WO1992019242A1 - Free amine benzophenanthridine alkaloid compositions - Google Patents
Free amine benzophenanthridine alkaloid compositions Download PDFInfo
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- WO1992019242A1 WO1992019242A1 PCT/US1992/002267 US9202267W WO9219242A1 WO 1992019242 A1 WO1992019242 A1 WO 1992019242A1 US 9202267 W US9202267 W US 9202267W WO 9219242 A1 WO9219242 A1 WO 9219242A1
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- benzophenanthridine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/60—Preparations for dentistry comprising organic or organo-metallic additives
- A61K6/65—Dyes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
- A61K6/884—Preparations for artificial teeth, for filling teeth or for capping teeth comprising natural or synthetic resins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
- A61K6/884—Preparations for artificial teeth, for filling teeth or for capping teeth comprising natural or synthetic resins
- A61K6/887—Compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
- A61K6/884—Preparations for artificial teeth, for filling teeth or for capping teeth comprising natural or synthetic resins
- A61K6/891—Compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0063—Periodont
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/005—Antimicrobial preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
- A61Q5/02—Preparations for cleaning the hair
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- benzophenanthridine alkaloids can act as topical contact antibacterial and antifungal agents. It is also known that such activity is produced in vivo by combination of the benzophenanthridine alkaloids with potentiating agents such as mineral or organic acid salts of zinc, tin, copper, iron, aluminum or other similar complex forming metal salts or organic compounds.
- a benzophenanthridine alkaloid can have one of two possible structures for its quinoline nucleus: an iminium structure or a free amine structure.
- the pH of the medium containing the alkaloid as well as chemical modifications can cause the alkaloid to convert from the iminium structure to a free amine structure.
- the iminium structure of the alkaloid has the necessary configuration and ionicity for transport across microorganism membranes and for chemical interaction with the biological system.
- the free amine alkaloid is thought to be inactive as an antibacterial or antifungal agent. It is also thought that the physical character of the free amine alkaloid may contribute to its lack of activity.
- the free amine alkaloid is often, but not always, substantially insoluble in aqueous media because of its hydrophobic structure.
- hydrophilic derivatives of the free amine alkaloid can be prepared and these derivatives have greater solubility in aqueous solutions.
- benzophenanthridine alkaloids Based upon the understanding of the biological activity of benzophenanthridine alkaloids as conveyed by the art, it is expected that these alkaloids would have no biological activity at an approximately neutral pH or above.
- the predominant structure of the alkaloid at this higher pH is the free amine.
- the biological activity is believed to be 'associated with the iminium structure, which is the predominant structure at the lower pH. Consequently, it is surprising to find according to the present invention that the benzophenanthridine alkaloids have increased biological activity at such higher pH's and very little activity at lower pH's which cause the iminium structure to be predominant.
- benzophenanthridine alkaloid derivatives having the free base structure are also biologically active.
- a further object is the development of appropriate parameters to maintain the benzophenanthridine alkaloid as the free amine.
- the present invention is directed to a pharmaceutical composition of a free amine benzophenanthridine alkaloid or derivative thereof in combination with a pharmaceutically acceptable carrier.
- the pharmaceutical composition is formulated either for local or systemic administration.
- the invention is as well directed to derivatives of the free amine benzophenanthridine alkaloids which preferably are water-soluble.
- these derivatives are synthetically modified benzophenanthridine alkaloids and polymer products composed of a water-soluble polymer coupled to the free amine alkaloid or synthetically modified form thereof.
- the benzophenanthridine alkaloid is maintained as the free amine either by control of the pH of the carrier, permanent synthetic alteration of the alkaloid structure into the free amine or formation of a chemically equilibrated free amine.
- the physical form of the free amine benzophenanthridine alkaloid is either a particulate form which can be suspended in the carrier, or a soluble form dissolved in the carrier. It is preferred that the free amine alkaloid be soluble in aqueous or aqueous-organic media.
