Low water soluble salts of venlafaxine, especially venlafaxine maleate, are provided. Such salts can provide a variety of dosage forms including hydrogel-based extended release dosage forms.

The present invention relates to low water-soluble venlafaxine salts, especially venlafaxine maleate, various forms thereof, and the use of the same in pharmaceutical compositions for treating depression and other conditions.
Venlafaxine is the common name for the compound 1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl]cyclohexanol, having the structure shown below.
U.S. Pat. No. 4,535,186 describes a class of hydroxycycloalkanephenethyl amines as being useful antidepressants and exemplifies the compound now known as venlafaxine hydrochloride as one of the suitable species. Venlafaxine hydrochloride is approved for sale in various countries including the United States of America. It is available as an immediate release tablet and as an extended release capsule, under the brand name EFFEXOR(copyright) (Wyeth Ayerst) and EFFEXOR XR(copyright) (Wyeth Ayerst) respectively.
Venlafaxine has been the subject of various research endeavors. For example, U.S. Pat. No. 5,043,466 describes a process for making cyclohexanol derivatives in a specified solvent composition. Example 3 of this patent shows the synthesis of venlafaxine as the hydrochloride salt thereof.
U.S. Pat. No. 6,274,171 and related EP 0 797 991A1 disclose encapsulated extended release formulations for venlafaxine hydrochloride. These patents indicate that commercial venlafaxine hydrochloride tablets were administered two or three times daily, but that due to variations in the drug concentration in the patient""s blood plasma caused by such a dosing regimen, unwanted side effects, especially nausea and vomiting were common. A once daily, encapsulated extended release dosage form is disclosed that provides a flattened drug plasma profile and reduces these side effects. The encapsulated dosage form is taught to comprise spheroids of venlafaxine hydrochloride, microcrystalline cellulose, and hydroxypropylmethylcellulose (HPMC). These spheroids are coated with a mixture of ethyl cellulose and HPMC. By providing an appropriate amount of the coating, the desired blood plasma profile can be obtained. An acceptable batch of coated spheroids will meet the following in vitro dissolution profile:
using USP Apparatus 1 (basket) at 100 rpm in purified water at 37xc2x0 C. The coated spheroids can be from a single batch or represent a blend of different batches.
U.S. Pat. No. 6,274,171 and EP 0 797 991 also state that forming an extended release dosage form of venlafaxine hydrochloride was difficult in part due to the high water solubility of the hydrochloride salt. In fact, these patents disclose that xe2x80x9c[n]umerous attempts to produce extended release tablets by hydrogel technology proved to be fruitless because the compressed tablets were either physically unstable (poor compressibility or capping problems) or dissolved too rapidly in dissolution studies.xe2x80x9d See U.S. Pat. No. 6,274,171 at column 4, lines 60-65 and EP 0 797 991 at page 3 lines 35-37. Unlike the encapsulated extended release formulations described in these patents, a hydrogel extended release venlafaxine hydrochloride tablet is taught to typically exhibit a dissolution profile wherein 40%-50% is released at 2 hours, 60%-70% is released at 4 hours, and 85%-100% is released at 8 hours.
WO99/22724 also discloses encapsulated venlafaxine hydrochloride extended release dosage forms. These formulations differ from those in U.S. Pat. No. 6,274,171 and EP 0 797 991 in that the spheroid is substantially free of HPMC. Apparently HPMC can be omitted from the spheroid when smaller amounts of venlafaxine hydrochloride are employed.
U.S. Pat. No. 6,197,828 and WO00/32556 discloses the use of individual (+) and (xe2x88x92) enantiomers, respectively, of venlafaxine as well as metabolites thereof. While the commercial venlafaxine hydrochloride is a racemate, these patents teach that various side effects may be reduced by using one isomer substantially without the presence of the other.
Although venlafaxine hydrochloride provides good pharmaceutical activity, it would be beneficial to find other forms of venlafaxine. In particular, venlafaxine forms that are easier handle would be advantageous. Venlafaxine hydrochloride is relatively aggressive towards handling equipment and is irritating to the skin, etc. of human personnel that handle the pure active. A venlafaxine form that is less aggressive and less irritating would be desirable. It is further desirable to provide a venlafaxine form that can be easily formulated into various dosage forms including hydrogel extended release tablets.
The present invention is based on the discovery of low water-soluble venlafaxine salts. Unlike venlafaxine hydrochloride, the low water-soluble salts of the present invention are more easily formulated into extended release formulations including hydrogel tablets. Thus, a first aspect of the present invention relates to a low water-soluble venlafaxine salt. Such salts exhibit lower water-solubility relative to venlafaxine hydrochloride and preferably 380 mg/ml or less.
A preferred low water-soluble venlafaxine salt is venlafaxine maleate. Accordingly, a second aspect of the invention relates to a venlafaxine maleate compound. The compound can be isolated and/or purified or it can be part of a composition. The compound can be in solid form including crystalline forms but is not limited thereto. A preferred compound is crystalline venlafaxine hydrogenmaleate anhydrate.
Another aspect of the present invention relates to a pharmaceutical composition comprising an effective amount of venlafaxine maleate and a pharmaceutically acceptable excipient. The composition can be an immediate release dosage form or an extended release dosage form and embraces tablets as well as pellets/beads/spheroids or other encapsulated forms. In one embodiment, the venlafaxine maleate is provided in a hydrogel tablet. The hydrogel tablet preferably provides sufficient extended release so that the tablet is a once daily dosage form.
An additional aspect of the present invention relates to a pharmaceutical composition comprising a low water-soluble venlafaxine salt and a hydrophilic matrix material. Such a composition includes finished hydrogel tablets as well as tabletting powder blends and other intermediates in making a final dosage form. The hydrogel tablet exhibits extended release such that no more than twice daily dosing and preferably once daily dosing can be achieved.
A further aspect of the invention relates to the use of a low water-soluble venlafaxine salt, and in particular venlafaxine maleate, in treating venlafaxine-treatable diseases or conditions. Hence the invention provides a method for treating a venlafaxine-treatable disease or condition, which comprises administering to a patient in need thereof an effective amount of a low water-soluble venlafaxine salt such as venlafaxine maleate. The low water-soluble salt is typically administered as an oral composition such as a tablet or capsule and is preferably administered once daily.
The present invention is based on the surprising discovery that various salts of venlafaxine are low water-soluble relative to the water solubility of venlafaxine hydrochloride. As used herein xe2x80x9clow water-solublexe2x80x9d venlafaxine salt means that the salt exhibits a water solubility that is less than two thirds the water solubility of venlafaxine hydrochloride, preferably less than half, more preferably one third and more preferably less than one quarter the water solubility of venlafaxine hydrochloride. In absolute values, a low water-soluble salt of venlafaxine preferably has a water solubility of 380 mg/ml or less, preferably 200 mg/ml or less, more preferably 150 mg/ml or less.
Such low water soluble salts include venlafaxine maleate compounds and venlafaxine benzenesulfonate (besylate) compounds and is expected to also include venlafaxine fumarate compounds, but is not limited thereto. Any salt of venlafaxine that exhibits a solubility within the above range is included within the meaning of low water soluble salts. Venlafaxine besylate compounds are more fully described in U.S. provisional patent application serial No. 60/367,734, filed Mar. 28, 2002, entitled xe2x80x9cVenlafaxine Besylate,xe2x80x9d the entire contents of which are incorporated herein by reference. For simplicity, the present invention will be described with reference to a venlafaxine maleate compound, but it should be understood that it equally applies to all low water-soluble venlafaxine salts.
A venlafaxine maleate compound is any form of the salt formed by venlafaxine and maleic acid. Typically the venlafaxine and maleate moieties are present in about a 1:1 molar ratio, which is referred to herein as xe2x80x9cvenlafaxine hydrogenmaleate.xe2x80x9d However, other ratios such as 2:1 or 3:2 are also possible due to the fact that maleic acid contains two acid groups, each having the potential to from a salt with a venlafaxine moiety. In addition, venlafaxine maleate is less aggressive, less irritating, and easier to handle than venlafaxine hydrochloride. Note that maleic acid is generally easier to handle than hydrochloric acid. Accordingly, venlafaxine maleate is easier to formulate into a variety of dosage forms, especially extended release dosage forms, than venlafaxine hydrochloride. The preferred form is the venlafaxine hydrogenmaleate.
Venlafaxine maleate compounds are low-water soluble venlafaxine salts. For example, venlafaxine hydrogenmaleate anhydrate exhibits a water solubility of about 370 mg/ml, i.e. 368 mg/ml, while venlafaxine hydrochloride exhibits a water solubility of about 570 mg/ml at ambient conditions.
The venlafaxine in the venlafaxine maleate compound of the present invention can be any form of venlafaxine. For example, venlafaxine has one optically active carbon, thus allowing for existence of two enantiomers and a racemate. Both enantiomers are pharmaceutically active. The venlafaxine maleate compound can be based on the racemate or mixture of enantiomers of venlafaxine or on the pure or substantially pure (+) or (xe2x88x92) enantiomer of venlafaxine (hereinafter referred to as (+)-venlafaxine maleate and (xe2x88x92)-venlafaxine maleate): all are included within the meaning of xe2x80x9cvenlafaxine maleatexe2x80x9d unless specifically noted otherwise.
The compound can be in isolated and/or purified form, but such is not required. The compound includes various physical forms of the salt including dissolved forms, oil or liquid forms, and solid forms including amorphous and crystalline forms.
The compound is typically in a crystalline form. Crystalline forms include venlafaxine maleate anhydrates, hydrates, and solvates. Preferably the venlafaxine maleate is venlafaxine maleate anhydrate, more preferably venlafaxine hydrogenmaleate anhydrate.
