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WO1993012774A1 - Microemulsions de dissolution de calculs - Google Patents

Microemulsions de dissolution de calculs Download PDF

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Publication number
WO1993012774A1
WO1993012774A1 PCT/US1992/010988 US9210988W WO9312774A1 WO 1993012774 A1 WO1993012774 A1 WO 1993012774A1 US 9210988 W US9210988 W US 9210988W WO 9312774 A1 WO9312774 A1 WO 9312774A1
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WIPO (PCT)
Prior art keywords
composition
microemulsion
cholesterol
calculi
group
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PCT/US1992/010988
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English (en)
Inventor
Kenneth G. Mayhan
Stephen L. Coulter
Christy L. H. Oviatt
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Baxter International Inc
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Baxter International Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/08—Ethers or acetals acyclic, e.g. paraformaldehyde

Definitions

  • the present invention relates in general to the treatmen of diseases characterized by cholesterol, plague and associate calculi deposits in man and animal. More particularly, th present invention is directed toward icroemulsion composition and methods for the contact dissolution or deaggregation o calculi deposits including biliary tract stones, arteria calculi, arterial plaque, calcified protheses, and kidne stones.
  • a particularly annoying disease associated with the formation of calculus is a form of gallbladder disease which is accompanied by the appearance and persistence of gallstones in the gallbladder.
  • This disease is characterized by biliary colic and frequently gallbladder disease patients also develop obstructive jaundice, pancreatitis, nausea and vomiting as well as extreme abdominal pain and tenderness. These symptoms are attributed to the presence of calculi or gallstones in the gallbladder or other parts of the biliary tract.
  • a traditional method for treating gallstone disease is to surgically remove the gallbladder with the problematic gallstones remaining intact inside the extracted gallbladder.
  • cholecystectomy This procedure, known as cholecystectomy, is major abdominal surgery and many gallstone disease patients can tolerate neither the surgical intervention nor the traumatic recovery associated with the surgery. Additionally, the costs of cholecystectomies and long post surgery recover times make this procedure particularly unattractive.
  • many medical practioners have turned to treatment procedures known as cholelitholysis, or methods for chemically dissolvinggallstones. These dissolution techniques initiallytargetedgallstones havinghigh cholesterol contents.
  • gallstones suitable for cholelitholysis are at least 75% and generally over 80% cholesterol.
  • One such cholesterol gallstone dissolution method involves orally administering bile acids to patients known to have mostly cholesterol gallstones.
  • cholelitholysis procedures includecholesterol contact dissolution techniques in which solvent capable of dissolving cholesterol is brought into direct contact with gallstones which are known to have high cholesterol contents.
  • this procedure is performed using a percutaneous puncture of the gallbladder with specialized catheters. The gallbladder is then continually irrigated with the solvent which is pumped through the catheter. During the irrigation process the cholesterol portion of gallstones gradually dissolves and is withdrawn from the gallbladder in the waste solvent.
  • cholelitholysis systems Another problem associated with all these cholelitholysis systems is their ineffectiveness in dissolving noncholesterol gallstones and the noncholesterol components of cholesterol gallstones.
  • Cholesterol gallstones almost always contain materials which are not soluble in solvents typically used to dissolve cholesterol. These noncholesterol components not only appear in cholesterol rich gallstones, but can be the major constituent of gallstones.
  • the noncholesterol components are primarily in the form of calcium bilirubinate, polymerized bilirubin and calcium carbonate. Of these components, the bilirubinates and polymerized bilirubin are frequently collectively referred to as pigment.
  • Biliary stones can be primarily pigment and generally contain small amounts of cholesterol with the calcium bilirubinate and polymerized bilirubin present within a glycoprotein matrix. These gallstones may also contain additional noncholesterol components including calcium carbonate, calcium phosphate, and calcium fatty acid salts such as calcium palmitate. Depending upon their appearance, density, hardness, and chemical composition, pigment gallstones can be further classified into brown pigmented and black pigmented stones. Other forms of calculi can have additional calcium species, e.g. calcium oxalate in kidney stones.
  • Black pigmented stones are generally less than 3 mm in diameter and have a dark rough surface. They are also comparatively hard with a nodular appearance. Brown pigmented stones are significantly softer than the black pigmented stones or the cholesterol rich stones. Brown pigmented stones are also lower in density and have a light brown or tan appearance. Their size tends to vary from about 1 mm to about 10 - 20 mm and often the brown pigmented stones have different geometrical shapes. Attempts at the contact dissolution of mixed gallstones having substantial cholesterol portions and small pigment content as well as attempts to dissolve stones having pigment and other cholesterol components have met with only limited success.
  • n-acetyl cysteine is attributed to its ability to split disulfide bonds of glycoproteins, thus reducing the amount of highly viscous glycoprotein mucous which often surrounds the gallstones and breaking up the glycoprotein matrix in the gallstones.