- Certain derivatives of the benzophenanthridine alkaloids that carry hydroxyl, amine, or similar groups have such increased water-solubility.
- An especially preferred water-soluble free amine alkaloid derivative is the polymer product formed by coupling the free amine alkaloid to a water- soluble polymer.
- the pharmaceutical carrier constitutes a physiologically compatible aqueous, aqueous-organic or organic medium of aerosol, liquid or solid design for diluting and suspending the base form alkaloid and assuring appropriate delivery to the biological treatment site.
- the carrier may also include further components appropriate for the route of administration and kind of treatment sought. No matter which route is to be adopted, a preferred component of the pharmaceutical carrier will be at least one buffering agent for maintaining the composition at a basic pH.
- a topical composition will also contain components for maintaining a substantially stable formulation of base form alkaloid.
- a systemic composition will contain sterile carrier and preferably anti-agglomerating agents, especially when the composition is to be administered by an intravenous route.
- compositions include a topical ointment, gel, suspension, solution, lotion or similar pharmacological formulation for external topical administration; an orally administrable gel, suspension, solution, disintegratable tablet, pill or capsule or similar pharmacological formulation for administration to the gastrointestinal tract; an aerosol or spray for administration to the nasal nares and lung; and an injectable gel, suspension, solution or similar pharmacological formulation for systemic administration.
- routes of administration correlate with the biological site to be treated.
- the invention also is directed to a method for treatment of a bacterial or fungal infection of a patient by administration to the patient of an effective amount of an appropriately selected version of the foregoing pharmaceutical composition.
- Topical administration of the liquid, gel or ointment applies to skin infections.
- Oral administration of the liquid or tablet form composition applies to infections of the GI tract.
- Nasal administration of the aerosol composition applies to localized external surface infections of the nasal cavity and lung.
- Venous, intramuscular or other systemic administration of the liquid composition applies to systemic infections.
- the benzophenanthridine alkaloid selected for the composition will have or will be modified to have a p a that causes it to adopt the free amine structure at the pH of the physiological fluid.
- benzophenanthridine alkaloids having the free amine structure exhibit antifungal and antibacterial activities in vitro and in vivo. Although it is not meant to be a limitation of this invention, it is believed that within the appropriate parameters, the free amine and not the iminium structure of the benzophenanthridine alkaloid possesses the predominant biological activity characteristic of this class of alkaloids. In retrospect, it appears that the iminium structure alone is not able to effectively inhibit or kill microorganisms. The iminium alkaloid apparently needs a metal salt potentiating agent to counteract the heretofore unknown biological deactivation caused by the iminium structure. In contrast, it has been found that such a metal salt potentiating agent is not necessary when the alkaloid is administered as the free amine.
- the pharmaceutical composition is a combination of the free amine benzophenanthridine alkaloid, and a pharmaceutically acceptable, aqueous, aqueous-organic or organic diluent carrier.
- the free amine alkaloid or its derivative either can be dissolved in the carrier or can be suspended as particles in the carrier.
- the novel intermediate of the invention be used, that is, the polymeric product composed of a water-soluble polymer coupled with the free amine alkaloid as a pendent group or terminal group. If suspended as particles, it is believed that the solid particulate partially dissolves to establish an equilibrium between the solubilized free amine alkaloid and the solid particulate.
- the carrier can also incorporate further components such as buffering agents, suspending agents, anti-agglomerating agents and the like.
- buffering agents such as buffering agents, suspending agents, anti-agglomerating agents and the like.
- the particular combination of carrier components incorporated will depend upon the route of administration chosen and the biological site to be treated. Those routes (and sites) include topical (skin, mucous membranes), systemic (muscle, venous, lymph, arteriole, peritoneal), oral (intestinal), aerosol or spray (lung and nasal) as well as cosmetic or shampoo (skin, hair), and oral care (mouth).
