MXPA02000805A - Preserved pharmaceutical formulations - Google Patents

Abstract

The present invention is directed to the use of the benzethonium chloride, alone or in combination with phenoxyethanol or phenyl ethyl alcohol, to provide anti-microbial activity in pharmaceutical compositions. The present invention also provides methods of using benzethonium chloride, alone or in combination with phenoxyethanol or phenyl ethyl alcohol, to inhibit microbial growth in pharmaceutical compositions.

Description

PHARMACEUTICAL FORMULATIONS WITH CONSERVATIVE DESCRIPTION OF THE INVENTION The present invention relates generally to the use of preservatives in multi-dose formulations. More specifically, the present invention relates to the use of benzethonium chloride alone or in combination with phenoxyethanol or phenylethyl alcohol, in multi-dose pharmaceutical formulations, comprising a variety of pharmaceutically active drug ingredients.

II. BACKGROUND OF THE INVENTION Sterility is one of the most important characteristics of pharmaceutical compositions. The maintenance of the sterility of pharmaceutical compositions is a function of both the sterilization method and the integrity of the packaging or application system.

For products intended to be for multiple dosing, antimicrobial agents should be added to the product formulation to protect the product from accidental microbial contamination during storage or use or both. This is true with respect to the dosage form of the composition. Stable multi-dose pharmaceutical formulations, which contain a variety of active ingredients, are seen by the pharmaceutical industry as particularly advantageous and commercially attractive. These formulations are generally, but not always, packaged in a way that allows the extraction of quantities partial forms of formulation at various times. This type of system is desirable, since it allows obtaining multiple doses from a single container, and permits the more controlled administration of the pharmaceutical composition as the formulation can be withdrawn and used, applied or administered in any way. partial quantity, and over a prolonged period. The nature of the use of multi-dose formulations imposes special requirements in the formulation. For example, the maintenance of the sterilization of a composition is particularly challenging, given the many opportunities for the introduction of microorganisms and others with; am inantes in the formulations. Repeated insertion of foreign elements, eg, gills or swabs, into the multi-dose container after formulation also creates a likelihood < i to introduce microorganisms in the reci pient. Additionally and alternatively, microorganisms can be introduced during the storage of the recipients or during the reconstitution of the formulations after freeze-drying and before their use, application or administration. The extended periods over which the container can be stored - especially during multiple introductions of foreign elements, and / or after the contaminants may have been introduced, demand that the formulation contain special additives to ensure the sterility of the contents. . To ensure that these formulations maintain optimally sterile properties, the United States Food and Drug Administration (USFDA) and regulatory agencies in other jurisdictions, including Europe and Japan require that all multi-dose compositions contain preservatives to prevent the growth of, or to kill in the affirmative, any microorganism that may be introduced into them. However, the development of multi-dose formulations containing preservatives is • etchant, because several active ingredients in pharmaceutical compositions tend to adversely interact with conservative compounds. The possible adverse interactions between preservatives and pharmacologically active ingredients include the degradation of the active ingredients, especially those stored for prolonged periods; inactivation, neutralization or alteration of the active ingredients; formulation of aggregates comprising the active ingredients and other additives or constituents of the formulations; and other interactions that inactivate, degrade or make the administration of the formulation for humans, by a dosage route, difficult, painful or otherwise undesirable. Additionally, it is noted that conservatives by themselves cause acute adverse reactions, such as allergic reactions or even attacks, in humans upon administration. Ideally, a preservative contained in a multi-dose pharmaceutical formulation should be effective at low concentration with a wide variety of microorganisms; soluble in the formulation; not toxic; compatible and non-reactive with the active ingredient as well as other additives; active with long-term stability; and non-reactive with container components or closure system. Sandeep Nema et al. Published lists of several excipients that have been included in the formulation of injectable products marketed in the United States. The antimicrobial agents listed in this review article are included in Table 1: Table 1 Antimicrobial Preservatives Frequency Range Benzalkonium Chloride 0.02% w / v Benzethonium Chloride 0.01% Benzyl Alcohol 74 0.75-5% Chlorobutanol 17 0.25-0.5% m-cresol 0.1-0.3% Myristyl Chloride 0.0195-0.169% Gamma-picolmium Paraben methyl 50 0.05-0.18% Paraben propyl 40 0.01-0.1% Phenol 48 0.2-0.5% 2-phenoxyethanol 0.50% Phenyl mercuric nitrate 0.001% Thimerosal 46 0.003-0.1% Despite the range of conservative agetes available, finding a conservative or combination of preservatives, reliable, largely non-reactive, useful in pharmaceutical compositions, remains elusive. Accordingly, there remains a need for a preservative or combination of preservatives that is minimally reactive with active ingredients in pharmaceutical forms; be minimally reactive with other additives commonly used in multiple dose pharmaceutical formulations; maintain the stability of the active ingredient and composition over a prolonged shelf life of the product; satisfy the pharmacopoeia criteria for conservative challenge tests; be safe in the concentrations used; and is administrable - by any parenteral, topical, ocular, inhaled or oral route - in a manner that is effective, and minimizes pain and the possibility of adverse reaction, for example, allergic reaction in the patient. lll. BRIEF DESCRIPTION OF THE INVENTION The present invention provides novel and particularly advantageous multi-dose pharmaceutical formulations containing a variety of active pharmaceutical ingredients and preservative benzethonium chloride alone or in combination with either phenoxyethanol or phenylethyl alcohol. Multi-dose pharmaceutical formulations containing a wide range of active ingredients and benzethonium chloride, in combination with either phenoxyethanol or phenethyl alcohol are also provided. Virtually any pharmacologically active ingredient can be used. In all the modalities of this invention, those ingredients specifically contemplated as being useful in the present invention, include agents used to treat the cardiovascular and gastrointestinal systems, as well as liver. Additional agents contemplated to be within the scope of the present invention include topical, hematological, antihistamine, antimicrobial, antiepileptic and anti-seizure agents, as well as agents used as sedatives, hypnotics, diuretics, psychopharmacological agents, antimicrobial agents, hormones. , proteins or peptides or any other active ingredient. These active agents can be used alone or in combination and remain within the scope of the present invention. In particularly preferred embodiments, one or more active ingredients are included in a pharmaceutical composition containing benzethonium chloride in combination with phenoxyethanol, since these two preservatives exhibit a synergistic anti-microbial effect in addition to the 9s modality that com When the active agent is activated as indicated above, an alternative embodiment of the present invention provides a pharmaceutical carrier composition, comprising any of the pharmaceutically active ingredients listed above, as well as a quantity of benzethonium chloride, or any of the active ingredients, as well as benzethonium chloride in combination with either phenoxyethanol or phenylethyl alcohol. In another preferred embodiment, the present invention provides a pharmaceutical bottle or package for containing any pharmacologically active protein retained with an effective amount of benzethonium chloride alone, b an effective amount of benzethonium chloride, in combination with phenoxyethanol or phenylethyl alcohol. Still other preferred embodiments of the present invention are methods for inhibiting microbial growth in compositions including one or more pharmacologically active agents. These methods include adding to the active ingredient or combination of active ingredients, the preservative benzethonium chloride alone, or in combination with either phenoxyethanol or phenylethyl alcohol IV. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a significant improvement over the state of the art. Multi-dose pharmaceutical formulations containing a wide range of active ingredients are provided, as well as the benzethonium chloride preservative alone, or in combination with either phenoxyethanol or phenylethyl alcohol. The compositions described are stable, sterile and easily administered. Furthermore, and very unexpectedly, the present invention discloses that phenoxyethanol and benzethonium chloride, when used in combination in a multi-dose pharmaceutical composition, have positive synergistic effects, resulting in a particularly advantageous composition. Specifically, this combination of preservatives exhibits the following characteristics: (1) antimicrobial synergistic effect, allowing to use a lower concentration of preservatives; (2) excellent compatibility with the active ingredients in various pharmaceutical formulations, at varying storage conditions, over prolonged periods and over a wide range of pHs; and (3) phenoxyethanol has a potential for a local anesthetic effect, making the composition particularly preferable for subcutaneous administration. The preserved pharmaceutical compositions described in the present invention can be comprised of virtually any dosage form, and can be admired via virtually any route of administration. Exemplary useful dosage forms include, but are not limited to, a liquid, suspension, emulsion, solution, mixture, cream, ointment, gel, oil, suppository, semi-solid, aerosol, powder, tablet or capsule. Exemplary administration routes of the preserved pharmaceutical compositions described herein, include parenteral, mucosal, ocular, auditory, oral, typical, suppository or inhalation. As used herein, the following terms have the following meanings: Pharmaceutically acceptable (or pharmacologically acceptable) - refers to molecular entities and compositions that do not produce an adverse, allergic, or otherwise unfavorable reaction when administered to an animal or a human, as appropriate. Pharmaceutically acceptable carrier - includes any and all solvents, dispersion media, coatings, antibacterial, isotonic and absorption refractors, buffers, excipients, flavorings, binders, lubricants, gels, surfactants and the like, which may be used as a means of a pharmaceutically acceptable substance Unit - a unit of biological activity as determined by xyphoxic polyemic mouse bioassay and compared to the standards of the World Health Organization, Any numerical value stated herein includes all values from the lowest value up to the highest value in increments of a unit, provided that there is a separation of at least two units between any lower value and any higher value. As an example, if it is stated that the concentration of a component or value of a process variable, such as, for example, osmolality, temperature, pressure, time and the like, is, for example, from 1 to 90, preferably from 20 up to 80, more preferably from 30 to 70, pretend that values such as 15 to 85, 22 to 68, 43 to 51, 30 to 32, etc., are explicitly listed in this specification. For values which are less than unq, a unit is considered to be 0.0001, 0.001, 0.01 or 0.1, as appropriate. There are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value listed to be considered for expressly stating in this application in a similar manner.

