Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/12—Oxygen or sulfur atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
  • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/10—Antioedematous agents; Diuretics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
  • C08F8/00—Chemical modification by after-treatment
  • C08F8/44—Preparation of metal salts or ammonium salts

Definitions

• the invention relates to water soluble complexes of normally water insoluble drugs such as chlorothiazide, aminobenzoic acid, furosemide and mixtures thereof wherein the complexing agent is a polyvinyl lactam such as polyvinylpyrrolidone, polyvinylpyrrolidone-halogen complex or mixtures thereof.
• the complexing agent is a polyvinyl lactam such as polyvinylpyrrolidone, polyvinylpyrrolidone-halogen complex or mixtures thereof.
• the invention also relates to the preparation of these complexes which involves dissolving the reactive components in an aqueous inert solvent combining the complexing agent and drug in a weight ratio of from about 1:1 to about 10:1 with agitation for a period of at least 5 minutes at a temperature above 3oC. and below the boiling point of the aqueous solvent solution under a pressure up to about 50 psig.
• Chlorothiazide (6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide) is a known antihypertensive and diuretic drug which is also used to treat congestive heart failure in animals.
• Furosemide (4-chloro-N-furfuryl-5-sulfamoyl anthranilic acid) is also a well known diuretic.
• administration of these compounds in solution is complicated by their water-insolubility.
• the water solubility of chlorothiazide is only 0.5 g. per liter at pH 6 and although this drug is soluble in alkaline aqueous solutions, it decomposes rapidly on standing.
• the meta- ortho- and para- amino benzoic acids are also well known water insoluble compounds and are used as dye intermediates, pharmaceuticals, vitamin adducts and nutritional substances for veterinary use. Because of their applications in pharmaceutical areas, it is important that no solvent having toxic or other deleterious side effects be employed for solubilization of these compounds in medicinal uses. Accordingly, it is an object of the present invention to provide a highly water soluble form of aminobenzoic acid, chlorothiazide and furosemide with no objectionable side effects. Another object is to provide a chlorothiazide in a water soluble form having fortified diuretic properties.
• mono- and multi- complexed water soluble products of the above drugs which are derived from the reaction between a polyvinyl lactam such as polyvinylpyrrolidone or a polyvinylpyrrolidone-halogen complex and the selected drug or mixture of drugs.
• a polyvinyl lactam such as polyvinylpyrrolidone or a polyvinylpyrrolidone-halogen complex
• These products are true complexs containing repeating units of the complexed drug and vinyl pyrrolidone moieties.
• the complexed product of this invention may also contain non-complexed vinyl lactam moiety sites of the general formula:
• n has a value of from 1 to 3.
• the product contains repeating units of the following structures involving hydrogen bonding.
• n is an integer having a value of from 1 to 3 and halo is iodine, chlorine or bromine, iodine being preferred.
• hydrogen bonding explains only one of the possible structures which can be attributed to the complex.
• hydrophobic bonding, as well as bonding by various forms of Van der Waals forces can be present to either a major or minor extent in the complex.
• the bonding between the polymer and drugs such as chlorothiazide and furosemide takes place through hydrophobic bonding in which the aromatic moieties of the drug compounds and the hydrocarbon chain of the poly(vinyl pyrrolidone) are responsible for the complexing interaction.
• the hydrophobic bonding force will bring the drug molecules and the polymer chain in close contact where short range dispersion forces become operative and contribute to the stabilization of the complex.
• This compound has a phenolic-type hydroxyl substituent, which complexes readily with poly(vinyl pyrrolidone). Nevertheless, the coprecipitate of this compound with poly(vinyl pyrrolidone) was found to be insoluble in water, while the coprecipitates of chlorothiazide and furosemide showed good water solubility.
• the complexed units in the polymer may occur in block, random or alternating distribution.
• the products of this invention contain at least 8 wt. % to about 30 wt. % preferably at least 12 wt. % complexed units, and usually at least 90% of the drug component can be complexed with the lactam.
• complexing is sufficient to retain properties associated with the drug.
• a mixture of drugs can be incorporated in the present complexes.
• One such mixture involves chlorothiazide fortified with furosemide in a ratio of 1:99 to 99:1, preferably between about 45:55 and about 60:40.
• the complexed state of the present products has been established by experiment showing that at gradual dilution from 2% to 0.01% in water, no free drug precipitated from the aqueous solution. Had the drug not complexed, it would have precipitated out of solution in this range of dilution.
• a complex water solubility of at least 15% is desired and water solubility as high as 25% and more has been achieved.
• the complexing agents of this invention are the poly(N-vinyl-2-pyrrolidone) and poly(N-vinyl-2-pyrrolidone)-halogen complex wherein the halogen most preferably is iodine or bromine.
