SK1082002A3 - Preserved pharmaceutical formulations - Google Patents

Abstract

The use of benzethonium chloride is described or in combination with phenoxyethanol or phenyl ethyl alcohol for antimicrobial action in pharmaceuticals compositions and methods for the use of benzethonium chloride, alone or in combination with phenoxyethanol or phenyl ethyl alcohol to inhibit microbial growth in pharmaceutical compositions.

Description

The present invention generally relates to the use of preservatives in multi-dose pharmaceutical compositions. More specifically, the present invention relates to the use of benzethonium chloride alone or in combination with phenoxyethanol or phenyl ethyl alcohol in multiple dose pharmaceutical compositions containing various kinds of pharmacologically active ingredients.

BACKGROUND OF THE INVENTION

Sterility is one of the most important properties of pharmaceutical formulations. Maintaining the sterility of pharmaceutical compositions is a function of both the method of sterilization and the integrity of the package or delivery system. For multi-dose products, antimicrobials must be added to the formulation of this product to protect the product from accidental microbial contamination during storage or use or during storage and use. This is true regardless of the pharmaceutical form of this composition.

The pharmaceutical industry is looking at. stable multi-dose pharmaceutical compositions containing different kinds of active ingredients as being particularly preferred and commercially attractive. These compositions are usually, but not always, packaged in a manner that allows the withdrawal of certain quantities at any time. This method is desirable because it allows multiple doses to be dispensed from a single package and allows a more controlled administration of the pharmaceutical composition, since the composition may be discontinued and reused, administered or administered in some form.

partial amount and over an extended period of time.

The nature of the use of multi-dose formulations imposes special formulation requirements. For example, maintaining the sterility of the composition is particularly problematic, since there are many opportunities for introducing microorganisms and other contaminants into the composition. Repeated introduction of foreign elements into the multiple dose container after formulation, for example needles or tampons, also creates the likelihood of introducing microorganisms into the container. In addition, and / or, the microorganisms may be introduced during filling of the containers or during dilution of these compositions after lyophilization and prior to use, application or administration. The extended period of time during which the packaging can be stored - especially during the re-introduction of foreign elements and / or after contaminants may have been introduced, requires that this formulation contain special excipients to ensure the sterility of the contents.

To ensure that these formulations maintain optimal sterile properties, the US Food and Drug Administration (FDA) and approval authorities in other jurisdictions, including Europe and Japan, require multi-dose formulations to contain preservatives to prevent or kill any microorganisms that may have been introduced. However, the development of multi-dose preservative-containing compositions is problematic since the various active ingredients in pharmaceutical compositions tend to interact adversely with preservative compounds.

Possible adverse interactions of preservatives and pharmacologically active ingredients include decomposition of the active ingredients, especially those stored for extended periods of time; inactivating, neutralizing or altering these active ingredients; forming aggregates containing these active ingredients and other excipients or constitutive excipients of these compositions; and other interactions that inactivate, disintegrate, or cause the administration of this composition to humans by any route of administration becomes difficult, painful or otherwise undesirable.

In addition, preservatives alone are known to cause acute adverse reactions, such as allergic reactions or even seizures, after administration. Ideally, a preservative present in a multiple dose pharmaceutical composition should be effective at low concentration against multiple species of microorganisms; it should be soluble in this formulation; non-toxic; compatible and should not react with the active ingredient as well as other excipients; effective with long-term stability; and should not react with the packaging or closure components.

FROM'

Sandeep Nemá et al. have published a list of various excipients which have been included in the formulation of injectables marketed in the USA. The antimicrobial preservatives listed in this article are listed in Table 1:

Table 1

Antimicrobial preservatives

preservative frequency Range Benzalkonium chloride 1 0.02% w / v Benzethonium chloride 4 0,01% Benzyl alcohol 74 0.75 to 5% chlorobutanol ¹⁷ 0.25-0.5% m-cresol 3 0.1-0.3% Myristyl gamma-picolinium chloride 2 0.0195 to 0.169% Paraben methyl 50 0.05 to 0.18% Paraben propyl 40 0.01-0.1% phenol 48 0.2-0.5% 2-Phenoxyethanol 3 0.50% Phenyl mercuric nitrate 3 0.001% thimerosal 46 0.003-0.01%

Despite the range of preservatives available, the finding of a broadly non-reactive preservative or combination of preservatives useful in pharmaceutical compositions remains unresolved. Accordingly, there remains a need for a preservative or combination of preservatives that will at least react with other excipients commonly used in multi-dose pharmaceutical formulations; which maintains the stability of the active ingredient and the composition over an extended shelf life of the product; meet the criteria of the US, European and Japanese Pharmacopoeia Antimicrobial Conservation Performance Test; it is safe in the concentrations used; and can be administered by any parenteral, topical, ocular, inhalation or oral route - in a manner that is effective and minimizes pain and the possibility of an adverse reaction, e.g. allergic reaction in the patient.

SUMMARY OF THE INVENTION

These drawbacks are largely overcome by the present invention, which consists in providing novel and particularly preferably multiple dose pharmaceutical compositions comprising various kinds of active pharmaceutical ingredients and a preservative benzethonium chloride, alone or in combination with either phenoxyethanol or phenylethyl alcohol. Also provided herein are multi-dose pharmaceutical compositions comprising a wide variety of active ingredients and benzethonium chloride in combination with either phenoxyethanol or phenylethyl alcohol. In fact, any pharmacologically active ingredient can be used. In all embodiments of the present invention, those ingredients that are particularly believed to be useful in the present invention include those used to treat the cardiovascular and gastrointestinal systems as well as the liver. Other agents believed to be within the scope of this invention include topical, hematologic, antihistaminic, antimicrobial, antiepileptic, and anti-seizure agents, as well as agents used as sedatives, hypnotics, diuretics, psychopharmacologics, antimigrenic drugs, hormones, proteins or peptides or any other active ingredient. These active ingredients can be used alone or in combination and remain within the scope of the invention. In particularly preferred embodiments, one or more active ingredients are contained in a pharmaceutical composition comprising benzethonium chloride in combination with phenoxyethanol, as the two preservatives exhibit a synergistic antimicrobial effect.

In addition to embodiments comprising the aforementioned active ingredient, alternative embodiments of the present invention provide a pharmaceutical carrier composition comprising any of the above active ingredients as well as any amount 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 vial or pharmaceutical container for any pharmacologically active ingredient preserved by an effective amount of benzethonium chloride alone, or an effective amount of benzethonium chloride in combination with phenoxyethanol or phenylethyl alcohol. '

Other preferred embodiments of the invention include methods for suppressing microbial growth in compositions comprising one or more pharmacologically active agents. These methods include adding a single preservative of benzethonium chloride, or in combination with either phenoxyethanol or phenylethyl alcohol, to the active ingredient or combination of active ingredients.

The present invention provides a significant improvement over the prior art. Provided herein are multi-dose pharmaceutical compositions containing a wide variety of active ingredients as well as a single preservative benzethonium chloride, or in combination with either phenoxyethanol or phenylethyl alcohol. These disclosed compositions are stable, sterile and easy to administer. Moreover, and most unexpectedly, the present invention reveals that when used in combination in a multi-dose pharmaceutical composition, phenoxyethanol and benzethonium chloride have positive synergistic effects which result in a particularly advantageous composition. Specifically, this combination of preservatives shows the following properties: (1) a synergistic antimicrobial effect that allows the use of a lower concentration of preservatives;

(2) excellent compatibility with the active ingredients in different pharmaceutical compositions under varying storage conditions over an extended period of time and over a wide range of pH; and (3) phenoxyethanol has the potential for local anesthetic effect, making this composition particularly preferred for subcutaneous administration.