A. Preservatives: Phenoxyethanol and benzethonium chloride The contemplated preservatives for use in accordance with the present invention are benzethonium chlorure, phenoxyethanol and phenylethyl alcohol, any variant of these preservatives and their structural analogues. It is contemplated specifically that any of these The preservatives can be used as the sole preservative in the presently described formulations, or they can advantageously be used in combination with one another. As shown herein, the formulations of the present invention that use a combination of phenoxyethanol and benzene chloride D? They try to have synergistic effects and therefore are particularly preferable. The benzethonium chloride, phenoxyethanol and phenylethyl alcohol can be used in the presently described formulations in any effective amount. The total conservative concentration is preferably between about 0.001% to about 4.0% of the total formulation. The particularly advantageous concentrations of the total preservative are those kept as low as possible to achieve the required antimicrobial effect, while the potency of adverse reactions is maximized. In preferred embodiments of the present invention, both benzethonium chloride and phenoxyethanol are used together. Surprisingly, when using these juices, these preservatives have a synergistic effect with each other. To achieve the equivalent antimicrobial effect, when used alone, the concentrations of benzethonium chloride or phenoxyethanol should be each greater than the concentration of natural preservative if they are used in combination and, in general, at least twice the conservative should be used if used alone. Thus, for example, if either benzethonium chloride or phenoxyethanol alone is used, approximately twice as much benzethonium chloride or phenoxyethanol will be required to achieve the same effect as an amount of benzethonium chloride in combination with phenoxyethanol. Additionally, even at this higher concentrations of benzethonium chloride and phenoxyethanol, the individual formulations may not meet the US, European or Japanese anti-microbial criteria. Preferred combination formulations include benzethonium chloride in concentrations from about 0.001 to about 0.1% in combination with phenoxyethanol, in concentrations from about 0.01 to about 1.0%. The most preferred combined formulations contain benzethonium chloride in a concentration from about 0.01% to about 0.02% and phenoxyethanol in a concentration from about 0.25% to about 0.5%. In another embodiment, the present invention includes benzethonium chloride in combination cor} phenylethyl alcohol. Preferred formulations include benzethonium chloride in concentrations from about 0.001 to about 0.1% together with phenylethyl alcohol, in concentrations from about 0.01 to about 1.0%. More preferred formulations contain benzethonium chloride in a concentration from about 0.15 to about 0.25% and phenylethyl alcohol in a concentration from about 0.2 to about 0.5%. A more preferred formulation in which benzene chloride and phenylethyl alcohol are used together, contains benzethonium chloride in a concentration of about 0.02% and phenolic alcohol in a concentration of about 0.25%.

B. Active ingredients Pharmaceutical formulations comprising preservatives as described herein, can be formulated using virtually any active ingredient. In particular, benzethonium chloride and phenoxyethanol have synergistic effects and are useful in multi-dose drug formulations comprising the following classes of active ingredients: cardiovascular; chemotherapeutic, gastrointestinal and liver; typical hematologic; antihistamine; antimicrobial; anti-epileptic or anti-attack agents; sedatives and hypnotics; diuretics; iñas; ophthalmic; hormones; proteins or peptides and others as necessary. The skilled practitioner will recognize which individual agents are useful in multi-dose formulations and can combine those agents with the appropriate amounts of benzethonium chloride, phenoxyethanol and / or phenylethyl alcohol as necessary, according to the individual needs of the formulator or demands of the manufacturer. formulation by itself. It should be readily apparent that agents listed in a group or class may be useful in other abdications, and that such alternative uses still fall within the scope of the present application. In other words, the classification of agents in this description is not intended to be limiting. It is likewise contemplated that the use of any active ingredient in combination with any other active ingredient, according to the presently described compositions and methods, is within the scope of the present invention.

