marked-up Language or HTML pages. Static pages are generated in advance and stored on disk. The server simply reads the page from the disk and sends it to the browser. However, many companies are now moving towards integration applications that allow users of the Web site to directly access information from the company""s existing applications. This could include checking the availability of products, querying bank account balances or searching problem databases. These applications require actual processing on the server system to dynamically generate the Web page. This dramatically increases the processing power required in the server.
There are several ways to deal with the growth of an Internet site, like purchasing an initial system that is much too large. This is one way to deal with Web site growth; however, most companies are not willing to invest large sums of money in a system that is much larger than they require, particularly since the benefits that they will gain from the site have yet to be proven. Most prefer to purchase a minimal initial system and upgrade as the site demonstrates its worth to the company. In this realm of solutions, load balancing between multiple servers is very often used. In this case, the load for the overall site is balanced between multiple servers. This allows scaling beyond the maximum performance available from a single system and allows for easy upgrading by simply installing additional servers and reconfiguring the cluster to use the additional servers. This solution can also provide the added benefit of higher server availability. The load-balancing software can automatically allow for the failure of a single server and balance the load between the remaining sites. Because the Internet model allows the distribution of services among different servers, called Internet Servers, it is definitively feasible not to tie an application to one specific server. Instead, the service belongs to a group of servers; so an additional computer can be added or removed when necessary. However, grouping the set of servers in a single entity implies that load balancing is efficiently performed between these servers so as to actually achieve optimum performance. A discussion on this and more on load balancing can be found, for example, in a paper by Dias et al., xe2x80x9cA Scalable and Highly Available Web Serverxe2x80x9d, Digest of Papers, Compcon 1996, Technologies for the Information Superhighway, Forty-first IEEE Computer Society International Conference (Cat. No. 96CB35911), pp. 85-92, February 1996.
Load-balancing products have made their way to the market. IBM""s eNetwork Dispatcher (eND) is one of those products now commercially available. It creates the illusion of having just one server by grouping systems together into a cluster that behaves as a single, virtual server. The service provided is no longer tied to a specific server system; so it is possible to add or remove systems from the cluster, or shutdown systems for maintenance, while maintaining continuous service for the clients. The balanced traffic among servers seems for the end users to be a single, virtual server. The site thus appears as a single IP (Internet Protocol) address to the world. All requests are sent to the IP address of the e Network Dispatcher machine, which decides with each client request which server is the best one to accept requests, according to certain dynamically set weights. Network Dispatcher routes the clients"" request to the selected server, and then the server responds directly to the client without any further involvement of eND. This makes it possible to have a small bandwidth network for incoming traffic (like Ethernet or token ring) and a large bandwidth network for outgoing traffic (like ATMxe2x80x94Asynchronous Transfer Mode or FDDIxe2x80x94Fiber Distributed Data Interface or Fast Ethernet). It can also detect a failed server and route traffic around it. General information on the way of performing load balancing between multiple servers and an eND product can be found in a xe2x80x98Redbookxe2x80x99 by IBM published by the Austin, Tex. center of the International Technical Support Organization (ITSO) and entitled xe2x80x9cLoad-Balancing Internet Serversxe2x80x9d under the reference SG24-4993 on December 1997.
Those products are great for what they have been designed for, i.e., load-balancing, and indeed allow building of a scalable Web site capable of coping with a rapidly growing demand for higher traffic. However, they have also created their own difficulties. Because there are now numerous sophisficated Web servers that allow handling dynamic Web pages, they need to be session-aware for every user accessing their service. Several techniques indeed exist to keep track of the context in which a particular user is accessing a Web server. They are of two kinds:
the contextual data is circulating, back and forth, in the IP packets exchanged between the client and the servers. For example, it can be part of the Web pages themselves.
or the contextual data is kept in the Web server active memory or on disk. This second solution is necessary whenever the amount of data needed to define each session context is too large to be practically transported over the network with each transaction between the client and the servers.
Then, load-balancing products such as eND manage not to randomly dispatch the traffic to the servers of their cluster. They keep track of the user requests which must end up in the same server while a session is active. To achieve this, the usual technique, well known in the art, comprises utilizing the IP address of the client. Then, each transaction coming from the same IP address is dispatched to the same server.