The preserved pharmaceutical compositions disclosed in this invention may be practically administered in any dosage form and may be administered by virtually any route of administration. Examples of preferred dosage forms include, but are not limited to, liquid, suspension, emulsion, solution, mixture, cream, ointment, gel, oil, suppository, semi-solid dosage form, aerosol, dust, tablet or capsule. Examples of routes of administration of the preserved pharmaceutical compositions disclosed in this invention include: parenteral, mucosal, ocular, aural, oral, topical, by lace and inhalation.

As used herein, the following terms will have the following meanings:

. Pharmaceutically acceptable (or pharmacologically acceptable) - refers to molecular entities and compositions that do not produce an adverse, allergic, or other unexpected reaction when administered to an animal or human.

Pharmaceutically acceptable carrier - includes any and all solvents, dispersion media, coatings, antibacterial and isotonic and absorption delaying agents, buffers, excipients, flavors, binders, glidants, gels, detergents and the like, which can be used as media for a pharmaceutically acceptable substance.

Unit - A unit of biological activity as determined by an exhypoxic polyeythemic mouse bioassay and compared to World Health Organization standards.

All numerical values given in the present invention include all values from a lower value to a higher value in increment of one unit, provided that there is a difference of at least two units between the lower value and any higher value. For example, if it is stated that the concentration of a component or the value of a process such as e.g. osmolality, temperature, pressure, time and the like are e.g. from 1 to 90, preferably from 20 to 80, more preferably from 30 to 70, means that values such as from 15 to 85, from 22 to 68, from 43 to 51, from 30 to 32, etc. are expressly calculated in this specification . For values that are less than one, 0.0001, 0.001, 0.01 or 0.1, respectively, is considered as one unit. These are only examples of what is specifically intended and all possible combinations of numerical values between the calculated lowest value and the highest value will be considered explicitly in this application in a similar manner.

A. Preservatives: phenoxyethanol and benzethonium chloride

Preservatives envisaged for use in the present invention are benzethonium chloride, phenoxyethanol and phenylethyl alcohol, all variants of these preservatives, and structural analogs thereof. It is specifically contemplated that any of these preservatives may be used as a separate preservative in the compositions disclosed herein, or may preferably be used in combination with each other. As disclosed herein, compositions of the present invention that employ a combination of phenoxyethanol and benethethonium chloride demonstrate that they have synergistic effects and are therefore particularly preferred.

Benezethonium chloride, phenoxyethanol and phenylethyl alcohol may be used in the compositions disclosed herein in any effective amount. The total preservative concentration is preferably between about 0.001% to about 4.0% of the total composition. Particularly preferred concentrations of total preservative are those that are kept as low as possible to achieve the desired antimicrobial effect, while minimizing the potential for adverse reactions.

In preferred embodiments of the present invention, both benzethonium chloride and phenoxyethanol are used together. Surprisingly, when used together, these preservatives have a synergistic effect with each other. In order to achieve an equivalent antimicrobial effect when used singly, the concentrations of benzethonium chloride or phenoxyethanol must be higher than the total preservative concentration when used in combination, and generally twice the amount of preservative when used alone. Thus, for example, if either benzethonium chloride or phenoxyethanol is used alone, approximately twice the amount of benzethonium chloride or phenoxyethanol will be required to achieve the same effect as the amount of benzethonium chloride in combination with phenoxyethanol. In addition, even at these higher concentrations of benzethonium chloride and phenoxyethanol, the individual compositions may not meet the American, European or Japanese antimicrobial approval criteria. Preferred combination formulations include benzethonium chloride at concentrations from about 0.001 to about 0.1% in combination with phenoxyethanol at concentrations from about 0.01 to about 1.0%. More preferably, the combination formulations comprise benzethonium chloride at a concentration of from about 0.01% to about 0.02% and phenoxyethanol at a concentration of from about 0.25% to about 0.5%.

In another embodiment, the invention includes benethethonium chloride in combination with phenylethyl alcohol. Preferred compositions include benzethonium chloride at concentrations from about 0.001 to about 0.1% together with phenylethyl alcohol at concentrations from about 0.01 to about 1.0%. More preferred embodiments comprise benzethonium chloride at a concentration of about 0.15 to about 0.25% and phenylethyl alcohol at a concentration of about 0.2 to about 0.5%. Most preferably, the composition in which benzethonium chloride and phenylethyl alcohol are used together comprises benzethonium chloride at a concentration of about .02% and phenylethyl alcohol at a concentration of about 0.25%.

B. Active Ingredients

Preservative-containing pharmaceutical compositions as disclosed in the present invention can be prepared using virtually any active ingredient. In particular, benzethonium chloride and phenoxyethanol have synergistic effects and are preferred in multi-dose pharmaceutical formulations containing the following classes of active ingredients: cardiovascular; chemotherapeutics, gastrointestinal and liver; topical; hematology; antihistamines; antimicrobials; anti-epileptic or anti-seizure agents; sedatives and hypnotics; diuretics; psychopharmacologics; anti-migraine agents; ophthalmics; hormones; proteins or peptides and others as appropriate.

One of ordinary skill in the art will recognize which individual substances are preferred in multi-dose formulations and may, as appropriate, combine these substances with appropriate amounts of benzethonium chloride, phenoxyethanol and / or phenylethyl alcohol according to the needs of the individual formulator or the needs of the formulation itself. It should be readily understood that substances in one group or class may be advantageous in other applications and that such alternative uses still fall within the scope of that application. In other words, we do not want the classification of substances in this disclosure to be restrictive. In addition, it is contemplated that the use of any active ingredient in combination with any other active ingredient according to the compositions and methods disclosed herein is within the scope of the present invention.

1. Agents acting on the cardiovascular system

In fact, any substance that directly or indirectly affects the heart or blood vessels can be used as a cardiovascular substance and as an active ingredient in formulations and methods using benzethonium chloride, alone or in combination with phenoxyethanol or. phenylethyl alcohol disclosed in the present invention. According to the present invention, specific classes of preferred cardiovascular agents include the following: sympathomimetics, α-adrenergic blockers, βadrenergic blockers, antimuscarinic agents, ganglioplegigas, or other agents that competitively prevent acetylcholine on postsynaptic nicotinic receptors and the digitalisers, blood vessels and antiarrhythmics; and ACE inhibitors. Agents affecting parenteral fluids and diuretics can also be used as cardiovascular agents and will be discussed in a separate part of the invention. Other agents used in cardiovascular applications that may be used in the present invention include antihypertensive and hypotensive agents. Antiandrenergic agents, saluretics and antihypertensive direct vasodilators are all functional antihypertensive or hypotensive classes of drugs.

Peripheral vasodilators are substances that augment arterioles and increase blood flow in a number of systemic vascular streams, particularly in the extremities. Therefore, centrally acting, reflective agents or ganglioplegics that reduce sympathetic tone in the periphery are peripheral vasodilators that can be used in the compositions disclosed herein. In addition, for peripheral vasodilators, sympathomimetics preferentially stimulating β ₂ -receptors are used, while adrenergic blockers are used as peripheral vasodilators to improve flow in specific vascular streams. Such agents are used in the treatment of vasospastic disorders such as Raynaud's disease, causalgia and reflex distrophies, vasospasms associated with arterial embolism and thrombophlebitis, trench leg, herpes zoster, decubitus ulcers and degenerative diseases of arterioles, such as obliterative thrombosis, obliterit thromboangiosis, obliterit thromboangiosis, gangrene. Specifically, any agent useful as a peripheral vasodilator is useful in the compositions and methods disclosed herein.