Cardiovascular Agents Virtually any entity that affects the heart or blood vessels, directly or indirectly, can be used as a cardiovascular agent and as an active agent in com positions and methods that employ benzethonium chloride. alone or in combination with phenoxyethanol or phenolic alcohol described herein. The specific classes of cardiovascular agents useful in accordance with the present invention include the following; sim patomiméticos; blocking drugs adrenergic; m ß-adrenergic blockers; anti-uscarinic agents blocking agents gang lions icos or other drugs that compete with acetylcholine at postsynaptic nicotinic receptors; digi: ales and their related medications, such as coronary and peripheral dilators and anti-dysrhythmic agents; and ACE inhibitors. Agents that affect parenteral fl uids and diuretics can also be used as cardiovascular agents. Agents that affect parenteral and diruretic fluids can also be used as cariovascular agents, and are discussed in a separate section herein. Additional agents used in cardi-vascular applications which can be used according to the present invention include antihypertensive and hypotensive agents Anti-adrenergic agents, saluretics and direct inti-hypotensive vasodilators are all antihypertensive or functional hypotensive classes of drugs. The peripheral vasodilators are substances, which dilate the arterioles and increase the blood flow in the numerous beds systemic vascular, especially the extremities. Thus, glanglial blocking drugs, or those acting as a reflex, acting centrally, which reduce the sympathetic tone to the periphery are peripheral vasodilators that can be used in the formulations described herein. In addition, sympathomimetics with stimulating actions of prominent ß2 receptors are used for their peripheral vasodilatory effects; while adrenergic blocking agents are used as peripheral vasodilators to improve flow through specific vascular beds. Such agents are used in the treatment of vasospastic disorders, such as Raynauds disease, causalgia and reflex dystrophy, vasospasm associated with arterial hypertension and thrombophlebitis, immersion foot, trench foot, shingles, decubitus ulcers and degenerative diseases. arterioles, such as thromboanginitis, obliterans, obliterans of arjterosclerosis, acrocyanosis and diabetic gangrene. It is contemplated of specific engineering that any agent useful as a perifonee vasodilator is useful in the compositions and methods currently described. Other cardiovascular agents useful in accordance with the present invention are also inagonal angiogenesis, such as organo nitrates and calcium channel blocking agents; antiplatelet agents, such as aspirin and sulfinpy-zone; vasopressor agents, such as those having vasoconstrictor or cardiotimulant activity that can be used to raise blood pressure under appropriate conditions, such as, for example, dopamine; cardiac glycosides, or other agents that act as direct cardiotonic agents in the myocardium to increase the force of contraction, including digoxin, digoxin, digoxin, dystopian, digitoxin, digoxin and fab immune; phosphodiesterase inhibitors, also known as inodilators, including amrinone, flosequin and milrinone lactate; and anti-dysrhythmic agents, such as β-adrenergic blocking drugs, cholinergic agents, anticholinesterase and β-agonist 3, including adenosine, amiodarone hydrochloride, bretylium tosylate, disopyramide phosphate, fecainide acetate, mexiletine hydrochloride, moricizine hydrochloride, procainamide hydrochloride, lidocaine hydrochloride, propafenone hydrochloride, quinidine gluconate, quinidine polygalacturonate, quinidine sulfate and tocanide hydrochloride. Additional cardiovascular agents that can be employed in the compositions and methods generally described include calcium channel blockers (CCBs), and other agents, known as calcium entry blockers, calcium channel blockers, and slow channel blockers, such as verapomil. , diltiazem, amlodipone, bepridyl hydrochloride, f = lodipine, isradipine, nicardipine hydrochloride, nifedipine and nimodipine (these agents have been found to effectively treat disorders of the central nervous system, such as stroke and migraine); Agen is affecting blood lipids (cardiovascular agents due to reaction of blood lipids with atherosclerosis), including aminosalicylic acid, cholestyramine resin, clofibrate, colestil hydrochloride, gemfibrozil, lovastatin, pravastatin sodium, probucol, simvastatin, d Sxtrotyrosine sodium, fish oils and Omega-3 fatty acids; and special-use cardiovascular medications, such as alprostadil. Any of the agents listed above, or their equivalents or the like, can be advantageously used in the compositions and methods currently described, used either alone or in combination with each other or any other active agent depending on the needs of the user. Formulator or intended application. 2. Gastrointestinal and Liver Agents Agents useful for treating gastrointestinal or liver disorders can be incorporated into pharmaceutical formulations comprising benzethonium chloride, alone or in combination with phenoxyethanol or phenylethyl alcohol, as described herein. The main categories of agents used in gastrointestinal or liver applications are antacids; H2 receptor antagonists; H + / K + ATPase inhibitors; medicines that intensify mucosal resistance; digestive, including pancreatic enzymes; laxatives, to ntidiarreics; emetics, antiemetics; prokinetic agent; and adsorbantes. Additional agents used in the treatment of gastrointestinal or liver disorders include immunosuppressive drugs, anti-inflammatory drugs, immunostimulants and antibiotics. Any of these various categories of agents can be used according to the com positions and methods described herein. Specific antacids that can be used include sodium bicarbonate, calcium carbonate, alumiumium hydroxide, hydroxyl magnesium; magnesium oxide magaldrate, magnesium trisylícate and aluminum compounds, such as aluminum carbonate gel or aluminum hydroxide gel. Antacids are commonly used in combination, and it is specifically contemplated that any combination of antacids or any other gastrointestinal or liver agent mentioned may be used in the pharmaceutical compositions and methods of the present disclosure. As stated, other agents used for the treatment of gastrointestinal or liver conditions include H2 receptor antagonists, which are generally histamine analogs, such as burimamide, cimetidine famotidine, nizatidine and ranitidine; H + / K ATPase inhibitors such as substituted benzimidazoles and omeprazole; agents that enhance mucosal protection including misoprostil, sucralfate; and digestive, such as choleretics (bile, bile acids and bile salts), hydrochloric acid, pancreatic enzymes, such as mixtures of lipase, amylasi and protease and ursodiol. Additional gastrointestinal and liver agents used in the treatment of gastrointestinal conditions include laxatives, such as volume-forming laxatives, such as those consisting of polysaccharides and cellulose derivatives that are non-digestible; emollient laxatives, such as sodium ducosate, or other surfactants which facilitate mixing of water and subsides. Lipid soluble ranks to soften feces, or stimulate the secretion of water in the gastrointestinal tract; lubricating laxatives, such as mineral oil, which allow an easier passage of stools due to an oily coating, or which inhibit colonic water reabsorption; saline laxatives, such as magnesium citrate and sodium phosphate, which exert an osmotic effect that increases the water content in stool volume; stimulant laxatives, such as bisacodyl, phenolphthalin and cinna, which work through various mechanisms that include inhibition of absorption, intensification of secretion and movement effects; and hyperosmotic laxatives, such as líictulose, which exert an osmotic effect and may have some effect on intestinal mobility. Other exemplary laxatives that may be used in accordance with the present disclosure include aloe, castor oil, magnesium sulfate, and sodium phosphate. Still other exemplary gastrointestinal or liver agents which may be incorporated in the present inventions include: emetics, such as apromorphine, morphine, rye ergot alkaloids, hydrogenated rye alkaloids, ig licis glycosides, copper sulfate, mustard, sodium chloride, zinc sulfate and veratro; and antiemetics of the following six groups: antipsychotics; such as phenothiazines, butyrophenones or other agents that act in the chemo-receptor trigger zone to block the energetic dopam receptors excited by apromorphine; unique antihistam, which gives the ivio to nausea of movement; anticholinergics, often in combination with D-amphetamine and scopolamine effective against movement nausea; cannabinoids, especially useful in the emesis of cancer therapy; antagonists of 5-HT3-receptors, such as ondansetron, blocking both 5-HT3-peripheral and central receptors and especially effective with: the emetogenic effects of chemotherapy; and other agents, such as trimethobenzamide, emetoclopramide, which block the dopamine receptors in the chemo-receptor trigger zone; diphenidol and scopolamine. Adsorbants are chemically inert pores that have the capacity to absorb gases, toxins and bacteria. Exemplary adsorbants which can be used as the active ingredient in the pharmaceutical formulations described herein and methods for their use, include activated carbon, kaolin, pectin, bismuth subcarbonate, bismuth subnitrate, magnesium trisilicate. Hepatic immunostimulants are also frequently used to treat chronic liver diseases, such as hepatitis B and hepatitis C. These drugs include interferon-a-2B, which is generally a recombinant drug. Again, all these agents are useful in the present compositions and methods. Many other medicaments with diverse actions in the gastrointestinal tract, but which fit purely in the above categories can also be used to treat gastrointestinal disorders and can be employed in pharmaceutical formulations as described herein. These other medications may include anise oil, methyl bromide of anosotropin, bismuth subcarbonate, camphor, camphor alcohol, caraway, caraway oil, cardamom oil, cardamom seed, tincture or cardamom compound, quinodiol, chlorabutanol, chloroform, lactase , lactulose and simethicone.

Topical medications Chemical agents can be applied to the skin and mucous membranes for effects located within the skin or membrane or for systemic effects. Such ages can also be referred to as topically active agents, and can be used in preserved pharmaceutical formulations, the preservative comprising benzethonium chloride alone, or in combination with either phenoxyethanol or phenylethyl alcohol. Topical agents can be protective, adsorbent, demulcent, emulsifying or cleaning agents. They can also be relatively inert and can have a particular value as vehicles and excipients. Additional useful topical agents include astringents, irritants, rubefacients, vesicants, hardening agents, caustics, escharotics, many keratolytic agents (de-scalers) and a variety of other dermatological agents including hypopigmenting and antipruritic agents. The protectors are any agent that isolate exposed surfaces of the skin or other membranes of harmful or annoying stimuli.