A venlafaxine maleate compound can be prepared by contacting a venlafaxine substrate with a maleate substrate. Typically the contacting occurs in a suitable solvent system. The venlafaxine maleate product can be isolated, if desired, by precipitation, evaporation, spray drying, or other conventional techniques known in the art.
The xe2x80x9cvenlafaxine substratexe2x80x9d includes any substance that provides a venlafaxine moiety or ion thereof and specifically includes racemic and enantiomeric venlafaxine base, a venlafaxine salt other than venlafaxine maleate, e.g. venlafaxine HCl, or a raw venlafaxine, i.e. a reaction product or reaction mixture comprising venlafaxine that has been obtained after the last step of production of venlafaxine. The venlafaxine substrate can be obtained by conventional processes and synthesis schemes known in the art. For example, U.S. Pat. Nos. 4,535,186, 5,043,466, and 6,197,828 all teach methods for making venlafaxine. Venlafaxine base in its isolated state is obtainable by neutralization of venlafaxine hydrochloride, extraction by ethyl acetate and evaporation of the solvent, according to the method disclosed in U.S. Pat. No. 6,197,828 and WO 00-32566. Alternatively, venlafaxine base can be obtained as a precipitate, preferably a filtratable precipitate, by the use of a contrasolvent, e.g. heptane, optionally with cooling and/or solvent removal, without the need to convert to a salt, as is more fully described in U.S. provisional patent application serial No. 60/367,736, filed Mar. 28, 2002, entitled xe2x80x9cVenlafaxine Free Base,xe2x80x9d the entire contents of which are incorporated herein by reference. Single enantiomers of venlafaxine free base can be made as described in J.Med.Chem. 1990, 33 (10), 2899-2905. Venlafaxine hydrochloride is commercially available and can be produced according to U.S. Pat. No. 4,535,186, EP 112669, U.S. Pat. Nos. 5,043,466, 6,197,828 and WO 01-07397. Other salts can be formed by methods analogous to those disclosed in these cited patent documents.
The xe2x80x9cmaleate substratexe2x80x9d includes any substance that provides a maleic acid moiety or ion thereof and specifically includes any form of maleic acid as well as a salt of maleic acid with a base. A preferred substrate is maleic acid. Maleate substrates are commercially available and/or may be prepared by methods known in the prior art.
The molar ratio of the substrates is not particularly limited and is generally about stoichiometric to the desired ratio. Typically a slight excess of maleate substrate is used. Commonly the molar ratio of venlafaxine substrate to maleate substrate is within the range of 0.8:1 to 1.2:1, more typically 0.9:1 to 1.1:1 or about 1:1. However, up to a significant excess of one substrate, especially the maleate substrate can be used. Such excess of either maleate or venlafaxine is typically in the range of 1.1 to 3.0:1, more typically 1.1 to 2:1. For economy reasons, excesses are normally kept small and typically the excess maleate substrate, if any, is provided in slight stoichiometric excess such as 1.01 to 1.5 times the molar amount of venlafaxine.
The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting maleate. Advantageously, both venlafaxine substrate and the maleate substrate are dissolvable in the solvent system, at least at elevated temperatures. In the process, a mixture, slurry, or solution of venlafaxine substrate and a solvent may be contacted with a maleate substrate, or conversely, a mixture, slurry, or solution of maleate substrate and a solvent may be contacted with venlafaxine substrate. In another embodiment, both partners may be combined with a solvent system prior to being contacted together, whereby the solvent system used for maleate substrate may be identical with or different from the solvent system used for the venlafaxine substrate. The solvent system can be comprised of a single solvent or a mixture of solvents. When two or more solvents are used, a two phase reaction scheme may be used wherein the venlafaxine substrate and maleate substrate are primarily reacted in one phase and the resulting venlafaxine maleate compound is primarily present in the other phase due to, inter alia, solubility differences, etc. Suitable solvents include water, a lower alcohol (C1-C6) such as methanol or ethanol, an aliphatic ketone such as acetone, an ether such as dioxane, an ester such as ethyl acetate, and mixtures thereof.
The temperature of contact of both substrates in the solvent system is from ambient to the boiling point of the solvent system, the later being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two phase solution are also possible, though a single solution is generally preferred.
The venlafaxine maleate compound can be isolated or recovered from the salt forming reaction by any convenient means. For example, the venlafaxine maleate compound can be precipitated out of a solution or reaction mixture. The precipitation may be spontaneous depending upon the solvent system used and the conditions. Alternatively, the precipitation can be induced by reducing the temperature of the solvent, especially if the initial temperature at contact is elevated. The precipitation may also be facilitated by reducing the volume of the solution/solvent or by adding a contra solvent, i.e. a liquid miscible with the solvent in which the venlafaxine maleate is less soluble. Seed crystals of venlafaxine maleate may also be added to help induce precipitation. The precipitated venlafaxine maleate compound can be isolated by conventional methods such as filtration or centrifugation, optionally washed and dried, preferably under diminished pressure.
Alternatively, the venlafaxine maleate compound can be isolated by evaporating away the solvent and collecting the residue. Such a method generally leads to an oil or solid amorphous form of venlafaxine maleate. Similarly, an amorphous solid form of the venlafaxine maleate compound can be recovered by spray drying or freeze drying a solution containing the venlafaxine maleate compound.
In a preferred mode, venlafaxine base is dissolved in acetone under heating, maleic acid is added to the solution under stirring, the mixture is heated to complete dissolution and the clear solution is allowed to cool. Venlafaxine maleate anhydrate crystallizes from the solution and is separated by filtration and dried.
Venlafaxine maleate prepared in solid state may be, if necessary, purified to the desired degree of purity. Venlafaxine maleate can be purified for instance by a (re)crystallization from a suitable solvent that may be identical or different from the solvent system used for its production. Examples of preferred suitable solvents for a purifying crystallization step are acetone, ethanol, water, and combinations thereof.
Single enantiomers of venlafaxine maleate may be prepared essentially as disclosed above, whereby the venlafaxine substrate comprises the single enantiomer of venlafaxine. Preferred substrates are single enantiomers of venlafaxine base or venlafaxine hydrochloride.
The venlafaxine maleate compound of the present invention can be formulated with a pharmaceutically acceptable excipient into a pharmaceutical composition. The pharmaceutical compositions of the present invention include the unit dosage form as well as the intermediate bulk formulations such as pellets, beads, powder blends, etc. Typically the composition is a finished dosage form also referred to as a unit dose. Dosage forms include oral dosage forms, topical dosage forms such as a transdermal patch, parenteral dosage forms such as an injectable solution, and rectal dosage forms such as a suppository, but is not limited thereto. Oral dosage forms are the most preferred due to the ease of administration and include solid oral dosage forms such as capsules, tablets, sachets/granules, and powders, as well as liquid oral dosage forms such as solutions, suspensions, and emulsions.
Pharmaceutically acceptable excipients are well known in the art and include diluents, fillers, binders, lubricants, disintegrants, glidants, colorants, pigments, taste masking agents, sweeteners, plasticizers, and any acceptable auxiliary substances such as absorption enhancers, penetration enhancers, surfactants, co-surfactants, and specialized oils. The proper excipient(s) are selected based in part on the dosage form, the intended mode of administration, the intended release rate, and manufacturing reliability. Examples of common types of excipients include various polymers, waxes, calcium phosphates, and sugars. Polymers include cellulose and cellulose derivatives such as HPMC, hydroxypropyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, and ethylcellulose; polyvinylpyrrolidones; polyethylenoxides; and polyacrylic acids including their copolymers and crosslinked polymers thereof, i.e. Carbopol(copyright) (B. F. Goodrich), Eudragit(copyright) (Rohm), polycarbophil and chitosan polymers. Waxes include white beeswax, microcrystalline wax, carnauba wax, hydrogenated castor oil, glyceryl behenate, glycerylpalmito stearate, saturated polyglycolyzed glycerate. Calcium phosphates include dibasic calcium phosphate, anhydrous dibasic calcium phosphate, and tribasic calcium phosphate. Sugars include simple sugars such as lactose, maltose, mannitol, fructose, sorbitol, sacarose, xylitol, isomaltose, and glucose as well as complex sugars (polysaccharides) such as maltodextrin, amylodextrin, starches, and modified starches.
Any form of the venlafaxine maleate can be used in the pharmaceutical composition. Preferred venlafaxine maleate forms are: crystalline venlafaxine hydrogenmaleate anhydrate, (+)-venlafaxine maleate anhydrate, and (xe2x88x92)-venlafaxine maleate anhydrate. The amount of venlafaxine maleate compound contained in a unit dosage form is an amount effective to treat one or more venlafaxine-treatable diseases or conditions as is hereinafter defined and can be determined by workers skilled in the art without undue experimentation. Generally this amount ranges from 2 mg to 300 mg. For oral dosage forms the amount is generally from 30 mg to 300 mg per unit dose. Contemplated doses include amounts of about 37.5 mg, 75 mg, 100 mg, 112.5 mg, 150 mg, 200 mg, and 300 mg strengths. For clarity, all amounts of venlafaxine maleate are expressed herein in terms of the weight of the free base contained in the venlafaxine maleate compound, as is conventional in the art.