Other cardiovascular agents of the invention include antianginals such as organonitrates and calcium entry blockers, antiplatelet agents such as aspirin and sulfinpyrazone; vasopressants such as those having a vasoconstrictor or cardiostimulatory effect and which can be used under appropriate conditions to increase blood pressure, such as dopamine, cardioglycosides or other substances that act as direct cardiotonics on the myocardium to increase contraction strength, including digitalis, deslanoside, digitoxin, digoxin, and digoxin immune fab; phosphodiesterase inhibitors, also known as inodilators, including amrinone, flosequin and milrinone lactate; and antiarrhythmic agents such as β-adrenergic blockers, cholinergic agents, anticholinesterase agonists, and β-agonists including adenosine, amiodarone hydrochloride, brethium tosilate, disopyramide phosphate, flecainide acetate, mexiletine hydrochloride, moricisin hydrochloride, lidicafine hydrochloride, lidicinocin hydrochloride, lidicinocin hydrochloride, procaininocone, procaine hydrochloride, quinidine gluconate, quinidine polygalacturonate, quinidine sulfate, and tocanide hydrochloride.

Other cardiovascular agents that can be used in the compositions and methods disclosed herein include calcium channel blockers (CCBs) and other agents known as calcium entry blockers, calcium antagonists, and slow channel blockers such as verapamil, diltiazem, amlodipine, bepridil hydrochloride, felodipine. , isradipine, nicardipine hydrochloride, nifedipine and nimodipine (these substances have been found to effectively treat central nervous system disorders such as stroke and migraine); blood lipid agents (cardiovascular agents due to blood lipid relationship to atherosclerosis) including aminosalicylic acid, cholestyramine, clofibrate, colestipol hydrochloride, gemfibrozil, lovastatin, pravastatin sodium, probucol, simvastatin, dextrotyrosine, dextrotyrosine; and special-use cardiovascular drugs such as alprostadil.

Any of the aforementioned substances or their equivalents or analogs may advantageously be used in the compositions and methods disclosed herein, used alone or in combination with each other or with another active agent, depending on the needs of the formulator or the intended application.

2. Agents acting on the gastrointestinal system and liver

Substances preferably used in the treatment of disorders of the gastrointestinal system or liver may be incorporated into pharmaceutical compositions comprising benzethonium chloride, alone or in combination with phenoxyethanol or phenylethyl alcohol, as disclosed herein. The main categories of substances used in gastrointestinal or liver applications are antacids; H ₂ receptor antagonists; H ⁺ / K ⁺ ATPase inhibitors; medicines that increase mucus resistance;

digestants, including pancreatic enzymes; laxatives; antidiaroiká; emetics; antiemetics; prokinetic agents; and adsorbents. Other agents used in the treatment of gastrointestinal or liver diseases include immunosuppressants, anti-inflammatory drugs, immunostimulants and antibiotics. Any of these several categories of substances can be used according to the compositions and methods disclosed in the present invention.

I

Specific antacids that may be used include sodium carbonate, calcium carbonate, aluminum hydroxide, magnesium hydroxide, magnesium oxide, magaldrate, magnesium silicate, and aluminum compounds such as aluminum carbonate gel or aluminum hydroxide gel. Antacids are commonly used in combination and it is expressly contemplated that any combination of antacids or other agents acting on the gastrointestinal system or liver may be used in the pharmaceutical compositions and methods of this disclosure.

As noted, other agents used in the treatment of disorders of the gastrointestinal system or liver 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; mucosal enhancers, including mizoprostil, sucralfate; and digestants such as choleretics (bile, bile acids and bile salts), hydrochloric acid, pancreatic enzymes such as mixtures of lipase, amylase and protease, and ursodiol.

Other agents acting on the gastrointestinal system and liver that are used in the treatment of gastrointestinal disorders include laxatives, such as bulk laxatives containing polysaccharides and cellulose derivatives that are indigestible; softening laxatives, such as sodium ducosate, or other surfactants, which help to form a mixture of water and fat-soluble substances to soften the stool or stimulate water secretion into the gastrointestinal tract; lubricating laxatives, such as mineral oils, which facilitate the passage of the stool due to the oil coating or which inhibit the reabsorption of water in the colon; saline laxatives such as magnesium citrate and sodium phosphate having an osmotic effect increasing the water content of the stool volume; stimulatory laxatives, such as bisacodyl, phenolphthalein and hay, which function under different mechanisms including inhibition of absorption, increased secretion and effect on motility; and hyperosmotic laxatives, such as lactulose, which have an osmotic effect and can also affect intestinal motility. Other examples of laxatives that may be used in this disclosure include aloe, castor oil, magnesium sulfate, and sodium phosphate.

Other examples of liver and gastrointestinal agents that may be included in the invention include: emetics such as apomorphine, morphine, hydrogenated ergot alkaloids, digitalis glycosides, copper sulfate, mustard, sodium chloride, zinc sulfate, and veratrum; and antiemetics of the following six groups: antipsychotics, such as phenothiazines, butyrophenones, or other agents that act in the chemoreceptor activation zone to block apomorphine-stimulated dopaminergic emetic receptors; antihistamines that provide relief for motion sickness; anticholinergics, often in combination with D-amphetamine and scopolamine, effective against kinetosis; cannabinoids, particularly beneficial in emesis after anticancer chemotherapy; 5-HT ₃ -receptor antagonists such as ondansetron, which blocks both peripheral and central 5-HT ₃ -receptors and is particularly effective against the emetogenic effects of chemotherapy; and other agents such as trimethobenzamide, emetoclopramide, which blocks dopamine receptors in the chemoreceptor activation zone; diphenidol and scopolamine.

Adsorbents are chemically inert powders that have the ability to adsorb gases, toxins and bacteria. Examples of adsorbents that can be used as active ingredients in the pharmaceutical compositions and methods of use disclosed herein include activated carbon, kaolin, pectin, bismuth subcarbonate, bismuth subnitrate, magnesium silicate. Hepatic immunostimulators are also frequently used in the treatment of chronic liver diseases such as hepatitis B and hepatitis C. These include interferon α-2B, which is generally a recombinant drug. Again, all of these substances are suitable in these compositions and methods.

Many other drugs with different effects on the gastrointestinal tract, but which do not exactly fall into the above categories, are also used in the treatment of disorders of the gastrointestinal system and can be used in the pharmaceutical compositions disclosed herein. Such other drugs include anise oil, anisotropin methyl bromide, bismuth subcarbonate, camphor, camphor alcohol, caraway, caraway oil, cardamom oil, cardamom seed, cardamom tincture or compound, quinodiol, chlorabutanol, chloroform, lactose and lactulose.

3. Topical drugs

Chemicals can be applied to the skin and mucosa for localized effects in the skin or mucosa or for systemic effects. Such substances may also be present

I can call them topically active substances and can be used in preserved pharmaceutical compositions containing preservative benzethonium chloride alone or in combination with either phenoxyethanol or phenylethyl alcohol. The topical substances may be preservatives, adsorbents, demulgents, emollients or cleaning agents. They may also be relatively inert and may also function as vehicles and excipients. Other topical agents include astringents, irritants, rubeficents, vesicles, sclerosing agents, caustics, escharotics, many keratolytic (desquamating) agents, and many other dermatologics, including hypopigmenting and antipruritic agents.

Protective agents are any substances that isolate the exposed surface of the skin or mucosa from harmful or irritant stimuli. Related substances, adsorbants and demulsants have a primary dermatological function. Examples of preservatives and adsorbents that may be used in the present invention include the following: powders such as starch or other carbohydrate powders, including those containing an antiseptic; absorbable dusts such as biosorb and ezone; dusts containing wound cleansing agents, such as those containing drops of dextranomer; bentonite; bismuth; boric acid; calcium carbonate; cellulose; maize starch; magnesium stearate; talc; titanium dioxide; zinc oxide; zinc stearate; aluminum hydroxide; dimethicone; petrolatum gauze; gelatin; lanolin and related compounds such as kaolin, mineral oils, olive and peanut oil; Vaseline; silicones; and zinc carbonate.