• the preferred products of this invention may contain halogen complexed and/or un-complexed N-vinyl-2-pyrrolidone units derived from poly(N-vinyl-2-pyrrolidone) having a K value between 12 and 30; although polymers from an oligomer to K-90 may also be employed in certain cases. Polymers of K-100 or more, because of their high solution viscosity, may limit the amount of drug which they can bring into solution in complexed form.
• the poly(N-vinyl-2-pyrrolidone)-halogen complex reactant of this invention can be prepared according to the process disclosed in co-pending U.S. application Serial No. 849,918, filed April 9, 1986 and entitled METHOD OF PREPARING A POLYVINYLPYRROLIDONE-HALOGEN
• the mole ratio of halogen to poly(N-vinyl-2-pyrrolidone) in the complex is generally between about 1:3 and about 1:15, preferably 1:8-12 so that the polymer contains a significant number of non-complexed sites on which additional complexing with drug can occur.
• the poly(N-vinyl-2-pyrrolidone)-halogen complex reactant of this invention can have a number average molecular weight between about 5,000 and about 150,000; between 15,000 and 50,000 being preferred.
• the complexes of the present invention are prepared by a relatively simple and direct process which involves dissolving the selected drug or drugs and the selected complexing agent in an inert solvent such as an aqueous alcoholic or alkali metal hydroxide solution to produce a solution containing between about 5% and about 25% by weight, preferably between about 8% and about 15% by weight of each reactant. It is recommended that solutions of the drug and complexing agent be prepared separately and then combined in the desired weight ratio of lactam to drug. For example, a weight ratio of from about 1:1 to about 10:1 has been found suitable.
• the resulting solution containing drug and complexing components are thoroughly mixed over a period of from about 5 minutes to about 3 hours at a temperature above 3oC. and below the boiling point of the solvent under atmospheric pressure up to a pressure of about 50 psig.
• aminobenzoic complexes of this invention can be prepared by separately dissolving the aminobenzoic acid and the vinyl lactam complexing agent in a C 1 to C 5 alcohol solution, preferably an ethanol solution.
• the vinyl lactam reactant can be defined by the formula
• n has a value of 1 to 3 and m has a value of from 5 to 3,500 or the halogen complex of this lactam, preferably the iodine or bromine complex of the lactam.
• the solutions are then preferably combined in a weight ratio of complexing agent to acid of between about 4-7:1, and thoroughly mixed at a temperature preferably between about 4oC. and about 100°C., most preferably from 10oC. to about 40oC.
• the mixture is agitated under these conditions for a period of from about 10 and about 30 minutes.
• the resulting mixture comprising a liquid alcohol phase and a solid muIticomplexed product phase is treated to remove solvent by any conventional means, such as rotary evaporation or freeze drying. Evaporation is conducted in vacuo, e.g. under a pressure of from about 2 to about 40 mm Hg, preferably not more than 20 mm Hg.
• the remaining solids are recovered and dried at a temperature between about 45oC. and about 100oC, preferably between about 50°C. and about 65°C. for a period of 1 to 24 hours.
• the dried product of the process is readily dissolved in water and the water solubility of the aminobenzoic acid in this multicomplexed form is increased from about 0.3% to at least 25% at room temperature.
• chlorothiazide complexes of this invention are similarly prepared by e.g. separately dissolving chlorothiazide or a chlorothiazide-furosemide 50/50 mixture and the complexing agent described above in an aqueous alkali metal hydroxide solution, e.g. a 1.8% to 5% sodium hydroxide or potassium hydroxide solution, to provide solutions preferably containing 8% to 15% by weight concentration of the respective reactants.
• an aqueous alkali metal hydroxide solution e.g. a 1.8% to 5% sodium hydroxide or potassium hydroxide solution
• the resulting solution at a pH of between about 7.5 and about 10, e.g. between 8 and 9, is thoroughly mixed at a temperature preferably between about 4oC. and about 100oC, most preferably between about 10oC. and about 40°C. for a period of from about 10 to about 30 minutes to produce the alkali metal salt of the drug moiety or moieties when mixtures are employed as the drug component.
• the resulting liquid mixture comprising the alkali metal salt moieties of the complex and aqueous alkali metal hydroxide solvent, is treated to remove solvent by any conventional means, such as rotary evaporation or freeze drying. Evaporation is conducted in vacuo, e.g. under a pressure of from about 2 to about 40 mm Hg, preferably not more than 25 mm Hg.
• the complexed salt liquid is recovered and dried at a temperature between about 45°C. and about 100°C, preferably between about 50°C. and about 65oC. in vacuo for a period of 1 to 24 hours to produce a solid salt complex.
• the dried complex is then mixed with water and the pH is adjusted to between about 3.5 and about 7, preferably to between about 5 and about 6.3 with a mineral acid, preferably HCl in a 1.8-5% aqueous solution, to convert the complexed alkali metal salt of the sulfamyl group to a sulfamyl radical and the metal carboxylate group to a carboxyl radical so as to produce the complexed product of the invention.