As mentioned above, oral dosage forms are preferred and include tablets, capsules, sachets/granules, and powders. Tablets can be soluble tablets, dispersible tablets, effervescent tablets, chewable tablets, lyophilized tablets, coated tablets including sugar coatings, enteric coatings, and gastro-soluble coatings, and modified release tablets including microencapsulated active substance tablets, matrix tablets, and coated tablets such as polymer coated extended release tablets and osmotic tablets of the mono-compartmental or bi-compartmental type. Capsules include hard gelatin capsules that can be filled with powder, pellets, granules, small tablets or mini-tablets. The capsule and/or the material placed within can be coated such as for enteric release or modified release. Soft capsules are also included and are more typically filled with liquids or dispersions, but are not limited thereto. Sachets or granules can be effervescent granules, coated granules, enteric granules, or modified release granules.
One embodiment of the present invention relates to an immediate release tablet. An xe2x80x9cimmediate releasexe2x80x9d as used herein means that at least 80% of the venlafaxine maleate in the tablet is dissolved by 30 minutes under a dissolution test using USP Apparatus 1 (basket) at 100 rpm in purified water at 37xc2x0 C. Any conventional immediate release composition can be used in formulating the venlafaxine maleate immediate release tablet. Typically such tablets contain one or more binders and/or diluents such as HPMC, microcrystalline cellulose, a calcium phosphate, lactose, and mannitol; a lubricant such as magnesium stearate; and optionally a disintegrant such as sodium starch glycollate, crosscarmellose or crosspovidone. Additional excipients such as colorants, antioxidants, etc can also be present.
More preferably, however, the solid oral dosage form is an extended release dosage form. This can be accomplished in either a tablet or a capsule form. An extended release dosage form as used herein means that in a dissolution test using USP Apparatus 1 (basket) at 100 rpm in purified water at 37xc2x0 C., less than 80% of the venlafaxine maleate is dissolved during the first two hours, more typically less than 50%, and preferably less than 30% of the venlafaxine maleate is dissolved during the first two hours. Extended release tablets or capsules generally allow for twice a day, or more preferably once a day dosing, to provide 24 hour therapeutic blood plasma levels of venlafaxine to the patient. In this regard, the most preferred dosage form is one which provides once daily dosing. Such a composition should meet the following in vitro dissolution profile:
using USP Apparatus 1 (basket) at 100 rpm in purified water at 37xc2x0 C. Most advantageously the extended release dosage from meets the above dissolution profile also in 0.1 N HCl aqueous solution.
In terms of in vivo performance, the extended release venlafaxine maleate pharmaceutical composition according to the present invention preferably exhibits on average a maximum venlafaxine blood plasma level not earlier than 4 hours, more preferably not earlier than 6 hours after administration of the composition. Typically the average peak plasma level is reached between 4 and 10 hours, more preferably between 6 and 8 hours after administration. In this regard, a preferred composition is bioequivalent to the commercially available EFFEXOR XR(copyright).
Extended release tablets can be formulated according to any of the known techniques such as those based on matrix technology, osmotic pressure technology, multiparticulates compressed into tablets, multilayer tablets having at least one layer based on one of the foregoing, as well as coated tablets, using known materials and methods.
Tablets employing a matrix, in either a monolithic tablet or in one or more layers optionally built on a tablet core, are generally the most common and frequently the easiest to form from a commercial manufacturing standpoint. The matrix provides a diffusion and/or erosion release of the drug. The matrix is generally composed of at least one type of matrix material selected from hydrophilic (hydrogel), inert, lipophilic, and biodegradable matrix materials. Materials used for each of these kinds of matrices in pharmaceutical oral dosage forms are well known in the art and are briefly described below.
A hydrophilic matrix material is generally a polymeric material that swells upon contact with water to form a diffusion barrier. Suitable materials include cellulose derivatives such as methylcelluloses (i.e. having a viscosity of 400 cP to 4000 cP), hydroxyethylcellulose, HPMC, and sodium carboxymethyl cellulose; polysaccharides such as galactomannanes, potassium alginates, sodium alginates, agar-agar, carrageen, arabic gum, and sterculia gum; polyacrylates such as CARBOPOL 934, EUDRAGIT LD 35; Noveon or polycarbophils; and other water swellable polymers such as polyvinyl alcohol.
Inert matrix materials provide a tortuous path for the drug to escape the dosage form thereby controlling diffusion of the drug. Such materials include ethylcellulose (ETHOCEL).
Lipophilic matrix materials work through a combination of erosion and diffusion. Examples of lipophilic materials include glyceryl palmitosterate (PRECIROL ATO 5), glyceryl behenate (COMPRITOL 888 ATO) and Hydrogenated castor oil (CUTINA HR).
Biodegradable matrix materials also operate through a combination of erosion and diffusion. Biodegradable materials include, for example, polyesters of lactic acid and glycolic acid, polyorthoesters, polyanhydrides and caprolactones. A further description of this technology is set forth in WO02/11701, WO92/04013, and EP 1 005 863.
Because venlafaxine maleate has a surprisingly lower water solubility than venlafaxine hydrochloride, venlafaxine maleate can be more readily formulated into conventional extended release forms including hydrogel tablets. Surprisingly, venlafaxine maleate can even be formulated into a once-a-day extended release hydrogel tablet. A xe2x80x9chydrogel tabletxe2x80x9d is one that contains a hydrophilic matrix material that swells or xe2x80x9cgelsxe2x80x9d upon contact with water to thereby slow the diffusion release of the active ingredient. Any of the above-described hydrophilic matrix materials can be used in forming venlafaxine maleate hydrogel tablets of the present invention.
Preferably a hydrogel tablet of the present invention comprises 10%-50% of a venlafaxine maleate compound, preferably a monohydrate form, and 30% to 75% of a hydrogel-forming agent, preferably an HPMC. In some embodiments it may be advantageous for the weight ratio of venlafaxine maleate to hydrogel-forming agent to be in the range of 0.8-1.2:1, preferably approximately 1:1, respectively. In addition to the venlafaxine maleate and hydrogel-forming agent, the composition may further comprise other suitable inert ingredients such as fillers and lubricants in order to assure good properties of the composition in the process of making final medicinal forms, particularly for compression into tablets. Suitable fillers are, e.g. calcium hydrogenphosphate, microcrystalline cellulose or lactose, suitable lubricants are magnesium stearate, precirol, sodium stearyl fumarate (Pruv) or talc.
The tablets of venlafaxine maleate according to the present invention may be produced by any standard tabletting technique, e.g. by wet granulation, dry granulation or direct compression. The tabletting methods that do not employ a solvent (xe2x80x9cdry processesxe2x80x9d) are generally preferable.
In general, dry granulation procedures comprise mixing the solid excipients (except lubricants), compacting the mixture in a compactor (e.g. a roller compactor), or double compression, milling the compacted mass, screening the milled granules, mixing with a lubricant and compressing the mixture into tablets. Direct compression procedures generally comprise mixing the solid excipients in one or more stages and compressing the uniform mixture into tablets. After tablet formation, the tablets may optionally be coated.
The tablets can be of any size and shape. In one preferred embodiment the tablets are small or mini-tablets in size. Small tablets have a diameter of 3-6 mm while mini-tablets have a diameter of 1-3 mm. One or more of the tablets can be taken as such or, more preferably one or more are loaded into a single capsule to provide a unit dose. Most preferably, the small or mini-tablets provide additive amounts of the venlafaxine maleate without modifying the release profile. For example, by making a hydrogel round small tablet of diameter 5 to 6 mm and containing 37.5 mg of venlafaxine (as maleate), capsules containing 37.5 mg, 75 mg, and 150 mg of venlafaxine maleate can be formed by filling a standard No. 0 capsule with 1, 2, or 4 of the small tablets, respectively. Such an additive effect is not as easily obtained with a proportionally larger hydrogel tablet. This is because the release is a function of the volume to surface area ratio. Scaling up the amount and size of a satisfactory 37.5 mg tablet will likely not result in a satisfactory release profile for the resulting 150 mg tablet, for example, because the volume to surface area ratio is different between the two tablets. For each desired single dosage level, a separate formulation, size and/or shape would be needed. Similar proportionality issues arise with other delayed release tablet technologies. By using small tablets in a single capsule, only one tablet formulation and shape is needed to produce multiple dosage strengths. Typically a small or mini-tablet contains 5 to 50 mg of venlafaxine maleate, especially 10, 25, 30, 37.5, 40, and 50 mg. Depending on the size of the tablet and the capsule from 1 to 10 or more small or mini-tablets can be placed in the capsule.
In addition to filling capsules with small or mini-tablets, an extended release capsule can be formed by filling it with more traditional pellets, beads, and/or spheres. The pellets can be coated with an extended release coating or composition. In addition, different populations of coated pellets can be used in a single capsule, each providing a different release characteristic so that the aggregate release is sustained over a long period; i.e. 12 to 24 hours. Alternatively, the bead population can be substantially homogeneous. A preferred capsule of the pellet type is described in the above-mentioned U.S. Pat. No. 6,274,171 and related EP 0 797 991A1 wherein the venlafaxine hydrochloride used in these patents is replaced with the venlafaxine maleate compound of the present invention.
The venlafaxine maleate compound of the present invention can be used to treat any disease or condition that is treatable by venlafaxine. A venlafaxine-treatable disease or condition is one that could be improved by a serotonin or norepinephrine uptake inhibitor and specifically includes, without limitation, depressions, panic disorder, generalized anxiety disorder, obesity, post-traumatic stress disorder, late luteal phase dysphoric disorder, attention deficit disorders, Gilles de la Tourette syndrome, bulimia nervosa, and Shy Drager syndrome. See published U.S. patent application U.S. Ser. No. 2001/0012855 A1 for a description of the uses of venlafaxine and salts thereof. The venlafaxine maleate compound of the present invention can be used to treat such conditions by administering an effective amount to a patient in need thereof. An effective amount is generally known in the art and/or determined using routine skill. Typically the effective amount for a human is 30 to 300 mg of venlafaxine per day. The patients used herein include human and non-human mammals such as dogs, cats, and horses. The route of administration is not particularly limited and includes peroral, parenteral, and transdermal administration. Preferably, the venlafaxine maleate compound is administered orally via one or two unit dosage forms, especially extended release tablets or capsules, as described above.