- a topical formulation may be a stable suspension of the free amine alkaloid in a buffered aqueous lotion with a thickening agent such as a carboxymethylcellulose or it may be a buffered aqueous solution of the polymer product.
- cosmetics and shampoos may be formulated to have greater fluidity than the topical lotions and gels.
- Systemic and aerosol or spray formulations may contain buffered aqueous carriers and the particle sizes in these instances will preferably be controlled so that formation of e boli is avoided.
- systemic, aerosol or spray formulations may be buffered aqueous solutions of the water-soluble free amine alkaloid derivatives such as, for example, the glycerol or gluconic acid derivative or the polymer product.
- Disintegratable tablets, pills and capsules with a solid carrier such as milk sugar need not be buffered but will contain alkaloids that maintain the free amine structure at the physiological pH of the gut.
- the benzophenanthridine alkaloids incorporated into the present invention constitute a class of alkaloids having a quinoline nucleus with two benzene rings fused at the 3,4 and 6,7 positions of the quinoline. Examples include sanguinarine, chelerythrine, and sanguilutine, chelilutine, chelirubine and sanguirubine. Many benzophenanthridine alkaloids are naturally occurring compounds present in certain plant tissues such as Sanquinaria canadensis, Macleava, and Argemone. The individual benzophenanthridine alkaloids obtained from natural plant sources may be used in the present invention. Methods for the extraction, separation and purification of the various benzophenanthridine alkaloids from plant tissue are known. See, for example U.S. Patent No. 4,818,533.
- Derivatives such as synthetically modified benzophenanthridine alkaloids, synthetically formed benzophenanthridine alkaloids, polymer products, and especially those derivatives which will maintain the free amine structure over a wide pH, may also be used.
- the synthetically modified benzophenanthridine alkaloids will preferably have substituents at the nitrogen and alpha carbon positions so that the free amine is rendered unable to convert to the iminium structure.
- Substituents for this purpose include hydroxyls, glycerols, glycols, alcohols, polyglycols, organic acids, organic amines and nucleophilic addition products obtained from the 8-oxyalkaloid having an amide moiety in place of the imine moiety.
- hydrophilic and polar substituents serve to increase the water solubility of the alkaloid such that it can be formulated in solution.
- a benzophenanthridine alkaloid or a derivative thereof is water-soluble if it dissolves to the extent of at least 100 ppm, preferably 1,000 ppm, and more preferably 10,000 ppm in water or aqueous media.
- a preferred water-soluble derivative of the free amine alkaloid is the polymer product formed by covalently coupling the free amine to a water-soluble polymer.
- any polymer carrying nucleophilic groups such as hydroxyl, amine or sulfide groups that are free or pendent can be covalently coupled to the iminium moiety of the acidified benzophenanthridine alkaloid through reaction of the nucleophilic groups of the polymer and iminium moiety of the alkaloid, that is, reaction with the carbon alpha to the alkaloid nitrogen.
- This alpha carbon coupling will convert the iminium group to a free amine and couple the free amine alkaloid to the polymer through the iminium carbon.
- a polymer in a second alternative, can be covalently coupled either (1) by a known electrophilic substitution method to one of the masked hydroxyl groups present within the two methylenedioxy groups of the alkaloid or (2) by known nucleophilic substitution methods through the methylenedioxy group.
- This alternative is especially useful when the nitrogen of the alkaloid is derivatized such that it is already a free amine and cannot form an iminium group. These reactions are known in the art.
- Examples include electrophilic substitution of the carboxylic acid halide groups of a derivatized polyacrylic acid or a small organic acid compound and the alkaloid hydroxyls, or nucleophilic substitution of an organic compound carrying a carbanion, such as alkyl or aryl lithium or a grignard reagent, with (a) the methylenyl group of the alkaloid, or (b) the carbonyi group alpha to the nitrogen of an 8-oxybenzophenanthridine alkaloid (i.e., with the carbonyi of the amide moiety of the 8- oxyalkaloid) .