Demulsants are protective substances which are mainly used to alleviate irritation, in particular mucous membranes or abraded tissues. Examples of demulsants that can be used in these disclosed pharmaceutical compositions include acacia, agar, benzoin, carbomer, gelatin, glycerin, glycerin lace, glyciris, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Other examples of demulsants include various ophthalmic solutions, such as those containing hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl alcohol, propylene glycol, sodium alginate or tragacanth.

Emollients are non-irritating, fatty or oily substances that can be applied topically, especially to the skin, but also to other mucous membranes. Examples of emollients suitable for use in the compositions and methods disclosed herein include lanolin, hydroxylated and acetylated form; isopropyl myristate and palmitate; oleyl alcohol; sodium lauryl sulfate; various animal fats and oils such as spermacet, mineral oils, paraffin and petrolatum; red petrolatum; vegetable oils, including castor oil, cocoa butter, coconut oil, corn oil, cottonseed oil, olive oil, peanut oil, persian oil, and sesame oil; waxes such as cetyl ester wax, cold cream, hydrophilic ointment, rose water ointment, spermacet and white or yellow wax; and various other emollients, including glycerin, petrolate, isopropyl myristate and myristyl alcohol. Oils extracted from shark liver (i.e. shark liver oil) can also be used as emolence.

Astringences include locally used protein precipitants that so little penetrate into cells that their effect is essentially limited to the cell surface and interstitial space. Astringents are used therapeutically to stop bleeding by blood coagulation and to suppress diarrhea, alleviate mucosal inflammation, promote healing, strengthen the skin, or reduce sweating. The astringents may advantageously be formulated and used according to the disclosed compositions and methods. Major astringents include salts of aluminum, zinc, magnesium or bismuth cations; certain other salts containing these metals (such as promanganates); and tannins or related polyphenol compounds. Acids, alcohols, phenols and other protein-precipitating agents may have astringent effects in a certain amount or concentration.

Antiperspirants and deodorants can be used as aerosols, sprays, solid deodorants and ball deodorants, creams and semi-solids to suppress excessive sweating and body odor. Antiperspirants are designed to reduce the secretion of skin secretions and / or inhibit bacterial degradation. Substances most commonly used as antiperspirants include aluminum chlorohydrates, aluminum chloride, buffered aluminum sulfate, and zirconyl chlorohydrates. Examples of antiperspirants include those aluminum chlorohydrates that are available in non-aqueous or salt formulations that vary in the ratio of aluminum to chlorine, as well as in complex compounds with polyethylene glycol or polypropylene glycol. Buffered aluminum sulphate (8% aluminum sulphate buffered with 8% sodium-aluminum lactate) may also be used. Other antiperspirants include glutaraldehyde, formaldehyde, metenamine, and scopolamine hydrobromide.

Other topical agents which may be advantageously used according to the disclosed compositions include irritants; rubefacients (substances that cause only hyperemia); vesicants; caustics or caustics and escharotics; keratolytics (desquamating agents); and cleaning compositions such as soaps, shampoos or detergents may also be used in the present invention.

4. Haematological substances

Haematological agents are any agents that affect blood, body fluids and electrolyte balance. These can also be used as active ingredients in pharmaceutical compositions containing benzethonium chloride, alone or in combination with phenoxyethanol. Examples of hematologic agents include plasma expanders such as dextran 40, dextran 70 and dextran75; antibodies and isoagglutinins, including blood-grouping and typing sera such as anti-A, anti-B and anti-Rh serum, immunoglobulins and immunosera; hemocoagulant proteins such as anti-haemophilic factor, anti-haemophilic factor cryoprecipitate, anti-thrombin III, anti-inhibitory coagulation complex and factor IX complex.

Other examples of hematological agents include anticoagulants or other agents that prolong blood clotting time, including those belonging to the three general types of anticoagulants: calcium binding agents, heparin and its substitutes, and prothrombopenic anticoagulants (oral anticoagulants). Examples of anticoagulants include ditumarol, anisindione, warfarin sodium, various dextrose citrate or sodium citrate solutions, calcium heparin, low molecular weight heparin, sodium heparin, dihydroergotamine mesylate, potassium oxalate, sodium citrate and sodium oxylate. Examples of thrombolytic agents include streptokinase, urokinase, plasminogen activator complex and streptokinase (APSAC), prourokinase (Pro-UK), tissue plasminogen activator (TPA), their recombinant forms, anistreplase and alteplase (recombinant). Examples of antiplatelet agents include aspirin, ticlopidine hydrochloride, dipyridamole, calcium channel blockers, β-adrenergic and anagrelide. All of these may be used according to the disclosed compositions and methods.

Anticoagulant antagonists can also be used as haematological agents in the disclosed compositions and methods. Examples of anticoagulant antagonists include vitamin K or its synthetic substitutes, menadiol sodium diphosphate, menadione, menadione sodium bisulfite, phytonadione, protamine sulfate. Fibrinolysin inhibitors such as aminocaproic acid, tranexamic acid; hemostatics and styptics such as alum, cellulose, collagen, absorbable gelatin powder or gelatin hemostatic tampon, and thrombin; electrolytes and system buffers such as ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, calcium glycerophosphate, calcium lactate, levulinate, dibasic calcium phosphate, dibasic calcium phosphate, calcium sulfate injection, , potassium chloride, potassium gluconate, potassium mixtures, potassium phosphates, mono and di-potassium phosphates, potassium and sodium phosphates, sodium acetate, sodium carbonate, sodium chloride, sodium citrate and citric acid solutions, sodium lactate injection, monobasic sodium phosphate, and tromethamine; and cation complexing agents such as cellulose sodium phosphate, deferoxamine mesylate, dimercaprol, calcium disodium edetate, penicillamine, sodium polystyrene sulfonate, succimer, trientin hydrochloride may also be used.

Finally, other hematological agents such as hematopoietics and other blood-forming agents are preferred according to the present invention. Hematopoietics are anti-anemics that help to produce red and white blood cells. Hematinics are anti-anemics that increase the hemoglobin content in the blood through erythropoiesis or by increasing the hemoglobin content in erythrocytes. Preferred hematopoietics include: iron and its compounds such as ascorbic acid, ferrous fumerate, ferrous gluconate, ferrous sulfate, iron dextran injection and polyferose; hematopoietic growth factors such as epoetin-α, filgrastim, sargramostin and other agents that control the proliferation and differentiation of progenitor stem cells found in bone marrow; anti-haemopoietic agents such as hemin, methylene blue, pentoxifylline, sodium nitrate and other substances that help to manage the increase in circulating erythrocytes.

5. Antihistamines

Antihistamines of different classes are preferred as active ingredient in pharmaceutical compositions containing benzethonium chloride, alone or in combination with phenoxyethanol or phenylethyl alcohol. Among the specific examples

Also classes of antihistamines that are useful in the disclosed compositions and methods include ethanolamines, ethylene diamines, alkylamines, phenothiavines and tiperidines.

Antihistamines are generally sedative and have an anticholinergic effect. Antihistamines particularly preferred in the present invention include H 1 -receptor antagonists and those that competitively inhibit the action of histamine at the receptors. In general, they do not block the release of histamine and therefore provide only palliative relief from allergic symptoms. Examples of antihistamines preferred according to the invention include: astemizole, brompheniramine maleate, carboxamine maleate, chlorpheniramine maleate, clemastine fumarate, cyproheptadine hydrochloride, cyclizine, dexbrompheniramine maleate, dexchlorpheniramine maleate, diphenhydramine hydrochloride, doxenhydrinate s, dimenhydrinate, dimenhydrinate, dimenhydrinate, dimenhydrinate, dimenhydrinate, methdilazine, methdilazine hydrochloride, phenindamine tartrate, prometazine hydrochloride, pyrilamine maleate, terfenadine, fexofenadine, theophylline, trimeprazine tartrate, tripelenamine citrate, trephalinine hydrochloride and triproladin hydrochloride.