The above description and details have been set forth with respect to venlafaxine maleate compounds, but also applies with equal force, mutatis mutandis, to all other low water-soluble venlafaxine salts. The entire disclosure in each of the patents mentioned in the above description is incorporated herein by reference. The invention will be further described with reference to the following non-limiting examples.


Composition and method for removing metal oxides from ferrous metals. The composition contains an ammonia derivative such as an amine, a strong mineral acid and an organic chelating agent for the metal oxides in an aqueous solution having an acidic pH of about 0.5-3.0. Metal oxides are most readily removed by applying the solution at elevated temperature.

1. Field of the Invention
This invention relates to a composition and method for removing metal oxides such as rust and mill scale from ferrous metals such as steel. More particularly, the invention relates to metal oxide removal from ferrous metals while avoiding corrosion and discoloration of the metal.
2. Description of the Prior Art
It is known to use citric acid and citrates for the removal of rust from ferrous metals, see for example U.S. Pat. No. 3,510,432. The disadvantage of such materials is that they leave a discoloration or black film on the rust-free metal.
Another reference teaching the use of citric acid is U.S. Pat. No. 3,492,238 which employs citric acid in combination with EDTA (ethylene diamine tetracetic acid). This reference employs the solution at a pH of about 6.0-7.0.
Triethanolamine has been employed in metal cleaning formulations as an inhibitor for acid attack on the metal substrate. It has been employed to avoid the blackening or discoloration of the cleaned metal. In this connection, reference is made to U.S. Pat. No. 1,723,923 which teaches the combination of triethanolamine in highly corrosive pickling baths such as cold concentrated sulphuric form or a heated more dilute form. Such pickling baths are corrosive to the plant in which they are used and present an ecologically unacceptable disposal problem.
U.S. Pat. No. 3,095,379 describes a metal cleaning composition which is the high temperature reaction product of citric acid and monoethanolamine. Such a formulation has been found to also leave an undesirable black coating on the cleaned metal surfaces.
Other references considered include the following: U.S. Pat. Nos. 2,006,216; 2,505,785; 2,994,664; 3,056,746; 3,282,848; 3,510,432; 3,589,859; and 3,779,935.
Attention is invited to the two parents of this application referenced above for the citation of additional prior art.

Metal oxide remover containing a strong mineral acid, chelating agent and a basic ammonia derivative


One or more superconductive cells are connected in series to provide voltage arising from the Hall effect when cooled to superconductor temperatures and immersed in a magnetic field. The magnetic field causes the Hall-effect voltage to develop across the London penetration depth, normal to the surface of each superconductive cell. Conductors connect the back side of one cell with the front side of the adjacent cell. Each superconductive cell is at least the thickness of one London penetration depth.

The Hall effect power generator design idea discussed within this document is based upon long accepted understandings of the physics of superconductors, as well as understandings of the forces which account for the appearance of Hall effect voltages wherever electric currents and magnetic fields are directed normal to one another. Its operation suggests that certain gaps have existed in physical theory, namely that an electric charge or a permanent magnet actively radiates power into space which is unaccounted for by the conventional measure of electromagnetic power, denominated the Poynting Vector.
A growing number of physicists and engineers have directed their attention toward such gaps in physical theory, sometimes discussed under names such as Scalar Electromagnetics, Zero-point energy, and others. An important aspect, relied upon by the present invention, is the difference between viewing the field of an electric charge or magnetic dipole as static (the conventional view) compared with a view of these fields as standing waves which, despite their constancy with respect to position, nevertheless radiate power into the surrounding space.
To illustrate the notion of such fields being standing waves, consider the manufacture of a simple permanent magnet. Just prior to the completion of the manufacture of the permanent magnet, there is no magnetic field present, then an instant later a magnetic field does in fact exist and can be detected. Scalar electromagnetics would view this discontinuity of the magnetic field, with the dividing line between the pre-manifest and post-manifest condition not traversing the entire universe instantaneously (a violation of Einstein's restraint on speed of light), but rather radiating out into the space surrounding the newly-made magnet at a speed model according to both a transverse and longitudinal-wave inclusive form of Maxwell's equations.
With the energy of the magnetic field associated with the manufactured magnet being zero just prior to its making, and then progressively increasing as the new field expands, the evidence that the magnet must in fact be radiating power becomes apparent. The alternative would be to view the information and energy resulting from the magnet's manufacture as spontaneously appearing throughout all of time and space instantaneously—a clear violation of the speed of light limitation imposed by Maxwell's equations as well as Einstein's Relativity Theory.


Compositions and methods for the prevention of adhesion development involve the administration of therapeutic formulations of a halogenated organic compound to a patient in need of treatment. The formulations can include suitable carriers for optimal administration.

It is well known that postoperative adhesions develop in the majority of patients following surgery. Adhesions can result in serious medical consequences and lifelong morbidity, including infertility, abdomino-pelvic pain, small bowel obstruction, and difficult reoperative procedures. Adhesions can manifest themselves shortly after the surgical procedure is performed, or many years thereafter, without any degree of predictability. Although adhesions are common in intraabdominal surgeries, adhesions can be a problem in virtually all types of surgeries. The haloorganic compounds of this invention, when formulated into pharmaceutical compositions, are useful in preventing or reducing the development of postoperative surgical adhesions, and therefore are of major clinical significance for the reduction of patient morbidity and mortality.
Postoperative surgical adhesions are generally believed to result from an injury or inflammation in the peritoneal cavity which produces a fibrous exudate. As a result of this exudate, the serosal tissue surfaces stick together. The fibrous exudate may be absorbed or invaded by fibroblasts to form a permanent fibrous adhesion.
Removal of fibrin before it is invaded by fibroblasts can prevent the development of permanent fibrous adhesions. Removal of fibrin occurs due to the fibrinolytic activity of the peritoneal cavity. Fibrinolytic activity can vary as a result of surgery, but it is absent from a peritoneal wound during the first 48 hours following surgery. However, there is a gradual increase in fibrinolytic activity after this time for up to eight (8) days when the peritoneum heals.
The mechanisms of peritoneal healing, and the alterations which result in postoperative adhesion development, are not well understood. Compositions which are currently approved by the U.S. FDA for use in the reduction of intraperitoneal adhesions theoretically serve as adhesion barriers that separate opposing, potentially adherable sites during the critical three to five day period of peritoneal repair.
Such compositions, including Intercede(trademark), which is manufactured and sold by Johnson and Johnson, and Seprafilm(trademark), which is manufactured and sold by Genzyme Corporation, are resorbable. i.e. reabsorbed in the surrounding tissue, and have been shown in clinical trials to reduce adhesions at the site where they are placed during a laparotomy. However, there is no clinical evidence that these compositions are of any benefit at sites within the patient removed form the site of application for the reduction of de novo adhesion formation, or for the reduction in adhesion reformation at such other sites. Similarly, there is no convincing clinical evidence that these materials are efficacious for surgical procedures performed by laproscopy, perhaps in part due to the difficulty in laproscopic placement of the material.
PCT published patent application WO 00/20642, published Apr. 13, 2000, discloses methods for the prevention of adhesion development by the administration of therapeutic formulations containing TIMP-1 antibodies to a patient. TIMP-1 is part of a family of inhibitors of metalloproteinase proteins, or TIMP""s, which regulate the catalytic activity of matrix metalloproteinases (MMP""s). The administration of antibodies to TIMP-1 to a patient is believed to alter the local levels of both TIMP-1 and MMP, and specifically to reduce the expression of TIMP-1, to thereby inhibit the development of adhesions.
Accordingly, there is perceived to be a need for an improved method for adhesion control and prevention which can be conveniently administered to a patient, and which is not restricted to the site of a particular surgical procedure. There is a particular need for such an, improved method which can also be used in connection with the rapidly growing field of laproscopic surgeries, and at sites throughout the body in addition to the abdominal cavity.
The present invention relates to methods for preventing or reducing the development of surgical adhesions, and compositions which can be used in such methods.
In one aspect, the invention includes a pharmaceutical formulation for preventing or reducing the development of surgical adhesions. The formulation contains, as an active ingredient, a halogenated organic compound of formula CR1OOR2, wherein R, is an alkyl group of 1 to 4 carbons, or a haloalkyl group of 1 to 4 carbons, and wherein R2 is selected from the group consisting of hydrogen, halogen, lower alkyl and lower haloalkyl, provided that either R1 or R2 must contain at least one halogen. The pharmaceutical formulation can also include suitable pharmaceutically acceptable carriers and adjuvants, as well as other therapeutic compounds which assist in the prevention of adhesions. The term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d denotes a carrier substance that potentiates, and does not significantly diminish, the effect of the active agent in the body.
The terms xe2x80x9cpreventxe2x80x9d and xe2x80x9cpreventingxe2x80x9d as used herein refer to inhibiting completely or partially a biological response, as well as inhibiting an increase in a biological response. For instance, prevention of adhesion development refers to partially or completely inhibiting adhesion formation and adhesion reformation, as well as inhibiting an increase in adhesion formation and adhesion reformation.
In a preferred embodiment, the halogenated compound of this invention is a halogenated acetic acid derivative, more preferably dichloroacetic acid or 2-chloropropionate. Prodrugs which form the halogenated compounds in the body can also be used, and are included within the scope of this invention. Additional modifications embraced by this invention include carriers which can be used to bind the halogenated compounds prior to administration, and which subsequently release the halogenated compounds in the body in active form. Suitable biocompatible carriers are well known to those skilled in the art.
