Title of Invention	POURABLE LIQUID VEHICLES.
Abstract	The present invention covers pourable liquid vehicles that can be combined with compositions, materials and substances. Among the benefits of such pourable liquid vehicles the compositions are retained on the moistened surface for a period of time sufficient to allow compositions, materials and substances to act on said surface, resisting erosion or run-off from additional moisture being applied. Such pourable liquid vehicles have a number of utilities including but not limited to cleaning and treating surfaces of objects as well as biological or living organisms, Including living creatures.

Title of Invention

POURABLE LIQUID VEHICLES.

Abstract

The present invention covers pourable liquid vehicles that can be combined with compositions, materials and substances. Among the benefits of such pourable liquid vehicles the compositions are retained on the moistened surface for a period of time sufficient to allow compositions, materials and substances to act on said surface, resisting erosion or run-off from additional moisture being applied. Such pourable liquid vehicles have a number of utilities including but not limited to cleaning and treating surfaces of objects as well as biological or living organisms, Including living creatures.

Full Text	POURABLE LIQUID VEHICLES CROSS REFERENCE This application claims priority under Title 35, United States Code 119(e) from Provisional Application Serial No. 60/153,260, filed September 11,1999. TECHNICAL FIELD The present invention relates to a pourable liquid vehicle. Concentrated levels of polyoxyalkylene block copolymers are useful in vehicles incorporated into products that are designed to deliver compositions, materials and substances to moistened surfaces and aqueous environment Acquiring moisture during use, the vehicle becomes sufficiently transformed from a liquid to a gel-like form that provides the a benefit to the user. For example, mucosal surfaces of the body contain sufficient water to allow the pourable liquid vehicle comprising concentrated polyoxyalkylene block copolymers to be effectively delivered to the desired site wherein the accompanying compositions, materials and substances tenaciously adhere to the moistened surfaces and resist dissolution or erosion by water or biological fluid. Such uses include, but are not limited to the delivery of personal health care compositions, formulations and compounds including, but not limited to, Pharmaceuticals (OTC and prescription), nutrients and the like. In the discipline of pharmaceutical compositions there are a wide variety of dosage forms. Examples include tablets, capsules, elixirs, syrups, liquid-filled capsules, suspensions, coated tablets or capsules for administration by mouth; gels, rinses, dentifrices, lozenges, sprays, medicated lollipops, liquid filled capsules for intra-oral administration; gels, suspensions or solutions for intra-ocular or intra-aural administration; suppositories and douches or enemas for intra-rectal or vaginal administration; and creams, ointments, gels, lotions and patches for topical application on the skin and scalp; and liquid suspension or solutions for injection by syringe, nasal gels, solutions, or suspensions for application into the nose with special applications or sprayers. The majority of these compositions are in the physical form of a fluid having a viscosity ranging from pourable liquids to stiff gels. Pourable liquids are often preferred since they are in The majority of these compositions are in the physical form of a fluid having a viscosity ranging from pourable liquids to stiff gels. Pourable liquids are often preferred since they are in the best form to be administered. For example, only liquids, or perhaps low viscosity gels, can be injected through a syringe, or poured from a bottle into a medicine cup, or drawn up into a syringe or medicine dropper, or squeezed from a dropper bottle into the eye or ear, or atomized into the nasal cavities, fa addition to the compatibility with pharmaceutical administration devices and with the mode of introduction into the body, it is often desirable for the composition to easily spread after application without the aid of manual action or devices. The eye drop compositions, for example, need to spread over the surface of the eye, as do swallowed liquids intended to coat the throat, esophagus, or stomach. This is similarly true of rectal enemas or vaginal douche compositions. In many cases, however, pharmaceutical dosage forms in form of pourable liquids are not necessarily desirable since once administered, such pourable liquids are easily removed from the intended treatment site. In such circumstances the therapeutic advantage of the composition may be significantly diminished or even lost completely. It is appropriate, therefore, to surmise mat for the purpose of being retained at the targeted site, it may be desirable for a particular pharmaceutical composition to be more viscous, even in the form of a gel mat is not readily flowable. It is, however, difficult or even impossible to administer such a viscous composition to its intended site to do the most good. For example, serious injury could occur when attempting to spread a gel on the surface of one's eye using a finger or more elaborate applicators. More problematic is coating the stomach lining, as this site is simply not accessible using simple self- administer applicators. There is, therefore, a need for pharmaceutical compositions mat are "smart"; that is, capable of being administered in a pourable liquid that are converted or transformed after administration into a vehicle having sufficient viscosity to essentially remain at the targeted site. Such compositions require a built-in chemical or physical triggering mechanism(s) that respond to conditions after application in or on a surface including the body. BACKGROUND OF THE INVENTION Attempts to develop such compositions have been ongoing for a significant period of time. Examples of such compositions include intra-ocular dosage forms as disclosed in Edsman, K., Carlfors, J., Petersson, R., Rheological Evaluation of Poloxamer as an in situ Gel for Ophthalmic Use. European Journal of Pharmaceutics Vol. 6 pp. 105-112 (1998) herein incorporated by reference. Compositions such as these are broadly described as primarily aqueous solutions of block co-polymer surfactants, other wise referred to as "poloxamers", that are commonly known in the art. When formulated in water as somewhat concentrated solutions, or with water and co-solvents, the poloxamer solution remains as a pourable liquid. The most commonly reported example of this type of system consists of poloxamer 407 at concentrations ranging from about 10% to 35% by weight of the composition in water. These compositions are administered at room temperature as liquids. They form a gel upon reaching body temperature. The trigger for converting these compositions to a gel, therefore, is body heat. In situ gelation of pharmaceutical compositions based on poloxamer that are biologically triggered are known in the art. For example Kim, C.K., Lee, S.W., Choi, H.G., Lee, M.K., Gao, Z.G., Kim, I.S., and Park, KM.: Trials of In Situ Gelling and Muqoadhcsjve Acetaminophen Liquid Suppository in Human Subjects. International Journal of Pharmaceutics vol. 174, pp. 201- 207 (1998) incorporated herein by reference. Kim et al. discloses liquid suppositories for enhancing absorption of the pain and fever relieving drug acetaminophen. U.S. Patent 5,256,396, issued October 26, 1993, to Colgate Palmohve Company, incorporated herein by reference, describes similar compositions containing poloxamer 407 and water at specified concentrations. Other products utilizing bio-triggers include those comprising poloxamer 407 at ranges preferably 12% to 17%. When combined with pharraaceutically active agents, these compositions are injected into the gingival space between the root of a tooth and the gum. Poloxamers represent a large family of polymers that vary in molecular weight as well as in the percentage or portion of the block copolymer mat is considered hydrophobia Compositions comprising other poloxamers from this family having similar liquid/gelling characteristics are somewhat predictable, lacking only in the understanding of the required concentration of poloxamer. While there is a large number of uses for such compositions, they all rely on the same general mechanism of temperature-induced gelation of aqueous poloxamer dispersions. Compositions known in the art are found to be inadequate, however, as the gel structure readily dissolves in aqueous environments. SUMMARY OF THE INVENTION The present invention covers pourable liquid vehicles used to deliver compositions, materials and substances to moistened surfaces and aqueous. The benefits of compositions formulated with such pourable liquid vehicles include retention of the compositions, materials and substances on the moistened surface. This in turn allow for effective delivery of a desired compositions, materials and substances in the vehicle that acts on targeted surface, resisting erosion or run-off even in an aqueous environment. Such pourable liquid vehicles have a number of utilities for delivery of all kinds of materials including but not limited to cleaning and treating surfaces of objects as well as biological or living organisms, including living creatures. Another object of this invention is to utilize such pourable liquid vehicles to deliver health care compositions and materials and substances to living creatures, particularly mammals, and roost particularly humans. Even another object of the present invention is to develop a method for effective delivery of health care compositions, materials and substances. DETAILED DESCRIPTION OF THE INVENTION Definitions Terms useful herein are defined below. Additionally, terms used in the art, as well as general concepts, are further described in Schramm, The Language of Colloid and Interface Science. American Chemical Society, (1993), incorporated herein by reference. The term "pourable liquid" as used herein means the physical state of the compositions of the present invention prior to formation of a gel. The term "moistened surface" as used herein means any living or non-living surface having sufficient moisture in or on it to trigger rapid conversion of a pourable liquid to a gel. The term "in situ gelation" as used herein means the conversion of a pourable liquid to a gel at a designated site or surface. As used herein, the term "gel" describes the substance resulting from the combination of the pourable liquid and water, or bodily fluid containing mostly water. The gel is sufficiently viscous to remain at the site applied to, or ultimately targeted for, over a period of time sufficient for the compositions, materials and substances in the gel to bring about a desired result at the site they are delivered to. The term "triggering device" as used herein means an stimulus external to the composition that induces the conversion of a pourable liquid to a gel. The term "shear" as used herein is the rate of deformation of a fluid when subjected to a mechanical shearing stress. In simple fluid shear, successive layers of fluid move relative to each other such that the displacement of any one layer is proportional to its distance from a reference layer. The relative displacement of any two layers divided by their distance of separation from each other is termed the "shear" or the "shear strain". The rate of change with tone of the shear is termed the "shear rate". A certain applied force is needed to produce deformation in a fluid. For a plane area around some point in the fluid and in the limit of decreasing area the component of deforming forces per unit area that acts parallel to the plane is the "shear stress". The "viscosity" of a viscous material, also called viscosity index, is defined as the ratio of the shear stress applied into the material, divided by the rate of shear which remits. Materials of a higher viscosity have a higher resistance to flow, or to forces which can induce flow, than a lower viscosity material. All viscosities listed herein are at a shear rate of about 50 per second unless otherwise indicated. All of the rheologic characteristics given herein can be measured in a controlled rate or a controlled stress rotational viscometer capable of some operation in a controlled rate mode, for Example Haake RS ISO by Haake GmbH, Karlsruhe, Germany; Cammed CSL 500 Controlled Stress Rheometer by TA Instruments, New Castle, Delaware; and Rheometric SR5, by Rheometric Scientific, Piscataway, NJ. Specifically, when subject to constant shearing rate of about 50 per second at normal ambient temperature (approx. 