- electrophilic substitution of the carboxylic acid halide groups of a derivatized polyacrylic acid or a small organic acid compound and the alkaloid hydroxyls or nucleophilic substitution of an organic compound carrying a carbanion, such as alkyl or aryl lithium or a grignard reagent, with (a) the methylenyl group of the alkaloid, or
- Functional groups added at other positions around the alkaloid ring can also operate as sites for polymer coupling either by the nucleophilic or electrophilic methods outlined above.
- Known reactions for polymer coupling to side chains can be employed for this purpose. Examples include hydroxy (phenoxy) addition to epoxides, carboxylic acid halides or isocyanates; activated coupling between hydroxyls or amines and carboxylic acids such as with carbodiimide or carbonyldiimidazole reagents; and ring opening such as a pendent epoxide reaction with a carboxylic acid group.
- alkaloid coupling to polymers include the polymeric products formed by reaction of polyvinyl alcohol, polyethyleneimine or polyethylene glycol with the alkaloid having the iminium structure under basic aqueous conditions to bond the iminium carbon of the alkaloid to the pendent oxygen or nitrogen group of the polymer. This coupling produces the free amine alkaloid coupled to the polymer.
- the product is soluble in aqueous media.
- Further preferred examples are the polymeric products formed by reaction of polyacrylic acid or a derivative thereof with the alkaloid derivative having the nitrogen permanently converted to the free amine, such as the 8-alkoxy derivative.
- the methylenedioxy group of the alkaloid derivative can be hydrolyzed and the resulting phenoxy-like compound coupled with polyacrylic acid through a carbodiimide coupling agent under less than stoichiometric conditions.
- the polyacrylic ester product is soluble in aqueous media.
- the pharmaceutically acceptable carrier diluents and components incorporated according to the invention provide desirable characteristics to the pharmaceutical composition. These characteristics include dose measurement, dissolution, dilution, thickening, particle suspension, pH buffering, sweetening, stabilization against degradation, bulking, filling, emulsification, thixotropy, aerosolization, coloring, cleaning, antisorption, anti-agglomeration, and the like.
- Appropriate liquid dilution media for the various routes include liquid compounds and compositions such as pharmaceutically compatible aqueous and/or organic diluents including lower (C- . to C 6 ) aliphatic alcohols, polyglycols, polyvinylpyrrolidones and copolymers thereof, water, chlorinated liquids and oils.
- Appropriate gases for aerosol formation of the liquid compositions include carbon dioxide, nitrogen, air and noble element gases.
- Appropriate solid diluents for the oral administration route and for bolus injection include milk, sugar, talc, soluble gums and polysaccharides and solid inert fillers.
- Additional components for the various routes include waxes, anionic, nonionic, and cationic surfactants, emollients, emulsifiers, buffering systems such as carbonate and phosphate buffering systems, colors, thixotropic agents, gelation agents such as alginate, gum agar and kaolin clay, thickening agents, talcs, clays, sterilizing agents, polyhydroxy organic compounds, fillers, extenders, poly aliphatic or fatty alcohols or esters, absorption control agents, skin colorants, cosmetic ingredients and suspension stabilizers. These components provide such properties as gelation, suspension stability, pH control, sterility, bulking, appropriate tactile sensation, color and the like to the composition.
- Topical pharmaceutical compositions will include such components as emulsifiers, buffering agents, gelation agents and the like formulated for appropriate pH adjustment.
- Systemically administrable pharmaceutical compositions will include buffering agents and physiologically acceptable diluents but will typically not include waxes, oils, clays and other materials used as bulking agents and gelling agents in topical formulations.
- Application of the pharmaceutical composition to oral care will include such formulations as gels in the nature of toothpaste and mouth rinse concentrates.
- Cosmetics and shampoos will include buffering systems as well as suspending agents for the alkaloid particulates.