Related agents, adsorbent and demulcent, mainly have a dermatological function. Exemplary protectants and adsorbents which may be used in the present invention include the following: fine powders, such as starch or other carbohydrate powders, including those containing an anti-septic; fine absorbable polvos, such as biosorb and ezon; powders containing agents that promote debridement of wounds, such as those containing beads of dextranomers; bentonite; bismuth boric acid; calcium carbonate; cellulose; cornstarch; magnesium stearate; talcum powder; titanium dioxide; zinc oxide; zinc stearate; aluminum hydroxide; dimethicone; petrolatum gauze; gelatins; I anolina and related compounds, such as kaolin, mineral oils, olive oil or peanut; petrolatum; silicones; and zinc carbonate. The demulcents are protective agents that are used primarily to alleviate irritation, in particular of mucous membranes or scoriated tissues. Demonstrating examples which can be used in the pharmaceutical formulations described include acacia, agar, benzoin, carbomer, gelatin, glycerin, glycerin suppositories, glycyrrhiza, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Additional demonstrators include several ophthalmic solutions, such as those comprising hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol 3l, propylene glycol, sodium alginate or tragacanth. The emollients are fat or oleaginous, soft substances, which can be applied locally, in particular to the skin, but also to other membranes. Exemplary receptive emollients for use in the compositions and methods described herein include lanolin, both hydroxylated and acetylated forms; myristate and isopropyl palmitate; oleyl alcorol; sodium lauryl sulfate; various animal fats and oils, such as spermaceti, mineral oils, paraffin and petrolatum; petrolatum ro; vegetable oils, including castor oil, cocoa butter, coconut oil, corn oil, cottonseed oil, olive oil, peanut oil, persian oil and oil sesame; waxes, such as cetyl ester waxes, skin cream, hydrophilic ointment; ointment of rose water, spermaceti and white or yellow wax; and other emollient derivatives including glycerin, petrolatum, isopropyl myristate and myristyl alcohol. The oil extracted from shark livers, (ie, shark liver oil), can also be useful as an emollient. The astringents include locally applied protein precipitants, which have such low cellular penetration capacity, that the action is essentially limited to the cell surface and the interstitial spaces. Astringents are used therapeutically to stop bleeding by coagulating the blood and stopping diarrhea, reducing inflammation of mucous membranes, promoting healing, hardening the skin or decreasing sweating. The astringents can be formulated and used manly according to the compositions and methods described. The main astringents include salts of the aluminum, zinc, manganese or bismuth cations; other salts containing these metals (such as, promanganates); and tannins or related polyphenolic compounds. Acids, alcohols, phenols and other substances that precipitate prateins can be astringent in the appropriate amount or concentration. Antitransplants and deodorants can be applied as sprays, atomization pads, rods and rotating ball liquids, creams and semisolids for excessive perspiration and body odor control. Antiperspirants are designed to decrease the flow and / or inhibit the bacterial degradation of skin secretions. The agents Most commonly used as antiperspirants include aluminum chlorohydrates, aluminum chloride, buffered aluminum sulfate and zirconyl chlorohydrates. Exemplary antiperspirants include those aluminum chlorohydrates available in anhydrous or salt formulations that differ in the ratio of aluminum to chlorine, as well as in complexes with polyethylene glycol or polypropylene glycol. The buffered aluminum sulphate (8% aluminum sulfate buffered with 8% aluminum sodium lactate) can also be used. Additional antiperspirants include glutaraldehyde, formaldehyde, methenamine and scopolamine hydrobromide. Other topical agents that can be advantageously used according to the disclosed compositions include irritants; rubefacient (agents that induce only hyperemia); vesicants; caustic or corrosive and escharotic; keratolytics (de-sizing agents); and cleansing preparations, such as soaps, shampoos or detergents, may also be used in accordance with the present invention. 4. Hematological agents Hematological agents are any agent that affects the balance of blood, body fluids and electrolytes. These can also be used as the active ingredient in pharmaceutical formulations containing benz-etonium chloride, alone or in combination with phenoxyethanol. Exemplary hematological agents include plasma extenders, such as dextran 40, dextran 70 and dextran 75; antibodies and isoagglutinins, include group and blood type sera, such as sera from a? ti-A, anti-B and anti-Rh blood groups, immunoglobulins and immune sera; blood aggregating proteins, such as antihemophilic factor, cryoprecipitate antiyl ophthalmic factor, antithrombin III, anti-inhibitor coagulant complex, and factor IX complex. Additional exemplary hematological agents include anticoagulants or other agents, which delay blood clotting, including those that fall into three general types of anticoagulants: calcium sequestrants, heparin and heparin substitutes, and prothrombopic anticoagulants (oral aticoagulants). Exemplary anticoagulants including ditumarol, anisundon, sodium warfarin, various solutions of citrate dextrose or sodium citrate solutions, calcium heparin, low molecular weight heparin, sodium heparin, dihydroergotamine mesylate, potassium oxalate, sodium citrate and sodium oxylate. Exemplary thrombolytic agents include streptokinase, urokinase, streptokinase-anisoylated plasminogen activator complex (APSAC), prourokinase (Pro-UK), tissue plasminogen activator (TPA), recombinant forms thereof, anistreplase and alteplase (recombinant). Exemplary antiplatelet agents include aspirin, ticlopidine hydrochloride, dipyridamole, calcium channel blockers, β-adrenergics and anagrelide. All of these agents can be employed in accordance with the formulations and methods described herein. Anticoagulant antagonists can also be used as hematological agents in the compositions and methods described. Exemplary anticoagulant antagonists include vitamin K or its synthetic substitutes, menadol sodium diphosphate, menadione, menadine sodium bisulfite, phytonadione, sulfate and protamine. Inhibitors of fibrinosis, such as aminocaproic acid, tranexamic acid; haemostatic and styptic, such as alum, cellulose, collagen, absorbable gelatin powder or gleatin sponge, and thrombin; electrolytes and systemic buffers, such as ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, calcium glycerophosphate, calcium lactate, calcium levulinate, calcium phosphate dibasic, tribasic calcium phosphate, injection of magnesium sulphate io, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, potassium phosphate, mono- and di-potassium phosphates, potassium and sodium phosphates, acetate of sodium, sodium bicarbonate, sodium chloride, sodium citrate and citric acid solution, lactate d 3 sodium injection, monobasic sodium phosphate and tromethamine; and cation complexing agents, such as cellulose sodium phosphate, deferoxamine mesylate, dimercaprol, disodium calcium edetate, penicillamine, sodium polystyrene sulfonate, succimer, trientine hydrochloride may also be used. Finally, additional hematological agents, such as hematopoietics and other agents that affect blood production, are useful according to the present invention. Hematopoietics are antianemic that help in the production of red and white blood cells.

The hematinics are antianemic that increase the hemoglobin content of the blood through erythropoiesis or through an increase in the hemoglobin content of erythrocytes. The Useful haematopoietics include: iron and iron compounds, such as ascorbic acid, ferrous fumarate, ferrous gluconate, ferrous sulfate, iron dextrose injection and polypherose; hematopoietic growth factors, such as, epoetin-a, filgrastim, sargramostin, and other agents that regulate the proliferation and differentiation of progenitor base cells found in the bone marrow; antihematopoietic agents, such as hemin, methylene blue, pentoxifylline, sodium nitrate and other agents that facilitate the handling of an increase in the number of circulating erythrocytes.