Typically, the pharmaceutical composition of the invention contains from about 1% to about 50% active ingredient, and preferably from about 2% to about 10% active ingredient. Human dosages in the range of from about 10 mg/kg to about 100 mg/kg can be used depending on the severity of the particular condition and the treatment protocol.
The pharmaceutical composition can be delivered to the subject by any route known in the art. For instance, the pharmaceutical composition can be administered systemically, such as orally or parenterally, or it may be administered locally. The pharmaceutical composition can also be delivered in a sustained release device. Alternatively, the pharmaceutical composition can be administered with an anti-adhesion adjuvant to obtain the benefits of a barrier compound and the adhesion prevention composition. The adjuvant may be used in the form of a gel, liquid or a solid membrane. Typical anti-adhesion adjuvants which are useful in this invention include commercial products such as Intercede(copyright) and Seprafilm(copyright).
In another aspect, this invention includes a method for preventing or reducing the development of surgical adhesions by treating a patient at risk of developing such adhesions with a therapeutic formulation containing, as an active ingredient, a halogenated organic compound of formula CR1OOR2, wherein R1 is selected from the group consisting of lower alkyl groups (of 1 to 4 carbons), or lower haloalkyl groups, and wherein R2 is selected from the group consisting of hydrogen, halogen, lower alkyl and lower haloalkyl, provided that either R1 or R2 must contain at least one halogen atom.
Although it is most common to use the pharmaceutical compositions of this invention for peritoneal surgery, the type of surgery in which the product is used may be any type where there is a risk of developing surgical adhesions associated with the surgery. In some embodiments, the subject can undergo a surgery selected from the group consisting of abdominal surgery, gynecological surgery, cardiac surgery, back surgery, neurosurgery, ligament and tendon surgery, and ophthalmic surgery.
This invention is based, in part, on the discovery that the development of adhesions is a response mechanism by the subject to a disruption in the preexisting vasculature supplying blood to the injured tissue present in the subject. Adhesions essentially represent a mechanism for resupplying oxygen nutrients to the injured tissue to promote healing.
Tissue which is injured as a result of a pathological process, or by a surgical procedure undertaken to treat a pathology, experience a disruption in the vasculature, resulting in the delivery of less oxygen and nutrients to the tissue. This, in turn, causes a buildup of metabolic wastes due to the impairment of the normal mechanisms of waste removal.
Tissue normally utilize an aerobic metabolism in which energy is derived by the cells from the oxidation of metabolic intermediates and oxygen to form carbon dioxide. This metabolic reaction is the primary route by which cells are able to derive the maximum number of ATP (energy) molecules possible by passing all carbon sources being metabolized from pyruvate through the Kreb""s (tricarboxylic acid) cycle. However, if the amount of oxygen is limited by the disruption of the vasculature delivering blood to the injured tissue, oxidative metabolism is hindered or rendered unable to occur. Such injury may be due, for instance, to a pathological process, to the cutting of blood vessels, to tying off vessels during surgery, or to the use of electrosurgical energy for sealing blood vessels. In such situations, the injured tissue produces markedly fewer ATP molecules. In addition, pyruvate is less likely to enter the Kreb""s cycle, but rather is converted into lactic acid which will build up in the affected, anoxic (hypoxic) tissues.
It is hypothesized that the body is able to sense the anoxia/hypoxia in the injured tissues, and in response, produces adhesions from adjacent tissue which subsequently become vascularized as a mechanism for resupplying oxygen and other nutrients to the tissue. This results in the attachment of tissues at non-physiologic locations, with the potential of untoward adverse clinical consequences.
While not intending to be bound by any particular theory, it is believed that the pharmaceutical compositions of this invention are effective in reducing the incidence of post-operative adhesions by stimulating the activity of the enzyme pyruvate dehydrogenase, so that virtually all pyruvate enters the Kreb""s cycle. This results in maximal ATP production, while simultaneously reducing the conversion of pyruvate into lactic acid. The tissue thus becomes less anoxic/hypoxic, and there is less stimulus to form an adhesion. The pharmaceutical formulation is advantageously administered to a subject prior to or during surgery, in order to be present during the peritoneal healing, and preferably for approximately three to five days following surgery.
The halogenated organic compounds of this invention include compounds of the general formula CR1OOR2, wherein R1 is selected from the group consisting of lower alkyl groups or lower haloalkyl groups, and wherein R2 is selected from the group consisting of hydrogen, halogen, lower alkyl groups and lower haloalkyl groups, provided that either R1, or R2 must contain at least one halogen atom. The term xe2x80x9clower,xe2x80x9d in the context of this invention, when used to modify xe2x80x9calkylxe2x80x9d or xe2x80x9chaloalkylxe2x80x9d, includes C1 to C4 alkyls or haloalkyls. Suitable halogens can include chloro, bromo, iodo and fluoro groups, although chloro is preferred. R1 is preferably a chloromethyl group, and R2 is preferably hydrogen. Preferably, the halogenated compounds use in this invention are dichloroacetic acid or 2-chloropropionate.
The halogenated organic compounds of this invention are well known compounds which are available from commercial sources. Alternatively, the halogenated organic compounds can be synthesized using techniques which are well known in the art to synthetic organic chemists. These compounds are biocompatible and have been found useful in unrelated therapeutic uses, such as, for instance, the treatment of severe lactic acidosis associated with septic shock, P. W. Stacpoole et al., The New England Journal of Medicine, 7, pages 390-396 (1983); and the treatment of diabetes mellitus and hyperlipoproteinemia, Stacpoole et al., The New England Journal of Medicine, 8, pages 526-530 (1978).
The halogenated compounds are administered to a subject in a pharmaceutical formulation to induce protection against postoperative surgical adhesion development associated with many common types of surgery. Adhesions are a common complication of surgery that involve abnormal union of tissue surfaces, often occurring during the healing process of injured cells, tissues and organs. Postoperative surgical adhesions are a major complication of abdominal, pelvic, gynecologic, cardiothoracic, orthopedic and neuro-surgeries. Adhesions may result after a trauma sustained by the body, such as a surgery or a wound, and may develop in a variety of areas in the body.
The type and degree of damage caused by adhesions is variable, ranging from life-threatening damage, as in the intestines due to ablockage, to extremely disabling damage, as in tendons or spinal cord, to chronic pain and infertility in the pelvic cavity, to the obstruction of further surgery in the pericardium. Adhesions that form in relation to intestinal surgery, e.g., bowel resection, hernia repair, etc., may cause obstruction of the intestine. Adhesions that form near a bone fracture site may reduce or hinder the normal movement in the area of repair by restricting the natural movement of tendons over the adjacent bone. Adhesions may also form in the vicinity of nerves and disrupt nerve transmissions with a resultant diminution of sensory or motor function. Postoperative development of pelvic adhesions remains a serious problem in patients undergoing gynecological surgery and is a principal cause of infertility. Postoperative adhesion development can necessitate difficult reoperations and an increase in injuries during subsequent surgeries. In general, the most common causes of pelvic adhesions in women are prior surgery, endometriosis and pelvic inflammatory disease.
Current clinical methods directed toward reducing the development of postoperative surgical adhesions generally rely on placement of a film or gel directly at the operative site, with the intention of creating a physical barrier between surfaces likely to become involved in adhesion development. These methods remain cumbersome for the surgeon to use.
Highly concentrated solutions of a number of polymers have been used to coat the surgical area before and during surgery so as to minimize tissue drying and to act as a cushion to prevent some of the manipulative trauma. Examples of these techniques are described in U.S. Pat. No. 4,819,617 to Goldberg et al. and U.S. Pat. No. 4,886,787 to De Belder et al. Among the materials used are polyvinylpyrrolidone (PVP), dextrans, hyaluronic acid, carboxymethylcelluloses, and a number of other polymers such as protein or polypeptide solutions. These materials do not entirely eliminate adhesions, but rather reduce the incidence of adhesion development. The compounds of this invention are believed to be significantly more effective for adhesion reduction than the barrier materials of the prior art.
It has now been discovered, according to the invention, that the administration of the compounds of the invention, locally or systemically, can induce protection against postoperative surgical adhesion development.
Thus, the compositions of the invention are useful for treating or preventing adhesions that form at a site and that have potential or actual deleterious effects. These include primary and secondary adhesions in the following sites: in the abdominal cavity, including intestine to intestine, and intestine to peritoneum; in the pelvic cavity, including adhesions of the uterus, ovaries or fallopian tubes to other structures including each other and the pelvic wall; in tendons and their support structures, including tendon to pulley or to synovium; in the repair of nerve sheaths; in the repair of the spinal column or disks; in the pericardium; in the treatment of joints for inflammation, and to prevent pannus formation; in the extraocular muscle, to prevent adhesions from limiting the field of vision; and in any situation in which adhesions form which can impair the function or cause pain.
The prevention of postoperative surgical adhesion development in a subject includes prophylactic treatment to prevent adhesion development following planned surgical procedures, as well as following emergency operations. In addition to the surgical procedures described above, elective surgeries include the following intraabdominal surgeries: right hemicolectomy; left hemicolectomy; sigmoid colectomy; subtotal colectomy; total colectomy; laparoscopic or open cholecystectomy; gastrectomy; pancreatectomy; splenectomy; liver, pancreas, small bowel, or kidney transplantation; lysis of adhesions; cesarean sections and other pelvic procedures, uterine surgery, etc. Emergency intraabdominal surgeries include those surgeries used to correct the following conditions: perforated ulcer (duodenal or gastric); perforated diverticulitis; obstructive diverticulitis; bowel obstruction; perforated appendicitis; blunt abdominal trauma; penetrating abdominal trauma; ruptured abdominal aortic aneurysm, cardiac surgeries, open and endoscopic orthopedic surgeries, neurosurgeries, gynecologic and pelvic surgeries, and surgeries to correct wound infections.