  • Varyin degrees of success in dissolving pigment stones have bee reported.
  • the amount to which the dissolution occurs depends upon the relative amounts of calcium components, and additional chemical considerations involving the composition of th pigment stones.
  • gallstones frequently exhibit alternating layers of cholesterol and noncholesterol components.
  • EDTA solutions are generally ineffective in dissolving any portion of stones having an outer exposed cholesterol layer or bilirubinate (complex or polymer) , even if the stone has a large overall calcium component.
  • the above described solvent systems have the disadvantage of being useful for dissolving either cholesterol portions or noncholesterol portions of calculi. That is, none of the known systems can effectively dissolve both pigment noncholesterol portions and cholesterol using a single cholelitholysis solvent system.
  • compositions and methods for dissolving calculi within body cavities which can reduce significant harm to tissue.
  • compositions for dissolving and/or deaggregating all components of calculi including cholesterol, plaques, calcium carbonate, calcium palmitate, calcium bilirubinate, polybilirubinates, and glycoprotein.
  • compositions for dissolving and/or deaggregating, on contact, the noncholesterol portions and the cholesterol portions of mixed calculi are also a need to provide compositions for dissolving and/or deaggregating, on contact, the noncholesterol portions and the cholesterol portions of mixed calculi.
  • compositions for dissolving and/or deaggregating on contact pigment calculi including both brown and black pigmented gallstones.
  • the present invention accomplishes the above described objectives by providing compositions and methods for effectively and safely dissolving and/or sufficiently deaggregating calculi deposited within body cavities.
  • the methods and composition of the present invention are well suited for effectively dissolving and/or deaggregating calculi which are primarily cholesterol or calculi having significant cholesterol and noncholesterol components.
  • the present invention provides compositions and methods which are believed to be suitable for the in vivo contact dissolution of cholesterol portions, pigment portions and other noncholesterol portions of gallstones without irreversible tissue damage.
  • the methods and compositions of the present invention are discussed in terms of their usefulness for dissolving biliary calculi, especially gallstones. However, those skilled in the art will appreciate that the methods and compositions disclosed herein are equally applicable to dissolving other types of calculi including arterial plaque, urinary bladder stones and kidney stones. Moreover, in vitro procedures for dissolving cholesterol and artificial or natural calculi such as combinations of cholesterol, calcium carbonate, calcium palmitate, calcium bilirubinate, calcium phosphate, polybilirubinates, and glycoproteins are also within the scope of the present invention. More particularly, the present invention provides stabl microemulsions of a water component, an oil component, and a least one surfactant.
  • the oil component is an organic compoun having a cholesterol solubility of at least 2g/dL at 25° C an is present in the microemulsion at a concentration which i sufficient for the microemulsion to dissolve a clinicall acceptable amount of cholesterol.
  • compositions of the present invention can be water-in- oil microemulsions or oil-in-water microemulsions.
  • the preferable form is an oil-in-water microemulsion.
  • Oils having sufficient cholesterol solubility to be suitable in the compositions of the present invention include alkyl ethers, aromatic hydrocarbons, alkyl esters, alkyl halocarbons, terpenes, aromatic ethers, alkyl hydrocarbons, aromatic esters, glycol ethers, alkyl ketones, aromatic ketones, cyclic ethers, essential oils, alcohols, polyalcohols, aprotic dipolar solvents, and unsaturated solvents.
  • Surfactants having utility in the compositions of the present invention include both ionic surfactants and nonionic surfactants. The nature of the preferred surfactant depends upon the intended utility of the microemulsion.
  • a preferred surfactant is one which forms a stable microemulsion when combined with the water component and sufficient amounts of the oil component to dissolve the desired amount of cholesterol.
  • the preferred surfactant has the capability of dissolving or enhancing the dissolution of the pigment and any other noncholesterol components present in the calculi.
  • Suitable additives for enhancing the dissolution of pigment calculi include mineral chelating agents and disulfide bond cleaving agents.
  • the chelating agents contribute to deaggregating calcium, magnesium and other mineral salts while the disulfide bond cleaving agents react with the disulfide bonds in the glycoproteins to produce smaller more easily dissolved compounds.
  • the present invention additionally provides methods for dissolving calculi which include the steps of providing a stable microemulsion of a water component, an oil component , and a surfactant and causing the stable microemulsion to contact the calculi for a length of time sufficient to dissolve a clinically significant amount of the calculi.
  • compositions of the present invention can be made using standard techniques known in the art for preparing microemulsions. Typically, microemulsification occurs almost spontaneously once the chemistry of the microemulsion system is established. That is, when the specific amounts of oil, water, and surfactant are known to form a stable microemulsion they can be combined in almost any order to form the microemulsion.