• a mineral acid preferably HCl in a 1.8-5% aqueous solution
• the resulting chlorothiazide or chlorothiazide and furosemide in this complexed form is stable and is found to have a water solubility increased from about 0.05% to at least 15% or more at room temperature.
• Poly(N-vinyl-2-pyrrolidone), K-30 (12.5 grams) was dissolved in 112.5 grams of a 2% aqueous sodium hydroxide solution and poured into a dropping funnel.
• Chlorothiazide (1.25 grams) dissolved in 11.25 grams of 2% aqueous sodium hydroxide solution and 1.25 grams of furosemide in 11.25 grams of 2% aqueous hydroxide solution were poured into separate dropping funnels.
• the solutions from each dropping funnel were gradually added to a 500 ml glass flask over a period of 15 minutes during which period they were thoroughly mixed at room temperature at atmospheric conditions. The contents of the flask was then subjected to rotary evaporation under 21 mm Hg vacuum at 80°C. to remove the water.
• the dried material which is the sodium salt of the complex was ground in a mortar to a particle fineness passing a 100 mesh screen.
• Example 1 was repeated and 3.5 grams of the dry complexed product were dissolved in 5.0 grams of distilled water. The resulting solution was adjusted to a pH of 6.2 with concentrated hydrochloric acid. This aqueous solution, containing 10.5% of chlorothiazide and furosemide, remained clear and its clarity did not diminish after standing for 1 week.
• Examples 1 and 2 are intended to set forth preferred embodiments of the present invention; however, many variations and modifications of the above experiment and complexed products will become apparent from the foregoing description and disclosure.
• alkali metal hydroxide solvents as well as other higher or lower molecular weight poly(N-vinylpyrrolidones) or other mole ratios of polymer to drug species can be employed to provide the corresponding complexes wherein the water solubility of chlorothiazide and furosemide is markedly increased.
• Example 4 The solutions were mixed and coprecipitated using the procedure of Example 1. Two grams of the resulting solid were placed in a screwcap jar and 20 grams of distilled water were added. After shaking for 1 hour, the solution was acidified to pH 5.5 with concentrated hydrochloric acid. The solid precipitated out of the solution, and remained insoluble even when it was diluted further with the addition of another 20 grams of distilled water and shaken overnight. EXAMPLE 4
• Chlorothiazide (5 grams) was dissolved in 45 grams of a 2% aqueous solution of sodium hydroxide and the solution added to a dropping funnel.
• 50 grams of the chlorothiazide solution and 200 grams of the polyvinylpyrrolidone solution were charged dropwise over a period of 15 minutes to a 500 milliliter flask and the resulting solution agitated for 15 minutes at room temperature.
• the pH of the reacting mixture was about 8.5 and the complex formed with the sodium salt of poly(N-vinyl-2-pyrrolidone) and chlorothiazide.
• the liquid reaction medium is then evaporated under about 20 mm Hg to remove the solvent and the resulting solid was dried under similar vacuum at 60°C. overnight.
• Chlorothiazide (5 grams) and poly(vinylpyrrolidone) K-15 (20 grams) respectively, were dissolved in 2% aqueous sodium hydroxide to form 10% solutions. These solutions were mixed and the mixture were dried as described in Example 1. The product was the sodium salt of the poly(vinylpyrrolidone)-chlorothiazide complex.
• the complex sodium salt solid (20 grams) was placed in a screwcap jar wherein it was agitated on a horizontal shaker with 18.0 grams of distilled water for a period of 1/2 hour. The pH was then adjusted to 6.5 with a concentrated aqueous hydrochloric acid solution to convert the complexed salt to the complexed product of the process and agitation was continued for 2 hours. At the end of this period, a clear solution having a pH of 6. 5 was obtained and the water solubility of the chlorothiazide in the complex was found to be 16.2%.
• Example 1 was repeated except that dimethyl formamide was substituted for the 2% sodium hydroxide solution. 1 gram of the resulting precipitate containing 0.2 grams of chlorothiazide was added to 99 grams of distilled water. After shaking for 24 hours at room temperature none of the chlorothiazide had dissolved in the water.
• Examples 1-2 and 4-6 are intended to set forth a preferred embodiment of the present invention; however, many variations and modifications of the above experiments and complexed products will become apparent from the foregoing description and disclosure.
• other alkali metal hydroxide solvents can be employed and other higher or lower molecular weight poly(N-vinylpyrrolidones) or poly(N-vinyl-caprolactams) or other mole ratios of polymer to chlorothiazide can be substituted to produce complexes wherein the chlorothiazide shows markedly increased water solubility.
• a 35% poly(N-vinyl-2-pyrrolidone) in aqueous solution was made up.