Histamine release inhibitors such as sodium chromalyn are also expected to be preferred; serotonin antagonists such as azatadine maleate and cyproheptadine hydrochloride. Any of the above classes of compounds, as well as those listed individually, may be used alone or in combination in pharmaceutical compositions containing one or more preservatives of benzethonium chloride, phenoxyethanol or phenylethyl alcohol.

6. Antibiotics

A wide variety of antibacterial agents can be used as the active ingredient in the pharmaceutical compositions and methods disclosed herein. Systemic antibacterial agents which may be used in the pharmaceutical compositions disclosed herein preserved by benzethonium chloride, alone or in combination with phenoxyethanol or phenylethyl alcohol, include sulfonamides such as sulfabenzamide, sulfadiazine, and sulfamethazine; antibiotics such as penicillin or other β-lactam antibiotics such as amoxycillin, ampicillin, disodium carbenicillin; cephalosporins such as cefadroxil, cefaclor and cefixime; carbapenems and monobactams such as astreonam and imipenem; β-lactamase inhibitors such as sulbactam sodium; aminoglycosides such as gentamicin sulfate, kanamycin sulfate, neomycin sulfate and tobramycin; macrolides such as azithromycin, erythromycin and spiramycin; polypeptides such as bacitracin, capreomycin sulfate, and vancomycin; tetracyclines such as doxycycline and tetracycline hydrochloride; and fluoroquinolones such as norfloxacin and ciprofloxycin hydrochloride. In addition, many other antibiotics are preferred according to this disclosure. Examples of such other antibiotics that may be used include amphotericin-B, cycloserine, and vancomycin hydrochloride. In addition, many other antimalarial, antiprotozoamic, fungicidal and antiviral agents, such as interferons, metisazone, and other antiviral agents are preferred in the compositions and methods disclosed herein.

7. Antiepileptic and anti-seizure agents

The substances used in the treatment of seizures can be used as the active ingredient in pharmaceutical compositions containing benzethonium chloride, alone or in combination with phenoxyethanol or phenylethyl alcohol. Examples of anti-seizure agents that can be used in this way include: phenytoin, carbamazepine, acetazolamide, chlorpromazine hydrochloride, clonazepam, diazepam, dilantin, dimenhydrinate, diphenhydramine hydrochloride, ephedrine sulfate, divalproex sodium, etosuximide, etotoin BP, felphenamine, etafine, fefen, pheltoinb , mefobarbital, parametradione, sodium phenobarbital, sodium phenitoin, primidone, sodium bromide, trimetadione, substituted dibenzoxazepines and sodium valproate. In addition, it is contemplated that any other substance used as an anti-seizure, anti-epileptic or anti-convulsant agent is preferred according to the pharmaceutical compositions disclosed herein for these specifically mentioned examples of anti-seizure drugs.

8. Sedatives and hypnotics

Substances that have a sedative effect or induce relaxation and soothing but not necessarily sleep, except for any hypnotic substances that induce sleep, can be used as the active ingredient in the pharmaceutical compositions and methods disclosed herein. In general, such agents have the ability to induce non-selective, reversible central nervous system depression. Sedatives and hypnotics can be divided into the following groups: benzodiazepines, barbiturates and other various sedative and hypnotic agents. Any of these groups can be used in the compositions disclosed herein. Specific examples of such agents include buclizine, diphenhydramine, benzodiazepine, methotrimeprazine, scopolamine, diazepam, flurazepam, lorazepam, pentobarbital, meprobamate, phenobarbital, chlorohydrate, chlorormezanone and metyprylon. Other and alternative examples of sedative and hypnotic agents include generally inorganic salts such as bromides; chloro derivatives such as chlorohydrate; acetylene alcohols such as etchlorvynol; cyclic ethers such as peraldehyde; carbamic acid alcohol esters; glycol esters of carbamic acid; diureides such as barbiturates; piperidinedione derivatives such as glutetimide; di-substituted quinazolones such as metacvalon; and various aromatic tertiary alkylamines such as antihistamines and parasympatholytics.

9. Diuretics

Diuretics are substances that decrease the volume of extracellular fluid, increase the urinary excretion of sodium chloride, and secondarily increase the volume of urine excreted by the kidneys. In fact, any substance having these effects may be classified as a diuretic and may be advantageous as an active ingredient in the pharmaceutical compositions and methods disclosed herein. Most diuretics block the reabsorption of sodium and / or chloride in the renal tubules. Diuretics can roughly be divided into the following groups: osmotic diuretics, carbonic anhydrase inhibitors, thiazides, potassium sparing diuretics such as spironolactone, triamterene and amiloride, loop diuretics or high ceiling diuretics. Examples of osmotic diuretics include glycerin, mannitol, isosorbide and urea.

Examples of diuretics inhibiting in renal tubules include carbonic anhydrase inhibitors such as acetazolamide, sodium steroacetazolamide, dichlorophenamide, metazolamide, mersalyl with theophylline. Other examples of preferred diuretics that inhibit renal tubules include benzothiadiazine and related diuretics such as bendroflumethiazide, benzthiazide, chlorothiazide, chlorotalidone, cyclotiazide, flumethiazide, hydrochlorothiazide, indapamide, metolazone, polytiazide, and chinetazofine, aminophenone, aminophenone, aminophile.

Examples of potassium-sparing diuretics include spironolactone, triamterene, amiloride, amiloride hydrochloride. Examples of loop diuretics include etacrynic acid, furosemide and bumetanide. In addition, as with all classes of substances, any combination of any of the above diuretics as active ingredients may also be used in the disclosed pharmaceutical compositions and is specifically intended to fall within their scope.

10. Psychopharmacological substances

Psychopharmaceuticals, alternatively also referred to as psychoactive or psychotropic agents, are widely used in the treatment of behavioral and mental disorders such as anxiety, delusions, hallucinations, paranoid states, catatonia, social isolation and autonomic nervous system dysfunctions. Psychopharmaceuticals can be divided into the following groups: antipsychotics, anxiolytics, antidepressants, psychogenic substances. Agents in all of these groups may be useful in the pharmaceutical compositions and methods disclosed herein.

Examples of preferred antipsychotic agents include antipsychotic agents classified in any of the following six groups: phenothiazines such as chlorpromazine; thioxanthenes such as chlorprothixene and thiothixene; butirophenones such as haloperidol; dihydroindolone derivatives such as molindone; dibenzoxazepines such as loxapine; and dibenzodiazepines such as clozapine. Examples of anxiolytics and other agents that have a sedative and anxiolytic effect include various antihistamines such as diphenhydramine; acetylene carbinols such as etchlorvynol; mono-thetaids such as carbromal; barbiturates such as phenobarbital; piperidinediones such as methylprylon;

propyl alcohol derivatives such as meprobamate; and benzodiazepines such as chlordiazepoxide.