However, this does not fit in the now frequent situations in which the end user and the server are on either side of a proxy, socks or fire-wall. All those devices, part of the Internet, are intended to deal with specific problems like, for example, the isolation of an intranet that must not be freely accessible by outsiders without any control, thus, leading to placement of a fire-wall at the intranet gateway, or a proxy, so the users within an intranet see the whole Internet through a common gateway device, somehow caching it, in an attempt to achieve better performance overall. In these situations, the client IP address is not actually known by the network dispatcher which establishes a TCP connection (the Transport Control Protocol of the Internet protocol suite) with the proxy, the socks or the fire-wall, rather than directly with the end-user. Therefore, the network dispatcher is no longer session aware, that is, it has no information that would allow it to decide that a particular end-user, for example located beyond a proxy, that was engaged in a transaction, such as buying a product from a virtual shop, an application that was first selected by the dispatcher on a particular server in the cluster of servers, has not yet completed. Then, further requests from the end-user, sometimes occurring after a long pause, could be dispatched differently by the network dispatcher just because it does its job of balancing the traffic towards a less busy server within the cluster with the obvious consequence that the new server is not aware of the transaction in progress.
There is another undesirable effect of having the end-users beyond a proxy for a load balancer. All the individual users within a group, for example, an intranet, then appear to the load balancer as a single user because their IP address is the same since it is the one of the proxy or fire-wall. Therefore, the load balancer which tends to maintain the dispatching of a given user towards the same server, in an attempt to not break sessions, at least while an inactivity timer has not elapsed, keep sending the traffic of the whole intranet to the same server. This seriously goes against what this kind of product is trying to achieve, i.e., load balancing. Although the individual users within a group would certainly enjoy not being served by the sometimes same busy server, because they are seen as being a single client by the load balancer, it is no longer possible to discriminate the individual users.
Thus, it is a broad objective of the invention to overcome the shortcomings, as noted above, of the prior art, and, therefore, enable a particular server, within a cluster of servers, to continue serving a given end-user while the current session is active and being able to discriminate the individual users within a group (intranet) so as to maintain a good load balancing over the cluster of servers.
For a more complete understanding of the present invention and for further advantages thereof, reference is now made to the following Detailed Description taken in conjunction with the accompanying drawings, in which:
It is a further object of the invention to improve the efficiency of the load balancer by requiring only one interrogation per session, thus, freeing it to dispatch even more transactions over the cluster of servers.
Further advantages of the present invention will become apparent to the ones skilled in the art upon examination of the drawings and detailed description. It is intended that any additional advantages be incorporated herein.
A method and system for preserving load balancing of client transactions, for the whole duration of the client sessions, in a Web site comprising a plurality of servers and including a load balancer accessed from a plurality of clients is described. Upon receiving a client initial request, the load balancer selects a particular server among the plurality of servers. Then, the initial request is forwarded to the selected server which issues, towards the client, a response uniquely referencing the selected server. Hence, all subsequent requests from the client are forwarded directly to the uniquely referenced server.
The method of the invention allows sending only the initial request of a client session to the load balancer of a Web site organized as a cluster of servers, thus, greatly enhancing the capability of the site to accept new session requests.
Moreover, the client sessions being effected directly between the client and the server which was initially selected, cannot be later broken by the load balancer.
Finally, the scheme works regardless of the fact that the client is beyond a proxy or a firewall, contrary to the previous art, that could only rely on the IP address of the client request to perform load balancing and to decide if a session has ended or not, leading to imperfect results both in terms of load balancing and broken sessions, especially when the actual IP address of the end user is masked by one of the above mentioned devices.

Method and system for dispatching client sessions within a cluster of servers connected to the world wide web

International Business Machines Corporation


An inhalator composed of a main body affording an inhalation conduit; a second body exhibiting a housing, into which a capsule can be at least partially inserted; the second body being rotatably coupled with the main body, and being able to rotate from an open position, in which the housing is accessible from outside for insertion of a capsule, and a closed position, in which the housing is in communication with the inhalation conduit; means for cutting off a portion of a capsule which projects from the housing during rotation of the second body from the open position to the closed position.

Inhalators of this type are known in the prior art and are constituted by a container comprising an inhalation conduit in communication with a chamber for housing a capsule containing a pharmaceutical substance to be inhaled. The housing chamber is elongate, and of a same shape as usual capsules for powder-form drugs, and is transversaly arranged with respect to a longitudinal development of the inhalation conduit. Means for breaking open the capsule are associated to the housing chamber and arranged at ends thereof, the means for breaking are constituted by two piercing devices, including a number of sharp teeth which penetrate the housing chamber. The teeth are kept in an external position in relation to the chamber by a plurality of springs and exhibit a portion which is external to the container in which it is possible to exert a pressure with the fingers to cause perforation of the capsule. The powder can at this point exit from the capsule and be inhaled.