  • Fig. 1 is a phase diagram indicating relative amounts o methyl-t-butyl ether, water, and benzalkonium chloride whic form stable microemulsions.
  • Fig. 2 a phase diagram indicating relative amounts o methyl-t-butyl ether, water, and Arquad HTL8MS which for stable microemulsions.
  • Fig. 3 is a phase diagram indicating relative amounts o methyl-t-butyl ether, water, and Ceraphyl® 65 which form stabl microemulsions.
  • Fig. 4 is a phase diagram indicating relative amounts o methyl-t-butyl ether, water, and Arquad® C-33 which form stable microemulsions.
  • Figs. 5 - 8 are graphs illustrating rates of cholesterol dissolution using compositions of the present invention over a one hour period.
  • the present invention provides stable microemulsions useful for dissolving and/or deaggregating calculi deposited in bodily cavities and ducts.
  • the compositions of the present invention are particularly applicable for the effective and safe treatment of biliary stone diseases, including gallstone disease.
  • the compositions and teachings of the present invention also have utility in the contact dissolution of kidney stones, urinary bladder stones, arterial plaque, and calcified deposits on implant devices such as pacemaker leads, heart valves, CSF shunts, stents, and other prosthetic devices such as mammary implants and penile implants.
  • the compositions can be utilized for the dissolution of cholesterol rich calculi or calculi having significant noncholesterol components as well as cholesterol components.
  • noncholesterol components refers to pigment compounds and mineral salts, polymers and complexes.
  • Pigmen components more specifically refers to bilirubinates an polybilirubinates which can dominate the content of both blac and brown pigment calculi.
  • Mineral salts and complexes ar typically calcium carbonate, calcium phosphate, calcium oxalat and fatty acid salts.
  • the present invention is based upon the discovery tha selected microemulsions have utility as a safe and effectiv composition for the contact dissolution of cholesterol an noncholesterol components of calculi.
  • the compositions of th present invention are unlike prior art contact dissolutio compositions which dissolve either cholesterol o noncholesterol components of calculi. According to the present invention, both cholesterol and noncholesterol components of calculi can be advantageously dissolved and/or deaggregate using a single microemulsion composition.
  • the amount of calculi dissolution which occurs is sufficient to dissolve clinically significant amounts of the calculi. More specifically, the compositions provided by the present invention will dissolve and/or deaggregate amounts of calculi sufficient to alleviate the symptoms of the disease. Alternatively, as further described below, the practice of the present invention will result in the dissolution of enough of the calculi to allow the residue to be aspirated from their enclosure.
  • the present invention provides stable microemulsions of a water component, an oil component selected from the group of organic compounds and combinations of organic compounds having a cholesterol solubility of at least 2g/dL, and at least one surfactant.
  • the amount of oil component present in the microemulsion is sufficiently high for the microemulsion to dissolve a clinically acceptable amount of the cholesterol portion present in the calculi.
  • the amount of water component and the amount of surfactant present in the microemulsion is the amount which, when combined with the amount of the oi component, form a stable microemulsion.
  • microemulsions are liquid dispersions of two mutually insoluble liqui components with each of the components having at least one an often two or three components.
  • the two insoluble liquid components are the oil component and the water component.
  • Surfactants act as a stabilizing force to form spherical dispersed phases having diameters in the colloidal range of about 20 - 80 nm.
  • stable microemulsions refers to microemulsions which do not separate into observable phases. Generally, micro- emulsions appear transparent, but when observed with high intensity light, the light is scattered and microemulsion system appears translucent or opalescent.
  • Organic compounds having sufficient cholesterol solubility to be useful in the oil component of the compositions of the present invention include alkyl ethers, aromatic hydrocarbons, alkyl esters, alkyl halocarbons, terpenes, aromatic ethers, alkyl hydrocarbons, aromatic esters, glycol ethers, alkyl ketones, aromatic ketones, cyclic ethers, essential oils, alcohols, polyalcohols, aprotic dipolar solvents, and unsaturated solvents.
  • organic compound as the oil component of the present microemulsions. That is, by combining more than one appropriate organic compound the cholesterol solubility of the resulting combination can be enhanced.
  • Particularly suitable organic compounds having sufficient cholesterol solubility include methyl-t-butyl ether, ethyl ether, diethyleneglycol monobutyl ether, diethyleneglycol onoethylether acetate, diethyleneglycol monomethyl ether, ethylbutyl ether, onooctanoin, glyceryl-1-mono-decanoate, glyceryl-l-2-dioctanoate, glycerol, butylene glycols, butyl acetates , 2 - et o y ethano 1 , chloroform, bromochlorofluoroethanes, 2-bromo-2-chloro-l, 1, 1 triflu
  • any surfactant having hydrophilic an lipophilic properties suitable for emulsifying the selected oi component and water can be utilized in the compositions of th present invention.