25°C), the present liquid compositions have a viscosity of less than aboyt 7 pascal seconds, preferably less than about 2 pascal seconds, more preferably less than about 1 pascal seconds. The value of a composition's triggered viscosity ratio ("T") is useful in determining the degree to which a composition exhibits the above described gelling characteristic. The formula and procedure for determining the triggered viscosity ratio is set forth below. It is desirable for the compositions of the present invention to exhibit a triggered viscosity ratio of at least about 1.3, preferably at least about 2, more preferably at least about 5, and most preferably at least about 10 wherein the triggered viscosity is defined by the following formula or ratio: T=hs/hc where hs= viscosity of the gel and where hc= viscosity of the pourable liquid The pourable liquid vehicle of the present invention must be selected and formulated so that the contacting and mixing said vehicles to a mucosal surface of the body, or with some other fluid in the body, triggers the conversion of the pourable liquid vehicle to a more viscous gel-like mixture. Examples of these fluids are saliva, gastric fluid, intestinal fluid, extracellular fluid present under the skin at the site of a subcutaneous injection, or in muscle tissue at the site of an intramuscular injection, cerebrospinal fluid, vaginal fluid, fluid exudate from an open wound or ulcer, tear fluid, rectal fluid, or any other bodily fluid of an animal which contains in large measure water. In other words, after the pourable liquid vehicle contacts with the bodily fluid, the viscosity of the pourable liquid vehicle becomes greater than the viscosity of either the pourable liquid vehicle itself prior to mixing, or the bodily fluid alone. The triggered viscosity ratio of a pourable liquid vehicle can be determined by one skilled in the art using appropriate viscosity measuring instruments, and is exemplified by the following method. First, the viscosity of the pourable liquid vehicle (hc is determined in a rheometer using a shear rate of 50 per second at 25°C. For the determination of h6 1 ml of the pourable liquid vehicle is placed onto the plate of a Haake RS150 rheometer. The temperature is controlled in the range of typical room temperature, about 25oC. A cover is used on the measuring system and a solvent-saturated atmosphere provided to prevent evaporation of water, cthanol, or other volatile components from the sample during the test A 35 mm diameter parallel plate measuring system is lowered onto the sample, leaving a gap of about 1 millimeter, and an equilibration shearing of approximately 10 per second is applied for 10 seconds. Then, a constant shearing rate of 50 per second is applied for 30 seconds. The viscosity hc is read from the instrument at the 30 second time point. For the determination of hs, two dilutions of the pourable liquid vehicle are made with water. The first dilution is made to contain 75% by weight of the pourable liquid vehicle, and 25% by weight of additional water. The second dilution is made to contain 50% by weight of pourable liquid vehicle and 50% by weight of additional water. The pourable liquid vehicle and water are combined in a vial and a tight seal applied to prevent evaporation of components. The vial contents are mixed in an unusual manner, by repeated centrifugation. This is necessary since some of the combinations are very viscous gels. Specifically, the vials are centrifuged (using for example a Beckman GS-6R centrifuge, available from Beckman Instruments, Palo Alto, CA) 20 minutes at 3000 RPM and 25°C for at least four separate centrifuge runs. After each run the vials are inverted. Additional runs are conducted in the centrifuge to ensure complete mixing. 1 ml of the gelled sample is then loaded onto the plate of the same rheometer used for the measurement of %, except that the temperature is controlled at the normal body temperature of a human, 37oC. An identical rheometer measurement program is used as for determination of hf. The triggered viscosity factor for both the 25% and 50% dilution of the sample is calculated from % and T\|, as described by the formula above. These two dilutions have been found to be useful for measuring the gelling functionality of the pourable liquid vehicles of the invention in a standardize method, because some of the pourable liquid vehicles may require a greater or lesser amount of water in order to trigger the gelling character. The use of other water dilutions for determination of hc, ranging from about 5% up to about 70%, would also be expected to provide a demonstration of the unique, gelling character of the invention, but the diluiton which yields a maximal value of T vines depending upon the exact pourableTiquid vehicle being tested. All percentages of the components comprising the invention are herein refer to the their weight in of the pourable liquid vehicle as a whole. The present invention is a pourabk liquid vehicle comprising: (a) from about 26% to about 100% polyoxyalkylene block copolymer; (b) from about 0% to about 70% glycol; and (c) from about 0% to about 50% water; wherein said vehicle is used to deliver compositions, materials and substances to moistened surfaces and aqueous environments said vehicle has a viscosity value hc less than or equal to 7 pascal-seconds and the value T greater man or equal to about 1.3. Polvoxvalkvlene Block Copolvmcr Polyoxyalkylene block copolymer herein referred to as "poloxamers" are nonionic block copolymers of ethylene oxide and propylene oxide corresponding to the following structure: wherein x, y, and x' have a value wherein said vehicle has a viscosity value hc less than or equal to 7 pascal-seconds and the value T greater than or equal to about 1.3. Preferable polyoxyalkylene block copolymors useful in the present invention include wherein x has a value from about 1 to about 130, y has a value from about 1 to about 72 and x' has a value from about 0 to about 130, wherein the average molecular weight of said copolymer is from about 3000 to about 15,000. More preferred is where x equals 37, y equals 58 and x' equals 37 and has a average molecular weight of 6500. Most preferred is wherein x equals 100, y equals 70 and x' equals 100 and has an average molecular weight of about 12,600; The poly(oxyethylene) segment is hydrophilic and the poly(oxypropylene) segment is hydrophobic. The level of the poloxamers useful in the present invention ranges from about 26% to about 100%, preferably from about 27.8% to about 95%, more preferably 30% to about 90% by weight of the pourabk liquid vehicle. In other words, providing the poloxamcr has the critical viscosities above, it can be used itself or when combined with other compositions, materials and substances. A family of poloxamers are available and vary in the number of blocks, the overall average molecular weight, and in the percentage of the molecule which is hydrophilic. A block refers to a single polyoxyethylene or polyoxypropylene segment. Di-block and tri-block polymers have been described. In the case of tri-block copolymers, the blocks can be arranged in the format of one polyoxypropylene block surrounded by 2 polyoxyethylene blocks, that being the most common poloxamer structure, or alternatively as one polyoxyethylene block surrounded by 2 polyoxypropylene blocks, the latter sometimes referred to as a reverse poloxamer. Poloxamers are available under the trade names of Lutrol, Monolan, or Pluronic. The chemical structure, synthesis, and properties have been described [(poly(ethylene oxide)/poly(propylene oxide)] block copolymer surfactants, Paschalis Alexandridis, Current Opinions in Colloid and Interface Science. Vol 2, pp. 478-489 (1997) herein incorporated by reference. For applications in the health care area, compositions embodying the present invention utilize a specific group of pharmaceutically acceptable block copolymers or poloxamers. These poloxamers are selected from the group consisting of Pluronic F127, P105, F108 and mixtures thereof, all available from BASF Corp. Glycols In addition to the poloxamers, it is desirable in some of the pourable liquid vehicles of the present invention to combine glycols with the poloxamers for controlling the viscosity of the pourable liquid vehicles. These glycols permit the pourable liquid vehicle to remain pourable while containing very high levels of the poloxamer so that administration is convenient, or so that the composition can readily pass through the bore of a syringe or other dosing apparatus. Additionally, these glycols provide solvent capacity for pharmaceutical actives or other composition components. The level of glycols in the present invention is from about 0% to about 70%, preferably from about from about 10% to about 70% and most preferably from about 7% to about 62% of the pourable liquid vehicle. Glycols are low molecular weight mono- and polyols and are selected from the group consisting of monosaccharides such as glucose (dextrose), fructose (levulose); disaccharides such as sucrose, lactose, maltose, cellobiose and other sugars, ribose, glycerin, sorbitol, xylitol, inositol, propylene glycol, galactose, mannose, xylose, rhamnose, glutaraldehyde, invert sugars, ethanol, honey, mannitol, polyethylene glycol, glycerol, and mixtures thereof. Preferred glycolsare selected from the group consisting of ethanol, glycerol and propylene glycol, and mixtures thereof. Absolute ethanol is available from Aaper Alcohol & Chemical Co., Shelbyville, KY Water In addition to the poloxamers, and, or the glycol, it is desirable in some of the pourable liquid vehicles of the present invention to include water. Water is useful at a level from about 0% to about 50%, preferably abort 1% to about 46%, most preferably from about 2% to about 41% of the pourable liquid vehicle. Preferred Embodiments Preferred embodiments of ibe present invention utilizing the combination of poloxamers, polyols and water include the following: 1. from about 26% to about 65% Pluronic F127, from about 22% to about 38% ethanol and from about 8% to about 45% water. 