- tinting agents, texturizing agents, cleaning agents, and soaps will be included in cosmetics and shampoos as appropriate.
- Orally administrable pharmaceutical compositions for treatment of intestinal infections will include buffering agents, suspending agents and antiabsorption agents.
- Aerosol or spray formulations of the pharmaceutical compositions can incorporate the free amine alkaloid in combination with an aerosol and/or liquid diluents and the like for inhalation into the lungs.
- a preferable aerosol is a gas-solid combination of an inert gas carrier with the alkaloid particulate material.
- a water dispersing agent optionally buffered with a buffering system may also be included.
- the pharmaceutical compositions may be prepared by known methods.
- the free amine alkaloid is to be dissolved in the formulations, it can be combined in concentrated form and then diluted to the appropriate dosage level. Alternatively, it can be directly compounded at the appropriate dosage level by dissolution in the carrier diluent or solvent followed by addition of other carrier components.
- the free amine alkaloid is to be used as a particulate in the formulations, it can be prepared by a number of methods. Grinding, milling, ball rolling, grating, pressing, mashing, dicing, spray drying and other similar methods for particle size reduction can be applied to large particles of the alkaloid as the free amine. Screening will appropriately select the desired maximum size of the alkaloid particles for inclusion in the pharmaceutical compositions. Double screening with maximum and minimum sizes can also be applied if appropriate.
- Controlled particle formation from a dissolved solution of the alkaloid will also produce the desired particulate.
- alkaloid particles of controlled sizes can be precipitated from aqueous medium.
- the alkaloid is dissolved in an aqueous medium under acidic conditions, the medium is neutralized to provide slightly basic conditions and a precipitating amount of alcohol is slowly added.
- the temperature of the precipitating medium, the rate of precipitation and the agitation of the precipitating medium the particulate size can be controlled within the appropriate parameters for particle size according to the invention.
- compositions of the present invention are useful for the treatment of topical, systemic and site specific infections of gram positive and gram negative bacteria, fungi, mycoplasma, spirochetes, ycobacteria, rickettsia and chlamydia.
- the free amine benzophenanthridine alkaloids possess a broad spectrum anti-infective activity.
- Gram negative and gram positive infections of bacteria such as those causing pneumonia, rickettsial diseases, chlamydial diseases, streptococcal diseases, staphylococcal diseases, neisseria diseases, clostridial diseases, anaerobic bacterial diseases, salmonella diseases as well as sporulate borne disease, leptospiral disease, and treponemal disease.
- Administration of the pharmaceutical composition of the present invention will generally follow the instructions and directions of an attending physician upon whose wisdom the ultimate choice of route of administration and dosage level will be based.
- Topical treatment of bacterial or fungal infected skin, mucous membrane and other epithelial infections can be accomplished by application of at least about 0.1 milligrams of free amine alkaloid per square centimeter of surface treated.
- the application rate will be from about 0.2 milligrams to about 50 milligrams per square centimeter of surface area treated.
- Especially preferred dosages include about 5mg to about lOmg per square centimeter of surface area treated.
- the routes of administration include intraperitoneal, intravenous, or any similar route that delivers the pharmaceutical composition to the appropriate body fluids.
- To treat bacterial infections at least about 1 milligram of free amine alkaloid per kilogram of body weight of the patient will be administered from 2 to about 4 times per day.
- Preferably the amount of free amine alkaloid administered per kilogram of patient body weight will be from about 2 to 5mg.
- For systemic fungal infections at least about 1 milligram per kilogram of patient body weight will be administered approximately 2 to 4 times per day.
- Mycoplasma will be effectively treated by administration of at least about 2 milligrams per kilogram of patient body weight 2 to about 4 times per day.
- the systemic administration such as by intravenous, arterial, intramuscular or subcutaneous delivery may be accomplished in a continuous manner through a slow drip or other periodic controlled or intermittent mode of introduction such as by injection.
