Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/74—Synthetic polymeric materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/74—Synthetic polymeric materials
  • A61K31/745—Polymers of hydrocarbons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/74—Synthetic polymeric materials
  • A61K31/785—Polymers containing nitrogen

Definitions

• This invention relates to quaternary ammo nium group-containing polymers. More particularly it concerns a family of such polymers that exhibit antimicrobial activity and their application as antimicrobials.
• the polymers of the invention may be classified as having a poly(vinylbenzyl quaternary ammonium) halide structure. In certain embodiments, they have a copolymer- structure with repeating
• polymeric quaternary compounds fill a well identified and recognized need for a polymeric antimicrobial agent similar to or surpassing known nonpolymeric species such as hexachlorophene, Zephiran and the like.
• a polymeric antimicrobial agent similar to or surpassing known nonpolymeric species such as hexachlorophene, Zephiran and the like.
• the present materials are less mobile and less likely to migrate or inappropriately penetrate or be absorbed into substrates. This permits their use in environments where penetration or displacement or volatilization are problems. Further, it permits residual antimicrobial activity to be imparted to surfaces and the like by the use of these materials.
• R is a 4 to 12 carbon atom alkyl and R' and R'' are each independently 1 to 4 carbon atom alkyls and X- is an anion such as halide, have antimicrobial activity.
• Such materials can be homopolymers but preferably are "copolymers. These polymers and copoly mers constitute aspects of this invention. Antimicrobial compositions based on them and their use constitute additional aspects.
• Molecular weights are expressed in daltons (D) and are determined by gel permeation chromatography comparison of experimental compounds with chemically similar standards of known molecular weight. Weights, temperatures and pressures are given in metric units unless otherwise noted.
• “Hygienically acceptable” refers to the property of being acceptable as a component of a material to be used to clean, disinfect or sterilize a human's or animal's physiological environment.
• “Physiologically acceptable” means non-toxic and usable in materials contacting or consumed by mammals including man.
• Machine unit means a discrete repeating unit within the polymer structure.
• the homopolymers and copolymers of this invention always contain a vinylbenzyl ammonium salt as a recurring mer unit. This unit has the structure
• R ' X " wherein R is a 4 to 12 carbon alkyl and R' and R'' are the same or different 1 to 4 carbon atom alkyls.
• X is a physiologically acceptable anion.
• R is a 6 to 10 carbon atom linear or branched alkyl - i.e. hexyl, 2-ethylhexyl, octyl, decyl, nonyl, heptyl,
• R' and R'' are 1 to 2 atom alkyls - that is methyl or ethyl. Usually and more preferably, R, and R'' are the same alkyl. The more preferred arrangement has R equal to an about 8 carbon atom alkyl. Most preferably R is n-octyl and R' and R'' are each methyl.
• Counterion X- may be any physiologically acceptable anion.
• usual preparative methods generally lead to a halide (e.g. Cl", I" or Br- ) with chloride ion being by far the most common.
• the polymers contain copolymeric units - herein the generic structure being depicted as -CU-.
• the units can be added for such down-to-earth purposes as to reduce the average cost per unit weight of the polymer or to "dilute" the active units and thus yield a more easily measured, handled or applied material.
• the copolymeric units can be added to achieve or enhance desired physical properties, as well. Such properties include greater antimicrobial activity, better solubility in aqueous or nonaqueous media, better irascibility in various media, enhanced dispersibility, enhanced film forming and the like.
• the first type of "CU” units are represented by styrene and similar vinylaromatics and lower alkenes or alkadienes such as ethylene, butadiene and the like.
• the second type of CU units are illustrated by vinyl acetamide, vinyl amine, vinyl amine quater- nized with hydroxyethylenes or similar water solubil- izers or with a hydrophobe such as dodecyls, or vinylbenzyl amine quaternized with three long chain alkyl hydrophobes or with three lower alkyl or hydroxyalkyl hydrophiles.
• Other units include for example vinyl acetate, vinyl alcohol, acrylic acid, acrylate and methacrylate esters; acrylamide and acrylamide derivatives including quaternized acrylamide; N-vinylimida- zole and derivatives thereof including quaternized N-vinylimidazoles; 4-vinylpyridine and derivatives thereof including quaternized 4-vinylpyridines ?
• N-vinylpyrrolidone and derivatives thereof vinylbenzyl ethers of polyethylene glycols and their monoalkyl ethers. These units are all known in the art as are the methods for their incorporation into copolymers. Mixtures of two or more CU units may, of course, be used.
• the CU's can be grouped as 2 to 6 carbon alkylenes or alkenylenes having pendent therefrom from 0 to 2 inclusive substituent groups selected from aryls, alkaryls, and aralkyls of 6-8 carbons, alkyls of 1-4 carbons, amides, hydroxyls, carboxylic acids, and their esters nitrogen-containing 5 or 6 atom heterocyclics and amine and ether-substituted aryls, alkaryls, and aralkyls.