The compounds of the invention are administered in an effective amount for inducing protection against postoperative surgical adhesion development. An effective amount for inducing protection against postoperative surgical adhesion development as used herein is that amount of pharmaceutical composition that will, alone or together with further doses or additional therapeutic compounds, inhibit or prevent the development of postoperative surgical adhesions.
The preparations of the invention when administered xe2x80x9cin conjunction withxe2x80x9d a surgical procedure, are administered close enough in time with the surgery or trauma that predispose the host to adhesion development, so that a protective effect against the particular disorder is obtained. The preparations may be administered long before the surgery, e.g., in the case of elective surgery (i.e., weeks or even months), preferably with booster administrations closer in time to (and even after) the surgery. Particularly in emergency situations, the preparations may be administered immediately before (minutes to hours) and/or after the surgery. It is important only that the preparation be administered close enough in time so as to enhance the subject""s response against adhesions, thereby increasing the chances of a successful host response and reducing the likelihood of adhesion development.
The present invention provides pharmaceutical compositions for medical use, which in some aspects comprise the compounds of the invention together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients. Thus the invention may also include pharmaceutical compositions in combination with an anti-infectious agent such as an antibacterial or anti-viral agent, an anti-inflammatory agent, an antibiotic, or other therapeutic agent, and a pharmaceutically acceptable carrier. The pharmaceutical compositions useful in the invention may be delivered separately with the other therapeutic agents, or in the form of therapeutic cocktails. A therapeutic cocktail includes a mixture of the pharmaceutical compositions of the invention and another therapeutic agent. In this embodiment, a common administration vehicle (e.g. tablet, implant, injectable solution, etc.) contains both the pharmaceutical composition and another therapeutic agent. Alternatively, the other therapeutic can be separately dosed if desired.
The precise amount of the therapeutic agent used in combination with the pharmaceutical compositions of the invention depends upon a variety of factors, including the particular pharmaceutical composition selected, the dose and dose-timing selected, the mode of administration, the nature of any surgical or medical procedure contemplated, and the characteristics of the subject. Where local administration is carried out, it will be understood that very small amounts may be required (nanograms and possibly picograms). The precise amounts selected can be determined without undue experimentation, particularly since a threshold amount is any amount which will favorably enhance the response.
Multiple doses of the pharmaceutical compositions of the invention are also contemplated. For instance, when being administered in conjunction with a surgical procedure, the compounds of the invention can be administered in multiple doses over a three week to one day period preceding surgery. Further, doses may be administered post surgery as well. Any regimen that prevents or retards the development of adhesions may be used, although optimum doses and dosing regimens are those that would not only inhibit the development of adhesion formation, but also would result in protection against adhesion development. Desired time intervals for the delivery of multiple doses of a particular pharmaceutical composition can be determined by one of ordinary skill in the art employing no more than routine experimentation.
The formulations of the invention are administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients.
The pharmaceutical composition may be administered per se (neat) or in the form of a pharmaceutically acceptable salt. When used in medicinal applications, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically acceptable salts thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
Suitable buffering agents include: acetic acid or its salt (1-2% w/v); citric acid or its salt (1-3% w/v); boric acid or its salt (0.5-2.5% w/v); succinic acid; and phosphoric acid or its salt (0.8-2% w/v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v) and thimerosal (0.004-0.02% w/v).
The pharmaceutical compositions of the invention contain an effective amount of a pharmaceutical composition optionally included in a pharmaceutically acceptable carrier. The term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d means one or more compatible solid or liquid filler, dilutants or encapsulating substances which are suitable for administration to a human or other animal. The term xe2x80x9ccarrierxe2x80x9d denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application of the composition. The components of the pharmaceutical compositions also are capable of being commingled with the pharmaceutical compositions of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.
Compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations, which can be isotonic with the blood of the recipient. Among the acceptable vehicles and solvents are water, Ringer""s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Carrier formulations suitable for subcutaneous, intramuscular, intraperitoneal or intravenous administrations may be found in Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.
The pharmaceutical compositions useful in the invention may be delivered in mixtures of more than one pharmaceutical composition. A mixture may consist of several pharmaceutical compositions.
A variety of administration routes are available. The particular mode selected will depend, of course, upon the particular pharmaceutical composition selected, the particular condition being treated, and the dosage required for therapeutic efficacy. The methods of this invention, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of an immune response without causing clinically unacceptable adverse effects. Preferred modes of administration include parenteral, injection, infusion, deposition, implantation, anal or vaginal supposition, oral ingestion, inhalation, topical administration. Injections can be intravenous, intradermal, subcutaneous, intramuscular, or interperitoneal. For example, the pharmaceutical composition can be injected directly into the surgical site for the prevention of adhesions. In some embodiments, the injections can be given at multiple locations. Implantation includes inserting implantable drug delivery systems, e.g., microspheres, hydrogels, polymeric reservoirs, cholesterol matrixes, polymeric systems, e.g., matrix erosion and/or diffusion systems and non-polymeric systems, e.g., compressed, fused, or partially-fused pellets. Inhalation includes administering the pharmaceutical composition with an aerosol in an inhaler, either alone or attached to a carrier that can be absorbed. For systemic administration, it may be preferred that the pharmaceutical composition is encapsulated in liposomes. The term xe2x80x9cparenteralxe2x80x9d includes subcutaneous injections, intravenous, intramuscular, intraperitoneal, and intrasternal injection or infusion techniques.
In certain preferred embodiments of the invention, the administration can be designed so as to result in sequential exposure to the pharmaceutical composition over some period of time, e.g., hours, days, weeks, months or years. This can be accomplished by repeated administrations of the pharmaceutical composition, by one of the methods described above, or alternatively, by a sustained-release delivery system in which the pharmaceutical composition is delivered to the subject for a prolonged period without repeated administrations. By sustained-release delivery system, it is meant that total release of the pharmaceutical composition does not occur immediately upon administration, but rather is delayed for some period of time. Release can occur in bursts or it can occur gradually and continuously. Administration of such a system can be, e.g., by long-lasting oral dosage forms, bolus injections, transdermal patches, and subcutaneous implants.
Examples of systems in which release occurs in bursts includes, e.g., systems in which the pharmaceutical composition is entrapped in liposomes which are encapsulated in a polymer matrix, the liposomes being sensitive to specific stimuli, e.g., temperature, pH, light or a degrading enzyme and systems in which the pharmaceutical composition is encapsulated by an ionically-coated microcapsule with a microcapsule core degrading enzyme. Examples of systems in which release of the pharmaceutical composition is gradual and continuous include, e.g., erosional systems in which the pharmaceutical, composition is contained in a form within a matrix, and effusional systems in which the pharmaceutical composition permeates at a controlled rate, e.g., through a polymer. Such sustained release systems can be e.g., in the form of pellets, or capsules.
In one particular embodiment, the preferred sustained release device is a biocompatible microparticle or microencapsulated product or implant that is suitable for implantation or administration to the mammalian recipient. Exemplary bioerodible implants that are useful in accordance with this method are described in PCT International application no. PCT/US/03307 (Publication No. WO 95/24929, entitled xe2x80x9cPolymeric Gene Delivery System.xe2x80x9d) The polymeric matrix preferably is in the form of a microparticle such as a microsphere (wherein the pharmaceutical composition is dispersed throughout a solid polymeric matrix) or a microcapsule (wherein the pharmaceutical composition is stored in the core of a polymeric shell). Other forms of the polymeric matrix for containing the pharmaceutical composition include films, coatings, gels, implants, and stents. The size and composition of the polymeric matrix device is selected to result in favorable release kinetics in the tissue into which the matrix is introduced. The size of the polymeric matrix further is selected according to the method of delivery which is to be used, typically injection into a tissue. The polymeric matrix composition can be selected to have both favorable degradation rates and also to be formed of a material which is bioadhesive, to further increase the effectiveness of transfer when the matrix is administered to a mucosal surface. The matrix composition also can be selected not to degrade, but rather to release by diffusion over an extended period of time. The biocompatible microsphere may be suitable for oral delivery. Such microspheres are disclosed in Chickering et al., Biotech. And Bioeng., (1996) 52:96-101 and Mathiowitz et al., Nature, (1997) 386:410-414 and PCT Patent Application No. WO97/03702.
Both non-biodegradable and biodegradable polymeric matrices can be used to deliver the pharmaceutical compositions to the subject. Biodegradable matrices are preferred. Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired, generally in the order of a few hours to a year or longer. Typically, release over a period ranging from between a few hours and three to twelve months is most desirable. The polymer optionally is in the form of a hydrogel that can absorb up to about 90% of its weight in water, and further optionally is cross-linked with multi-valent ions or other polymers.
Bioadhesive polymers of particular interest include bioerodible hydrogels described by H. S. Sawhney, C. P. Pathak and J. A. Hubell in Macromolecules, (1993) 26:581-587, the teachings of which are incorporated herein by reference, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), polyhyaluronic acids, poly(isobutyl Miiiethaerylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl)methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate).
Other sustained release delivery systems useful according to the invention include, but are not limited to, fatty acids and a medicinal pump. Preferably the fatty acids are C9-C20 fatty acids.
The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing the pharmaceutical composition into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the pharmaceutical composition into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product. The pharmaceutical composition may be stored in a lyophilized condition.