  • the choice o surfactant is also dependent upon tissue compatibilit considerations.
  • the surfactant preferably ha acceptable gallbladder mucosa compatibility characteristics.
  • Suitable nonionic surfactants include polyethylene oxides, polypropylene oxides, polybutyleneoxides, mixed polyalkylen oxides, Tweens®, Tritons® (available from Rohm and Haas) Tergitol 25-L-91® and Tergitol 15-S-15® (available from Unio Carbide) , sorbitans, lecithin and proteins, such as albumin.
  • Ionic surfactants having utility in the practice of the presen invention include the cationic quaternary ammonium salts, an quaternary ammonium polymers.
  • Anionic surfactants havin suitability as emulsifiers in the compositions of the presen invention include bile acids, fatty acids, fatty acid soaps, and polycarboxylates.
  • the preferred ionic surfactants ar the quaternary ammonium salts and bile acids.
  • the stabl microemulsions of the present invention can include more tha one surfactant or a co-surfactant.
  • thes compounds are typically prepared by reacting ammonia or primary, secondary, or tertiary amine with an alkyl halide t form an ionic salt of the halide ion and amine.
  • ammonia or primary, secondary, or tertiary amine with an alkyl halide t form an ionic salt of the halide ion and amine.
  • Particularly suitable quaternary ammonium salts include benzalkonium chloride, dodecyltrimethyl ammonium chloride, mixed trialkyl ammonium chloride, dodecyltrimethyl ammoniu bromide, cetylpyridinium chloride, trimethylalkyl ammoniu bromide, Arquad HTLB®, Arquad C-33®, Ceraphyl 65®, Arquad 218- 100P®. All of these are commercially available. Arquad® is available from Akzo Chemicals Inc. , and Ceraphyl 65® is available from Van Dyk & Co., Inc.
  • the amount of oil component present in the present microemulsions is sufficient to dissolve a clinically sufficient amount of cholesterol calculi.
  • the amount of water component and the amount of surfactant present in the microemulsion is the amount which, when combined with the selected quantity of oil, form a stable microemulsion.
  • the relative amounts of each component can vary from a small amount to a major component of the microemulsion. Accordingly, the oil component, water, and surfactant can vary from 5 wt% to 80 wt% of the microemulsion.
  • surfactants are the specific intended use for the microemulsion.
  • the surfactant need not necessarily have specific calculi dissolution properties. That is, the oil component provides the microemulsion with cholesterol dissolution properties and the surfactant primarily serves to emulsify the oil components and water.
  • microemulsions which are useful for the contact dissolution of cholesterol and cholesterol rich biliary calculi include a water component, an oil component selected from the group of organic compounds or combination of organic compounds having a cholesterol solubility of at least 2g/dL at 25° C, and surfactanthaving a hydrophilic-lipophilic balance suitable for the water component and the oil component to form a stable microemulsion.
  • the oil component is present in the microemulsion in an amount sufficient to dissolve a clinically acceptable amount of cholesterol.
  • Hydrophilic-lipophilic balance refers to the relative degree to which a surfactant is hydrophilic as opposed lipophilic.
  • the surfactan preferably has a relatively high balance of hydrophilic t lipophilic portions or a relatively low balance of hydrophili to lipophilic portions.
  • the selected surfactant i preferably among those surfactants having the ability t enhance the dissolution of bilirubinates and polybilirubinate or pigment components of the calculi.
  • suitable surfactants are selected from the group consisting o quaternary ammonium salts, lecithin, and bile acids.
  • microemulsions which are useful for the contac dissolution of calculi having cholesterol, noncholesterol, an pigment portions include a water component, an oil componen selected from the group of organic compounds having cholesterol solubility of at least 2g/dL at 25° C, an surfactant having a pigment solubility of at least 2g/dL at 25° C.
  • the oil component is present in an amount sufficient for the microemulsion to dissolve clinically acceptable amounts of cholesterol and surfactant is present in amounts sufficient to dissolve clinically acceptable amounts of pigment.
  • gallstone calculi in addition to cholesterol and pigment, gallstone calculi often include additional non- cholesterol components such as calcium phosphate, calcium carbonate, bile acid salts, fatty acid salts, and glycoproteins.
  • the compositions of the present invention can further include additives for enhancing the dissolution of these noncholesterol components.
  • the microemulsions of the present invention can further include chelating agent for dissolving or reacting with calcium complexes and other mineral complexes.
  • the microemulsions of the present invention can include disulfide cleaving agent for reacting with the disulfide bonds of the glycoproteins.
  • these additives are water soluble and thus are a portion of the water component of the present microemulsions.