- the dosage levels will cause blood levels of the alkaloid of approximately at least about 1 milligram per liter of blood.
- a water or body fluid soluble free amine alkaloid is used in such compositions for systemic administration.
- Treatment of microbial and fungal infections on internal surfaces in contact with the outside environment, i.e., the epithelial tissue of the lungs or the gastrointestinal tract can be accomplished by administration of at least about 1 milligram of the alkaloid per kilogram of patient body weight from 2 to about 4 times per day.
- effective administration can be obtained by application of an elixir, a drench, a suspension, a rinse, a gel, a tablet, a pill or a capsule formulated to release up to about 50mg of free amine alkaloid per dose with up to about 3 doses per day.
- formulations will preferably include an antiabsorption agent to facilitate maintenance of the free amine alkaloid within the gut.
- Control of the dosage for inhalator administration to the lungs can be accomplished by the combination of the aerosol gas, and pharmaceutically acceptable diluents such as water and a buffering system.
- the inhalator can be designed according to known methods to administer an appropriate volume of the composition for treatment of inner lung surfaces. Typically an amount of at least about 1 milligram of free amine alkaloid per kilogram of patient body weight for 2 to about 4 times per day by inhalator administration may be made.
- the particles will have sizes within a range for appropriate function of the intended treatment.
- a topical suspension may contain particles small enough to deliver an extremely large surface area but not so small that they are difficult to manipulate during formulation.
- a systemic suspension may contain particles within a controlled size range so that emboli are avoided.
- a gastrointestinal suspension may contain large particles relative to the systemic suspension so that GI absorption is minimized. It will be understood, therefore, that a particle size range will vary according to the particular purpose for which the free base alkaloid is used. Generally, however, particles within a range of from about 0.01 micron to about 10 mm will be appropriate for these purposes.
- the lower end of this range is preferred for those uses most appropriately associated with a high surface area of particulate solid. Such instances would include effective topical, systemic and inhalator administration.
- the upper end of this range is preferred for those uses most appropriately associated with a need to minimize absorption. Such instances would include administration for gastrointestinal treatment and for sustained release by intramuscular, subcutaneous or similar routes.
- the particulate size of the free amine alkaloid is to be used for pharmaceutical compositions in systemic or inhalator administration, it is preferred that a particle size of no more than about 3 microns be used in this route of administration. This upper particle size limitation will avoid the possibility of the formation of internal emboli.
- the free amine alkaloid as a particulate solid may also be directly implanted as a bolus, disintegratable tablet or injectable suspension, gel and the like into specific sites of the human or animal patient.
- This procedure is useful for isolated tissue infections.
- a moderately water-soluble free amine alkaloid is used in this instance so that systemic transport is minimized. It is also useful for sustained release of small amounts of the free amine alkaloid which results from the embodiment having a low solubility in body fluids.
- Periodontal diseases, diseases of the liver, lymphatic diseases, and diseases of organs that are not amply bathed in body fluids or blood can be treated according to this method of administration.
- Sanguinarine chloride is converted to 8- ethoxydihydrosanguinarine by a precipitation procedure.
- the yield of 8-ethoxydihydrosanguinarine is 60-75%.
- About 20.0 g of sanguinarine chloride is combined with about 3.3 L of ethanol to provide a concentration of about 6 g sanguinarine chloride/liter of ethanol.
- the solution is heated to about 65°C for 30 minutes with overhead stirring at about 400 rpm.
- the hot solution is filtered under vacuum through filter paper and about 370 ml of a 2% sodium hydroxide/ethanol solution is added to provide about 18.5 ml of 2% sodium hydroxide/ethanol per g of sanguinarine chloride.
- the resulting solution is stirred for about 15 minutes, the solution is allowed to cool to room temperature and let stand for 16-24 hours for precipitate formation.
- the precipitate is collected by vacuum filtration and dried for 12-24 hours in a drying oven at 40 C.