Antihistamines Antihistamines, of a variety of classes, are useful as the active agent in pharmaceutical formulations containing benzethonium chloride alone, or in combination with either phenoxyethanol or phenylethyl alcohol. Exemplary specific classes of antihistamines that are useful in the disclosed compositions and methods include ethanolamines, ethylenediamines, alkylamines, phenothiavines and thiperidines. Antihistamines are generally sedative and exhibit an anticholinergic activity. Antihistamines particularly useful in the present invention include those which are Hi-receptor antagonists and act by competitively antagonizing the effects of histamine at the receptor sites. They generally do not block the release of histamine and, hence, offer only palliative relief of allergic symptoms. Exemplary antihistamines useful in accordance with the present invention include: astemizole, brompheniramine maleate, carboxamine maleate, chlorpheniramine maleate, clemastine fumarate, cirpoheptadine hydrochloride, cyclizine, dexbromfeniramine maleate, dexchlorpheniramine maleate, diphenhydramine hydrochloride, dimenhydrinate, diphenylpyraline hydrochloride, doxylamine succinate, hydroxyzine hydrochloride, meclizine, methylazine, methylazine hydrochloride, tartrate fenindamine, promethazine hydrochloride, pyrilamine maleate, terfenadine, fexofenadine, teofin, trimeprazine tartrate, tripelenamine citrate, trefalinamine hydrochloride and triproladine hydrochloride. It is also contemplated that; histamine release inhibitors, such as sodium cromalin, are useful; serotonin antagonists, such as azatadine maleate and cirpohetadine hydrochloride. Any of the above classes of compounds, as well as those individually listed, may be used sohs or in combination in pharmaceutical formulations containing one or more of the preservatives of benzethonium chloride, phenoxyethanol or phenylethyl alcohol. 6. Antibiotics A wide range of antibacterial agents can be used as the active ingredient in the pharmaceutical formulations and methods described herein. Systemic antibacterial agents that can be used in the pharmaceutical formulations described herein preserved with benzethonium chloride alone, or in combination with either phenoxyethanol or phenylethyl alcohol, include sulfonamides, such as sulfabenzamide, sulfadiazine and sulfamethazine; antibiotics, such as penicillin, or other ß-lactam antibiotics, such as amoxicillin, ampicilin, disodium carbenylcyanate; cephalosporins, such as cefadroxil, cefaclor and cefixime; carbapenems and monobactams, such as aztreonam and imipenem; ß-lactamase inhibitors, such as sodium sulbactam; amoglycosides, such as gentamicin sulfate, kanamycin sulfate, neomycin sulfate and tobramycin; macrolides, such as azithromycin, erythromycin and spiramycin; polypeptides, such as bacitracin, its capreomine and vancomycin lysine; tetracyclines, such as doxycycline and tetracycline hydrochloride; and fluoroq or inolones, such as norfloxacir a hydrochloride and ciprofloxacin. Additionally, various other antibiotics are also useful in accordance with the present disclosure. Various exemplary antibiotics that may be used include amphotericin-B, cycloserine, and vancomycin hydrochloride. Additionally, various other anti-ilarial, antiprotozoal and antifungal and antiviral agents, such as interferons, metyasazone and other antiviral substances, are useful in the compositions and methods described.

Antiepileptic and anti-seizure agents The agents used for the treatment of seizure disorders can be used as the active agent in pharmaceutical formulations containing benzethonium chloride alone or in combination with phenoxyethanol or phenylethyl alcohol. Exemplary nti-attack agents that can be used in this manner include: nytoin, carbamazepine, acetazolamide, chloropromazine hydrochloride, clonazepam, diazepam, dilantin, dimehydrinate, diphenhydramine hydrochloride, ephedrine sulfate, divalproex sodium, ethosuxim, ethotoin BP, felbamate, sulfate magnesium, mephenytoin, mephobarbital, parametadione, sodium phenobarbital, sodium phenytoin, prinidone, sodium bromide, trimethadione, substituted dibenzoxazepines and sodium valproate. In addition to these exemplarily listed anti-seizure drugs, any other agent used as an anti-seizure, antiepileptic or anticonvulsant agent is specifically contemplated as being useful in accordance with the pharmaceutical formulations described herein. 8. Sedatives and hypnotics Agents that have the effect of a sedative or the effect of inducing relaxation and rest, but not necessarily sleep, in addition to any hypnotic agent, the induce sleep, can be used as the active agent in the pharmaceutical formulations and methods described in the present. In general, agents of these types have the ability to induce a non-selective, reversible depression of the central nervous system.

The sedatives and hypnotics can be divided into three groups: benzodiazepines, barbiturates and other sedative and hypnotic agents. Either of these: groups may be useful in the formulations described. Specific examples of these types of agents include buclizine, diphenhydraphine, benzodiazepine, methotrimeprazine, scopolamine, diazepam, furazepam, lorazepam, pentobarbital, meprobamate, phenobarbital, c-hydrochloride, chlormezanone and methyprilon. Alternative and additional exemplary sedative and hypnotic agents include, in general, inorganic salts, such as bromides; chlorine derivatives, such as chlorohydrates; acetylenic alcohols, such as etichlorvinol; cyclic ethers, ta is like peraldehyde; esters of carbamic acid of alcohols; carbamic acid esters of glycols; diureides, such as barbiturates; piperidinedione derivatives, such as glutethimide; disinstituted quinazolones, such as methaqualone; and various aromatic tertiary alkylamines, such as antihistamines and parasympatholytics.

Diuretics Diuretics are agents that reduce the volume of extracellular fluid, intensify the urinary excretion of sodium chloride and, secondly, increase the volume of urine excreted by the kidneys. Virtually any substance having these effects can be classified as a diuretic and may be useful as the active agent in the pharmaceutical formulations and methods described herein. Most diuretic agents block the reabsorption of sodium and / or chloride in the renal tubules. Widely, diuretics can be separated into the following groups: osmotic, anhydrase and carbonic inhibitors, thiazides, sparse potassium diuretics, such as spironolactone. , triamterene and amiloride, high ceiling or curly diuretics. Exemplary osmotic diuretics include glycerin, mannitol, isosorbide and urea. Exemplary renal tubule inhibitor diuretics include carbonic anhydrase inhibitors, such as acetazolamide, sodium steroacetazolamide, dichlorphenamide, methazolamide, mersalil with theophylline. Diuretics that inhibit exemplary useful renal tubules Additional agents include benzothiadiazine and related iriethics, such as bendroflumethiazide, benzthiazide, chlorothiazide, chlorothalidone, cyclothiazide, flumetiazide, hydrochlorothiazide, indapam ida, metolazone, polyatazine and quinhetazone, amnofin, caffeine, theobromine and probenecid. Potentially poor potassium diuretics may include spironolactone, triamterene, amoryoride, amyloid hydrochloride. Di eretic curl detergents include ethacrynic acid, furosemide and bumetanide. Additionally, as with all groups of agents, any combination of the diuretics listed above can also be used as active agents in the described pharmaceutical formulations and are specifically contemplated as being within their scope. 1 0. Psychopharmacological agents Psychopharmacological agents, referred to alternatively as psychoactive or psychotropic agents, are widely used in the treatment of behavioral disorders and mental disorders, such as anxiety, illusion, hallucinations, paranoid states, catatonia, social separation and autonomic nervous system dysfunctions. Psychopharmacological agents can be divided into the following groups: antipsychotics, anti-anxiety agents, antidepressants, psychogenic agents. Agents in all of these groups may be useful in the pharmaceutical formulations described and methods described herein. Exemplary useful antipsychotic agents include antipsychotic agents classified in any of the following six groups: phenothiazines, such as ck rpromazine; thioxanthenes, such as chlorprothixene and thiothixene; butyrate nonas, such as haloperidol; dihydroindole ina derivatives, such as molindone; dibenzoxazepines, such as loxapine; and dibenzodiazepines;, such as clozapine. Exemplary antianxiety agents, or other agents having sedative and antianxiety applications, include antihistamine immune agents, such as diphenhydramine; carbonides to ceti lenses, such as ethchlorvinol; monoureids, such as carbrorjnal, barbiturates, such as phenobarbital; piperidinediones, such as methylpylon; propyl alcohol derivatives, such as meprobat; and benzodiazepines, such as chlordiazepoxide. Exemplary antidepressants that can be used in the compositions and methods described herein include any agent that arouses the symptoms of major depressive disorders and may result in increased performance of behavior. Specific exemplary anti-depressants include those which can be classified as tricyclic antidepressants, such as imramine hydrochloride, imamine pamoate, amitriptyline hydrochloride, amoxapine, desipramine hydrochloride, doxepin, protriptyline hydrochloride and trimipramine.

