CA2383570C - Pourable liquid vehicles - Google Patents

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.

Description

PCILTRABLE LIQUID VBHICL.ES

TECHNICAL FIELD
Conc.entrated levels of polyoxyalkylene block copolymers are usefnl in vehicles imcorporated into products that arc dcsigned to deliver compositions, matarials and substanees to moistened siafaaes and aqueous enviranment Acquiring moisture during use, the vehicle becomes sufficiently transformed from a tiqnid to a gel-h7ce form that provides the a benefit to the uscr. For eaample, mucosal surfaces of the body contain suff;cient water to allow the pourable liquid vehicle comprising conceabated polyoxyalkylene block copolymers to bc effectively delivered to the desired site whereia the accornpanying compositions, materials and substances tenaciously adhere to the moistcned surfaccs and resist dissolution or erosion by water or biological fluid. Such uses include, but are not limited to the delivery of parsonal 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, eliacirs, syrups, liquid-filled capsules, suspensions, coated tablets or capsules for administration by mouth; gels, rinses, dentifrices, lozenges, sprays, medicated lollipops, liquid fi11ed capsules for intra-oral administration;
gels, suspensions or solutions for intra-oaular 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 sldn and scalp; and liquid suspension or solutions for injection by sytinge, nasal gels, solutions, or-suspensions for application into the nose with special applications or spmycrs=

I

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 toe a ~isteied. For czample; on liquids, , or perliaps Iow viscosity 'gels, eati 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. In addition to the compatibility with pharinaceutical 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 conipositions, 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 that 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 that 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 that 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. Exampies of such compositions include intra-ocular dosage forms as disclosed in Edsman, K., Carlfors, J., Petersson, R., Rheolo[tical Evaluation of Poloxamer as an In Situ Gel for Ophthalmic Use, European Journal of Pharmaceutics Vol. 6 pp.105-112 (1998) 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 concautrated solutions, or with water and co-solvents, the poloxamer solution remains as a pourable liquid. The most conunonly reported example of this type of system consists of poloxanier 407 at concentrations ranging from about 10% to 35% by weight of the composition in water. These compositions arc adnrinistered 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 exantple Kim, C.K., Lee, S.W., Choi, H.G., Lee, M1C., Gao, Z.G., Kim, I.S., and Park, K.M.: Trials of In Situ Gellina and Mucoadhesive Acetaminotihen Liquid Suppositorv in Human Subiects. International Journal of Pharmaceutics vol. 174, pp. 201-207 (1998) . 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 Palmolive Company, describes similar conipositions 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 pharmaceutically active agents, these compositions are injected into the gingival space between the root of a tooth and the gtun-Poloxamers represent a large family of polymers that vary in molecular weight as well as in the percentage or portion of the block copolymer that is considered hydrophobic.
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 vehiclcs 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 Idnds of materials including but not limitsd to cleaning and treating surfaces of oTbjects as welras~iologieal or living organisms, ii-cluding living creatures.
Another aspect of this invention is to utilizc such pourable liquid vehicles to deliver health care compositions and materials and substances to living creatures, particularly mammals, and most particularly humans. Even another aspect of the present invention is to develop a method for effective delivery of health care compositions, materials and substances.
In accordance with an aspect of the present invention, there is provided a pourable liquid vehicle comprising:
(a) from 26% to 80% 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 rlf less than or equal to 7 pascal-seconds and a value T greater than or equal to about 1.3.
In accordance with an aspect of the present invention, there is provided a pourable liquid vehicle of the present invention, wherein the polyoxyalkylene block copolymer coiresponds to the following structure:

HO---(CH2CH2O)X -((2H2CHO)y - - (CHZCHZO)X -H

wherein x has a value from about I to about 130, y has a value from about 1 to about 72, and x' has a value from 0 to about 130, and wherein the polyoxyalkylene block copolymer has an average molecular weight of from about 3000 to about 15,000.
In accordance with an aspect of the present invention, there is provided a pourable liquid vehicle of the present invention, comprising:
(a) from 37% to 77% polyoxyalkylene block copolymer having values for x equal to 37, y equal to 58 and x' equal to 37; and an average molecular weight of 6500;
(b) from 2% to 28% ethanol; and (c) from 10% to 45 % water.
In accordance with an aspect of the present invention, there is provided a use of a composition at a moistened site on or in a mammal for delivery of the pharmacologically active agents to said mammal wherein the composition comprises the pourable liquid vehicle of any one of Claims 1 through 3;
wherein said vehicle has a viscosity rlf less than or equal to 7 pascal-seconds and the value of the triggered viscosity ratio, T, greater than or equal to about 1.3.

DETAILED DESCRIPTION OF THE INVENTION
Definitions Terms useful herein are defined below. Additionally, tcrms usod in the art, as well as general concepts, are fiuther described in Schranun, The Language of Coll2id and Interface Science, American Chemical Society, (1993). ' 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 hercin 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 time of the shear is termed the "shear rate".

4a 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 results. 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 150 by Haake GmbH, Karlsruhe, Germany;
Carrimed 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 about 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= rl8/ '11f where rIg = viscosity of the gel and where rlf= 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 Tiquid vehicle itself prior to mixing, or the-bo-dily 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 ('qf) is determined in a rheometer using a shear rate of 50 per second at 25 C. For the determination of rlf, 1 ml of the pourable liquid vehicle is placed onto the plate of a Haake RS 150 rheometer.
The temperature is controlled in the range of typical room temperature, about 25 C. A cover is used on the measuring system and a solvent-saturated atmosphere provided to prevent evaporation of water, ethanol, 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 rlf is read from the instrument at the 30 second time point.

For the determination of rlg, 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 rlf, except that the temperature is controlled at the normal body temperature of a human, 37 C.
An identical rheometer measurement program is used as for determination of rlf. The triggered viscosity factor for both the 25% and 50% dilution of the sample is calculated from rlf and qg 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 rlg , 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 wlzich yields a maximal value of T
vanes depending upon e exact pourable iqui ve ic e 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 pourable liquid vehicle comprising:
(a) from about 26% to about 100% polyoxyalkylene block eopolymer;
(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 suFfaces and aqueous environments said vehicle has a viscosity value tlr less than or equal to 7 pascal-seconds and the value T greater than or equal to about 1.3.
Polyoxyalkylene Block Conolymer Polyoxyalkylene block copolymer herein referred to as "poloxamers" are nonionic block copolymers of ethylene oxide and propylene oxide corresponding to the following structure:

HO-(CH2CH2O)X -(CHZCHO)y-- (CH2CH2O)X,-H
wherein x, y, and x' have a value wherein said vehicle has a viscosity value rlf less than or equal to 7 pascal-seconds and the value T greater than or equal to about 1.3.
Preferable polyoxyalkylene block copolymers useful in the present invention include wherein x has a value from about 1 to about 130, y has a value from about I 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 pourable liquid vehicle. In other words, providing the poloxamer 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 amanged in the format o one po yoxypropylene bloOc surrou6ded-Fy-2-'polyoxyeEliy).ene 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)/po]y(propyiene oxide)] block copolymer surfactants, Paschalis Alexandridis, Current Qpinions in Colloid and Interface Science. Vo12, pp. 478-489 (1997) ' 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.
Glvcols 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), fiuctose (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 about 1% to about 46%, most preferably from about 2% to about 41% of the pourable liquid vehicle.
Preferred Embodiments Preferred embodiments of the present invention utilizing the combination of poloxamers, polyols and water include the following:

l. 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, methylxanthines, antioxidants, steroids, bronchodilators, antivirals, biologics, analgesics, anesthetics, antiarthritics, antiasthmatics, urinary tract disinfectives, anticoagulants, anticonvulsants, antidepressants, antidiabetics, antineoplastics, 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 (3-lactum antibiotics, such as cefoxitin, n-formamidoyl thienamycin and other thienamycin derivatives, tetracyclines, chloramphenicol, 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 Diphenhydramine, Azelastine, Acrivastine, Levocarbastine, Mequitazine, Astemizole, Ebastine, Loratadine, Cetirizine, Terfenadine, Promethazine, Dimenhydrinate, Meclizine, Tripelennamine, Carbinoxamine, Cyproheptadine, Azatadine, Brompheniramine, Triprolidine, Cyclizine, Thonzylamine, Pheniramine, and mixtures thereof.
Antitussives, including, Hydrocodone, Noscapine, Benzonatate, Diphenhydramine, Chlophedianol, Clobutinol, Fominoben, Glaucine, Pholcodine, Zipeprol, Hydromorphone, Carbetapentane, Caramiphen, Levopropoxyphene, Codeine, Dextromethorphan, 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, Tolmetin, 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, Lodoxamide, Nedocromil, and mixtures thereof.
Leukotriene Anta og nists, including, Zileuton and others.
Methylxanthines, including, Caffeine, Theophylline, Enprofylline, Pentoxifylline, Aminophylline, Dyphylline, and mixtures thereof.
Antioxidants or radical inhibitors, including, Ascorbic acid, Tocopherol, Pycnogenol, and mixtures thereof.

Steroids, preferably intranasally administered steroids, including, Beclomethasone, Fluticasone, Budesonide, Mometasone, Triamcinolone, Dexamethasone, Flunisolide, Prednisone, Hydrocortisone and mixtures thereof Bronchodilators, preferably for inhalation, including, Albuterol, Epinephrine, Ephedrine, Metaproterenol, Terbutaline, Isoetharine, Terbutaline, Isoetharine, Pirbuterol, Bitolterol, Fenoterol, Rimeterol, Ipratroprium, and mixtures thereof.
Antivirals, including, Amantadine, Rimantadine, Enviroxime, Nonoxinols, Acyclovir, Alpha-Interferon, Beta-Interferon, and mixtures thereof.
Biologics, 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, indomethacin, 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.
Antipsychotics such as prochlorperazine, lithium carbonate, lithium citrate, thioridazine, molindone, fluphenazine, trfluoperazine, perphenazine, amitriptyline, triflupromazine, and mixtures thereof.
Antihypertensive 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.
Antiprotozoa s ss chlorarriphenicol; choroquine, frimetlioprim,~famethoxazole, and mixtures thereof.
For treatment of vaginal and urethral 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, sulfamethoxazole 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 Component % (w/w) Dextromethorphan Base 1.47 Vehicle' 98.18 Sodium Saccharin 0.3 Monoammonium Glycerizinate 0.05 Flavors and Colors Flavors and Colors 1. Vehicle contains (w/w%):
Pluronic F127 55.51% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 26.48%
Water 18.01%
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 Component % (w/w) Dextromethorphan Base 1.47 Chlorophenarimine Maleate 0.26 Vehicle' 97.92 Sodium Saccharin 0.3 Monoammonium Glyzeriziinate 0.05 Flavors and Colors As Desired 1. Vehicle contains (w/w%):
Pluronic F127 55.66% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 26.55%
Water 17.79%
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.
Example III: Demulcent composition for the treatment of sore throat.
Component % (w/w) Vehicle' 96.845 Menthol 1.00 Benzocaine 2.00 Eucalyptus Oil 0.005 Sodium Saccharin 0.10 Monoammonium Glyzeriziinate 0.05 Flavors and Colors As Desired 1. Vehicle contains (w/w%):
Pluronic F108 56.79% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 21.69%
Water 21.52%
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.

Example IV: Composition for the rectal delivery of acetaminophen.

Component % (w/w) Vehicle' 95.0 Acetaminophen 5.0 1. Vehicle contains (w/w%):
Pluronic P105 44.21% (BASF Specialty Chemicals, Mount Olive, N.J.) Propylene Glycol 52.63%
Water 3.16%
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.
Example V: Composition for the topical delivery of an analgesic.
Component % (w/w) Vehicle' 98.0 Ketoprofen 2.0 Perfumes As Desired 1. Vehicle contains (w/w%):
Pluronic F127 56.12% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 3 0.61 %
Water 13.27%
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.
Example VI: Composition for the topical delivery of an analgesic Component % (w/w) Vehicle' 95.0 Ibuprofen 5.0 Perfumes As Desired 1. Vehicle contains (w/w%):
Pluronic P105 63.16% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 18.95%
Water 17.89%
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.