Examples of antidepressants that may be used in the compositions and methods disclosed herein include any agent that relieves the symptoms of severe depressive disorders and may lead to increased behavioral activity. Typical examples of antidepressants include those that can be classified as tricyclic antidepressants such as imipramine hydrochloride, imipramine pamoate, amitriptyline hydrochloride, amoxapine, desipramine hydrochloride, doxepin, protriptyline hydrochloride, and trimipramine. Other examples of antidepressants may be classified as monoamine oxidase inhibitors such as isocarboxazide, phenelzine sulfate and tranylcypromine sulfate. Other examples of antidepressants include second generation antidepressants such as amoxapine, maprotalin, trazodone, fluoxetine and buproprion,

Psychogenic substances are other substances that cause temporary deviations in the mental state of human subjects or deviations in animal behavior. These may also be useful in the pharmaceutical compositions disclosed herein and include, for example, cannabis, lysergic acid diethylamide, and mescaline.

11. Antimigrenic

Various agents that counteract dilatation of blood vessels associated with migraine in the brain can be used in the treatment of migraine and can be used as an active ingredient in the pharmaceutical compositions disclosed herein. Examples of anti-migraines include rial alkaloids, various ergotamines, and sumatriptan succinate.

Substances that are used to stimulate uterine smooth muscle, known as oxytotics, are often reported in relation to substances used in the treatment of migraine. These agents may also be useful as active agents in the disclosed pharmaceutical compositions. Examples of preferred oxytotics include carboprost tromethamine, cyproheptadine, dinoprostone, methylergonovine maleate, methysergide maleate, oxytocin and sodium chloride.

12. Hormones

Hormones or other agents that are secreted by endocrine or ductless glands and non-glandular tissues that serve to integrate metabolic processes may be useful as an active ingredient in the pharmaceutical compositions and methods disclosed herein. The hormones may be derivatives of amino acids, steroids or various other substances. Examples of hormones that can be used according to the methods and compositions disclosed herein include sematropins, including growth hormones; gonadotropic hormones such as follicle stimulating hormone or luteinizing hormone; prolactin; thyrotropic hormones; adrenocorticotropic hormones; or other pituitary hormones. Other examples of hormones that are useful in the compositions and methods disclosed herein include human chorionic gonadotropin; corticotropin; and bromocriptine. Other preferred hormones include mid-lobe hormones such as intermedin or melanocytes stimulating hormone; posterior lobe hormones such as oxytocin and vasopressin.

The adrenal hormones may also be useful in the compositions and methods disclosed herein. Examples of adrenal hormones include adrenal corticosteroids such as cortisone and cortisone acetate, dexamethasone, hydrocortisone, prednisone and various forms of prednisolone. Also preferred is glyburide; parathyroid hormones such as calcitriol and dihydrotachysterol; and pancreatic hormones, such as insulin and glucagon, in any of its forms. Thyroid hormones include substances that modulate energy metabolism and certain non-energy functions of the body. Preferred thyroid hormones include calcitonin, thyroglobulin and thyroid.

Other hormones that can be used include sex hormones that can be classified as estrogenic hormones, pre-gestational hormones, and androgenic hormones. Estrogenic hormones and pre-gestational hormones are known as ovarian hormones. They can be used in both synthetic and natural forms. Examples of ovarian hormones include estradiol and its various forms, estrone and quinestrol. Examples of synthetic estrogens include dienestrol, mestranol and norethindrone. The second type of ovarian hormone is progesterone. Examples of gestagens include ethynodiol diacetate and norethindrone. This medicine is related substances that suppress the effects of estrogen by various mechanisms. Such agents may also be useful as an active ingredient in the compositions disclosed herein and include, for example, clomiphene citrate and tamoxifen citrate.

Androgenic hormones are those produced primarily in the testes. Examples of preferred androgenic hormones include testosterone, cyproterone acetate, danazol, finasteride, oxymetolone, testolactone, and various analogous testosterone compounds and derivatives such as testosterone cypionate, testosterone enanthate and testosterone propionate.

13. Proteins or peptides

Various proteins or peptides may be useful as active ingredients in the pharmaceutical compositions disclosed herein. This is one of the advantages of using a benzethonium chloride preservative, alone or in combination with phenoxyethanol or phenylethyl alcohol, that they are practically compatible with peptides and proteins in solution with both recombinant and gene-activated forms of proteins. Examples of proteins that can be used include many of those already mentioned, such as erythropoietin, insulin, granulocyte colony stimulating factor (GCSF), hormones, enzymes, vaccines and steroids.

14. Anti-tumor agents

The antitumor agents, or even combinations of antitumor agents, may be formulated into multiple dose formulations with benzethonium chloride and phenoxyethanol. Such antitumor agents that may be used in such compositions, either alone or in combination, include, but are not limited to, tamoxifen, taxotere, doxorubicin, cisplatin, cyclophosphamide, interferon, tumor necrosis factor, methotrexate, or variants thereof.

C. Other ingredients of the formulation

Optimally disclosed compositions and methods will vary according to factors such as the active ingredient (s), the time it will be stored, the conditions under which it will be stored and used, including the pharmaceutical form of the composition and the particular patient population who may be served. Adjustments to this composition can be made according to the needs of the formulator, applicator and patient by adjusting the components of these compositions and their relative concentrations, including the amounts of benzethonium chloride, phenoxyethanol and phenylethyl alcohol. Other components of the multi-dose formulations of the invention may include water, a buffer, a β-H modifier, a surfactant or an anti-adsorbant, a wetting agent, a gel substance, a desiccant, an osmolality modifier or, in dependence on the desired dosage form, any other excipient or carrier.

Composition properties that can be adjusted include, for example, pH and osmolality. For example, it may be desirable to achieve a composition having a pH and osmolality similar to human blood or tissues in order to support the efficacy of the composition when administered parenterally. Alternatively, alternative properties may be adjusted to support the efficacy of the disclosed compositions when administered by other routes.

Buffers are useful in the present invention, inter alia, for the possibility of adjusting the overall pH of the pharmaceutical composition (particularly when administered parenterally). Many buffers known in the art, such as various salts of organic or inorganic acids, bases or amino acids, can be used in these compositions, including various forms of citrate, phosphate, tartrate, succinate, adipate, maleate, lactate, acetate, carbonate or carbonate ions. Particularly preferred buffers for use in parenterally administered forms disclosed in the compositions of the invention include sodium or potassium buffers, especially sodium phosphate. In a preferred embodiment for parenteral dosing, sodium phosphate is used at a concentration of about 20 mM to achieve a pH of about 7.0. A particularly effective sodium phosphate buffer system comprises monobasic sodium phosphate monohydrate and dibasic sodium phosphate heptahydrate. If this combination of monobasic and dibasic sodium phosphate is used, the preferred monobasic phosphate concentration is from 0.5 to 1.5 mg / ml and the dibasic from about 2.0 to 4.0 mg / ml, with a preferred concentration of about 0.9 mg / ml for monobasic and about 3.4 mg / ml for dibasic phosphate. The pH of the composition varies according to the amount of buffer used.

Depending on the dosage form and the intended route of administration, it may be advantageous to use buffers at different concentrations or to use other excipients to adjust the pH of the composition to include other ranges. Preferred pH ranges in the compositions of the invention include a pH of from about 2.0 to about 12.0.

Surfactants may also be useful in the compositions disclosed herein. Surfactants or antiadsorbants that have been shown to be preferred include polyoxyethylene sorbitans, polyoxyethylene sorbitan monolaureate, polysorbate-20 such as Tween-20 ™, polysorbate-80, hydroxycellulose and genapol. By way of example, when any surfactant is used in the present invention to produce a parenterally administrable composition, it is preferred to use it at a concentration of about 0.01 to about 0.5 mg / ml.

Other preferred excipients can be readily determined by those skilled in the art according to the particular needs or intended uses of the compositions and the needs of the formulator. One such particularly preferred other substance is sodium chloride, which is suitable for adjusting the osmolality in the compositions to achieve the desired resulting osmolality. Particularly preferred osmolalities for parenteral administration of the disclosed compositions are in the range of about 270 to about 330 mOsm / kg. The optimum osmolality for parenterally administered compositions, especially injectable, is about 300 Osm / kg and is obtainable by using sodium chloride at concentrations of about 6.5 to about 7.5 mg / ml, with a sodium chloride concentration of about 7.0 mg / ml being particularly effective.