Exemplary alternative antidepressants can be classified as monoamine oxidase inhibitors, such as isocarboxazid, phenelzine sulfate, and tranilcylpyrin sulfate. Still other exemplary antidepressants include second generation anti-depression drugs, such as amoxapine, maprotaline, trazodoha, fluoxetine and buproprion. Psychogenic agents are other agents that induce temporal abnormalities of the mental state of human subjects or of the They can also be useful in the pharmaceutical formulations described herein and include, for example, cannabis, lysergic acid, diethylamide and mescaline. eleven . Anti-Migraine Agents Several agents that function to counteract cerebral vasodilation associated with mucosa can be used in the treatment of migraine and can be employed as the active agent in the pharmaceutical formulations c described herein. Antiparhanic antimigraine medicines include ergot alkaloids, various ergotamines and sumatriptan succinate. Frequently related to the agents that are used to treat migraine, they are found in people used to stimulate the soft muscle of the uterus known to be oxytocic. These agents may also be useful as the active agents in the pharmaceutical formulations described. Oxytocical specimens include carboprost tromethamine, cyproheptadine, di noprostone, methylergonovine maleate, methysergide maleate, oxytocin, and sodium chloride. 1 2. Hormones Hormones, or any other agent secreted by the endocrine glands or internal secretion and non-glandular tissues, which serve to integrate metabolic processes, may be useful as the active ingredient in the pharmaceutical formulations and methods described. . Hormones can be derived from amino acids, steroids, or a variety of other various substances. Exemplary hormones that can be used according to the methods and compositions described include sematropins, including growth hormones; gonadotropic hormones, such as follicle-stimulating hormone, or luteinizing hormone; prolactin; thyrotropic hormones; adrenal corticotropic hormone; or virtually any other pituitary hormone. Additional exemplary hormones that are useful in the formulations and methods described include human chorionic gonadotropin; corticotropin; and bromocriptine. Additional useful hormones include those of the intermediate lobe, such as intermediate or melanocyte stimulating hormone; Posterior pituitary hormones including oxytocin and vasopressin. Adrenal hormones may also be useful in the formulations and methods described. Exemplary adrenals include adrenal corticosteroids, such as cortisone and cortisone acetate, dexamethasone, hydrocortisone, prednisone and various forms of prednisolone. Glyburide are also useful; parathyroid hormones, such as calcitriol and dihydrotaquistef-ol; and pancreatic hormones, such as insulin and glucagon, in any of its forms. Thyroid hormones include agents that modulate? the metabolism of energy and certain non-energetic functions of the body. Useful thyroid hormones include calcitonin, thyroglobulin and thyroid. Additional hormones that can be used include sex hormones, which can be classified as estrogenic hormones, progestational hormones and androgenic hormones. Both the estrogenic hormones and the progestational hormones are known collectively as ovarian hormones. They can be used in synthetic as well as natural versions. Exemplary ovarian hormones include estradiol and various forms of radiol, estrone and quinestrol. Exemplary synthetic estrogens include cestrol, mestranol and noretrindrone. A second type of ovarian hormone is progesterone. Exemplary progesterones include diacetate d3-teinodiol and norethindrone. Related to these medications are the agents, which have the effect of suppressing the effects of estrogen, through a variety of mechanisms. Such agents may also be useful as the active ingredient in the formulation described herein and include, for example, clomiphene citrate and tamoxifen citrate. Androgenic hormones are those usually produced in the testes. Exemplary useful androgenic hormones include testosterone, cyproterone acetate, danazol, finasteride, oxymetholone, testolactone, and various analogs and testosterone derivatives, such as testosterone cipionate, testosterone lactate, and testosterone propionate. 13. Proteins or peptides Several proteins or peptides may be useful as the active ingredient in the pharmaceutical formulations currently described. It is an advantage of the use of the preservative benzethonium chloride, alone or in combination with phenoxyethanol or phenylethyl alcohol, which are particularly compatible with peptides and proteins in solution, including both recombinant and activated forms of protein. genes. Exemplary proteins that may be used include many that have been previously mentioned, such as erythropoietin, insulin, granulocyte colony stimulating factor (GCSF), hormones, enzymes, vaccines, and steroids. 14. Anti-neoplastic agents Anti-neoplastic agents, or even combinations of anti-neoplastic agents, can be formulated in multi-dose compositions with benzethonium chloride and phenoxyethanol. Such anticancer and antihistaminal agents, which may be used in such formulations, either alone or in combination, include without limitation, tamoxifen, taxotere, doxorubicin, cisplatin, cyclophosphamide, an interferon, a tumor necrosis factor, methotrexate or variants. of these agents.

C. Other Composition Components The compositions and methods described above will vary according to factors, such as the active ingredient or ingredients, amount of time the formulation will be stored, conditions under which it will be stored and used, including the dosage form. of the composition, and the population of particular patients to which it can be administered. Adjustments to the formulation by adjusting the constituents of the formulations and their relative concentrations, including the amounts of benzethonium chloride, phenoxyethanol and phenylethyl alcohol, can be done as needed according to the needs of the formulator, administrator or patient. The constituent elements Further of the multi-dose formulations of the present invention may include ag ua, a buffer, a pH adjusting agent, a surfactant or anti-adsorbent, a wetting agent, a gelling agent, a drying agent, an osmolality adjusting agent, or virtually any other additive or carrier, depending on the desired dosage form. Formulation characteristics that can be modified include, for example, pH and osmolality. For example, it may be desired to achieve a formulation that has a pH and osmolality similar to that of blood or human tissues in order to facilitate the effectiveness of the formulation when it is administered parenterally. Alternatively, to promote the effectiveness of the compositions described, when administered via other administration routes, alternative characteristics may be modified. The buffers are useful in the present invention for, among other purposes, handling the total pH of the pharmaceutical formulation (especially desired for parenteral injection). A variety of buffers known in the art can be used in the present formulations, such as various salts of organic or inorganic acids, bases or amino acids and including various forms of citrate, phosphate, tartrate, succinate, adip ato, maleate ions. , lactate, acetate, bicarbonate or carbonate. Particularly advantageous buffers for use in parenterally administered forms of the compositions described in the present invention include sodium or potassium buffers, in particular sodium phosphate. In a preferred embodiment for dosing parenterally, sodium phosphate is used at a concentration approaching 20 μM to reach a pH of about 7.0. A particularly effective phosphate or sodium buffer system comprises monohydrate monohydrate? sodium phosphate and dibasic sodium phosphate heptahydrate, When this combination of monobasic and dibasic sodium phosphate is used, the advantageous concentrations of each are about 0.5 to about 1.5 mg / ml of r-. monobasic and approximately 2.0 to approximately 4.0 mg / μl dibasic, with p referred concentrations of approximately 0.9 mg / ml of monobasic and approximately 3.4 mg / ml of dibasic phosphate. The pH of the formulation changes according to the amount of buffer used. Depending on the dosage form and intended route of administration, it may be useful, alternatively, to use buffers in different concentrations or use other additives to adjust the pH of the com position to cover other ranges. Useful pH ranges for compositions of the present invention include a pH of about 2.0 at a pH of about 12.0. It can also be advantageous to use surfactants in the forms described in I - present. The surfactants or antiadiasins that are tested include polyoxyethylene sorbitan, polyoxyethylene sorbitan monolaurate, polysorbate-20, such as Tween-20 vM, polysorbate-80, hydroxyellosin and genapol. By way of example, when any surfactant is employed in the present invention for Producing a parenterally administrable composition is advantageous use it at a concentration of approximately 0.01 to approximately 0.5 mg / μl. Additional useful additives are readily determined by those skilled in the art, according to the particular needs or intended uses of the compositions and formulators. One of such additional substances particularly useful is sodium chloride, which is useful for adjusting the osmolality of the formulations to achieve the desired osmolality desired. Particularly preferred osmolalities for parenteral administration of the compositions described are in the range of about 270 to about 330 mOsm 'kg. The optimum osmolality for admistated com positions. parenterally, particularly injectables, is about 300 Osm / kg and is achievable by the use of sodium chloride in concentrations of about 6.5 to about 7.5 mg / μl, a sodium chloride concentration of about 7.0 mg / μl being particularly effective.