2. from about 52% to about 60% Pluronic F108, from about 20% to about 25% ethanol and from about 17% to about 27% water. 3. from about 25% to about 50% Pluronic P105, from about 45% to about 65% propylene glycol and from about 5% to about 20% water. 4. from about 37% to about 77% Pluronic P105, from about 12% to about 28% ethanol, and from about 10% to about 45% water 5. from about 26% to about 49% Pluronic F127, from about 2% to about 12% ethanol, from about 30% to about 68% propylene glycol, and from about about 7% to about 40% water. Materials to be Delivered As previously stated, the pourable liquid vehicles of the present invention are useful as delivery vehicles for desired compositions, materials and substances that may be dispersed into them. This could range from compositions, materials and substances that are desired to remain on. an applied surface for a period of time to deliver a benefit. Examples include antimicrobials for cleansing surfaces including sinks, toilets and shower tile; to body wounds; oral treatment of gingival. and buccal tissues as well as teeth surfaces; agricultural uses including elimination of undesirable plants, animals, viruses, bacteria insects, and the like. The present invention is particularly useful for delivery health care compositions, materials and substances. These materials can range from dietary compositions to promote nutrition or weight loss to pharmacologically effective amount of a agents selected from the group consisting of antibacterial substances, antihistamines, antitussives, anti-inflammatories, expectorants/mucolytics, mast cell stabilizers, leukotriene antagonists, methylxanthincs, antioxidants, steroids, bronchodilators, antivirals, biologies, analgesics, anesthetics, antiarthritics, antiasthmatics, urinary tract disinfectives, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antincoplastics, antipsychotics, antihypertensives, muscle relaxants, antiprotozoals, and mixtures thereof. Preferred embodiment of the present invention relates to compositions including pharmaceutically acceptable polyoxyalkylene block copolymer and glycols in combination with a pharmacologically active agent. Suitable classes of agents that can be administered by embodiments of the present invention include: Antibacterial substances such as P-lactum antibiotics, such as cefoxitin, n-formamidoyl thienamycin and other thienamycin derivatives, tetracyclines, chlorampbenicol, neomycin, gramicidin, bacitracin, sulfonamides; aminoglycoside antibiotics such as gentamycin, kanaranycin, amikacin, sisomicin and tobramycin; nalidixic acids and analogs such as norfloxacin and the antimicrobial combination of fluoroalanine/pentizidone; nitrofurazones, and mixtures thereof. Antihistamines. including, Hydroxyzine, Pyrilamine, Phenindamine, Dexchlorpheniramine, Clemastine Diphenhydrarrune, Azelastine, Acrivastine, Levocarbastine, Mequitazine, Astemizole, Ebastine, Loratadine, Cetirizine, Terfenadinc, Promethazine, Dimenhydrinate, Meclizine, Tripelennamine, Carbinoxamine, Cyprohcptadine, Azatadine, Brompheniramine, TriproHdine, Cyclizine, Thonzylamine, Pheniramine, and mixtures thereof; Antitussives. including, Hydrocodone, Noscapine, Benzonatate, Diphenhydramine, Chlophedianol, Clobutinol, Fominobcn, Glaucine, Pholcodine, Zipeprol, Hydromorphone, Carbetapentane, Caramiphen, Levopropoxyphene, Codeine, Dcxtromethorphan, and mixtures thereof. Antiinflammatories. preferably Non-Steroidal Anti-inflammatories (NSAIDS) including, Ketoprofen, Indoprofen, Indomethacin, Sulindac, Diflunisal, Ketorolac, Piroxicam, Meclofenamate, Benzydamine, Carprofen, Diclofenac, Etodolac, Fenbufen, Fenoprofen, Flurbiprofen, Mefenamic, Nabumetone, Phenylbutazone, Pirprofen, Tohnetin, Ibuprofen, Naproxen, Sodium naproxen, Aspirin, and mixtures thereof. Expectorants/Mucolytics. including, Ambroxol, Bromhexine, Terpin, Guaifenesin, Potassium iodide, N-Acetylcysteine, and mixtures thereof. Mast Cell Stabilizers, preferably intranasally, or orally administered mast cell stabilizers, including, Cromolyn, Oxatamide, Ketotifen, Lodoxamidc, Nedocromil, and mixtures thereof. Leukotricnc Antagonists, including, Zileuton and others. Methvlxanthines. including, Caffeine, Theophylline, Enprofylline, Pentoxifylline, Aminophylline, Dyphylline, and mixtures thereof. Antioxidants or radical inhibitors, including, Ascorbic acid, Tocopherol, Pycnogenol, and mixtures thereof. Steroids, preferably intranasaliv administered steroids, including. Beclomethasone, Fluticasone, Budesonide, Mometasone, Triamcinolone, Dexamethasone, Flunisolidc, Prednisone, Hydrocortisone and mixtures thereof. Bronchodilators. preferably for inhalation, including, Albuterol, Epinephrine, Ephedrine, Metaproterenol, Terbutaline, Isoetharine, Terbutaline, Isoetharine, Pirbuterol, Bitoherol, Fenoterol, Rimetcrol, Ipratroprium, and mixtures thereof. Antivirals. including, Amantadine, Rimantadine, Enviroxime, Nonoxinols, Acyclovir, Alpha-Interferon, Beta-lnterferon, and mixtures thereof. Biologies, including, cytokine and celladhesion molecule inhibitors, ICAM antagonists, interleukin agonists or antagonists, hormones, polypeptides, amino acids, nucleotides, antibodies, and mixtures thereof. Analgesics such as aspirin, acetaminophen, diflunisal, and mixtures thereof. Anesthetics such as lidocaine, procaine, benzocaine, xylocaine, and mixtures thereof. Antiarthritics such as phenylbutazone, indomcthacin, sulindac, dexamethasone, ibuprofen, allopurinol, oxyphenbutazone, probenecid, and mixtures thereof. Antiasthma drugs such as theophylline, ephedrine, beclomethasone dipropionate, epinephrine, and mixtures thereof. Urinary tract disinfectives such as sulfamethoxazole, trimethoprim, nitrofurantoin, norfloxacin, and mixtures thereof. Anticoagulants such as heparin, bishydroxycoumarin, warfarin, and mixtures thereof. Anticonvulsants such as diphenylhydantoin, diazepam, and mixtures thereof. Antidepressants such as amitriptyline, chlordiazepoxide, perphenazine, protriptyline, imipramine, doxepin, and mixtures thereof. Antidiabetics such as insulin, tolbutamide, tolazamide, acetohexamide, chlorpropamide, and mixtures thereof. Antineoplastics such as adriamycin, fluorouracil, methotrexate, asparaginase, and mixtures thereof. Antipsvchotics such as prochlorperazinc, lithium carbonate, lithium citrate, thioridazine, molindone, fluphenazine, trfluoperazine, perphenazine, amitriptyline, triflupromazinc, and mixtures thereof. Antihvpertensive such as spironolactone, methyldopa, hydralazine, clonidine, chlorothiazide, deserpidine, timolol, propranolol, metoprolol, prazosin hydrochloride, reserpine, and mixtures thereof. Muscle relaxants such as melphalan, dantrolene, cyclobenzaprine, methocarbamol, diazepam, and mixtures thereof. Antiprotozoals such as chloramphenicol. chloroquine, trimethoprim, sulfamethoxazole, and mixtures thereof. For treatment of vaginal and urethra] conditions requiring antifungal, amoebicidal, trichomonoacidal agents or antiprotozoals, the following agents can be used: polyoxyethylene nonylphenol, alkylaryl sulfonate, oxyquinoline sulfate, miconazole nitrate, sulfanilamide, candicidin, sulfisoxazole, nystatin, clotrimazole, metronidazole and mixtures thereof; antiprotozoals such as chloramphenicol, chloroquine, trimethoprim, sulfamcthoxazole and mixtures thereof; antiviral effective compounds such as acyclovir and interferon. Spermicidals can be used such as nonoxynal. EXAMPLES Example I: Composition for the treatment of cough Preparation: Add the dextromethorphan base, sodium saccharin, and monoammonium glycerizinate into a clean vessel. Add ethanol and then the poloxamer and water. Mix until clear and uniform. Example II: Composition for the treatment of cough and decongestion Preparation: Mill and screen the chlorophenarimine maleate to reduce the product particle size. Add the chlorophenarimine maleate, dextromethorphan base, sodium saccharin, and monoammonium glycerizinate into a clean vessel. Add ethanol to the vessel. Subsequently, add poloxamer and water to the vessel. Mix until the suspension is uniform. Preparation: Mill and screen the menthol and benzocaine to reduce the product particle size. Add the menthol, benzocaine, sodium saccharin, and monoammonium glycerizinate into a clean vessel. Add eucalyptus oil, ethanol to the vessel. Subsequently add the poloxamer and water to the vessel. Mix until uniform. Preparation: Mill and screen the acetaminophen to reduce the particle size. Add the acetaminophen into a clean vessel. Add propylene glycol to the vessel. Subsequently add the poloxamer and water to the vessel. Mix until uniform Preparation: Screen the ketoprofen to reduce the particle size. Add the ketoprofen into a clean vessel. Add ethanol to the vessel. Subsequently add poloxamer and water to the vessel. Mix until uniform. Preparation: Screen the ibuprofen to reduce the particle size. Add the ibuprofen into a clean vessel. Add ethanol to the vessel. Subsequently add the poloxamer and water to the vessel. Mix until uniform. Preparation: Mill and screen the menthol and triclosan monophosphate to reduce particle size. Add the menthol, triclosan monophophate, sodium saccharin, and monoammonium glycerizinate into a clean vessel. Add propylene glycol to the vessel. Subsequently add the poloxamer and water to the vessel. Mix until uniform. •Preparation: Add the dibasic sodium phosphate, monobasic potassium phosphate, disodium EDTA, benzalkonium chloride and oxymetazoline HC1 into a clean vessel. Add tyloxapol, chlorhexidine gluconate, and ethanol to the vessel. Subsequently add, the poloxamer and water to the vessel. Mix until uniform. Preparation: Add the beta estradiol and propylene glycol into a clean vessel. Subsequently add the poloxamer and water to the vessel. Mix until uniform. 1. Vehicle contains 100.0% (w/w%) Pluronic L62 (BASF Specialty Chemicals, Mount Olive, NJ.) Preparation: Mill and screen the promethazine HCl to reduce particle size. Add the poloxamer and the Promethazine HCl into a clean vessel. Mix until uniform. 