  • Chelating agents which are useful additives in the compositions of the present invention include ethylenediaminetetracetic acid, ethylenediamine, triethanolamine, polyethyleneimine, dimercaptopropanol, sodium tripolyphosphate, triethylenetetramine, triethylenetetra ine 2HC1. Of these, preferred chelating agents are EDTA and sodium tripolyphosphate.
  • chelating agents utilized in the present invention are present at a concentration of from about 0.5 wt% to about 20 wt% in the microemulsion. Preferable concentrations range from about 1 wt% to about 5 wt%.
  • Disulfide bond cleaving agents useful in the compositions of the present invention include n-acetyl cysteine, dithiothreitol, penicillamine, andmercapto-1-methylimidazole. N-acetyl cysteine and dithiothreitol in particular enhance the dissolution of calculi having some glycoprotein matrix when utilized in the compositions of the present invention. Typically disulfide cleaving agents are present from about 1 wt% to about 10 wt%.
  • the pigment calculi and gallstone dissolution properties of the present invention are enhanced with the presence of certain amino acids, proteins, and bile acids including cholic acid and chenodeoxycholic acid.
  • certain amino acids, proteins, and bile acids including cholic acid and chenodeoxycholic acid.
  • albumin and carnosine as well as arginine at concentrations ranging from at least 1 wt% are useful additives for the compositions of the present invention.
  • microemulsions can exist as a water-in-oil microemulsion or an oil-in-water microemulsion.
  • water is dispersed in oil and oil is the continuous component.
  • oil is dispersed in water and water is the continuous component.
  • the two types can invert from one to the other b adding more of one component or changing the type of surfactan or the hydrophilic-lipophilic balance of the surfactant.
  • the compositio is an oil-in-water microemulsion. That is, the continuou component is water and the oil component is in the form o dispersed colloidal droplets. In this configuration, th composition can exhibit superior tissue compatibility.
  • preferred exemplary embodiments of the presen invention are oil-in-water microemulsions useful for dissolvin and/or deaggregating calculi, including noncholesterol an cholesterol portions of calculi. These preferred embodiment are microemulsions of water, methyl-t-butyl ether (MTBE) , an a quaternary ammonium salt.
  • MTBE methyl-t-butyl ether
  • a stabl microemulsion is a composition which includes 60 wt% MTBE, 10 wt% H 2 0, and 30 wt% benzalkonium chloride.
  • Another stabl microemulsion of the same components is a composition whic includes 10 wt% MTBE, 45 wt% H 2 0, and 45 wt% benzalkoniu chloride.
  • the firs mentioned microemulsion is particularly suitable for dissolving or deaggregating calculi having significant cholesterol content and some pigment content and/or other noncholesterol components. This is due to the higher amount of MTBE which is sufficient to dissolve a clinically significant amount of cholesterol.
  • the second mentioned microemulsion is more suitable for dissolving or deaggregating calculi having high pigment content. This is attributed to the higher amount of benzalkonium chloride present in the microemulsion which enhances the dissolution of pigment.
  • these preferred embodiments can additionally include additives for enhancing the dissolution of other noncholesterol components of calculi.
  • the water component preferably include from 0.5 wt% to 5 wt% EDTA and from 0.5 wt% to 10 wt% of at least one disulfide bond cleaving agent selected from the group consisting of acetyl cysteine and penicillamine.
  • Methods for utilizing these compositions to dissolve calculi include providing a stable microemulsion and then causing the microemulsion to contact the biliary calculi for a length of time sufficient to dissolve a clinically acceptable amount of the calculi.
  • the stable microemulsion includes a water component, an oil component having a cholesterol solubility of at least 2g/dL, and one or more surfactants.
  • the water component can additionally include additives such as the disulfide bond cleaving agents and chelating agents discussed above.
  • Causing the solution to contact the calculi can be carried out using methods for perfusing liquids into enclosed cavities such as hollow ducts, organs or even arterial systems of a patient. Such methods include percutaneous catheter placement, endoscopic retrograde biliary catheter placement, or placement of a catheter in a localized area by surgical means. Following catheter placement, the solution is flushed through the catheter and into the cavity where it contacts the calculi. The solution and dissolved portions of calculi are then removed through the catheter and fresh solution is perfused into the cavity. This perfusing technique is typically accomplished using a syringe or pumping system.
  • compositions of the present invention are particularly useful for the dissolution of gallstones in the gallbladder and less frequently in the biliary tract.
  • these compositions are also useful for dissolving combination of cholesterol, calcium carbonate, calcium phosphate, calciu palmitate, calcium bilirubinate, polybilirubinates, an mucoglycoproteinates.
  • length of time which are sufficient to dissolve and/or deaggregate clinically acceptable amount of calculi varies and can depen upon the type of calculi involved as well as the number an size of the calculi deposits.
  • in viv applications require time considerations which are differen from the times required for in vitro applications.