EP 1 238 680 discloses an inhaler comprising: means to hold the capsule inside said cover, with an open compartment, of circular shape, placed directly inside the cover, into which the capsule is placed, resting on the circular groove of said compartment; means to hold the pieces of the case of the capsule, after it has been split, and to prevent the powder from aggregating, with a reservoir having a series of slots on its walls that hold the bigger pieces inside, while letting the powder pass through; means to close the container, with a cover, which holds the capsule and closes the horizontal chamber, having two outer protrusions on its walls that stop under the inner protrusions of the chamber, preventing the cover from accidentally escaping from its place; means to allow the cover to rotate, thanks to the circular shape of the same cover and the chamber, so as to split the capsule with a simple rotation of the cover, in any direction, till a blade element reaches and cuts the capsule; means to split the capsule, with an element, consisting of a circular plate comprising a hole, whose vertical axis is laterally moved from the one of the inhaler, which holds the lower part of the capsule, so that, by rotating said element, the blade below cuts the lower part of the capsule.
The known-type inhalators exhibit numerous drawbacks,
A main drawback is the presence of a relatively high number of components, considering the presence of the piercing devices, the springs and the maneuvering ends of the piercing devices. Some of these components are in relative motion with respect to the container and there is therefore a liability of malfunctioning or jamming. These components also require careful assembly operations in order to function correctly, which lead to an increase in cost of the inhalator.
Prior art inhalators also exhibit some functional defects. Firstly, perforation of the capsule does not guarantee complete exit of the medicinal substance, as the openings created are at ends of the capsule and small in size. To favour exit of the substance the inhalator has to be shaken and several inhalations performed, and still without the certainty of hag consumed all of the capsule's contents. The position of the housing chamber, which is aligned with the inhalation conduit, is such that the passage of the medicinal substance from the chamber to the inhalation conduit is considerably obstructed. To favour inhalation the device has to be inclined in order to raise the inhalation chamber, and consequently the medicinal substance is not directly aspirated into the trachea but enters partly into contact with the inside of the mouth and is thus less effectively absorbed by the patient.
A further drawback of the inhalators of known type is that the cut portion of the capsule falls into the reservoir together with the powder. A part of the powder may remain entrapped in this cut portion of the capsule, or the cut portion may lay into the reservoir obstructing the flow of the powder through the inhaler, in both cases causing au incomplete inhalation of the powder
The main aim of the present invention is to obviate the above-described drawbacks by providing an inhalator for single-dose mixtures in capsules, which is characterized by having a limited number of components.
A further aim of the resent invention is to provide an inhalator in which the medicinal mixture is made available for inhalation by being completely transferred to the inhalation conduit.
A further aim of the present invention is to provide an inhalator in which the mixture is inhaled by means of a simple drawing-in of breath by the user.
With reference to the figures of the drawings, 1 denotes in its entirety the inhalator of the invention. It comprises a main body 2 having an inhalation conduit 3. The main body 2 comprises a first surface 10 which extends more-or-less planarly and parallel to the longitudinal axis of the inhalation conduit 3 and exhibits a hole 8 for communication with the inhalation conduit 3.
Advantageously the main body 2 can be made of a transparent material.
The inhalator 1 further comprises a second body 4 which exhibits a second surface 14 which is complementarily shaped with respect to the first surface 10 and is in contact there-with. A housing 5 is afforded in the second surface 14, in which a capsule 30 can be at least partially inserted. The second body 4 is rotatably coupled to the main body 2 so that it can rotate from an open position, in which the housing 5 is accessible from the outside for insertion of a capsule 30, to a closed position, in which the housing 5 is aligned with the hole 8.
Advantageously, the second body 4 can be made of a transparent material.
The inhalator 1 further comprises means for cutting 11 for cutting away, as will be better explained herein below, a portion of the capsule 30 which projects from the housing 5 during rotation of the second body 4 from the open position to the closed position.
The first surface 10 is, overall, shaped as a segment of a circle with an apex thereof located in an intermediate position with respect to the longitudinal 5 development of the inhalation conduit 3. The first surface 10 comprises a pivot 12 which is perpendicular to the first surface 10 and is arranged in about the same position as the apex of the first surface 10; the first surface 10 exhibits a guide spur 13 which is perpendicular to the first surface 10 and has a lateral projection 13a and a strike surface 13b. The lateral projection 13a is an undercut afforded on a lateral surface of the spur 13 so that the portion of pivot 12 which is close to the first surface 10 has a smaller section than the remaining portion of the pivot 12.