• copolymer units are vinylbenzyl -amines quaternized by hydrophilic groups such as hydroxy alkyls of from 1 to 4 carbon atoms, particularly vinylbenzyl amines quaternized with three 2-hydroxyethylenes (i.e. with a triethanolamine structure) .
• hydrophilic groups such as hydroxy alkyls of from 1 to 4 carbon atoms, particularly vinylbenzyl amines quaternized with three 2-hydroxyethylenes (i.e. with a triethanolamine structure) .
• Such units are represented structurally as
• copolymer units are vinylbenzyl ethers of poly(ethyleneglycols) or their monoalkyl ethers, particularly methyl ethers. Such units are represented structurally as
• the polymeric quaternary amines of this invention have at least about 10 mer units on average in each polymer molecule. Preferably they contain from 10 to about 2000 mer units. This gives rise to molecular weights for the homopolymer of from about 3000 to about 600,000 and for copolymers, of from about 1000 to a million or so, depending upon the unit and proportions employed. More preferably the number of mer units is from about 20 to about 1000.
• the proportion of copolymeric mer units in the polymer can vary from 0 (homopolymer) to about 90% of the total. Among copolymers, those having at least about 20% of copolymer unit (CU's) are generally preferred. With less than this level, often the products have essentially the properties of the homopolymer. This means that structurally the polymers can be represented as follows:
• R is a 4 to 12 carbon atom alkyl and R' and R'' are 1 to 4 carbon alkyls and n is 10 to 2000 and X is an anion; and (copolymer)
• the polymers of this invention can be prepared by the general process of: a. polymerizing vinylbenzyl halide plus any optional comonomer units using free-radical catalysis, and b. reacting the resulting poly (vinylbenzyl halide) with tertiary amine to yield the desired quaternary amine which is thereafter recovered.
• the polymerization reaction is carried out with the monomer (s) in solution in an inert organic, often aromatic reaction medium such as toluene, benzene, tetrahydrofuran, or methylethyl ketone. It is of advantage to have an inert atmosphere, such as argon, over the reaction zone.
• a free-radical initiator such as a peroxide, or for example, AIBN (azobisisobutyronitrile) is employed in amounts of from 0.01 to 0.5% wt (basis monomer).
• the reaction is carried out at elevated temperatures, for example at temperatures of from 50 to 150°C, most commonly at the reflux temperature of the reaction medium. Elevated pressures may be employed to achieve temperatures above atmospheric reflux.
• the reaction takes a substantial period - often as long as several days. Of course, this period is related .to the temperature employed with higher temperature requiring shorter time and lower temperature requiring longer times. As a guideline, at 75-80 °C reaction temperature the reaction is complete in 18 to 24 hours.
• the polymeric intermediate product is recovered such as by precipitation following nonsolvent addition.
• the rnolecular weight of the resulting polymer can be varied by changing reaction conditions, such as the monomer and free radical initiator concentrations, solvent composition, and the reaction temperature as is known in the art.
• the coupling of the tertiary amine to the poly(vinylbenzyl halide) is carried out in a relatively polar organic solvent system such as THF or alkanols or mixtures thereof.
• a relatively polar organic solvent system such as THF or alkanols or mixtures thereof.
• solvent systems are tetrahydrofuran (THF), methanol, ethanol, isopropanol, isobutanol, THF:ethanol, THF:isopropanol, and THF: isobutanol.
• THF tetrahydrofuran
• methanol ethanol
• isopropanol isobutanol
• THF:ethanol ethanol
• THF isobutanol.
• a preferred solvent system is 1:1 THF: isopropanol.
• the reaction is carried out by admixing the poly(vinylbenzyl halide) and the tertiary amine in the reaction medium and heating.
• the amount of tertiary amine should be controlled. If a homopolymer product is desired - i.e. with all available benzyl halide groups reacted — it is of advantage to add an excess of amine, such as from above 1.0 to 1.5 or more equivalents of amine per mole of available benzyl halide. The excess is employed only to speed the reaction. In fact, the amine will react relatively quantitatively with available halide sites.
• tertiary amine when it is desired to react only a portion of the available halide sites with tertiary amine, less tertiary amine should be added.
• tertiary amine when a 1:1 equivalent tertiary amine: trialkanol amine copolymer is desired, one generally adds about 0.5 equivalent of trialkyl amine, basis available sites.
• This reaction is complete in 24 hours at 60-80 °C .
• the reactants are relatively heat stable so higher temperatures such as up to 150°C can be employed without adversely affecting the reaction ' s yield.