  • the contact dissolution of stones using perfusion technique can require more than one treatment procedure with eac treatment procedure requiring up to 8 hours. Treatmen procedures can extend over a period of several days.
  • a particularly advantageous feature of the present inventio is the ability of these microemulsions to simultaneousl dissolve and or deaggregate cholesterol and noncholestero components of calculi.
  • Prior art methods for the contac dissolution of calculi require contacting the calculi with a least two separate compositions.
  • One of these is organi solvent for dissolving cholesterol and the other is generall aqueous based for dissolving the noncholesterol components.
  • the prior ar methods are particularly tedious because they require, fo example, alternating treatment procedures with organic base and aqueous based compositions.
  • the presen invention provides compositions and methods which avoids th use of different solutions.
  • compositions of the present invention ar believed to have improved biocompatibility in that th potentially tissue damaging cholesterol solvents which can b incorporated in the microemulsions are shielded from tissue by the aqueous components.
  • compositions of the present invention are much less flammable and do not present the same fire and explosion hazards associated with the use of low flash point organic solvent compositions which do not incorporate nonflammable components, such as water.
  • compositions of the present invention can be prepared using techniques known in the art for preparing microemulsions.
  • the microemulsions of the present invention will form spontaneously and very little or no agitation is required. In forming spontaneously, it is not meant to imply that a stable microemulsion forms instantaneously.
  • the stable microemulsions of the present invention will form spontaneously once sufficient interaction between the components occurs. Additionally, the specific order of adding the water component, oil component, and surfactant does not appear to be significant and the components can be combined in any convenient order. For some applications, it may be desirable to include pH buffering agents in the microemulsions to maintain the composition at a specific pH.
  • compositions having quaternary ammonium salts are generally more effective in dissolving pigment components when the pH is maintained above pH 6 or 7. Accordingly, preparing the microemulsions of the present invention can further include adding pH buffers in the form of organic or inorganic buffering salts to the water component.
  • a preferred surfactant and oil component as well as the desired amount of oil component are pre-selected, but the specific proportions of water, oil, and surfactant suitable for producing a microemulsion are not known.
  • Preparing a microemulsion in this case can be accomplished by combining the selected amount of oil component with preferred surfactant. Next adding water to the combination of oil and surfactant can result in reaching the correct combination to form a microemulsion.
  • a microemulsion does not form with the desired amount of o component and/or surfactant it may be necessary to choose different surfactant and add a co-surfactant.
  • the following non-limiting examples further illustra methods for preparing the compositions of the present a invention and their in vitro utility.
  • EXAMPLE 1 A total of twenty different combinations of benzalkoni chloride, water and methyl-t-butyl ether were prepared combining preselected amounts of each of the components. Ea of the twenty resulting mixtures was evaluated for its abili to form an oil-in-water microemulsion. Stable microemulsio were characterized by an apparent single phase transpare system. Table I indicates the proportion by weight of ea component and whether or not the combination results in microemulsion. All microemulsion formed below are oil-i water. Table I
  • Table I The data illustrated in Table I is plotted in Fig. 1 as a ternary phase diagram.
  • the shaded area indicates stable microemulsion compositions.
  • Those compositions having higher amounts of MTBE are more suitable for the contact dissolution of calculi having significant portions of cholesterol.
  • compositions having higher amounts of benzalkonium chloride are more suitable for the contact dissolution of calculi having greater pigment content and some cholesterol.
  • EXAMPLE 2 A total of twelve different combinations of Arquad HTL8MS® (a quaternary ammonium salt available from Akzo Chemicals Inc.), water, and methyl-t-butyl ether were prepared by combining preselected amounts of each of the components. Each of the twelve resulting mixtures was evaluated for its ability to form a stable microemulsion. Stable microemulsions were characterized by an apparent single phase transparent system. The phase diagram shown in Fig. 2 indicates the proportions of each component used in each of the twelve mixtures. Those mixtures shown as an 0 are stable microemulsions.
  • Arquad HTL8MS® a quaternary ammonium salt available from Akzo Chemicals Inc.
  • EXAMPLE 3 A total of twenty-three different combinations of Ceraphyl 65® (a quaternary ammonium salt available from Van Dyk & Co., Inc.), water, and methyl-t-butyl ether were prepared by combining preselected amounts of each of the components. Each of the twenty-three resulting mixtures was evaluated for its ability to form a stable microemulsion. Stable microemulsions were characterized by an apparent single phase transparen system. The phase diagram shown in Fig. 3 indicates th proportions of each component used in each of the twenty-thre mixtures. Those mixtures shown as an 0 are stabl microemulsions.
  • Ceraphyl 65® a quaternary ammonium salt available from Van Dyk & Co., Inc.