1. Vehicle contains 100.0% (w/w%) Pluronic L62 (BASF Specialty Chemicals, Mount Olive, N.J.) 2. Carbopol 974 available from B. F. Goodrich Company, Brecksville. Ohio Preparation: Mill the promethazine HC1 to reduce particle size. Sieve the carbojner and promethazine HC1 and add to a clean vessel. Add the poloxamer. Mix until uniform. Preparation: Add propylene glycol and poloxamer to a clean vessel (main mix). While stirring, heat the mixture as appropriate to sufficiently melt the poloxamer. Once a uniform solution is obtained remove from beat source and continue mixing. In a separate vessel (alcohol pre-mix) add alcohol, dextromethorphan base and monoammonium glyzeriziinate and mix until uniform. In another vessel (water pre-mix), add water, EDTA, sodium saccharin, acesulfame and sodium metabisulfite. Mix until all materials are dissolved. Add the alcohol containing prcmix to the main mixing vessel containing the poloxamer. Mix until uniform. While stirring, add the water containing premix to the main vessel and continue to mix until uniform. Subsequently, add desired flavor component and mix until uniform. The preparation has a viscosity (hc)of 0.67 Pascal seconds and a triggered viscosity ratio at a 50% dilution with water of 10.5 Example XIV: Composition for the Treatment of Cough Add propylene glycol and poloxamer to a clean vessel (main mix). While stirring, heat the mixture as appropriate to sufficicatly melt the poloxamer. Once a uniform solution is obtained remove from heat source and continue mixing. In a separate vessel (alcohol pre-mix) add alcohol, dextromethorphan base and monoammonium glyzeriziinate and mix until uniform. In another vessel (water pre-mix), add water, EDTA , sodium saccharin, acesulfame and sodium metabisulfite. Mix until all materials arc dissolved. Add the alcohol containing premix to the main mixing vessel containing the poloxamer. Mix until uniform. While stirring, add the water containing premix to the main vessel and continue to mix until uniform. Subsequently, add desired flavor component and mix until uniform. The proportions of poloxamer: glycol: water in the preparation is 29.08 :46.31 : 24.61 The preparation has a viscosity (%)of 0.97 Pascal seconds and a triggered viscosity ratio at a 50% dilution with water of 4.95. Example XV: Composition for the Treatment of Cough Add propylene glycol and poloxamer to a clean vessel (main mix). While stirring, heat the mixture as appropriate to sufficiently melt the poloxamer. Once a uniform solution is obtained remove from heat source and continue mixing. In a separate vessel (alcohol pre-mix) add alcohol, dextromethorphan base and monoammonium glyzeriziinate and mix until uniform. In another vessel (water pre-mix), add water, EDTA , sodium saccharin, acesulfame and sodium metabisulfitc. Mix until all materials are dissolved. Add the alcohol containing premix to the main mixing vessel containing the poloxamer. Mix until uniform. While stirring, add the water containing premix to the main vessel and continue to mix until uniform. Subsequently, add desired flavor component and mix until uniform. The proportions of poloxamer: glycol: water in the preparation is 40.27 : 46.31 : 13.42 The preparation has a viscosity (%)of 2.14 Pascal seconds and a triggered viscosity ratio at a 50% dilution with water of 6.05. Example XVI: Composition for the Treatment of Cough Preparation: Weigh the dextromethorphan into a clean vessel, add the ethanol and begin mixing. Add propylene glycol and mix until uniform and clear. Add Pluraflo and mix. Add Glyerine and mix until uniform. Add propylene glycol and Pluraflo to a clean vessel (main mix). Stir, heat the mixture as appropriate to sufficiently melt the poloxamer. Once a uniform solution is obtained remove from heat source and continue mixing. In a separate vessel (alcohol pre-mix) add alcohol, dextromethorphan base and monoammonium glyzeriziinate and mix until uniform. In another vessel (water prc-mix), add water, EDTA , sodium saccharin, acesulfame and sodium metabisulfite. Mix until all materials are dissolved. Add the alcohol containing premix to the main mixing vessel containing the poloxamer. Mix until uniform. While stirring, add the water containing premix to the main vessel and continue to mix until uniform. Subsequently, add desired flavor component and mix until uniform. The proportions of poloxamer: glycol: water in the preparation is 29.08 :46.31 : 24.61 Preparation: Add propylene glycol, Plurafio, glycerine and ethanol to a clean vessel. While stirring, add* ofloxacin. Stir unit a clear solution is obtained. Subsequently, add perfume and mix until uniform. Preparation: Add glycerine, ethanol and Pluraflo to a clean vessel. Add Timolol. Cover tightly and stir until a clear solution is obtained. Preparation: Add propylene glycol and poloxamer to a clean vessel (main mix). While stirring, heat the mixture as appropriate to sufficiently melt the poloxamer. Once a uniform solution is obtained remove from heat source and continue mixing. In a separate vessel (alcohol pre-mix) add alcohol, omeprazole base and monoammonium glyzeriziinate and mix until uniform. In another vessel (water pre-mix), add water, EDTA , sodium saccharin, acesulfame and sodium metabisulfite. Mix until all materials are dissolved. Add the alcohol containing premix to the main mixing vessel containing the poloxamer. Mix until uniform. While stirring, add the water containing premix to the main vessel and continue to mix until uniform. Subsequently, add desired flavor component and mix until uniform. Preparation: Add alcohoi, propylene glycol, and phenylpropanolaminc to a clean vessel and begin mixing. Subsequently, add, Pluraflo and glycerol to the vessel. Mix until uniform. This liquid may be filled into hard gelatin capsules which are then banded to prevent leakage, or it may be used as the fill for a soft elastic gelatin capsule. One capsule is made to contain 0.75 ml of the liquid, and taken 3 times daily provides controlled release of the phenylpropanolamine active. After swallowing, the gelatin shell dissolves in the gastrointestinal tract and the liquid fill immediately transforms in to a slow dissolving gel which provides controlled release of the phenylpropanolamine. Preparation: Add propylene glycol, ethanol, glycerine and morphine sulfate into a clean vessel and begin mixing. Subsequently, add poloxamer (Pluraflo) and mix until uniform. The composition provides pain relief when 1 mL is injected intramuscularly. m CLAIM: 1. A. pourable liquid vehicle comprising: (a) from 26% to 97% by weight of a polyoxyalkylene block copolymer (b) from 10% to 70% by weight of a glycol; and (c) from 1% to 46% by weight of water; wherein said vehicle is used to deliver compositions, materials, and substances to moistened surfaces and aqueous environments, wherein said vehicle has a viscosity value hc less than or equal to 7 pascal-seconds and a value T greater than or equal to 1.3. 2. The pourable liquid vehicle as claimed in claim 1, wherein the polyoxyalkylene block copolymer corresponding to the following structure: CH3 \| HO -(CH2CH2O)x-(CH2CHO)x-(CH2CH2O)x- H wherein x has a value from 1 to 130, y has a value from 1 to 72, and x' has a value from 0 to 130, and wherein the polyoxyalkylene block copolymer has an average molecular weight of from 3000 to 15,000 wherein said vehicle has a viscosity value hc less than or equal to 7 pascal-seconds and the value T greater than or equal to 1.3. 3. The vehicle as claimed in claim 2, comprising from 27.8% to 95% of the pharmaceutically acceptable polyoxyalkylene block copolymer wherein said vehicle has a viscosity hc less than or equal to 2 pascal- seconds and value T is greater than or equal to 2. 4. The composition as claimed in claim 2, comprising from 30% to 90% of the pharmaceutically acceptable polyoxyalkylene block copolymer wherein said vehicle has a viscosity hc less than or equal to 2 pascal- seconds and value T is greater than or equal to 5. 5. The composition as claimed in claim 1, comprising from 10% to 70% glycol. 6. The composition as claimed in claim 5, wherein said glycol is selected from the group consisting of monosaccharides, disaccharides, ribose, glycerin, sorbitol, xylitol, inositol, propylene glycol, galactose, mannose, xylose, rthamnose, glutaraldehyde invert sugars, ethanol, honey, mannitol, polyethylene glycol, glycerol, and mixtures thereof. 7. The composition as claimed in claim 1, comprising from 1% to 46% water. 8. A pourable liquid vehicle comprising: (a) from 26% to 100% polyoxyallcylene block polymer; (b) from 0 to 70% glycol; and (c) from 0% to 50% water, wherein said vehicle is used to deliver pharmaceutically active agents to moistened surfaces and aqueous environments wherein said vehicle has a viscosity value hc less than or equal to 7 pascal- seconds and the value T greater than or equal to 1.3. 9. The pourable liquid vehicle as claimed in claim 8, wherein the polyoxyallcylene block copolyner corresponding to the following structure: CH3 \| HO - (CH2CH2O)x _ (CH2CHO)x — (CH2CH2O)x- H wherein x has a value from 1 to 130, y has a value from 1 to 72, and x' has a value from 0 to 130, and wherein the polyoxyallcylene block copolymer has an average molecular weight of from 3000 to 15,000 wherein said vehicle has a viscosity value hc less than or equal to 7 pascal-seconds and the value t greater than or equal to 1.3. 10. The vehicle as claimed in claim 9, comprising from 27.8% to 95% of the pharmaceutically acceptable polyoxyalkylene block copolymer and vehicle has a viscosity hc less than or equal to 2 pascal-seconds and value T is greater than or equal to 2. 11. The vehicle as claimed in claim 10, comprising from 30% to 90% of the pharmaceutically acceptable polyoxyalkylene block copolymer wherein said vehicle has a viscosity hc less than or equal to 2 pascal- seconds and value T is greater than or equal to 10. 12. The vehicle as claimed in claim 9, wherein x has a value from 1 to 130, y has a value from 1 to 72 and x' has a value from 0 to 130, in said polyoxyalkylene block copolymer, and wherein the average molecular weight of said copolymer is from 3000 to 15,000. 13. The vehicle as claimed in claim 8, comprising from 7% to 62% glycol. 14. The vehicle as claimed in claim 13 wherein said glycol is selected from the group consisting of monosaccharides, disaccharides, ribose, glycerin, sorbitol, xylitol, inositol, propylene glycol, galactose, mannose, xylose, rhamnose, glutaraldehyde, invert sugars, ethanol, honey, mannitol, polyethylene glycol, glycerol, and mixtures thereof. 15. The vehicle as claimed in claim 8 comprising from 2 % to 41% water. 16. The vehicle as claimed in claim 8 comprising: (a) from 26% to 65% polyoxyalkylene block copolymer having a value x equal to 100, y equal to 70 and x' is equal to 100 and has an average molecular weight of 12,600; (b) from 2% to 38% ethanol; and (c) from 8% to 45% water. 17. The composition as claimed in claim 8 comprising: (a) from 25% to 50% polyoxyalkylene block copolymer having a value x equal to 37, y equal to 58 and x' is equal to 37 and has a average molecular weight of 6500; (b) from 45% to 65% propylene glycol; and (c) from 5% to 20% water. 18. The composition as claimed in claim 8 comprising: (a) from 52% to 60% polyoxyalkylene block copolymer having a value x equal to 128, y equal to 58 and x' is equal to 128 and has an average molecular weight of 14,600; (b) from 25 to 25% ethanol; and (c) from 17% to 27% water. 19. The composition as claimed in Claim 8 comprising: (a) from 37% to 77% polyoxyalkylene block copolymer having a x equal to 37, y equal to 58 and x' is equal to 37 and has a average molecular weight of 6500; (b) from 2% to 28% ethanol; and (c) from 10% to 45% water. 20. The composition as claimed in claim 8 comprising: (a) from 26% to 49% polyoxyalkylene block copolymer having a value x equal to 100, y equal to 70 and x' is equal to 100 and has an average molecular weight of 12,600; (b) from 2% to 12% ethanol; and (c) from 30% to 68% propylene glycol; and (d) from 7% to 40% water. The present invention covers pourable liquid vehicles that can be combined with compositions, materials and substances. Among the benefits of such pourable liquid vehicles the compositions are retained on the moistened surface for a period of time sufficient to allow compositions, materials and substances to act on said surface, resisting erosion or run-off from additional moisture being applied. Such pourable liquid vehicles have a number of utilities including but not limited to cleaning and treating surfaces of objects as well as biological or living organisms, Including living creatures.