The means for cutting 11 comprise a cutting edge 11a, arranged peripherally on the first surface 10, which exhibits a sawtooth shape. As the first surface 10 and the second surface 14 are in contact, during the rotation of the second body 4 from the open position to the closed position the portion of the capsule 30 projecting from the housing 5 interferes with the cutting edge 11a, and is cut by the sawtooth edge of the cutting edge. The cut portion remains external of the inhalator.
The inhalation conduit 3 exhibits a first opening 6 for aspiration of air from the outside, arranged on the first surface 10, and a second mouth 7 for inhalation of a single-dose mixture. The hole 8 is arranged on the first surface 10 in an intermediate position between the first and the second mouths 6 and 7. The second mouth 7 is used by the user to aspirate the medicinal mixture, while air passes through the first mouth 6 to enter the inhalator. To facilitate inlet of air through the first mouth 6, a channel can be afforded on the first surface 10, extending from the edge of the first surface 10 to the first mouth 6. In a correct use of the inhalator, once the capsule 30 has been cut, the inhalator is gripped in such a way that the housing 5 is vertical and the cut end of the capsule 30 is facing downwards. The medicinal mixture falls from the capsule 30 into the inhalation conduit through the hole 8 and into the flow of air which is taken in through the first mouth 6 and entrained towards the second mouth 7 by the inhaling action exerted by the user.
The inhalation conduit 3 exhibits a longitudinal section which is similar to a venturi tube and the hole 8 is arranged at the smallest-section end, i.e. the gullet end. The medicinal mixture which drops down from the capsule 30 is very effectively drawn into the air flow in transit towards the mouth of the user, and the depression which is created in the gullet section of the conduit 3 draws any residues of medicinal mixture left in the capsule 30 or the hole 8 into the conduit 3. To prevent blockage, the hole 8 internally comprises a baffle 9 arranged across a diameter of the hole 8.
The second body 4 comprises a seating 15 which faces onto the second surface 14 and is predisposed to be inserted on the pivot 12 and to achieve a rotatable coupling between the main body 2 and the second body 4, in which coupling the first surface 10 and the second surface 14 are in reciprocal contact, one sliding on the other. The seating 15 is afforded in the breadth of the second body 4 and is oriented so that a lateral surface thereof is arranged perpendicular to the second surface 14. In the illustrated embodiment, the seating 15 exhibits a C-shaped transversal section and the pivot 12 has a cylindrical shape with a lateral flat area enabling the main body 2 and the second body 4 to be unhinged in a predetermined angular position.
The second body 4 further exhibits a ledge 16 made along an edge of the second body 4, a shape of which complements the undercut 13a of the guide spur 13 and which is predisposed to interact in contact with the undercut 13a. When the main body 2 and the second body 4 are coupled, the ledge 16 is inserted below the undercut 13a and rotations that tend to separate the first surface 10 and second surface 14 are prevented.
The second body 14 further comprises a strike surface 17, perpendicular to the longitudinal development of the ledge 16, arranged at an end of the ledge 16 itself, and predisposed to meet the strike surface 13b of the guide spur 13. The contact between the strike surface 17 and the strike surface 13b defines a limit to angular displacement between the first surface 10 and the second surface 14, which limit is the closed position.
To ease opening and closing of the inhalator, the second body 4 comprises a transversal maneuvering surface 18, perpendicular to the second surface 14 and extending on the opposite side of the second body 4 with respect to the second surface 14. By acting on the maneuvering surface 18 it is extremely simple to perform a cutting action on a capsule 30 inserted in the housing 5.
The inhalator of the invention offers important advantages.
First of all, it basically comprises only two components, assembly of which is extremely simple. The inhalator is thus decidedly economical to produce and is practically without risk of jamming or malfunctioning.
Secondly, the arrangement of the housing for the capsule, as well as the complete cutting-open thereof, make the contents of the capsule fully available for inhalation, giving the user the certainty of having completely inhaled the correct dose. If transparent materials have been used, the user can fully check, even more easily, that he or she has completed inhalation of the full dose.
Thirdly, as the medicinal mixture is deposited internally of the inhalation conduit and internally of the flow of air created by the user's aspiration, the inhalator can be kept in a horizontal position. In this horizontal position, the longitudinal axis of the inhalation conduit is aligned with the mouth of the user, which enables the medicinal powders to reach the trachea without depositing on the internal parts of the mouth.