  • EXAMPLE 4 A total of thirteen different combinations of Arquad C-33 (a quaternary ammonium salt available from Akzo Chemical Inc.), water, and methyl-t-butyl ether were prepared b combining preselected amounts of each of the components. Eac of the thirteen resulting mixtures was evaluated for it ability to form a stable microemulsion. Stable microemulsion were characterized by an apparent single phase transparen system. The phase diagram shown in Fig. 4 indicates th proportions of each component used in each of the thirtee mixtures. Those mixtures shown as an O are stabl microemulsions.
  • Arquad C-33 a quaternary ammonium salt available from Akzo Chemical Inc.
  • microemulsions were formed by first preparin a base microemulsion of 45 wt% pentanol, 25 wt% sodium ⁇ odecy sulfate, (SDS) and 30 wt% water and then adding various amount of MTBE. These microemulsions were then evaluated for thei ability to dissolve cholesterol by gradually an gravimetrically adding cholesterol to the microemulsion an determining the degree of dissolution after twelve hours. Th relative amounts of each of the four components and th cholesterol solubility of each four component microemulsion i illustrated in Table II. The cholesterol solubility is base on the total microemulsion system. Amount Base Microemulsion 45 wt% pentanol, 25 wt% SD 30 wt% water
  • microemulsions were formed by first preparin a base microemulsion of 45 wt% pentanol, 25 wt% sodium dodecyl sulfate, (SDS) and 30 wt% water and then adding various amounts of Halothane. These microemulsions were then evaluated for their ability to dissolve cholesterol by gradually and gravimetrically adding cholesterol to the microemulsion and determining the degree of cholesterol dissolution after twelve hours.
  • SDS sodium dodecyl sulfate
  • the relative amounts of each of the four components and the cholesterol solubility of each four component microemulsion is illustrated in Table III. The cholesterol solubility is based on the amount of the total microemulsion system.
  • microemulsions Four component water-in-oil microemulsions were formed b first preparing a base microemulsion of 33.3 wt% pentanol, 33. wt% Tergitol 15-S-15®, available from Union Carbide, and 33. wt% water and then adding MTBE. These microemulsions were the evaluated for their ability to dissolve cholesterol b gradually and gravimetrically adding cholesterol to th microemulsion and determining the degree of cholestero dissolution after twelve hours. The relative amounts of eac of the four components and the cholesterol solubility of eac four component microemulsion is illustrated in Table IV. Th cholesterol solubility is based on the amount of the tota microemulsion system.
  • Example 8 Nine 3-component microemulsions were prepared with varyin amounts of MTBE, water, and a variety of surfactants. Th cholesterol solubility of each microemulsion was determined b quantitatively transferring increasing amounts of cholestero into known amounts of the microemulsion and observing th clarity of the of the microemulsion. Table V indicates th relative quantity of MTBE, water, and surfactant as well as th type of surfactant and the cholesterol solubility of eac microemulsion. The first three microemulsions shown in Tabl V are water-in-oil microemulsion and the remaining six are oil in-water microemulsions. Table V
  • Examples 5 - 8 illustrate the effective dissolution of cholesterol in microemulsion systems prepared from various surfactants, water and an oil component having cholesterol solubility.
  • Example 9 Two microemulsions containing buffering salts in the water component were prepared by combining a selected amount of benzalkonium chloride with a selected amount of water buffered to pH 7 with phosphate buffering salts. The pH of the solution was then adjusted with concentrated KOH solution to a pH of 8. Finally, a selected amount of MTBE was added to the combination of aqueous and surfactant components. The following microemulsions of benzalkonium chloride, buffered aqueous component, and MTBE were successfully prepared.
  • Pigment 'and other noncholesterol portions of huma gallstones were isolated from a number of different types o gallstones by extracting human stones with MTBE and isolatin the residue.
  • a 40%/20%/40% benzalkonium chloride/MTBE/buffere H 2 0 microemulsion was prepared according to the metho described in Example 9. 2 wt% n-acetyl cysteine and 1 wt% EDT was also added to the buffered H 2 0.
  • the ability of the microemulsion to dissolve th noncholesterol and pigment portion of the gallstones wa demonstrated by accurately weighing 10 - 15 mg of the residu obtained after MTBE extraction to 10 mL of the 40%/20%/40 microemulsion.
  • Example 11 Four separate microemulsions were prepared usingMTBE as th oil component and three different surfactants as the surfactan component. Each of the microemulsions were then tested fo their ability to dissolve cholesterol by pumping th microemulsion in and out of a container of cholesterol spheres. The rate at which the cholesterol disappeared was determine by weighing the undissolved cholesterol at given time intervals. An equal amount of cholesterol was also dissolved with MTBE using similar techniques for comparison.
  • Fig. 5 illustrates the rate at which cholesterol dissolves using a microemulsion of 35wt% benzalkonium chloride, 50 wt% MTBE, and 15 wt% H 2 0 compared with the dissolution of cholesterol with neat MTBE.