Full Text

POURABLE LIQUID VEHICLES
CROSS REFERENCE
This application claims priority under Title 35, United States Code 119(e) from Provisional
Application Serial No. 60/153,260, filed September 11,1999.
TECHNICAL FIELD
The present invention relates to a pourable liquid vehicle.
Concentrated levels of polyoxyalkylene block copolymers are useful in vehicles
incorporated into products that are designed to deliver compositions, materials and substances to
moistened surfaces and aqueous environment Acquiring moisture during use, the vehicle
becomes sufficiently transformed from a liquid to a gel-like form that provides the a benefit to the
user. For example, mucosal surfaces of the body contain sufficient water to allow the pourable
liquid vehicle comprising concentrated polyoxyalkylene block copolymers to be effectively
delivered to the desired site wherein the accompanying compositions, materials and substances
tenaciously adhere to the moistened surfaces and resist dissolution or erosion by water or
biological fluid. Such uses include, but are not limited to the delivery of personal health care
compositions, formulations and compounds including, but not limited to, Pharmaceuticals (OTC
and prescription), nutrients and the like.
In the discipline of pharmaceutical compositions there are a wide variety of dosage
forms. Examples include tablets, capsules, elixirs, syrups, liquid-filled capsules, suspensions,
coated tablets or capsules for administration by mouth; gels, rinses, dentifrices, lozenges, sprays,
medicated lollipops, liquid filled capsules for intra-oral administration; gels, suspensions or
solutions for intra-ocular or intra-aural administration; suppositories and douches or enemas for
intra-rectal or vaginal administration; and creams, ointments, gels, lotions and patches for topical
application on the skin and scalp; and liquid suspension or solutions for injection by syringe,
nasal gels, solutions, or suspensions for application into the nose with special applications or
sprayers.
The majority of these compositions are in the physical form of a fluid having a viscosity
ranging from pourable liquids to stiff gels. Pourable liquids are often preferred since they are in
The majority of these compositions are in the physical form of a fluid having a viscosity
ranging from pourable liquids to stiff gels. Pourable liquids are often preferred since they are in
the best form to be administered. For example, only liquids, or perhaps low viscosity gels, can be
injected through a syringe, or poured from a bottle into a medicine cup, or drawn up into a
syringe or medicine dropper, or squeezed from a dropper bottle into the eye or ear, or atomized
into the nasal cavities, fa addition to the compatibility with pharmaceutical administration
devices and with the mode of introduction into the body, it is often desirable for the composition
to easily spread after application without the aid of manual action or devices. The eye drop
compositions, for example, need to spread over the surface of the eye, as do swallowed liquids
intended to coat the throat, esophagus, or stomach. This is similarly true of rectal enemas or
vaginal douche compositions.
In many cases, however, pharmaceutical dosage forms in form of pourable liquids are not
necessarily desirable since once administered, such pourable liquids are easily removed from the
intended treatment site. In such circumstances the therapeutic advantage of the composition may
be significantly diminished or even lost completely. It is appropriate, therefore, to surmise mat
for the purpose of being retained at the targeted site, it may be desirable for a particular
pharmaceutical composition to be more viscous, even in the form of a gel mat is not readily
flowable. It is, however, difficult or even impossible to administer such a viscous composition to
its intended site to do the most good. For example, serious injury could occur when attempting to
spread a gel on the surface of one's eye using a finger or more elaborate applicators. More
problematic is coating the stomach lining, as this site is simply not accessible using simple self-
administer applicators.
There is, therefore, a need for pharmaceutical compositions mat are "smart"; that is,
capable of being administered in a pourable liquid that are converted or transformed after
administration into a vehicle having sufficient viscosity to essentially remain at the targeted site.
Such compositions require a built-in chemical or physical triggering mechanism(s) that respond
to conditions after application in or on a surface including the body.
BACKGROUND OF THE INVENTION
Attempts to develop such compositions have been ongoing for a significant period of
time. Examples of such compositions include intra-ocular dosage forms as disclosed in Edsman,
K., Carlfors, J., Petersson, R., Rheological Evaluation of Poloxamer as an in situ Gel for
Ophthalmic Use. European Journal of Pharmaceutics Vol. 6 pp. 105-112 (1998) herein
incorporated by reference. Compositions such as these are broadly described as primarily
aqueous solutions of block co-polymer surfactants, other wise referred to as "poloxamers", that
are commonly known in the art. When formulated in water as somewhat concentrated solutions,
or with water and co-solvents, the poloxamer solution remains as a pourable liquid. The most
commonly reported example of this type of system consists of poloxamer 407 at concentrations
ranging from about 10% to 35% by weight of the composition in water. These compositions are
administered at room temperature as liquids. They form a gel upon reaching body temperature.
The trigger for converting these compositions to a gel, therefore, is body heat.
In situ gelation of pharmaceutical compositions based on poloxamer that are biologically
triggered are known in the art. For example Kim, C.K., Lee, S.W., Choi, H.G., Lee, M.K., Gao,
Z.G., Kim, I.S., and Park, KM.: Trials of In Situ Gelling and Muqoadhcsjve Acetaminophen
Liquid Suppository in Human Subjects. International Journal of Pharmaceutics vol. 174, pp. 201-
207 (1998) incorporated herein by reference. Kim et al. discloses liquid suppositories for
enhancing absorption of the pain and fever relieving drug acetaminophen.
U.S. Patent 5,256,396, issued October 26, 1993, to Colgate Palmohve Company,
incorporated herein by reference, describes similar compositions containing poloxamer 407 and
water at specified concentrations. Other products utilizing bio-triggers include those comprising
poloxamer 407 at ranges preferably 12% to 17%. When combined with pharraaceutically active
agents, these compositions are injected into the gingival space between the root of a tooth and the
gum.
Poloxamers represent a large family of polymers that vary in molecular weight as well as
in the percentage or portion of the block copolymer mat is considered hydrophobia
Compositions comprising other poloxamers from this family having similar liquid/gelling
characteristics are somewhat predictable, lacking only in the understanding of the required
concentration of poloxamer. While there is a large number of uses for such compositions, they
all rely on the same general mechanism of temperature-induced gelation of aqueous poloxamer
dispersions. Compositions known in the art are found to be inadequate, however, as the gel
structure readily dissolves in aqueous environments.
SUMMARY OF THE INVENTION
The present invention covers pourable liquid vehicles used to deliver compositions,
materials and substances to moistened surfaces and aqueous. The benefits of compositions
formulated with such pourable liquid vehicles include retention of the compositions, materials
and substances on the moistened surface. This in turn allow for effective delivery of a desired
compositions, materials and substances in the vehicle that acts on targeted surface, resisting
erosion or run-off even in an aqueous environment. Such pourable liquid vehicles have a number
of utilities for delivery of all kinds of materials including but not limited to cleaning and treating
surfaces of objects as well as biological or living organisms, including living creatures.
Another object of this invention is to utilize such pourable liquid vehicles to deliver
health care compositions and materials and substances to living creatures, particularly mammals,
and roost particularly humans. Even another object of the present invention is to develop a
method for effective delivery of health care compositions, materials and substances.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Terms useful herein are defined below. Additionally, terms used in the art, as well as
general concepts, are further described in Schramm, The Language of Colloid and Interface
Science. American Chemical Society, (1993), incorporated herein by reference.
The term "pourable liquid" as used herein means the physical state of the compositions
of the present invention prior to formation of a gel.
The term "moistened surface" as used herein means any living or non-living surface
having sufficient moisture in or on it to trigger rapid conversion of a pourable liquid to a gel.
The term "in situ gelation" as used herein means the conversion of a pourable liquid to a
gel at a designated site or surface.
As used herein, the term "gel" describes the substance resulting from the combination of
the pourable liquid and water, or bodily fluid containing mostly water. The gel is sufficiently
viscous to remain at the site applied to, or ultimately targeted for, over a period of time sufficient
for the compositions, materials and substances in the gel to bring about a desired result at the site
they are delivered to.
The term "triggering device" as used herein means an stimulus external to the
composition that induces the conversion of a pourable liquid to a gel.
The term "shear" as used herein is the rate of deformation of a fluid when subjected to a
mechanical shearing stress. In simple fluid shear, successive layers of fluid move relative to each
other such that the displacement of any one layer is proportional to its distance from a reference
layer. The relative displacement of any two layers divided by their distance of separation from
each other is termed the "shear" or the "shear strain". The rate of change with tone of the shear
is termed the "shear rate".
A certain applied force is needed to produce deformation in a fluid. For a plane area
around some point in the fluid and in the limit of decreasing area the component of deforming
forces per unit area that acts parallel to the plane is the "shear stress".
The "viscosity" of a viscous material, also called viscosity index, is defined as the ratio
of the shear stress applied into the material, divided by the rate of shear which remits. Materials
of a higher viscosity have a higher resistance to flow, or to forces which can induce flow, than a
lower viscosity material. All viscosities listed herein are at a shear rate of about 50 per second
unless otherwise indicated. All of the rheologic characteristics given herein can be measured in a
controlled rate or a controlled stress rotational viscometer capable of some operation in a
controlled rate mode, for Example Haake RS ISO by Haake GmbH, Karlsruhe, Germany;
Cammed CSL 500 Controlled Stress Rheometer by TA Instruments, New Castle, Delaware; and
Rheometric SR5, by Rheometric Scientific, Piscataway, NJ.
Specifically, when subject to constant shearing rate of about 50 per second at normal
ambient temperature (approx. 25°C), the present liquid compositions have a viscosity of less than
aboyt 7 pascal seconds, preferably less than about 2 pascal seconds, more preferably less than
about 1 pascal seconds.
The value of a composition's triggered viscosity ratio ("T") is useful in determining the
degree to which a composition exhibits the above described gelling characteristic. The formula
and procedure for determining the triggered viscosity ratio is set forth below.
It is desirable for the compositions of the present invention to exhibit a triggered
viscosity ratio of at least about 1.3, preferably at least about 2, more preferably at least about 5,
and most preferably at least about 10 wherein the triggered viscosity is defined by the following
formula or ratio:
T=hs/hc
where hs= viscosity of the gel and
where hc= viscosity of the pourable liquid
The pourable liquid vehicle of the present invention must be selected and formulated so
that the contacting and mixing said vehicles to a mucosal surface of the body, or with some other
fluid in the body, triggers the conversion of the pourable liquid vehicle to a more viscous gel-like
mixture. Examples of these fluids are saliva, gastric fluid, intestinal fluid, extracellular fluid
present under the skin at the site of a subcutaneous injection, or in muscle tissue at the site of an
intramuscular injection, cerebrospinal fluid, vaginal fluid, fluid exudate from an open wound or
ulcer, tear fluid, rectal fluid, or any other bodily fluid of an animal which contains in large
measure water. In other words, after the pourable liquid vehicle contacts with the bodily fluid,
the viscosity of the pourable liquid vehicle becomes greater than the viscosity of either the
pourable liquid vehicle itself prior to mixing, or the bodily fluid alone.
The triggered viscosity ratio of a pourable liquid vehicle can be determined by one
skilled in the art using appropriate viscosity measuring instruments, and is exemplified by the
following method. First, the viscosity of the pourable liquid vehicle (hc is determined in a
rheometer using a shear rate of 50 per second at 25°C. For the determination of h6 1 ml of the
pourable liquid vehicle is placed onto the plate of a Haake RS150 rheometer. The temperature is
controlled in the range of typical room temperature, about 25oC. A cover is used on the
measuring system and a solvent-saturated atmosphere provided to prevent evaporation of water,
cthanol, or other volatile components from the sample during the test A 35 mm diameter parallel
plate measuring system is lowered onto the sample, leaving a gap of about 1 millimeter, and an
equilibration shearing of approximately 10 per second is applied for 10 seconds. Then, a
constant shearing rate of 50 per second is applied for 30 seconds. The viscosity hc is read from
the instrument at the 30 second time point.
For the determination of hs, two dilutions of the pourable liquid vehicle are made with
water. The first dilution is made to contain 75% by weight of the pourable liquid vehicle, and
25% by weight of additional water. The second dilution is made to contain 50% by weight of
pourable liquid vehicle and 50% by weight of additional water. The pourable liquid vehicle and
water are combined in a vial and a tight seal applied to prevent evaporation of components. The
vial contents are mixed in an unusual manner, by repeated centrifugation. This is necessary since
some of the combinations are very viscous gels. Specifically, the vials are centrifuged (using for
example a Beckman GS-6R centrifuge, available from Beckman Instruments, Palo Alto, CA) 20
minutes at 3000 RPM and 25°C for at least four separate centrifuge runs. After each run the vials
are inverted. Additional runs are conducted in the centrifuge to ensure complete mixing. 1 ml of
the gelled sample is then loaded onto the plate of the same rheometer used for the measurement
of %, except that the temperature is controlled at the normal body temperature of a human, 37oC.
An identical rheometer measurement program is used as for determination of hf. The triggered
viscosity factor for both the 25% and 50% dilution of the sample is calculated from % and T|, as
described by the formula above. These two dilutions have been found to be useful for measuring
the gelling functionality of the pourable liquid vehicles of the invention in a standardize method,
because some of the pourable liquid vehicles may require a greater or lesser amount of water in
order to trigger the gelling character. The use of other water dilutions for determination of hc,
ranging from about 5% up to about 70%, would also be expected to provide a demonstration of
the unique, gelling character of the invention, but the diluiton which yields a maximal value of T
vines depending upon the exact pourableTiquid vehicle being tested.
All percentages of the components comprising the invention are herein refer to the their
weight in of the pourable liquid vehicle as a whole.
The present invention is a pourabk liquid vehicle comprising:
(a) from about 26% to about 100% polyoxyalkylene block copolymer;
(b) from about 0% to about 70% glycol; and
(c) from about 0% to about 50% water;
wherein said vehicle is used to deliver compositions, materials and substances to moistened
surfaces and aqueous environments said vehicle has a viscosity value hc less than or equal to 7
pascal-seconds and the value T greater man or equal to about 1.3.
Polvoxvalkvlene Block Copolvmcr
Polyoxyalkylene block copolymer herein referred to as "poloxamers" are nonionic block
copolymers of ethylene oxide and propylene oxide corresponding to the following structure:

wherein x, y, and x' have a value wherein said vehicle has a viscosity value hc less than or equal
to 7 pascal-seconds and the value T greater than or equal to about 1.3. Preferable
polyoxyalkylene block copolymors useful in the present invention include wherein x has a value
from about 1 to about 130, y has a value from about 1 to about 72 and x' has a value from about 0
to about 130, wherein the average molecular weight of said copolymer is from about 3000 to
about 15,000. More preferred is where x equals 37, y equals 58 and x' equals 37 and has a
average molecular weight of 6500. Most preferred is wherein x equals 100, y equals 70 and x'
equals 100 and has an average molecular weight of about 12,600;
The poly(oxyethylene) segment is hydrophilic and the poly(oxypropylene) segment is
hydrophobic. The level of the poloxamers useful in the present invention ranges from about 26%
to about 100%, preferably from about 27.8% to about 95%, more preferably 30% to about 90%
by weight of the pourabk liquid vehicle. In other words, providing the poloxamcr has the critical
viscosities above, it can be used itself or when combined with other compositions, materials and
substances.
A family of poloxamers are available and vary in the number of blocks, the overall
average molecular weight, and in the percentage of the molecule which is hydrophilic. A block
refers to a single polyoxyethylene or polyoxypropylene segment. Di-block and tri-block
polymers have been described. In the case of tri-block copolymers, the blocks can be arranged in
the format of one polyoxypropylene block surrounded by 2 polyoxyethylene blocks, that being
the most common poloxamer structure, or alternatively as one polyoxyethylene block surrounded
by 2 polyoxypropylene blocks, the latter sometimes referred to as a reverse poloxamer.
Poloxamers are available under the trade names of Lutrol, Monolan, or Pluronic. The chemical
structure, synthesis, and properties have been described [(poly(ethylene oxide)/poly(propylene
oxide)] block copolymer surfactants, Paschalis Alexandridis, Current Opinions in Colloid and
Interface Science. Vol 2, pp. 478-489 (1997) herein incorporated by reference.
For applications in the health care area, compositions embodying the present invention
utilize a specific group of pharmaceutically acceptable block copolymers or poloxamers. These
poloxamers are selected from the group consisting of Pluronic F127, P105, F108 and mixtures
thereof, all available from BASF Corp.
Glycols
In addition to the poloxamers, it is desirable in some of the pourable liquid vehicles of
the present invention to combine glycols with the poloxamers for controlling the viscosity of the
pourable liquid vehicles. These glycols permit the pourable liquid vehicle to remain pourable
while containing very high levels of the poloxamer so that administration is convenient, or so that
the composition can readily pass through the bore of a syringe or other dosing apparatus.
Additionally, these glycols provide solvent capacity for pharmaceutical actives or other
composition components. The level of glycols in the present invention is from about 0% to about
70%, preferably from about from about 10% to about 70% and most preferably from about 7% to
about 62% of the pourable liquid vehicle.
Glycols are low molecular weight mono- and polyols and are selected from the group
consisting of monosaccharides such as glucose (dextrose), fructose (levulose); disaccharides such
as sucrose, lactose, maltose, cellobiose and other sugars, ribose, glycerin, sorbitol, xylitol, inositol,
propylene glycol, galactose, mannose, xylose, rhamnose, glutaraldehyde, invert sugars, ethanol,
honey, mannitol, polyethylene glycol, glycerol, and mixtures thereof. Preferred glycolsare selected
from the group consisting of ethanol, glycerol and propylene glycol, and mixtures thereof.
Absolute ethanol is available from Aaper Alcohol & Chemical Co., Shelbyville, KY
Water
In addition to the poloxamers, and, or the glycol, it is desirable in some of the pourable
liquid vehicles of the present invention to include water. Water is useful at a level from about
0% to about 50%, preferably abort 1% to about 46%, most preferably from about 2% to about
41% of the pourable liquid vehicle.
Preferred Embodiments
Preferred embodiments of ibe present invention utilizing the combination of poloxamers,
polyols and water include the following:
1. from about 26% to about 65% Pluronic F127, from about 22% to about 38% ethanol
and from about 8% to about 45% water.
2. from about 52% to about 60% Pluronic F108, from about 20% to about 25% ethanol
and from about 17% to about 27% water.
3. from about 25% to about 50% Pluronic P105, from about 45% to about 65%
propylene glycol and from about 5% to about 20% water.
4. from about 37% to about 77% Pluronic P105, from about 12% to about 28% ethanol,
and from about 10% to about 45% water
5. from about 26% to about 49% Pluronic F127, from about 2% to about 12% ethanol,
from about 30% to about 68% propylene glycol, and from about about 7% to about
40% water.
Materials to be Delivered
As previously stated, the pourable liquid vehicles of the present invention are useful as
delivery vehicles for desired compositions, materials and substances that may be dispersed into
them. This could range from compositions, materials and substances that are desired to remain
on. an applied surface for a period of time to deliver a benefit. Examples include antimicrobials
for cleansing surfaces including sinks, toilets and shower tile; to body wounds; oral treatment of
gingival. and buccal tissues as well as teeth surfaces; agricultural uses including elimination of
undesirable plants, animals, viruses, bacteria insects, and the like.
The present invention is particularly useful for delivery health care compositions,
materials and substances. These materials can range from dietary compositions to promote
nutrition or weight loss to pharmacologically effective amount of a agents selected from the
group consisting of antibacterial substances, antihistamines, antitussives, anti-inflammatories,
expectorants/mucolytics, mast cell stabilizers, leukotriene antagonists, methylxanthincs,
antioxidants, steroids, bronchodilators, antivirals, biologies, analgesics, anesthetics, antiarthritics,
antiasthmatics, urinary tract disinfectives, anticoagulants, anticonvulsants, antidepressants,
antidiabetics, antincoplastics, antipsychotics, antihypertensives, muscle relaxants, antiprotozoals,
and mixtures thereof.
Preferred embodiment of the present invention relates to compositions including
pharmaceutically acceptable polyoxyalkylene block copolymer and glycols in combination with a
pharmacologically active agent. Suitable classes of agents that can be administered by
embodiments of the present invention include:
Antibacterial substances such as P-lactum antibiotics, such as cefoxitin, n-formamidoyl
thienamycin and other thienamycin derivatives, tetracyclines, chlorampbenicol, neomycin,
gramicidin, bacitracin, sulfonamides; aminoglycoside antibiotics such as gentamycin,
kanaranycin, amikacin, sisomicin and tobramycin; nalidixic acids and analogs such as
norfloxacin and the antimicrobial combination of fluoroalanine/pentizidone; nitrofurazones, and
mixtures thereof.
Antihistamines. including, Hydroxyzine, Pyrilamine, Phenindamine,
Dexchlorpheniramine, Clemastine Diphenhydrarrune, Azelastine, Acrivastine, Levocarbastine,
Mequitazine, Astemizole, Ebastine, Loratadine, Cetirizine, Terfenadinc, Promethazine,
Dimenhydrinate, Meclizine, Tripelennamine, Carbinoxamine, Cyprohcptadine, Azatadine,
Brompheniramine, TriproHdine, Cyclizine, Thonzylamine, Pheniramine, and mixtures thereof;
Antitussives. including, Hydrocodone, Noscapine, Benzonatate, Diphenhydramine,
Chlophedianol, Clobutinol, Fominobcn, Glaucine, Pholcodine, Zipeprol, Hydromorphone,
Carbetapentane, Caramiphen, Levopropoxyphene, Codeine, Dcxtromethorphan, and mixtures
thereof.
Antiinflammatories. preferably Non-Steroidal Anti-inflammatories (NSAIDS) including,
Ketoprofen, Indoprofen, Indomethacin, Sulindac, Diflunisal, Ketorolac, Piroxicam,
Meclofenamate, Benzydamine, Carprofen, Diclofenac, Etodolac, Fenbufen, Fenoprofen,
Flurbiprofen, Mefenamic, Nabumetone, Phenylbutazone, Pirprofen, Tohnetin, Ibuprofen,
Naproxen, Sodium naproxen, Aspirin, and mixtures thereof.
Expectorants/Mucolytics. including, Ambroxol, Bromhexine, Terpin, Guaifenesin,
Potassium iodide, N-Acetylcysteine, and mixtures thereof.
Mast Cell Stabilizers, preferably intranasally, or orally administered mast cell stabilizers,
including, Cromolyn, Oxatamide, Ketotifen, Lodoxamidc, Nedocromil, and mixtures thereof.
Leukotricnc Antagonists, including, Zileuton and others.
Methvlxanthines. including, Caffeine, Theophylline, Enprofylline, Pentoxifylline,
Aminophylline, Dyphylline, and mixtures thereof.
Antioxidants or radical inhibitors, including, Ascorbic acid, Tocopherol, Pycnogenol, and
mixtures thereof.
Steroids, preferably intranasaliv administered steroids, including. Beclomethasone,
Fluticasone, Budesonide, Mometasone, Triamcinolone, Dexamethasone, Flunisolidc, Prednisone,
Hydrocortisone and mixtures thereof.
Bronchodilators. preferably for inhalation, including, Albuterol, Epinephrine, Ephedrine,
Metaproterenol, Terbutaline, Isoetharine, Terbutaline, Isoetharine, Pirbuterol, Bitoherol,
Fenoterol, Rimetcrol, Ipratroprium, and mixtures thereof.
Antivirals. including, Amantadine, Rimantadine, Enviroxime, Nonoxinols, Acyclovir,
Alpha-Interferon, Beta-lnterferon, and mixtures thereof.
Biologies, including, cytokine and celladhesion molecule inhibitors, ICAM antagonists,
interleukin agonists or antagonists, hormones, polypeptides, amino acids, nucleotides, antibodies,
and mixtures thereof.
Analgesics such as aspirin, acetaminophen, diflunisal, and mixtures thereof.
Anesthetics such as lidocaine, procaine, benzocaine, xylocaine, and mixtures thereof.
Antiarthritics such as phenylbutazone, indomcthacin, sulindac, dexamethasone,
ibuprofen, allopurinol, oxyphenbutazone, probenecid, and mixtures thereof.
Antiasthma drugs such as theophylline, ephedrine, beclomethasone dipropionate,
epinephrine, and mixtures thereof.
Urinary tract disinfectives such as sulfamethoxazole, trimethoprim, nitrofurantoin,
norfloxacin, and mixtures thereof.
Anticoagulants such as heparin, bishydroxycoumarin, warfarin, and mixtures thereof.
Anticonvulsants such as diphenylhydantoin, diazepam, and mixtures thereof.
Antidepressants such as amitriptyline, chlordiazepoxide, perphenazine, protriptyline,
imipramine, doxepin, and mixtures thereof.
Antidiabetics such as insulin, tolbutamide, tolazamide, acetohexamide, chlorpropamide,
and mixtures thereof.
Antineoplastics such as adriamycin, fluorouracil, methotrexate, asparaginase, and
mixtures thereof.
Antipsvchotics such as prochlorperazinc, lithium carbonate, lithium citrate, thioridazine,
molindone, fluphenazine, trfluoperazine, perphenazine, amitriptyline, triflupromazinc, and
mixtures thereof.
Antihvpertensive such as spironolactone, methyldopa, hydralazine, clonidine,
chlorothiazide, deserpidine, timolol, propranolol, metoprolol, prazosin hydrochloride, reserpine,
and mixtures thereof.
Muscle relaxants such as melphalan, dantrolene, cyclobenzaprine, methocarbamol,
diazepam, and mixtures thereof.
Antiprotozoals such as chloramphenicol. chloroquine, trimethoprim, sulfamethoxazole,
and mixtures thereof.
For treatment of vaginal and urethra] conditions requiring antifungal, amoebicidal,
trichomonoacidal agents or antiprotozoals, the following agents can be used: polyoxyethylene
nonylphenol, alkylaryl sulfonate, oxyquinoline sulfate, miconazole nitrate, sulfanilamide,
candicidin, sulfisoxazole, nystatin, clotrimazole, metronidazole and mixtures thereof;
antiprotozoals such as chloramphenicol, chloroquine, trimethoprim, sulfamcthoxazole and
mixtures thereof; antiviral effective compounds such as acyclovir and interferon. Spermicidals
can be used such as nonoxynal.
EXAMPLES
Example I: Composition for the treatment of cough
Preparation:
Add the dextromethorphan base, sodium saccharin, and monoammonium glycerizinate
into a clean vessel. Add ethanol and then the poloxamer and water. Mix until clear and uniform.
Example II: Composition for the treatment of cough and decongestion
Preparation:
Mill and screen the chlorophenarimine maleate to reduce the product particle size. Add
the chlorophenarimine maleate, dextromethorphan base, sodium saccharin, and monoammonium
glycerizinate into a clean vessel. Add ethanol to the vessel. Subsequently, add poloxamer and
water to the vessel. Mix until the suspension is uniform.
Preparation:
Mill and screen the menthol and benzocaine to reduce the product particle size. Add the
menthol, benzocaine, sodium saccharin, and monoammonium glycerizinate into a clean vessel.
Add eucalyptus oil, ethanol to the vessel. Subsequently add the poloxamer and water to the
vessel. Mix until uniform.
Preparation:
Mill and screen the acetaminophen to reduce the particle size. Add the acetaminophen
into a clean vessel. Add propylene glycol to the vessel. Subsequently add the poloxamer and
water to the vessel. Mix until uniform
Preparation:
Screen the ketoprofen to reduce the particle size. Add the ketoprofen into a clean vessel.
Add ethanol to the vessel. Subsequently add poloxamer and water to the vessel. Mix until
uniform.
Preparation:
Screen the ibuprofen to reduce the particle size. Add the ibuprofen into a clean vessel.
Add ethanol to the vessel. Subsequently add the poloxamer and water to the vessel. Mix until
uniform.
Preparation:
Mill and screen the menthol and triclosan monophosphate to reduce particle size. Add