D. Preparation of compositions

The compositions described herein can be prepared in water suitably mixed with a surfactant such as hydroxypropyl cellulose or polyoxyethylene sorbitans. In many cases, it may be preferred to include isotonic agents, for example, sugars or sodium chloride, as mentioned above. Prolonged absorption of the injectable compositions may be achieved by the use in the compositions of agents which delay absorption, for example, aluminum monostearate or gelatin. The disclosed compositions do not require a high content of added alcohols in order to achieve or maintain their antimicrobial effect. For example, a composition with an alcohol content of greater than 55% or greater than 75% or even greater than 90% is not necessary. Other materials that may be used include, but are not limited to, lecithin, urea, ethylene oxide, propylene oxide, hydroxypropylcellulose, methylcellulose, or polyethylene glycol.

Aqueous compositions (inocula) as described herein may contain an effective amount of the desired 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 carriers and substances for pharmaceutically active substances is well known in the art. Unless any conventional medium or substance is incompatible with the active ingredient, its use in these therapeutic compositions is contemplated. Supplementary active ingredients may also be included in the formulations described above.

A proteoglycan, such as erythropoietin, may be formulated into a neutral or salt form. Pharmaceutically acceptable salts include acid addition salts (formed by free amino groups of the protein) and those formed by inorganic acids such as hydrochloric or phosphoric acid, or by such organic acids as acetic, oxalic, tartaric, mandelic and the like. Salts formed by free carboxyl groups may also be derived from inorganic bases such as sodium, potassium, ammonium, calcium or ferric hydroxide and from such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.

The therapeutic compositions of the invention are preferably administered in the form of injectable formulations, either as liquid solutions or suspensions; solid forms suitable for solutions or suspensions in liquid for injection may also be prepared. The compositions of the invention may also be administered as inhalers in aerolized form. Based on the needs of the formulator, applicator or treatment object, the compositions disclosed herein may in fact take any form, including liquid, suspension, emulsion, solution, oil, mixture, cream, ointment, gel, lace, semi-solid, aerosol, powder, tablet or capsule. . A typical composition comprises a pharmaceutically acceptable carrier. For example, the composition may contain 10 mg, 25 mg, 50 mg or up to about 100 mg of human serum albumin per milliliter of phosphate buffered saline.

The compositions described in this invention may be placed in an ampoule, bottle, tube, syringe, inhaler or other container for single or multiple administration. Such containers may be made of glass or a polymeric material such as polypropylene, polyethylene or polyvinyl chloride. Preferred containers may have a seal or other closure system, such as a rubber stopper, which can be punctured by a needle to take a single dose and which is closed again after withdrawal of the needle. All such containers for injectable liquids, lyophilized formulations, reconstituted lyophilized formulations, or reconstitutable dusts for injection known in the art or for administration of aerosol formulations are intended to be used in the compositions and methods disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

One skilled in the art will recognize that many formulations or compositions containing a preservative of benzethonium chloride can be prepared, alone or in synergistic combination with phenoxyethanol or in combination with phenyl ethyl alcohol. The following is only one example of such a formulation or composition. This example is intended to be illustrative only and will not limit the scope of the invention.

Example 1

An effective antihistaminic composition may be formulated as follows: An effective amount of fexofenadine; xylitol; sorbitol; glycerin; saccharin sodium; benzethonium chloride at a concentration of about 0.005%; Phenoxyethanol in an amount of 0.25% sodium hydroxide to adjust the pH.

references

U. U.S. Pat. No. 4,806,524, Kawagachi et al.

U. U.S. Pat. 5,503,827, Woog et al. ,,

U. A. U.S. Pat. 5,661,125, Stricklan et al.

Handbook of Pharmaceutical Excipients, Second Edition, 1994

L.A. Trissel, Manual of Injectable Drugs Ed. 8, American Society of Hospital Pharmacists, Inc. 1994 Medical References, ed. 48, 1994 Medical references, ed. 50, 1996

Sandeep Nema, R.J. Washkuhn and R.J. Brendel, Excipients and Their Use in Injectables, PDA Journal of Pharmaceutical Sciences & Technology, Vol. 51 (4), July-August 1997.

FROM'

Claims (52)