The pharmaceutical compositions can be suspended in a liquid, e.g., in dissolved form or colloidal form. The liquid can be a solvent, partial solvent, or non-solvent. In many cases, water or an organic liquid can be used.
The pharmaceutical compositions are administered to the subject in a therapeutically-effective amount. By therapeutically-effective amount it is meant that amount which is capable of at least partially preventing, reversing, reducing, decreasing, ameliorating, or otherwise suppressing adhesions. A therapeutically-effective amount can be determined on an individual basis and is based, at least in part, on consideration of the age, sex, size, and health of the subject; the type of pharmaceutical composition used, the type of delivery system used; the time of administration; and whether a single, multiple, or controlled-release dose regimen is employed. A therapeutically-effective amount can be determined by one of ordinary skill in the art employing such factors and using no more than routine experimentation.
The dosage concentration of the pharmaceutical composition actually administered is dependent, at least in part, upon the final concentration of the pharmaceutical composition that is desired at the site of action, the method of administration, the efficacy of the particular pharmaceutical composition, the longevity of the particular pharmaceutical composition, and the timing of administration. Preferably, the dosage form is such that it does not substantially deleteriously affect the subject. The dosage can be determined by one of ordinary skill in the art employing such factors and using no more than routine experimentation.
The term xe2x80x9csubject,xe2x80x9d as used herein, means a human or non-human mammal, including but not limited to, a dog, cat, horse, cow, pig, sheep, goat, primate, rat, and mouse.


Pallet systems are described that can be formed of corrugated paperboard without the necessity of any attachment materials such adhesives, staples, or the like. Individual stringers of a pallet matrix are interwoven together, with stringer notches interlocking with notches of crossing stringers from both above and below any one stringer. Systems can be easily and quickly assembled and, should the need arise, can be quickly repaired, for instance by replacement of one or more individual runners. Systems can also exhibit extremely high strength, and can withstand greater than about 20,000 pounds of static compression at less than about ⅜ inch deflection.

Pallets, also referred to as skids, carriers, and base pads, have been utilized to store and transport goods for many years. Traditionally, pallets were formed of steel or lumber cut from any of a variety of trees. More recently, less expensive materials have been introduced for formation of pallets including plastics, wood-based composites (e.g., plywood, particle board, etc.), and corrugated paperboard.
There are problems with existing systems. For instance, pallets constructed of steel, wood and wood by-products are ecologically wasteful, heavy, and expensive. Plastic pallet systems are also ecologically wasteful, in that they utilize non-renewable resources. In addition, plastic pallets are often quite heavy and present disposal problems, as they are generally not formed of recyclable materials.
Existing corrugated paperboard pallet systems provide some beneficial characteristics, in that they are generally much lighter than systems formed of other materials, and they are less expensive than other systems, but problems still exist. For instance, most corrugated paperboard pallet systems require some form of attachment material, usually adhesives, to be constructed. Attachment materials can have detrimental effects on recyclability of the pallet as well as increase formation costs. In addition, corrugated paperboard pallets tend to have much lower limits with regard to compressive force able to be withstood. For example, corrugated paperboard pallets can typically withstand compressive forces of approximately 3000 pounds of static compression.
What are needed in the art are improved pallet systems, and in particular, those formed of corrugated paperboard. More specifically, what are needed are pallet systems that can be formed entirely of recyclable materials, can be completely assembled quickly and easily without the need of additional materials for attaching pallet pieces together, can be formed to any desired size, are easily repairable, and can withstand high loads.


A system and method for endoluminal grafting of a main anatomical conduit (e.g., the aorta) and various branch conduits (e.g., side branch vessels such as the carotid, innominate, subclavian, intercostal, superior mesenteric, celiac, or renal arteries-or furcations such as the iliac arteries) which emanate from the main anatomical conduit. The grafting system generally comprises i) a primary graft having at least one opening therein and ii) at least one branch graft which is passable through the opening of the primary graft and into the branch conduit(s) such that the proximal end of each branch graft is in substantially fluid-tight sealing contact with the primary graft. Also disclosed is a specific system and method for grafting a bifurcated anatomical conduit (e.g., the aorto-iliac bifurcation) though only a single access opening (puncture site or incision) and a new balloon-anchorable guidewire system which is useable in the performance of such grafting of bifurcated anatomical conduits and numerous other medical procedures.

The present invention relates generally to medical devices and methods, and more particularly to a system and method for endoluminal grafting of blood vessels or other tubular anatomical conduits which have furcations or side branches extending therefrom.
Endoluminal grafting is a relatively noninvasive method for placing a tubular graft within the lumen of an anatomical conduit, such as a blood vessel. In certain cardiovascular applications of the technique, an endovascular graft may be implanted within an aneurysmic segment of a blood vessel (i.e., a blood vessel which has a region of localized dilatation wherein the blood vessel wall has become distended and weakened) to form a prosthetic flow conduit through the aneurysm, and to effectively isolate weakened portion of the blood vessel wall from the hemodynamic forces and pressures of the flowing blood.
The prior art has included numerous endovascular grafts of varying design. In general, these endovascular grafts typically comprise: a tube of pliable material (e.g., expanded polytetrafluoroethylene (ePTFE) or woven polyester) in combination with a graft anchoring component (e.g., a stent, a frame, a series of wire rings, hooks, barbs, clips, staples, etc.) which operates to hold the tubular graft in its intended position within the blood vessel. Most commonly, the graft anchoring component is formed of a radially expandable stent or frame which is either a) incorporated into the body of the tubular graft or b) formed separately from the graft and deployed within the graft lumen, and which is expandable to exert outwardly directed radial pressure against the surrounding blood vessel wallxe2x80x94thereby frictionally holding the graft in place. In operation, endovascular grafts which incorporate radially expandable graft anchoring devices are initially disposed in a radially collapsed configuration which is sufficiently compact to allow the graft to be transluminally advanced through the vasculature until it reaches the intended site of implantation. Thereafter, the graft (and the accompanying graft anchoring device) expands to a radially expanded configuration which is large enough to exert the desired outwardly-directed pressure against the blood vessel wall. In some embodiments, hooks, barbs, or other projections formed on the graft anchoring device, will insert into the wall of the blood vessel to ensure that the graft will be firmly held in its desired position, without slipping or migrating after implantation. These radially expandable graft anchoring devices are generally classifiable as either a.) self-expanding or b) pressure-expandable. Graft anchoring devices of the xe2x80x9cself-expandingxe2x80x9d are usually formed of a resilient material (e.g., spring metal) or shape memory alloy which automatically expands from a radially collapsed configuration to a radially expanded configuration, when relieved of surrounding constraint (e.g., a surrounding tubular sheath or catheter wall). On the other hand, those of the xe2x80x9cpressure-expandablexe2x80x9d variety are typically formed of malleable wire or other plastically deformable material which will deform to a radially expanded configuration in response to the exertion of outwardly directed pressure thereagainstxe2x80x94as by inflation of a balloon or actuation of another pressure-exerting apparatus which has been positioned within the graft anchoring device.
Endovascular grafting is a clinically viable alternative to traditional surgery in patients who suffer from aneurysms of the aorta. Indeed, may patients who are diagnosed with aortic aneurysms are in relatively poor health, and may be characterized as poor surgical risks. Moreover, the traditional surgical approach to repair of aortic aneurysms requires cross-clamping of the aorta above the aneurysm, which can result in ischemic damage to organs or other untoward results. Nonetheless, if allowed to remain untreated, a substantial percentage of aortic aneurysms may ultimately dissect or rupture, with catastrophic consequences. Thus, endovascular grafting offers a potential means for repair of aortic aneurysms, without the risks and potential complications of traditional aneurysm repair surgery.
Depending on which region(s) of the aorta is/are involved, the aneurysm may extend into areas of bifurcation (i.e., the inferior end of the aorta where it bifurcates into the iliac arteries) or segments of the aorta from which smaller xe2x80x9cbranchxe2x80x9d arteries extend. In this regard, the various types of aortic aneurysms may be classified on the basis of the region(s) of aneurysmic involvement, as follows:
A. Thoracic Aortic Aneurysms:
Aneurysms involving the ascending thoracic aorta
Aneurysms involving the aortic arch and branch arteries which emanate therefrom (i. e., the subclavian arteries)
B. Thoracoabdominal Aortic Aneurysms:
Aneurysms involving the descending thoracic aorta and branch arteries which emanate therefrom (i.e., thoracac intercostal arteries) and/or the suprarenal abdominal aorta and branch arteries which emanate therefrom (i.e., renal, superior mesenteric, celiac and/or intercostal arteries).
C. Abdominal Aortic Aneurysms:
Aneurysms involving the pararenal aorta and the branch arteries which emanate therefrom (i.e., the renal arteries)
Anneurysms involving the infrarenal aorta with or without illiac involvement
Unfortunately, not all patients diagnosed with aortic aneurysm are presently considered to be candidates for endovascular grafting. This is largely due to the fact that most of the endovascular grafting systems of the prior art are not designed for use in regions of the aorta from which side branches (i.e., carotid, innominate, subclavian, intercostal, superior mesenteric, celiac or renal arteries) extend. In fact, most of the clinical experience with endoaortic grafting has been for the treatment of infrarenal aneurysms, with or without illiac involvement. Examples of endovascular grafting methods and systems useable to treat such infrarenal anneurysms include those described in the following U.S. Pat. No. 4,577,631 (Kreamer); U.S. Pat. No. 5,211,658 (Clouse); U.S. Pat. No. 5,219,355 (Parodi et al.); U.S. Pat. No. 5,316,023 (Palmaz et al.); U.S. Pat. No. 5,360,443 (Barone et al.); U.S. Pat. No. 5,425,765 (Tifenbrun et al.); U.S. Pat. No. 5,609,625; (Piplani et al.); U.S. Pat. No. 5,591,229 (Parodi et al.); U.S. Pat. No. 5,578,071 (Parodi); U.S. Pat. No. 5,571,173 (Parodi); U.S. Pat. No. 5,562,728 (Lazarus et al.); U.S. Pat. No. 5,562,726 (Chuter); U.S. Pat. No. 5,562,724 (Vorwerk et al.); U.S. Pat. No. 5,522,880 (Barone et al.); and U.S. Pat. No. 5,507,769 (Marin et al.).