the menthol, triclosan monophophate, sodium saccharin, and monoammonium glycerizinate into
a clean vessel. Add propylene glycol to the vessel. Subsequently add the poloxamer and water to
the vessel. Mix until uniform.
•Preparation:
Add the dibasic sodium phosphate, monobasic potassium phosphate, disodium EDTA,
benzalkonium chloride and oxymetazoline HC1 into a clean vessel. Add tyloxapol, chlorhexidine
gluconate, and ethanol to the vessel. Subsequently add, the poloxamer and water to the vessel.
Mix until uniform.
Preparation:
Add the beta estradiol and propylene glycol into a clean vessel. Subsequently add the
poloxamer and water to the vessel. Mix until uniform.
1. Vehicle contains 100.0% (w/w%) Pluronic L62 (BASF Specialty Chemicals, Mount Olive, NJ.)
Preparation:
Mill and screen the promethazine HCl to reduce particle size. Add the poloxamer and the
Promethazine HCl into a clean vessel. Mix until uniform.
1. Vehicle contains 100.0% (w/w%) Pluronic L62 (BASF Specialty Chemicals, Mount Olive, N.J.)
2. Carbopol 974 available from B. F. Goodrich Company, Brecksville. Ohio
Preparation:
Mill the promethazine HC1 to reduce particle size. Sieve the carbojner and promethazine
HC1 and add to a clean vessel. Add the poloxamer. Mix until uniform.
Preparation:
Add propylene glycol and poloxamer to a clean vessel (main mix). While stirring, heat
the mixture as appropriate to sufficiently melt the poloxamer. Once a uniform solution is
obtained remove from beat source and continue mixing. In a separate vessel (alcohol pre-mix)
add alcohol, dextromethorphan base and monoammonium glyzeriziinate and mix until uniform.
In another vessel (water pre-mix), add water, EDTA, sodium saccharin, acesulfame and sodium
metabisulfite. Mix until all materials are dissolved.
Add the alcohol containing prcmix to the main mixing vessel containing the poloxamer.
Mix until uniform. While stirring, add the water containing premix to the main vessel and
continue to mix until uniform. Subsequently, add desired flavor component and mix until
uniform.
The preparation has a viscosity (hc)of 0.67 Pascal seconds and a triggered viscosity ratio
at a 50% dilution with water of 10.5
Example XIV: Composition for the Treatment of Cough
Add propylene glycol and poloxamer to a clean vessel (main mix). While stirring, heat
the mixture as appropriate to sufficicatly melt the poloxamer. Once a uniform solution is
obtained remove from heat source and continue mixing. In a separate vessel (alcohol pre-mix)
add alcohol, dextromethorphan base and monoammonium glyzeriziinate and mix until uniform.
In another vessel (water pre-mix), add water, EDTA , sodium saccharin, acesulfame and sodium
metabisulfite. Mix until all materials arc dissolved.
Add the alcohol containing premix to the main mixing vessel containing the poloxamer.
Mix until uniform. While stirring, add the water containing premix to the main vessel and
continue to mix until uniform. Subsequently, add desired flavor component and mix until
uniform.
The proportions of poloxamer: glycol: water in the preparation is 29.08 :46.31 : 24.61
The preparation has a viscosity (%)of 0.97 Pascal seconds and a triggered viscosity ratio
at a 50% dilution with water of 4.95.
Example XV: Composition for the Treatment of Cough
Add propylene glycol and poloxamer to a clean vessel (main mix). While stirring, heat
the mixture as appropriate to sufficiently melt the poloxamer. Once a uniform solution is
obtained remove from heat source and continue mixing. In a separate vessel (alcohol pre-mix)
add alcohol, dextromethorphan base and monoammonium glyzeriziinate and mix until uniform.
In another vessel (water pre-mix), add water, EDTA , sodium saccharin, acesulfame and sodium
metabisulfitc. Mix until all materials are dissolved.
Add the alcohol containing premix to the main mixing vessel containing the poloxamer.
Mix until uniform. While stirring, add the water containing premix to the main vessel and
continue to mix until uniform. Subsequently, add desired flavor component and mix until
uniform.
The proportions of poloxamer: glycol: water in the preparation is 40.27 : 46.31 : 13.42
The preparation has a viscosity (%)of 2.14 Pascal seconds and a triggered viscosity ratio
at a 50% dilution with water of 6.05.
Example XVI: Composition for the Treatment of Cough
Preparation:
Weigh the dextromethorphan into a clean vessel, add the ethanol and begin mixing. Add
propylene glycol and mix until uniform and clear. Add Pluraflo and mix. Add Glyerine and mix
until uniform.
Add propylene glycol and Pluraflo to a clean vessel (main mix). Stir, heat the mixture as
appropriate to sufficiently melt the poloxamer. Once a uniform solution is obtained remove from
heat source and continue mixing. In a separate vessel (alcohol pre-mix) add alcohol,
dextromethorphan base and monoammonium glyzeriziinate and mix until uniform. In another
vessel (water prc-mix), add water, EDTA , sodium saccharin, acesulfame and sodium
metabisulfite. Mix until all materials are dissolved.
Add the alcohol containing premix to the main mixing vessel containing the poloxamer.
Mix until uniform. While stirring, add the water containing premix to the main vessel and
continue to mix until uniform. Subsequently, add desired flavor component and mix until
uniform.
The proportions of poloxamer: glycol: water in the preparation is 29.08 :46.31 : 24.61
Preparation:
Add propylene glycol, Plurafio, glycerine and ethanol to a clean vessel. While stirring,
add* ofloxacin. Stir unit a clear solution is obtained. Subsequently, add perfume and mix until
uniform.
Preparation:
Add glycerine, ethanol and Pluraflo to a clean vessel. Add Timolol. Cover tightly and
stir until a clear solution is obtained.
Preparation:
Add propylene glycol and poloxamer to a clean vessel (main mix). While stirring, heat
the mixture as appropriate to sufficiently melt the poloxamer. Once a uniform solution is
obtained remove from heat source and continue mixing. In a separate vessel (alcohol pre-mix)
add alcohol, omeprazole base and monoammonium glyzeriziinate and mix until uniform. In
another vessel (water pre-mix), add water, EDTA , sodium saccharin, acesulfame and sodium
metabisulfite. Mix until all materials are dissolved.
Add the alcohol containing premix to the main mixing vessel containing the poloxamer.
Mix until uniform. While stirring, add the water containing premix to the main vessel and
continue to mix until uniform. Subsequently, add desired flavor component and mix until
uniform.
Preparation:
Add alcohoi, propylene glycol, and phenylpropanolaminc to a clean vessel and begin
mixing. Subsequently, add, Pluraflo and glycerol to the vessel. Mix until uniform. This liquid
may be filled into hard gelatin capsules which are then banded to prevent leakage, or it may be
used as the fill for a soft elastic gelatin capsule.
One capsule is made to contain 0.75 ml of the liquid, and taken 3 times daily provides
controlled release of the phenylpropanolamine active. After swallowing, the gelatin shell
dissolves in the gastrointestinal tract and the liquid fill immediately transforms in to a slow
dissolving gel which provides controlled release of the phenylpropanolamine.
Preparation:
Add propylene glycol, ethanol, glycerine and morphine sulfate into a clean vessel and
begin mixing. Subsequently, add poloxamer (Pluraflo) and mix until uniform.
The composition provides pain relief when 1 mL is injected intramuscularly.
m CLAIM:
1. A. pourable liquid vehicle comprising:
(a) from 26% to 97% by weight of a
polyoxyalkylene block copolymer
(b) from 10% to 70% by weight of a glycol; and
(c) from 1% to 46% by weight of water;
wherein said vehicle is used to deliver
compositions, materials, and substances to moistened
surfaces and aqueous environments, wherein said
vehicle has a viscosity value hc less than or equal
to 7 pascal-seconds and a value T greater than or
equal to 1.3.
2. The pourable liquid vehicle as claimed in claim 1,
wherein the polyoxyalkylene block copolymer
corresponding to the following structure:
CH3
|
HO -(CH2CH2O)x-(CH2CHO)x-(CH2CH2O)x- H
wherein x has a value from 1 to 130, y has a value
from 1 to 72, and x' has a value from 0 to 130, and
wherein the polyoxyalkylene block copolymer has an
average molecular weight of from 3000 to 15,000
wherein said vehicle has a viscosity value hc less
than or equal to 7 pascal-seconds and the value T
greater than or equal to 1.3.
3. The vehicle as claimed in claim 2, comprising from
27.8% to 95% of the pharmaceutically acceptable
polyoxyalkylene block copolymer wherein said vehicle
has a viscosity hc less than or equal to 2 pascal-
seconds and value T is greater than or equal to 2.
4. The composition as claimed in claim 2, comprising
from 30% to 90% of the pharmaceutically acceptable
polyoxyalkylene block copolymer wherein said vehicle
has a viscosity hc less than or equal to 2 pascal-
seconds and value T is greater than or equal to 5.
5. The composition as claimed in claim 1, comprising
from 10% to 70% glycol.
6. The composition as claimed in claim 5, wherein said
glycol is selected from the group consisting of
monosaccharides, disaccharides, ribose, glycerin,
sorbitol, xylitol, inositol, propylene glycol,
galactose, mannose, xylose, rthamnose,
glutaraldehyde invert sugars, ethanol, honey,
mannitol, polyethylene glycol, glycerol, and
mixtures thereof.
7. The composition as claimed in claim 1, comprising
from 1% to 46% water.
8. A pourable liquid vehicle comprising:
(a) from 26% to 100% polyoxyallcylene
block polymer;
(b) from 0 to 70% glycol; and
(c) from 0% to 50% water,
wherein said vehicle is used to deliver
pharmaceutically active agents to moistened surfaces
and aqueous environments wherein said vehicle has a
viscosity value hc less than or equal to 7 pascal-
seconds and the value T greater than or equal to
1.3.
9. The pourable liquid vehicle as claimed in claim 8,
wherein the polyoxyallcylene block copolyner
corresponding to the following structure:
CH3
|
HO - (CH2CH2O)x _ (CH2CHO)x — (CH2CH2O)x- H
wherein x has a value from 1 to 130, y has a value
from 1 to 72, and x' has a value from 0 to 130, and
wherein the polyoxyallcylene block copolymer has an
average molecular weight of from 3000 to 15,000
wherein said vehicle has a viscosity value hc less
than or equal to 7 pascal-seconds and the value t
greater than or equal to 1.3.
10. The vehicle as claimed in claim 9, comprising from
27.8% to 95% of the pharmaceutically acceptable
polyoxyalkylene block copolymer and vehicle has a
viscosity hc less than or equal to 2 pascal-seconds
and value T is greater than or equal to 2.
11. The vehicle as claimed in claim 10, comprising from
30% to 90% of the pharmaceutically acceptable
polyoxyalkylene block copolymer wherein said vehicle
has a viscosity hc less than or equal to 2 pascal-
seconds and value T is greater than or equal to 10.
12. The vehicle as claimed in claim 9, wherein x has a
value from 1 to 130, y has a value from 1 to 72 and
x' has a value from 0 to 130, in said
polyoxyalkylene block copolymer, and wherein the
average molecular weight of said copolymer is from
3000 to 15,000.
13. The vehicle as claimed in claim 8, comprising from
7% to 62% glycol.
14. The vehicle as claimed in claim 13 wherein said
glycol is selected from the group consisting of
monosaccharides, disaccharides, ribose, glycerin,
sorbitol, xylitol, inositol, propylene glycol,
galactose, mannose, xylose, rhamnose,
glutaraldehyde, invert sugars, ethanol, honey,
mannitol, polyethylene glycol, glycerol, and
mixtures thereof.
15. The vehicle as claimed in claim 8 comprising from 2
% to 41% water.
16. The vehicle as claimed in claim 8 comprising:
(a) from 26% to 65% polyoxyalkylene
block copolymer having a value x equal to
100, y equal to 70 and x' is equal to 100
and has an average molecular weight of
12,600;
(b) from 2% to 38% ethanol; and
(c) from 8% to 45% water.
17. The composition as claimed in claim 8 comprising:
(a) from 25% to 50% polyoxyalkylene
block copolymer having a value x equal to
37, y equal to 58 and x' is equal to 37 and
has a average molecular weight of 6500;
(b) from 45% to 65% propylene glycol; and
(c) from 5% to 20% water.
18. The composition as claimed in claim 8 comprising:
(a) from 52% to 60% polyoxyalkylene block
copolymer having a value x equal to
128, y equal to 58 and x' is equal to 128 and
has an average molecular weight of 14,600;
(b) from 25 to 25% ethanol; and
(c) from 17% to 27% water.
19. The composition as claimed in Claim 8 comprising:
(a) from 37% to 77% polyoxyalkylene
block copolymer having a x equal to 37, y
equal to 58 and x' is equal to 37 and has a
average molecular weight of 6500;
(b) from 2% to 28% ethanol; and
(c) from 10% to 45% water.
20. The composition as claimed in claim 8 comprising:
(a) from 26% to 49% polyoxyalkylene block
copolymer having a value x equal to
100, y equal to 70 and x' is equal to 100 and
has an average molecular weight of
12,600;
(b) from 2% to 12% ethanol; and
(c) from 30% to 68% propylene glycol; and
(d) from 7% to 40% water.
The present invention covers pourable liquid vehicles that can be combined
with compositions, materials and substances. Among the benefits of such
pourable liquid vehicles the compositions are retained on the moistened
surface for a period of time sufficient to allow compositions, materials and
substances to act on said surface, resisting erosion or run-off from additional
moisture being applied. Such pourable liquid vehicles have a number of
utilities including but not limited to cleaning and treating surfaces of objects
as well as biological or living organisms, Including living creatures.