D. Preparation of the compositions The formulations described herein can be prepared in water conveniently mixed with a surfactant, such as hydroxypropylcellulose or polyoxyethorbinobitanos. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride as described above. Prolonged absorption of the injectable compositions can be caused by the use in the compositions of agents that retard absorption, for example, aluminum monostearate or celatin. The formulations described do not require high levels of additional alcohols in order to achieve or maintain their anti-microbial effect. For example, a composition with an alcohol level greater than 55% or greater than 75% or even greater than 90% is not necessary. Other agents, which may be employed include, but are not limited to, lecithin, urea, ethylene oxide, propylene oxide, hydroxypropylcellulose, methylated Ice or polyethylene glycol. Aqueous compositions (inocula) as described herein, may include an effective amount of a pharmacologically active agent dissolved or dispersed in a pharmaceutically acceptable aqueous medium. Such compositions are also referred to as inocula. The use of pharmaceutically acceptable carrier medium and agents for pharmaceutically active substances is well known in the art. Unless any conventional means or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Complementary active ingredients may also be incorporated into the compositions as described above. A proteoglycan, such as erythropoietin can be formulated in a composition in a neutral or salt form. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and those which are formed with inorganic acids, such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic , tartaric, mandelic and the like Salts formed with free carboxyl groups can also be derived from inorganic bases such as, for example, hydroxides of sodium, potassium, ammonium, ferric calcium, and such organic bases as isopropylamine, trimethylamine, his tidine, procaine and the like, The therapeutic compositions of the present invention are advantageously administered in the form of injectable compositions either as liquid solutions or suspensions; Suitable solid forms for solution in, or suspension in, liquid before injection can also be prepared. Alternatively, the compositions of the present i? They can be administered as inhalants in an aerosolized form. Depending on the needs of the formulator, administrator or the subject of the treatment, the compositions described herein can take virtually any form including liquid, suspension, emulsion, solution, oil, mixture, cream, ointment, gel, suppository, semi-solid, spray, powder, tablet or capsule. A normal composition comprises a pharmaceutically acceptable carrier. For example, the composition may contain 10 mg, 25 mg, 50 μg or up to about 100 mg of human serum albumin per milliliter of phosphate buffered saline. The present invention may be contained in a bottle, tube, syringe, inhaler or other container for single or multiple administrations. Such containers may be made of glass or a polymeric material, such as polypropylene, polyethylene or polyvinyl chloride, for example. Preferred containers may include a seal, or other closure system, such as a rubber stopper that can be penetrated by a needle, in order to remove a simple dose and then re-seal on the removal of the syringe. All such containers for injectable liquids, lyophilized formulations, lyophilized formulations reconstituted or reconstitutable powders for injection known in the art or for the administration of aerosolized compositions, are contemplated for use in the compositions and methods disclosed herein.

EXAMPLES It will be recognized by one skilled in the art that many formulations or compositions comprising the benzethonium chloride preservative alone, or in synergistic combination with phenoxyethanol, or in combination with phenylethyl alcohol can be prepared. Below is only one example of such formulation or composition. This example is intended to be illustrative only and is not intended to limit the scope of the invention.

Example 1: An effective antihistamine composition can be formulated as follows: An effective amount of fexofenadine; xylitol; sorbitol; glycerin; sodium saccharin; benzethonium chloride in a concentration of approximately 0.005%; phenoxyethanol in an amount of 0.25% and sodium hydroxide, to adjust the pH.

REFERENCES U.S. Patent No. 4,806,524 to Kawagachi et al U.S. Patent No. 5,503,827 to Woog et al. US Patent no. 5.66, 1125 for Stricklan et al. Handbook of Pharmaceutical Excipients, second edition 1994. L.A. Trissel, "Handbook on Inceptible Drugs", Ed.8, American So ciety of Hospital Pharmacists, Inc. 194.

Physicians' Desk Reference, ed. 48, 1994. Physicians' Desk Reference, ed. fifty, nineteen ninety six. Sandeep Nema, R.J. Washkuhn, and R.J. Brendel, "Excipients and Their Use in Injectable Products" (Excipients and their use in injectable products), PDA Journal of Pharmaceutical Sciences & Technology, Vol. 51 (4), July-August 1997.

Claims (30)