Most if not all of the endovascular grafts which have been designed for use in treating infrarenal aneurysms require that a proximal xe2x80x9cneckxe2x80x9d (e.g., at least two (2) centimeters of non-aneurysmic aorta) exist inferior to the renal arteries, in order to provide a region where the superior end of the graft may be securely anchored in place, without blocking or restricting blood flow into the renal arteries. The deployment of endovascular grafts within regions of the aorta from which branch arteries extend (e.g., regions of the aorta from which the renal, superior mesenteric, celiac, intercostal, and/or subclavian arteries emanate) present additional technical challenges because, in those cases, the endovascular graft must be designed, implanted and maintained in a manner which does not impair the flow of blood into the branch arteries.
U.S. Pat. No. 5,425,765 (Tifenbrun et al.) has described an endovascular graft which has one or more openings or fenestrations formed at specific locations, to allow blood to flow from the aorta into one or more branch arteries. However, such fenestrations do not form discrete conduit(s) through which blood is channeled into each branch artery. As a result, the area surrounding the fenestrations could be prone to i) the leakage of blood into the space between the outer surface of the aortic graft and the surrounding aortic wall or ii) post-implantation migration or movement of the graft causing misalignment of the fenestration(s) and the branch artery(ies)xe2x80x94with resultant impairment of flow into the branch artery(ies).
Thus, in view of the above-discussed limitations and shortcomings, there remains a need in the art for the development of new endovascular grafting systems and methods which a) may be useable for endovascular grafting in regions of a blood vessel (e.g., aorta) from which branch blood vessels (e.g., carotid, innominate, subclavian, intercostal, superior mesenteric, celiac, renal or iliac arteries) extend, and/or b) may enable more aortic aneurysm patients to be considered as candidates for endovascular repair, and/or c) may otherwise advance the state of the art of endovascular grafting to improve patient outcomes or lessen complications.
The present invention provides a system and method for edoluminal grafting of a blood vessel or other anatomical conduit, in a region where one or more branch anatomical conduit(s) (e.g., side branches, furcations, etc.) extend from the anatomical conduit.
In accordance with the present invention, there is provided an endoluminal grafting system which comprises:
a) a primary graft which comprises;
i) a first pliable tube (e.g., a tube formed of woven polyester, expanded polytetrafluoroethylene (ePTFE), or other biocompatable material) having a lumen extending longitudinally therethrough;
ii) at least one branch opening (e.g., an aperture) formed in the first pliable tube;
iii) a first connector (e.g., a groove, slot, depression, or other engageable surface) associated with (e.g., formed around or positioned adjacent to) the branch opening; and,
iv) a primary graft anchoring device (e.g., a radially expandable stent, frame, series of rings, and/or adhesive, suture(s), staple(s), etc. for holding the graft in place) which is operative to hold the first pliable tube in a substantially fixed position within the lumen of the anatomical conduit, such that the branch opening is in alignment with the branch anatomical conduit; and,
b) a branch graft which comprises;
i) a second pliable tube having a proximal end, a distal end, and a lumen extending longitudinally therethrough;
ii) a second connector (e.g., a ring, rib, ridge, protrusion or other engageable surface) associated with the proximal end of the second pliable tube, said second connector being engageable with said first connector to connect the proximal end of the second pliable tube to the first pliable tube such that fluid which flows through the lumen of the primary graft may pass through said branch opening and into the lumen branch graft.
In some applications, it will be desirable for the branch graft component of the above-summarized endoluminal grafting system to further include, or to be used in conjunction with,
iii) a branch graft anchoring device (e.g., a radially expandable stent, frame, rings, and/or an adhesive, suture(s), staple(s), etc.) which is operative to hold at least the distal end of the branch graft in contact with the surrounding wall of the branch anatomical conduit.
Still further in accordance with the present invention, the above-summarized endoluminal grafting system may be implanted within the branched anatomical conduit by a method which comprises the following procedural steps:
a) transluminally advancing the primary graft into the branched anatomical conduit;
b) positioning the primary graft within the anatomical conduit such that the branch opening is aligned with the branch anatomical conduit;
c) utilizing the primary graft anchoring device to anchor the primary graft within the anatomical conduit;
d) transluminally advancing the branch graft into the lumen of the primary graft;
e) passing the distal end of the branch graft through the branch opening and into the branch anatomical conduit; and,
f) advancing the branch graft into the branch anatomical conduit until the second connector on the proximal end of the branch graft engages the first connector of the primary graft, thereby connecting the branch graft to the primary graft such that body fluid (e.g., blood) may flow from the lumen of the primary graft, through the branch opening, and through the lumen of the branch graft.
Still further in accordance with the present invention, the above summarized method may optionally include step of:
g) utilizing a branch graft anchoring device to anchor at least the distal end of the branch graft to the surrounding wall of the branch anatomical conduit.
Still further in accordance with the present invention, there is also provided a method for implanting a modular, bifurcated endoluminal graft within a bifurcated anatomical conduit (i.e., a conduit having a main portion(e.g., aorta), a first furcation (e.g., right iliac) and a second furcation (e.g., left iliac), through a single access opening (e.g., cut down incision or percutaneous puncture site). This method generally comprises the steps of:
a. providing a modular endoluminal graft which comprises i) a primary graft which is configured to be positioned in the main portion and first furcation of the anatomical conduit, and which has an opening formed therein, and ii) a branch graft which has a proximal end and a distal end and which is configured to be positioned in the second furcation of the anatomical conduit with its proximal end connected to the opening formed in the main graft;
b. forming an access opening which leads into the first furcation of the anatomical conduit;
c. advancing the bifurcated primary graft through the access opening and positioning the primary graft in the main portion and first furcation of the anatomical conduit;
d. advancing a curved guide catheter having an internal angle of curvature less than 90 degrees, into the main portion of the primary graft;
e. advancing a guidewire having a distal end, through the curved guide catheter, such that the distal end of the guidewire passes out of the curved guide catheter, through the opening formed in the primary graft, and into the second furcation of the anatomical conduit;
f. advancing a catheter having the branch graft mounted thereon, over the guidewire until the distal end of the branch graft extends into the second furcation of the anatomical conduit and the proximal end of the branch graft is connected to the opening formed in the primary graft; and,
g. removing said guidewire and said catheter. In some applications of this method, an anchorable guidewire may be inserted in step e and the guidewire will then be anchored in the second furcation of the anatomical conduit, to prevent the guidewire form being inadvertently pulled out of the second furcation during the procedure. In procedure wherein such anchorable guidewire is used, the anchoring apparatus of the guidewire will be actuated prior to step f and will be deactuated prior to step g.
Still further in accordance with the invention, there is provided a new anchorable guidewire system which is useable in conjuntion with the above-sumarized method for implanting a bifurcated endoluminal graft and/or with various other medical or surgical procedures. This anchorable guidewire system comprises;
a) a balloon-anchorable guidewire which comprises:
i) an elongate guidewire having a proximal end and a distal end;
ii) a balloon formed on the guidewire at a first location;
iii) a lumen which extends longitudinally through the guidewire from its proximal end to said balloon, said lumen being useable to pass inflation fluid into and out of said balloon; and,
b) an inflation syringe/lumen-plugging apparatus which comprises:
i) a syringe having a plunger and a barrel, said syringe being connectable to the proximal end of the guidewire such that when the plunger of said syringe is advanced in a first direction it will force inflation fluid through said lumen in the distal direction and into said balloon and, when said plunger is retracted in a second direction it will draw inflation fluid out of said balloon and through said lumen in the proximal direction; and,
ii) a lumen-plugging member releasably mounted on the plunger of the syringe such that, when the plunger is advanced in the first direction to a predetermined point, the lumen-plugging memeber will become inserted into the guidewire lumen and is subsequently releasable from the plunger, said lumen-plugging member being thereby operative to prevent inflation fluid from escaping from said lumen when the syringe is removed.
In operation, the balloon-anchorable guidewire is inserted to its desired position and the inflation syringe/lumen-plugging apparatus is attached to its proximal end. The syringe plunger is then advanced in the distal direction, thereby inflating the balloon and anchoring the distal end of the guidewire at a desired position within the body. After the plunger has been advanced far enough to cause the lumen blocking member to be inserted into the proximal end of the guidewire lumen, the lumen blocking member is released (e.g., broken away or disconnected) from the plunger, and the lumen blocking member is allowed to remain inserted in proximal end of the lumenxe2x80x94acting as a plug to prevent fluid from escaping from the lumen. The syringe may then be detached and removed from the proximal end of the guidewire, and one or more catheters or other transluminal devices may be advanced and/or retracted over the proximal end of the guidewire. Thereafter, when it is desired to remove the guidewire, the exteriorized portion of the guidewire is cut (e.g., transected by a pair of standard scissors), thereby allowing the inflation fluid to leak from the balloon and out of the guidewire lumen. After the balloon has been deflated in this manner, the guidewire may be extracted and removed from the body.

System and method for edoluminal grafting of bifurcated or branched vessels