- the crystals are analyzed for 8-ethoxydihydrosanguinarine purity by infrared spectroscopy specification. This process can also be applied to chelerythrine, macarpine, chelilutine, chelirubine, and sanguilutine as well as Ci-C 3 alkyl, halogen, amide, hydroxy and alkoxy substituted derivatives thereof.
- the 8-substituted base forms of benzophenanthridine alkaloids having a Cj-C ⁇ alkoxy or hydroxy group at the 8 position can be prepared by substituting the appropriate alcohol (or water) for the ethanol in the foregoing method.
- the starting materials are isoquinoline alkaloids that belong to the benzophenanthridine class. They are of botanical origin and can be obtained from sources including various species in the Papaveraceae, Fumariaceae and Rutaceae families. Preferably Macleava from the Papaveraceae family can be used. Macleava, for example, contains sanguinarine at sufficiently high levels to use isolation techniques for commercial extraction and purification of sanguinarine chloride (SaCl) . The isolated sanguinarine chloride is converted to a base form using hydroxide and alcohol.
- Liquid formulations with varying amounts of 8- hydroxydihydrosanguinarine chloride or 8- ethoxydihydrosanguinarine were prepared as follows.
- SaOET 8-hydroxydihydrosanguinarine
- 8- ethoxydihydrosanguinarine are fairly insoluble in water, they were added to the formulation after all other ingredients were combined. These formulations at 0.1 - 1.0% by weight SaOET or SaOH are dispersions and are at about pH 8 as opposed to about pH 4 for sanguinarine chloride formulations.
- compositions of injectable suspensions, gels, shampoos and the like can be prepared by first combining the formulation medium with the other ingredients and then mixing in the free amine benzophenanthridine alkaloid.
- the following formulations can be prepared following this protocol and using the amounts of ingredients indicated.
- Toothpaste Formulation This formulation contains finely divided free base alkaloid (1 to 100 microns) suspended in a gel.
- the free amine alkaloid has a particle size within the range from about 0.1 to 2 microns.
- the suspension is agitated to thoroughly mix it immediately before injection.
- Nonabsorbable Oral Formulation The free amine alkaloid can be formulated as particles from 0.01 to 5mm in size. 8-H drox dihydrosanguinarine 0.020
- the composition After mixing, the composition is added to a pumpable misting inhalator device.
- the particulate free amine alkaloid has a particle size of from 0.1 to 1 micron.
- the colorless nature of the solution was an indication that if the alkaloid was present it had converted to the free amine structure.
- An aliquot of the clear solution (1ml) was taken and measured by UV spectrophotometry. The UV spectrum was off-scale relative to the standard curve for sanguinarine chloride. To the analyzed aliquot was added 1 drop 6 N HC1 which produced a very orange cloudy solution. This reaction indicated cleavage of the alkaloid from the polymer.
- the acidified sample (1ml) was diluted with 9ml H 2 0 to yield a clear, orange solution.
- the UV spectrum of the sample was taken but was too high to analyzed.
- the sample (2ml) was diluted with 2ml H 2 0 and the UV spectrum again taken. Based upon the extinction coefficient for sanguinarine, this sample contained 32.4ppm of sanguinarine, equivalent to 2592 ppm of the original polymer-alkaloid compound in water.
- the sanguinarine chloride was present at a concentration of 0.2 molar or 2,000 ppm.
- Runs 1, 4 and 5 appeared to be clear with no precipitate. Runs 2 and 3 contained much precipitate. After filtration, UV spectra were taken which indicated incorporation of the sanguinarine into the polyethylene glycol structure as a terminal group bound to the terminal hydroxyl of the glycol. The resulting polymer product was completely water soluble in all instances.
- the traditional time kill assay was modified into a highly sensitive test method to detect the bactericidal activity of a test agent.