1. REIV NDICATIONS 1. A pharmaceutical composition comprising a pharmacologically active ingredient and an amount of benzethonium chloride and an amount of phenoxyethanol, wherein the amounts of benzethonium chloride and phenoxyethanol are effective to inhibit microbial growth, and wherein the composition is not formulated for composition. Topical 2. The composition of claim 1, further defined as comprising benzethonium chloride in a concentration from about 0.001 to about 1.0%, and phenoxyethanol in a concentration from about 0.01 to about 2.0%. The composition of claims 1, 2, 45, 46 or 47, wherein said pharmacologically active ingredient is a cardiovascular agent 4. The composition of claim 3, wherein said cardiovascular agent is diltiazem, digoxin, dopamine, digitalis, procainamide hydrochloride, lidocaine, verapomil or levostatin. 5. The composition of claims 1, 2, 45, 46 or 47, wherein said pharmacologically active ingredient is an agent for the treatment of the gastrointestinal system or liver. 6. The composition of claim 5, wherein said agent for the treatment of the gastrointestinal system or the liver is an antacid, a digestive or an emetic. 7. The composition of claim 5, wherein said agent for the treatment of the gastroin testinal system or the liver is lipase, furosamide, morphine, scopolamine, ranitidine. 8. The composition of claim 44, wherein said pharmacologically active ingredient is a topically active agent. The composition of claim 8, wherein said topically active agent is bentonite, zinc oxide, dimethicone or glycerin. The composition of claim 1, 2, 45, 46 or 47, wherein said pharmacologically active agent is a hematological agent. 11. The composition of claim 10, wherein said hematological agent is heparin, streptokinase, urokinase, tissue plasminogen activator or aspirin 12. The composition of claims 1, 2, 45, 46 or 47, wherein said pharmacologically active agent is an antihistamine 13. The composition of claim 12, wherein said antihistamine is theophylline diphenhydramine, hydrazine or fexofenadine 14. The composition of reivipication 12, wherein said antihistamine is fexofenadine 15. The composition of Claim 14, which comprises about 0.005% benzethonium chloride and about 0.25% phenoxyethanol. 16. The composition of claims 1, 2, 45, 46 or 47, wherein said pharmacologically active ingredient is an antimicrobial. 17. The composition of claim 16, wherein said antimicrobial is penicillin, amoxicillin, kanamycin, neomycin, erythromycin, tetracycline, doxycycline, norfloxacin, or cyclosporin. The composition of claims 1, 2, 45, 46 or 47, wherein said pharmacologically active agent is an anti-epileptic or anti-tailing agent. The composition of claim 18, wherein said anti-epileptic or anti-seizure agent is phenytoin, dilantin or phenobarbital. 20. The composition of claims 1, 2, 45, 46 or 47, wherein said pharmacologically active agent is a sedative or hypnotic. 21. The composition of the indication 20, wherein said sedative or hypnotic is scopolamine, fexo enadine or methaqualone. 22. The composition of claims 1, 2, 45, 46 or 47, wherein said pharmacologically active agent is a diuretic. 23. The composition of claim 22, wherein said diuretic is furosemide, amiloride, aminophyllira or theobromide. 24. The composition of claims 1, 2, 45, 46 or 47, wherein said pharmacologically active ingredient is a psychopharmacological agent. The composition of claim 24, wherein said psychopharmacological agent is an anti-psychotic or an antidepressant. 26. The composition of claims 1, 2, 45, 46 or 47, wherein said pharmacologically active ingredient is an anti-migraine agent. 27. The composition of claims 1, 2, 45, 46 or 47, wherein said pharmacologically active agent is a hormone. 28. The composition of claims 1, 2, 45, 46 or 47, wherein said pharmacologically active agent is a protein or peptide. 29. The composition of claims 1, 2, 45, 46 or 47, further comprising a second active agent. 30. The composition of claim 29, wherein said second active agent is a cardiovascular agent, an agent for the treatment of gastrointestinal disorders, a topically active agent, a hematological agent, an antihistaminéi, an antimicrobial, an antiepileptic, an agent anti-seizure, a sedative, a hypnotic, a diuretic, a psychopharmacological agent, an anti-migraine agent, a hormone, a protein or a peptide 31. The composition of claims 1, 2, 45, 46 or 47, wherein said composition is a liquid, suspension, emulsion, solution, mixture, cream, inhalant, aerosol, gel, ointment, suppository, powder, tablet. 32. The composition of claims 1, 2, 45, 46 or 47, wherein said composition is administrable in a parenteral, topical, oral, auditory, ocular, mucosal, suppository or inhalation manner. 33. A pharmaceutical carrier composition for use as a non-topical administered carrier of a pharmaceutically active ingredient, wherein said carrier comprises an amount of benzene chloride - > and an amount of phenoxyethanol, wherein the amounts of benzethonium chloride and phenoxyethanol are effective to inhibit microbial growth in said composition. 34. The pharmaceutical carrier composition of claim 33, further defined in that it comprises benzethonium chloride in a for administration by a selected route of the following: parenteral, mucosal, ocular, auditory, oral, suppository, inhalation, 38. The vial of claim 37, further defined as comprising benzethonium chloride in a concentration from about 0.001 to about 1.0% and phenoxyethanol in a concentration from about 0.01 to about 2.0%. 39. The bottle of claim 37 or 38, wherein said pharmacologically active ingredient is a cardiovascular agent, an agent for the treatment of gastrointestinal disorders, a hematological agent, an antihistamine, an antimicrobial, an antiepileptic, an anti-seizure agent, a sedative, a hypnotic, a uretic, a psychopharmacological agent, an anti-migraine agent, a hormone, a protein or a peptide. 40. A pharmaceutical package for containing multiple dosages of a pharmacologically active ingredient, wherein said bottle contains a solution comprising said active ingredient and an amount of benzethonium chloride and an amount of phenoxyethanol, wherein the amounts of the and phenoxyethanol are effective to inhibit the microbial growth in said composition, the binder is present in a concentration of approximately 0.001% up to approximately 0.005% and the phenoxyethanol being present in a concentration of approximately 0.01% to approximately 0.25%, said solution being formulated for administration by a selected route of the following: parenteral, mucosal, ocular, auditory, oral, suppository, inhalation. 41 The pharmaceutical pack of claim 40, wherein said pharmacologically active network is a cardiovascular agent, an agent for the treatment of gastrointestinal disorders, a topically active agent, a hematological agent, an antihistamine, an antimicrobial, an antiepileptic, a anti-seizure agent, a sedative, a hypnotic, a diuretic, a psychopharmacological agent, an anti-migraine agent, an ormone, a protein or a peptide. 42. A method for inhibiting microbial growth in a non-topically administrable solution comprising a pharmacologically active ingredient, said method comprising admixing benzethonium chloride and phenoxyethanol to said solution. 43. The method of claim 42, wherein the benzethonium chloride is added in a concentration from about 0.001 to about 1.0%, and phenoxyethanol is added at a concentration from about 0.01 to about 2.0%. 44. The method of claims 42 or 43, wherein the pharmacologically active protein is a cardiovascular agent, an agent for the treatment of gastrointestinal disorders, a hematological agent, an antimicrobial agent, an anti-epileptic agent, a anti-attack agent, a sedative, a hypnotic, a diuretic, a psychopharmacological agent, an anti-migraine agent, a hormone, a protein or a peptide. 45. A pharmaceutical composition comprising a pharmacologically active ingredient, an amount of benzethonium chloride and an amount of phenoxyethanol, wherein the amounts of Benzethonium and phenoxyethanol are effective for inhibiting microbial growth, and wherein benzethonium chloride is present in a concentration from about 0.001 to about 0.005% and phenoxyethanol is present in a concentration from about 0.01 to about 0.25. %. 46. A pharmaceutical composition comprising a pharmacologically active ingredient and an amount of benzethonium chloride and an amount of phenoxyethanol, wherein the amounts of benzethonium chloride and phenoxyethanol are effective in inhibiting microbial growth, and in where the composition is formulated for administration by a selected route of the following: parenteral, mucosal, ocular, auditive, oral, suppository, inhalation. 47. The pharmaceutical composition of claim 46, further defined in that it comprises benzethonium cyclobenzoate at a concentration ranging from 100 to 400% by weight, and phenoxyethanol in a concentration from about 0.01 to about 2.0%. . 48. A porl composition; Pharmaceutical agent for use as a carrier of a pharmaceutically active ing network, wherein said carrier comprises a quantity of benzethonium chloride and an amount of phenoxyethanol, wherein the amounts of benzethonium chloride and phenoxyethanol are effective to inhibit growth. microbial in accordance with the position, and wherein the benzethonium element is present in a concentration from about 0.001 to about 0. 005%, and the phenoxyethanol is present in a concentration from about 0.01 to about 0.25%. 49. A pharmaceutical-based composition for use as a carrier of a pharmaceutically active ingredient, wherein a carrier comprises a quantity of benzethonium chloride and an amount of phenoxyethanol, wherein the amounts of benzethonium chloride and phenoxyethanol are effective to inhibit microbial growth in said composition, and where the porter is formulated for administration by a selected route of the following: parenteral, mucosal, ocular, auditory, oral, suppository, inhalation 50. The composition of pharmaceutical carrier of claim 33, further defined in that it comprises benzethonium chloride in a concentration of about 0.001 to about 1.0%, and phenoxyethanol in a concentration of about 0.01 to about 2.0%. 51 A method for inhibiting microbial growth in a solution comprising a pharmacologically active ingredient, said method comprising admixing benzethonium chloride and phenoxyethanol with a sol ution, wherein the benzethonium chloride is added to be present in a co-ordination of a 0.001 to about 0.005% and phenoxyethanol is added to be in a concentration from about 0.01 to about 0.25%. 52. The method of re-vitiation 46, wherein a pharmacologically active ingredient is a cardiovascular agent, an agent for the treatment of gastrointestinal disorders, an agent topically. active, a blood agent), an anti-histamine, an antimicrobial, an antiepileptic, an anti-seizure agent, a sedative, a hypnotic, a diuretic, a psychopharmacological agent, an anti-migraine agent, a hormone, a protein or a peptide: gone.