• a separate ethanol solution of iodine and hydriodic acid, in a mole ratio of 4:1 was separately prepared.
• Example 7 parts A and B were repeated except that o-aminobenzoic acid was substituted for p-aminobenzoic acid.
• the double complexed product recovered after drying in the vacuum oven was subjected to the solubility test described in Example 7.
• the amount of o-aminobenzoic acid dissolved in the form of the double complex was 13 grams corresponding to 27.1% solubility in water.
• the solubility of the uncomplexed o-aminobenzoic acid in water was tested and found to be 0.5%.
• Examples 7-9 are intended to set forth preferred embodiments of the present invention; however, many variations and modifications of the above experiments and complexed products will become apparent from the foregoing description and disclosure.
• other alcohol solvents can be employed for the reacting species as well as other poly(N-vinylpyrrolidone)-halogen complexes such as the bromine or chlorine complex to provide multicomplexes wherein the aminobenzoic acid shows markedly increased water solubility.
• Example 7 The procedure in Example 7 was repeated except that p-dimethylamino benzoic acid was substituted for p-amino-benzoic acid.
• Para-aminobenzoic acid and poly(N-vinyl-2-pyrrolidone) K-30 were each separately dissolved in ethanol to provide 10% solutions.
• a 200 g. solution containing 20 g. of the aminobenzoic acid and 1000 grams of the poly(vinylpyrrolidone) solution were then charged dropwise into a 2000 milliliter glass flask over a period of 10 minutes. The mixture was stirred for an additional 10 minutes, after which the flask was placed on a rotary evaporator and ethanol was removed in vacuo. The remaining complexed product of solid p-aminobenzoic and/poly(N-vinyl-2-pyrrolidone) was recovered and dried in vacuo at 60oC. overnight.
• Example 11 The experiment of Example 11 was repeated, except that poly(N-vinyl-2-pyrrolidone) K-12 was substituted for K-30 and the mole ratio of poly(vinylpyrrolidone) to p-aminobenzoic acid was maintained at 4:1.
• the resulting dried solid complexed compound (21.6 grams) was placed in a screwcap jar with 9 grams of distilled water and agitated for 24 hours at room temperature to yield a clear viscous solution.
• the water solubility of the p-aminobenzoic acid in the p-aminobenzoic acid/polyvinylpyrrolidone complexed product of this experiment was found to be 32.5%.
• p-arainobenzoic acid (1 gram) was placed in a screwcap jar with 99 grams of distilled water and the mixture was agitated for 24 hours at room temperature. After this extended mixing time, the aqueous phase contained almost the original amount of solid aminobenzoic acid. The water solubility of the aminobenzoic acid was found to be 0.5%.
• Example 11 The experiment of Example 11 was repeated except that m-aminobenzoic acid was substituted for p-amino benzoic acid and K-15 poly(N-vinyl-2-pyrrolidone) was substituted for K-30 poly(N-vinyl-2-pyrrolidone). After repeating the solubility test described in Example 11, the water solubility of the m-aminobenzoic acid in the resulting m-aminobenzoic acid/poly(N-vinyl-2-pyrrolidone) complex was found to be 6.3%.
• Example 11 The experiment of Example 11 was repeated except that o-aminobenzoic acid was substituted for p-amino benzoic acid. Twenty grams of the resulting amorphous solid complex of o-aminobenzoic acid/poly(N-vinyl-2-pyrrolidone) were then placed in a screwcap jar where it was mixed with 10 grams of distilled water at room temperature and agitated for 6 hours. At the end of this period, a clear solution was obtained and the water solubility of o-aminobenzoic acid in the complex was found to be 25.0%.
• Example 16 The complexing reaction reported in Example 16 was repeated except that poly(N-vinyl-2-pyrrolidone) K-12 was substituted for poly(N-vinyl-2-pyrrolidone) K-30 and the mole ratio of polymer to o-aminobenzoic acid was maintained at 4:1.
• the resulting o-aminobenzoic acid/poly(N-vinyl-2-pyrrolidone) complex product was recovered and after drying, 21.6 grams of the solid complex was placed in a screwcap jar where it was agitated with 9 grams of distilled water at room temperature for 24 hours. After this period, a clear solution was obtained and the water solubility of the o-aminobenzoic acid in the complex was found to be 32.5%.
• Examples 11, 12, 14, 16 and 17 are intended to set forth preferred embodiments of the present invention; however, many variations of the above experiments and complexed products will become apparent from the foregoing description and disclosure.
• other alcohol solvents can be employed as well as other higher or lower molecular weight poly(N-vinylpyrrolidones) or poly(N-vinyl-caprolactams) can be substituted to produce complexes wherein the aminobenzoic acid shows markedly increased water solubility.

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• 1987
  • 1987-04-06 JP JP62502395A patent/JPH01502816A/ja active Pending
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