Documents:

IN-PCT-2002-290-KOL-FORM-27.pdf

in-pct-2002-290-kol-granted-abstract.pdf

in-pct-2002-290-kol-granted-assignment.pdf

in-pct-2002-290-kol-granted-claims.pdf

in-pct-2002-290-kol-granted-correspondence.pdf

in-pct-2002-290-kol-granted-description (complete).pdf

in-pct-2002-290-kol-granted-examination report.pdf

in-pct-2002-290-kol-granted-form 1.pdf

in-pct-2002-290-kol-granted-form 18.pdf

in-pct-2002-290-kol-granted-form 2.pdf

in-pct-2002-290-kol-granted-form 3.pdf

in-pct-2002-290-kol-granted-form 5.pdf

in-pct-2002-290-kol-granted-gpa.pdf

in-pct-2002-290-kol-granted-reply to examination report.pdf

in-pct-2002-290-kol-granted-specification.pdf

in-pct-2002-290-kol-granted-translated copy of priority document.pdf

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Patent Number

225485

Indian Patent Application Number

IN/PCT/2002/290/KOL

PG Journal Number

46/2008

Publication Date

14-Nov-2008

Grant Date

12-Nov-2008

Date of Filing

27-Feb-2002

Name of Patentee

THE PROCTER AND GAMBLE COMPANY ,

Applicant Address

ONE PROCTOER & GAMBLE PLAZA, CINCINNATI, OH

Inventors:

#	Inventor's Name	Inventor's Address
1	HAYES, JERRY, WILLIAM,II	5836 BLUE SPRUCE LANE, CINCINNATI, OH 45224
2	LINDMAN, BJORN, OLOF	OSTRA VALLGATAN 19, S-223 61 LUND, SKANE IAN
3	IVANOVA, ROUJA, HRISTOVA	HELMHOLTZRING 2A 98693 ILMENAU
4	ALEXANDRIDIS, PASCHALIS	70 AUTUMN CREEK LANE, APT. K. EAST AMHERST, NY 14051-2914
5	DOBROZSI, DOUGLAS, JOSEPH	9273 KIMPERGROVE LANE, LOVELAND, OH 45140

PCT International Classification Number

A61K 47/10, 7/48

PCT International Application Number

PCT/US00/24732

PCT International Filing date

2000-09-11

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/153,260	1999-09-11	U.S.A.