• temperatures from about 50 to 150 °C and times of 1 to 24 hours can be employed with temperatures of 60 to 140oC being preferred.
• reactants with the benzyl halide sites for example trialkanolamines
• the coupling of the second material may be carried out in the same reaction medium without intermediate isolation of the product.
• the coupling of the second material generally employs similar reac tion conditions to those used to couple the first.
• the polymers of this invention are characterized as having antimicrobial activity. In this use they are formulated into antimicrobial compositions such as by being admixed with an hygienically accep- table carrier or vehicle.
• This antimicrobial activity gives the materials utility as preservatives for ophthalmic, solutions, especially wetting solutions, .cleaning solutions, cushioning solutions and soaking solutions for hard and soft contact lenses.
• the materials offer a special advantage of not absorbing and concentrating within the lens as roonomeric antimicrobials and preservaties have been known. to do.
• Other utilities are as preserva tives and/or antimicrobials for hair care, and topical pharmaceutical products.
• Other uses include incorporation in intra-vaginal anti-infectives, spermicides, therapeutic skin care (anti-acne) preparations and use as persistent deodorants or antimicrobials for body cavities such as the abdomen, lungs, or GI tract and the like.
• the products can he formulated with various cleanser components to form persistent disinfectants for home or hospital use.
• the products are generally admixed with a suitable carrier or medium such as sterile water or saline, gel salve bases, and the like in an antimicrobially effective amount which amount is defined to be an amount sufficient to effect the desired antimicrobial or preserving action.
• a suitable carrier or medium such as sterile water or saline, gel salve bases, and the like
• antimicrobially effective amount which amount is defined to be an amount sufficient to effect the desired antimicrobial or preserving action.
• Such amounts vary from as little as 10 - 20 ppm to as much as 1000 ppm (in finished product form) or up to 5% in concentrated formulations.
• the antimicrobial formulations are prepared by conventional means of admixing, grinding and the like.
• the polymers can be considered to be like other water-soluble salts and may be treated accordingly. No special formulation techiques are usually required.
• a taffy-like precipitate formed was collected, was rinsed in water, redissolved in THF, filtered, precipitated in petroleum ether, redissolved in THF and finally precipitated in methanol. The precipitate was collected and vacuum dried for nine hours at 60°C.
• the product was a powder having an average molecular weight by qel permeation chromatography comparison with polystyrene of 6.4 X 10 3 .
• Triethanolamine (2.0 g, 13.4 mmole) was added to the reaction product of Part B, followed by 30 ml of isopropanol. The reaction mixture was then refluxed another 24 hours. At the conclusion of this reaction period, the homogeneous mixture was cooled, diluted to three times its original volume with water, and the volatile constituents removed by in vacuo distillation (rotary evaporator). The residue, after concentration to one-half volume, was diluted with three volumes of 20% aqueous isopropanol and .ultrafiltered through a 10,000 molecular-weight-cutoff cartridge (Amicon H1P10) with ten diavolumes of deionized water. The retentate was then concentrated by ultrafiltration to 100 ml and lyophilized to yield 2.46 g fluffy white solid of the formula
• Example I The preparation of Example I was repeated substituting for dimethyloctylamine in equivalent amounts as follows:
• Example I 0.5 ratio vinylbenzylchloride: n-dodecyl-4 vinyl pyridinium chloride M.
• the preparation of Example I is repeated substituting trimethylamine for triethanolamine.
• a typical antimicrobial solution is prepared by dissolving 0.5% by weight of the product of Example I in sterile water, in a 25%/75% isopropanol/sterile water mixture, in a sterile saline solution adjusted to give isotonicity, and in an isotonic contact lens wetting solution containing 1% by weight poly(vinylalcohol).
• An antimicrobial cleansing composition comprising 10% of the dry polymer of Example II and 90% powdered surfactant is prepared. When this composition is dissolved in water an antimicrobial solution results .
• An antimicrobial salve is formulated by admixing 1% of the powder of Example I in a pharmaceutically acceptable poly saccharride gel.
• Example I, II, III, IV, V, and VI were tested for antimicrobial activity.
• Zephiran ⁇ a commercially accepted antimicrobial
• comparative materials 1, 2 and 3 were also evaluated. Two basic test methods were used.
• MIC Minimum Inhibition Concentration
• Example III >250 >48
• Example IV ⁇ 50 0.17
• Example V ⁇ 100 0.6
• Example VI ⁇ 250 4 Comparative 1 >250 >48 Comparative 2 >250 >48 Comparative 3 >250 24

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• 1982
  • 1982-09-14 EP EP19820903009 patent/EP0087473A4/fr not_active Withdrawn
  • 1982-09-14 WO PCT/US1982/001244 patent/WO1983001002A1/fr not_active Application Discontinuation

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