- the time kill assay was used to study the mode of action of the following benzophenanthridine alkaloids: sanguinarine chloride (SaCl), 8-hydroxydihydrosanguinarine (SaOH) and 8-ethoxydihydrosanguinarine (SaOET) and the polyethylene glycol sanguinarine polymer (PEG-Sa) at different pHs.
- the time-kill procedure used is briefly described as follows. The test microorganism was suspended in phosphate buffered saline (PBS) containing the test agent at the proper pH. Temperature was maintained at 37°C.
- PBS phosphate buffered saline
- test solution aliquots of test solution were removed and spread plated to agar plates composed of the appropriate growth media. The plates were then incubated and the colony forming units/mL (CFU/mL) were enumerated. Test agents were assayed at concentrations roughly twice the minimum inhibitory concentration (MIC) of SaCl for the test microorganism. PBS without test agent served as negative control. Bactericidal or fungicidal activity was demonstrated by a decrease in the mean value CFU/mL over time.
- CFU/mL colony forming units/mL
- Table 2 shows the bacterial activity of SaCl, SaOET, and SaOH at pH 8 compared to pH 6. Results demonstrate that at pH 8, where SaCl converts to the free amine, there is clearly bactericidal activity due to SaCl, SaOH and SaOET while at pH 6 no activity is detected.
- Table 3 demonstrates the bactericidal activity of SaCl and chelerythrine chloride (ChCl) at pH 6, 7 and 8. Results indicate that SaCl antibacterial activity increased with increasing pH, as does ChCl using the Gram-positive bacteria, E. faecalis . SaCl is more active than ChCl, at each corresponding pH. This may be related to the fact that ChCl has a higher pKa than SaCl. More iminium form is present with ChCl than with SaCl at the pHs tested perhaps explaining the lesser activity of ChCl.
- Table 4 demonstrates the antifungal activity of
- SaCl increases with increasing pH using the yeast C. albicans as indicator microorganism.
- Table 4 indicates that the water-soluble polymeric free amine is also antibacterial at pH 8.
- the bactericidal activity of SaCl is also antibacterial at pH 8.
- SaOET, and SaOH was enhanced with increasing pH using the Gram-negative bacteria E. coli as test microorganism.
- the bacteriocidal activity of both SaCl and ChCl was enhanced with increasing pH, using the Gram-positive bacteria E. faecalis as test microorganism.
- the fungicidal activity of SaCl was enhanced with increasing pH, using the yeast C. albicans as test microorganism.
- the water-soluble polymeric (PEG) free amine form of sanguinarine was bactericidal at pH 8 using E. coli as test microorganism.
- the free amine form of sanguinarine appeared more bactericidal and fungicidal than the iminium form of sanguinarine at the pH ranges tested.
Abstract
Description
Claims
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US696,093 | 1976-06-14 | ||
US07/696,093 US5175000A (en) | 1987-06-30 | 1991-05-06 | Free amine benzophenanthridine alkaloid compositions |
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WO1992019242A1 true WO1992019242A1 (en) | 1992-11-12 |
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PCT/US1992/002267 WO1992019242A1 (en) | 1991-05-06 | 1992-03-20 | Free amine benzophenanthridine alkaloid compositions |
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US (2) | US5175000A (en) |
EP (1) | EP0583389A1 (en) |
AU (1) | AU2001892A (en) |
WO (1) | WO1992019242A1 (en) |
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EP2133079A1 (en) * | 2008-06-12 | 2009-12-16 | Indena S.P.A. | Compositions for the treatment of vaginal infections with chronic inflammation |
WO2010083436A1 (en) * | 2009-01-15 | 2010-07-22 | Rutgers, The State University Of New Jersey | Benzo [c] phenanthridines as antimicrobial agents |
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Also Published As
Publication number | Publication date |
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EP0583389A1 (en) | 1994-02-23 |
US5395615A (en) | 1995-03-07 |
AU2001892A (en) | 1992-12-21 |
US5175000A (en) | 1992-12-29 |
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