A pharmaceutical composition comprising a pharmacologically active substance and an amount of benzethonium chloride and an amount of phenoxyethanol in which the amounts of benzethonium chloride and phenoxyethanol are effective to inhibit microbial growth and wherein the composition is not formulated for topical administration. 2. The composition of claim 1, further defined as comprising benzethonium chloride at a concentration of from about 0.001 to about 1.0% and phenoxyethanol at a concentration of from about 0.01 to about 2.0%. Composition according to claims 1, 2, 45, 46 or 47, characterized in that the pharmacologically active ingredient is a cardiovascular agent. Composition according to claim 3, characterized in that the cardiovascular substance is diltiazem, digoxin, dopamine, digitalis, procainamide hydrochloride, lidocaine, verapamil or levostatin. Composition according to claims 1, 2, 45, 46 or 47, characterized in that the pharmacologically active ingredient is a substance for the treatment of the gastrointestinal system or the liver. The composition of claim 5, wherein the agent for treating the gastrointestinal system or liver is an antacid, a digestant or an emetic. Composition according to claim 5, characterized in that the substance for the treatment of the gastrointestinal system or liver is lipase, furosemide, seas, scopolamine, ranitidine. Composition according to claim 44, characterized in that the pharmacologically active ingredient is a topically active substance. Composition according to claim 8, characterized in that the topically active substance is bentonite, zinc oxide, dimethicone or glycerin. Composition according to claims 1, 2, 45, 46 or 47, characterized in that the pharmacologically active ingredient is a hematological. Composition according to claim 10, characterized in that the hematological agent is heparin, streptokinase, urokinase, tissue plasminogen activator or aspirin. Composition according to claims 1, 2, 45, 46 or 47, characterized in that the pharmacologically active substance is an antihistamine. . 13. The composition of claim 12, wherein the antihistamine is theophylline, diphenhydramine, hydroxyzine, or fexofenadine. The composition of claim 12, wherein the antihistamine is fexofenadine. 15. The composition of claim 14, comprising about 0.005% benzethonium chloride and about 0.25% phenoxyethanol. Composition according to claims 1, 2, 45, 46 or 47, characterized in that the pharmacologically active substance is an antimicrobial. 17. The composition of claim 16 wherein the antimicrobial agent is penicillin, amoxycillin, kanamycin, neomycin, erythromycin, tetracycline, doxycycline, nerfloxacin, or cyclosporine. Composition according to claims 1, 2, 45, 46 or 47, characterized in that the pharmacologically active substance is an anti-epileptic or anti-seizure substance. 19. The composition of claim 18 wherein the anti-epileptic or anti-seizure agent is phenytoin, dilantin or phenobarbital. Composition according to claims 1, 2, 45, 46 or 47, characterized in that the pharmacologically active substance is a sedative or a hypnotic. The composition of claim 20, wherein the sedative or hypnotic is scopolamine, fexofenadine or metacvalon. Composition according to claims 1, 2, 45, 46 or 47, characterized in that the pharmacologically active substance is a diuretic. 23. The composition of claim 22, wherein the diuretic is furosemide, amiloride, aminophylline or theobromide. Composition according to claims 1, 2, 45, 46 or 47, characterized in that the pharmacologically active substance is a psychopharmacological substance. 25. The composition of claim 24, wherein the psychopharmacological agent is an antipsychotic or antidepressant. Composition according to claims 1, 2, 45, 46 or 47, characterized in that the pharmacologically active substance is an anti-migraine. 27. A composition as claimed in claim 1, 2, 45, 46 or 47, wherein the pharmacologically active substance is a hormone. 28. A composition according to claim 1, 2, 45, 46 or 47. characterized in that the pharmacologically active substance is a protein or a peptide. The composition according to claim 1, 2, 45, 46 or 47, further comprising a second active ingredient. The composition of claim 29, wherein the second active agent is a cardiovascular agent, a gastrointestinal disorder, a topically active agent, a hematologic agent, an antihistamine, an antimicrobial, an anti-epileptic, an anti-seizure, a sedative, a hypnotic, a diuretic. a psychopharmacological, anti-migraine, hormone, protein or peptide. Composition according to claims 1, 2, 45, 46 or 47, characterized in that the composition is a liquid, suspension, emulsion, solution, mixture, cream, inhalant, aerosol, gel, ointment, suppository, powder, tablet . 32. The composition of claim 1, 2, 45, 46 or 47, wherein the composition can be administered parenterally, via the mucosa, topically, by suppository, by inhalation, orally, aurally, or ocularly. A pharmaceutical carrier composition for use as a non-topically administered carrier for a pharmaceutical active ingredient, wherein the carrier comprises an amount of benzethonium chloride and an amount of phenoxyethanol in which the amounts of benzethonium chloride and phenoxyethanol are effective to inhibit microbial growth in the composition. 34. The pharmaceutical carrier composition of claim 33, further defined as comprising 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%. 35. A pharmaceutical carrier composition according to claim 33 or 34, wherein the pharmaceutical active ingredient is a cardiovascular agent, a substance for treating gastrointestinal disorders, a topically active substance, a hematological, an antihistamine, an antimicrobial, an antiepileptic, an anti-seizure, a sedative, hypnotic, diuretic, psychopharmacological, anti-migraine, hormone, protein or peptide. 36. A pharmaceutical carrier composition according to claim 48, 49 or 50, wherein the pharmaceutical active ingredient is a cardiovascular agent, a substance for treating gastrointestinal disorders, a topical agent, a hematological, an antihistamine, an antimicrobial, an antiepileptic agent. , an anti-seizure, a sedative, a hypnotic, a diuretic, a psychopharmacological, an anti-migraine, a hormone, a protein, or a peptide. 37. A multiple dose ampoule of a pharmacologically active ingredient, characterized in that the ampoule contains a solution containing the active ingredient and an amount of benzethonium chloride and an amount of phenoxyethanol in which the amounts of benzethonium chloride and phenoxyethanol are effective to inhibit microbial growth in the formulation. , in this solution formulated for administration by any of the routes selected from parenteral, mucosal, ocular, aural, oral, suppository, by inhalation. 38. The vial of claim 37, further comprising benzethonium chloride at a concentration of from about 0.001 to about 1.0% and phenoxyethanol at a concentration of from about 0.01 to about 2.0%. 39. The ampoule of claim 37 or 38, wherein the pharmacologically active ingredient is a cardiovascular agent, a substance for treating gastrointestinal disorders, a hematological agent, an antihistamine, an antimicrobial, an anti-epileptic, an anti-seizure agent, a sedative, a hypnotic agent, a diuretic. , an anti-migraine, a hormone, a protein, or a peptide. 40. A multiple dose pharmaceutical package of the pharmacologically active ingredient, wherein the ampoule contains a solution containing the active ingredient and an amount of benzethonium chloride and an amount of phenoxyethanol in which the amounts of benzethonium chloride and phenoxyethanol are effective to inhibit microbial growth. in this composition, benzethonium chloride is present at a concentration of from about 0.001% to about 0.07% and phenoxyethanol is present at a concentration of from about 0.01% to about 0.45%, in this solution formulated for administration by any of the routes selected from following: parenteral, mucosal, ocular, aural, oral, suppository, by inhalation. 41. The pharmaceutical package of claim 40, wherein the pharmacologically active ingredient is a cardiovascular agent, a substance for treating gastrointestinal disorders, a topical agent, a hematological, an antihistamine, an antimicrobial, an antiepileptic, an anti-seizure, a sedative, , a diuretic, a psychopharmacological, an anti-migraine, a hormone, a protein, or a peptide. 42. A method of inhibiting microbial growth in a solution which is not intended for topical administration and which comprises a pharmacologically active substance, comprising adding benzethonium chloride and phenoxyethanol to said solution. 43. The method of claim 42, wherein benzethonium chloride is added at a concentration of about 0.001 to about 1.0% and phenoxyethanol is added at a concentration of about 0.01 to about 2%. 0%. 44. The method of claim 42 or 43, wherein the pharmacologically active ingredient is a cardiovascular agent, a gastrointestinal disorder, a hematological, an antihistamine, an antimicrobial, an anti-epileptic, an anti-seizure, a sedative, a hypnotic, diuretic, psychopharmacological, anti-migraine, hormone, protein or peptide. 45. A pharmaceutical composition comprising a pharmacologically active ingredient, an amount of benzethonium chloride and an amount of phenoxyethanol in which the amounts of benzethonium chloride and phenoxyethanol are effective to inhibit microbial growth, and wherein the benzethonium chloride is present at a concentration of about 0.001% to about 0.005% and phenoxyethanol is present at a concentration of from about 0.01% to about 0.25%. 46. A pharmaceutical composition comprising a pharmacologically active ingredient, an amount of benzethonium chloride and an amount of phenoxyethanol in which the amounts of benzethonium chloride and phenoxyethanol are effective to inhibit microbial growth, and wherein the composition is formulated for administration by any of the routes selected from following: parenteral, mucosal, ocular, aural, oral, suppository, by inhalation. 47. The pharmaceutical composition of claim 46, further defined, comprising benzethonium chloride at a concentration of about 0.001 to about 1.0% and phenoxyethanol at a concentration of about 0.01 to about 2.0%. 48. A pharmaceutical carrier composition for use as a carrier for a pharmaceutical active ingredient, wherein the carrier comprises an amount of benzethonium chloride and an amount of phenoxyethanol in which the amounts of benzethonium chloride and phenoxyethanol are effective to inhibit microbial growth in the composition and wherein the benzethonium chloride is present at a concentration of from about 0.001% to about 0.005% and the phenoxyethanol is present at a concentration of from about 0.01% to about 0.25%. 49. A pharmaceutical carrier composition for use as a carrier for a pharmaceutical active ingredient, wherein the carrier comprises an amount of benzethonium chloride and an amount of phenoxyethanol in which the amounts of benzethonium chloride and phenoxyethanol are effective to inhibit microbial growth in the composition and wherein carrier formulations for administration by any of the routes selected from parenteral, mucosal, ocular, aural, oral, suppository, by inhalation. 50. The pharmaceutical carrier composition of claim 33, further defined as comprising benzethonium chloride at a concentration of about 0.001 to about 1.0% and phenoxyethanol at a concentration of about 0.01 to about 2.0%. 51. A method which inhibits microbial growth in a solution comprising a pharmacologically active ingredient, comprising adding benzethonium chloride and phenoxyethanol to the solution, wherein the benzethonium chloride is added to be at a concentration of about 0.001 to about 0.005% and phenoxyethanol. is added to be at a concentration of from about 0.01 to about 0.25%. 52. The method of claim 46, wherein the pharmacologically active ingredient is a cardiovascular agent, a substance for treating gastrointestinal disorders, a topically active agent, a hematologic agent, an antihistamine, an antimicrobial, an antiepileptic, an anti-seizure agent, a sedative, a hypnotic, a diuret. , an anti-migraine, a hormone, a protein, or a peptide.