Example VII: Composition for the delivery of an oral antimicrobial Component 7% (w/w) Vehicle' 98.57 Triclosan Monophosphate 0.28 Menthol 1.00 Sodium Saccharin 0.10 Monoammonium Glyzeriziinate 0.05 Flavors and Colors As Desired 1. Vehicle contains (w/w%):
Pluronic F108 55.80% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 21.30%
Water 22.90%
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.
Example VIII: Composition for the intranasal delivery of a decongestant Component % (w/w) Vehicle' 99.32 Oxymetazoline HCl 0.05 Tyloxapol 0.15 Dibasic Sodium Phosphate 0.04 Monobasic Potassium Phosphate 0.13 Benzalkonium Chloride 0.04 Chlorhexidine Gluconate 0.26 Disodium EDTA 0.01 1. Vehicle contains (w/w%):
Pluronic F127 40.27% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 26.18%
Water 33.55%
Preparation:
Add the dibasic sodium phosphate, monobasic potassium phosphate, disodium EDTA, benzalkonium chloride and oxymetazoline HCI 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.
Example X: Composition to vaginally deliver hormonal replacement therapy Component % (w/w) Vehicle' 99.99 Beta Estradiol 0.01 Perfumes As desired 1. Vehicle contains (w/w%):
Pluronic P105 45.00% (BASF Specialty Chemicals, Mount Olive, N.J.) Propylene glycol 48.00%
Water 7.00%
Preparation:
Add the beta estradiol and propylene glycol into a clean vessel. Subsequently add the poloxamer and water to the vessel. Mix until uniform.

Example XI: Composition for the rectal delivery of an antiemetic Component % (w/w) Vehicle' 99.75 Promethazine HCI 0.25 1. Vehicle contains 100.0% (w/w%) Pluronic L62 (BASF Specialty Chemicals, Mount Olive, N.J.) Preparation:
-- - Mill and screen the promethazine HCI to re uce particle size. Add t peooxamer and t e Promethazine HCl into a clean vessel. Mix until uniform.
Example XII: Composition for the rectal delivery of an antiemetic Component % (w/w) Vehicle' 98.75 Carbomer z 1.00 Promethazine HCI 0.25 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 HCl to reduce particle size. Sieve the carbomer and promethazine HCl and add to a clean vessel. Add the poloxamer. Mix until uniform.

Example XIII: Composition for the Treatment of Cough Component % (w/w) Dextromethorphan Base 2.20 Vehicle' 95.15 Sodium Metabisulfite 0.10 Disodium EDTA 0.10 Sodium Saccharin 0.40 Monoammonium Glyzeriziinate 0.15 Acesulfame 0.50 Flavor 1.40 1. Vehicle contains (w/w%):

Pluronic F127 33.56% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 10.51%
Water 13.42%
Propylene glycol 42.51 %