  • the microemulsion was pumped at 8.5 cycles/min with a flow rate of 13 cc/min.
  • the MTBE was pumped at 23 cycles/min and a flow rate of 77 cc/min.
  • Fig. 6 illustrates the rate at which cholesterol dissolves using a microemulsion of 40 wt% Ceraphyl, 50 wt%, 10 wt% buffered H 2 0 at pH 8 compared with the dissolution of cholesterol with MTBE.
  • the microemulsion was pumped at a flow rate of 11 cc/min.
  • the MTBE was pumped at a flow rate of 79 cc/min.
  • Fig. 7 illustrates the rate at which cholesterol dissolves using a microemulsion of 23 wt% lecithin, 58 wt% MTBE and 19 wt% H 2 0 compared with the dissolution of cholesterol with MTBE.
  • microemulsion was pumped at a flow rate of 35 cc/min and the MTBE at 77 cc/min.
  • Fig. 8 illustrates the rate at which cholesterol dissolves using the emulsion shown in Fig. 7 with 0.2 wt% sodium deoxycholic acid added.
  • the microemulsion was pumped at a flow rate of 34 cc/min and 10 cycles/min.
  • compositions of the present invention are attributed to both their improved biocompatibility over prior art cholesterol dissolution systems and their ability to dissolve both cholesterol and noncholesterol components calculi with a single composition.
  • the . improv biocompatibility is due to the presence of the water compone of the microemulsion which effectively shields the mucos tissue from potentially harsh solvents.
  • t compositions of the present invention include generall mutually insoluble components in a single uniform syste Collectively, these components can provide chemica functionalities for dissolving and/or deaggregating calculi Microemulsions of these components provide an effective singl vehicle for the contact dissolution of cholesterol an noncholesterol portions of calculi.

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Abstract

L'invention se rapporte à des compositions et des procédés de dissolution par contact de calculs situés dans les cavités du corps humain, et plus particulièrement les calculs biliaires. Lesdites compositions sont des microémulsions d'un composant aqueux, d'un composant huileux et d'au moins un tensio-actif. Le composant huileux est un composé organique présentant une capacité de dissolution dans le cholestérol d'au moins 2g/dL. Ces compositions sont utilisées pour la dissolution simultanée des fractions cholestéroliques et non cholestéroliques contenues dans les calculs.
PCT/US1992/010988 1991-12-20 1992-12-17 Microemulsions de dissolution de calculs Ceased WO1993012774A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5824635A (en) * 1996-04-26 1998-10-20 Keys; Robert O. Cationic compositions containing hydroxyester
US5830842A (en) * 1996-04-26 1998-11-03 Witco Corporation Hydroxyesters as coupling agents for surfactant formulations
CN113491682A (zh) * 2020-04-01 2021-10-12 宁海德宝立新材料有限公司 胆结石溶石剂
CN113509456A (zh) * 2020-04-09 2021-10-19 宁海德宝立新材料有限公司 一种二乙二醇丁醚溶石剂
CN113521039A (zh) * 2020-04-17 2021-10-22 宁海德宝立新材料有限公司 一种新型溶石剂
CN113521040A (zh) * 2020-04-22 2021-10-22 宁海德宝立新材料有限公司 一种介入性溶解胆结石的溶石剂

Citations (1)

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Publication number Priority date Publication date Assignee Title
DE3530945A1 (de) * 1985-08-29 1987-03-12 Falk Pharm Praeparate Gmbh Co Spuelfluessigkeit fuer die lyse von gallensteinen

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
DE3530945A1 (de) * 1985-08-29 1987-03-12 Falk Pharm Praeparate Gmbh Co Spuelfluessigkeit fuer die lyse von gallensteinen

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 114, no. 18 Columbus, Ohio, US; abstract no. 171211w, *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5824635A (en) * 1996-04-26 1998-10-20 Keys; Robert O. Cationic compositions containing hydroxyester
US5830842A (en) * 1996-04-26 1998-11-03 Witco Corporation Hydroxyesters as coupling agents for surfactant formulations
CN113491682A (zh) * 2020-04-01 2021-10-12 宁海德宝立新材料有限公司 胆结石溶石剂
CN113509456A (zh) * 2020-04-09 2021-10-19 宁海德宝立新材料有限公司 一种二乙二醇丁醚溶石剂
CN113509456B (zh) * 2020-04-09 2023-04-07 宁海德宝立新材料有限公司 一种二乙二醇丁醚溶石剂
CN113521039A (zh) * 2020-04-17 2021-10-22 宁海德宝立新材料有限公司 一种新型溶石剂
CN113521040A (zh) * 2020-04-22 2021-10-22 宁海德宝立新材料有限公司 一种介入性溶解胆结石的溶石剂

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