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, dextromethorphan base and monoanunonium 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.
The preparation has a viscosity (rlf)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 Component % (w/w) Dextromethorphan Base 2.20 Vehicle' 95.15 Sodium Metabisulfite 0.10 Disodium EDTA 0.10 Sodium Saccharin 0.40 Monoammonium Glyzeriziinate 0.15 Acesulfame 0.50 Flavor 1.40 1. Vehicle contains (w/w%):
Pluronic F127 29.08% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 10.51%
Water 24.61%
Propylene glycol 35.80%
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, 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 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 (,qf)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 Component % (w/w) Dextromethorphan Base 2.20 Vehicle' 95.15 Sodium Metabisulfite 0.10 Disodium EDTA 0.10 Sodium Saccharin 0.40 Monoammonium Glyzeriziinate 0.15 Acesulfame 0.50 Flavor 1.40 1. Vehicle contains (w/w%):
Pluronic F127 40.27% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 10.51%
Water 13.42%
Propylene glycol 35.80%
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, 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 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 (rlf)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 Component % (w/w) Dextromethorphan Base 2.20 Vehicle' 97.8 Flavors As desired 1. Vehicle contains (w/w%):
Pluraflo 1220 40.90% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 10.22%
Propylene Glycol 46.83%
Anhydrous glycerine 2.05 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 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.
The proportions of poloxamer : glycol : water in the preparation is 29.08 :
46.31 : 24.61 Example XVII : Composition for the Treatment of Otitis Component % (w/w) ofloxacin 0.30 Vehicle' 98.95 Perfume 0.75 1. Vehicle contains (w/w%):
Pluraflo 1220 45.48% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 5.05%
Propylene Glycol 41.23%
Anhydrous glycerine 8.24 Preparation:
Add propylene glycol, Pluraflo, 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.
Example XVIII : Composition for the Treatment of Glaucoma Component % (w/w) Timolol maleate 0.25 Vehicle' 99.75 1. Vehicle contains (w/w%):
Pluraflo 1220 92.73% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 2.11%
Anhydrous glycerine 5.16 Preparation:
Add glycerine, ethanol and Pluraflo to a clean vessel. Add Timolol. Cover tightly and stir until a clear solution is obtained.
Example XIX : Composition for the Treatment of Ulcers Component % (w/w) Omeprazole (Free Base) 2.00 Vehicle' 95.89 Sodium Metabisulfite 0.10 Disodium EDTA 0.10 Sodium Saccharin 0.25 Monoammonium Glyzeriziinate 0.11 Acesulfame 0.35 Flavor 1.20 1. Vehicle contains (w/w%):
Pluronic F127 34.07% (BASF Specialty Chemicals, Mount Olive, N.J.) Ethanol 10.43%
Water 13.32%
Propylene glycol 42.18%
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 monoanunonium 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.

Example XX: Composition for the Controlled Release of an Appetite Suppressant Component % (w/w) Phenylpropanolamine 3.3 Vehicle' 96.5 Sodium Metabisulfite 0.10 Disodium EDTA 0.10 1. Vehicle contains (w/w%):
Pluraflo 1220 70.12% (BASF Specialty Chemicals, Mount Olive, N.J.) Propylene glycol 11.27 Ethanol 2.26%
Anhydrous glycerine 16.35 Preparation:
Add alcohol, propylene glycol, and phenylpropanolamine 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 inunediately transforms in to a slow dissolving gel which provides controlled release of the phenylpropanolamine.

Example XXI: Composition for the injection of an Analgesic Per one I.OmL injection Component % (w/w) Morphine Sulfate 1.0 Vehicle' 99.0 1. Vehicle contains (w/w%):
Pluraflo 1220 52.63% (BASF Specialty Chemicals, Mount Olive, N.J.) Propylene glycol 35.79%
Ethanol 3.16%

Anhydrous glycerine 8.42%

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.

Claims (4)

WHAT IS CLAIMED IS:

1. A pourable liquid vehicle comprising:

(a) from 26% to 80% 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 .eta.f less than or equal to 7 pascal-seconds and a value T greater than or equal to about 1.3.

2. The pourable liquid vehicle according to Claim 1 wherein the polyoxyalkylene block copolymer corresponds to the following structure:

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 0 to about 130, and wherein the polyoxyalkylene block copolymer has an average molecular weight of from about 3000 to about 15,000.

3. The pourable liquid vehicle of Claim 2 comprising:
(a) from 37% to 77% polyoxyalkylene block copolymer having values for x equal to 37, y equal to 58 and x' equal to 37; and an average molecular weight of 6500;
(b) from 2% to 28% ethanol; and (c) from 10% to 45% water.

4. Use of a composition at a moistened site on or in a mammal for delivery of the pharmacologically active agents to said mammal wherein the composition comprises the pourable liquid vehicle of any one of Claims 1 to 3.