MXPA99005481A - Use of low molecular weight amino alcohols in ophthalmic compositions - Google Patents
Use of low molecular weight amino alcohols in ophthalmic compositionsInfo
- Publication number
- MXPA99005481A MXPA99005481A MXPA/A/1999/005481A MX9905481A MXPA99005481A MX PA99005481 A MXPA99005481 A MX PA99005481A MX 9905481 A MX9905481 A MX 9905481A MX PA99005481 A MXPA99005481 A MX PA99005481A
- Authority
- MX
- Mexico
- Prior art keywords
- composition
- amino
- further characterized
- compositions
- methyl
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 166
- 150000001414 amino alcohols Chemical class 0.000 title abstract description 26
- 230000000845 anti-microbial Effects 0.000 claims abstract description 32
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229920005862 polyol Polymers 0.000 claims abstract description 21
- CBTVGIZVANVGBH-UHFFFAOYSA-N Aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 claims abstract description 18
- 150000003077 polyols Chemical class 0.000 claims abstract description 17
- 150000003973 alkyl amines Chemical class 0.000 claims abstract description 15
- 229940058020 2-amino-2-methyl-1-propanol Drugs 0.000 claims abstract description 11
- IOAOAKDONABGPZ-UHFFFAOYSA-N 2-amino-2-ethylpropane-1,3-diol Chemical compound CCC(N)(CO)CO IOAOAKDONABGPZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- UXFQFBNBSPQBJW-UHFFFAOYSA-N 2-amino-2-methylpropane-1,3-diol Chemical compound OCC(N)(C)CO UXFQFBNBSPQBJW-UHFFFAOYSA-N 0.000 claims abstract description 10
- JCBPETKZIGVZRE-UHFFFAOYSA-N 2-aminobutan-1-ol Chemical compound CCC(N)CO JCBPETKZIGVZRE-UHFFFAOYSA-N 0.000 claims abstract description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- KGBXLFKZBHKPEV-UHFFFAOYSA-N Boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 9
- 239000004327 boric acid Substances 0.000 claims description 8
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 7
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 239000000600 sorbitol Substances 0.000 claims description 7
- 101700013721 ADAL Proteins 0.000 claims description 5
- -1 borate compound Chemical class 0.000 claims description 5
- 239000008213 purified water Substances 0.000 claims description 5
- ZGTMUACCHSMWAC-UHFFFAOYSA-L disodium;2-[2-[carboxylatomethyl(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 4
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 2
- 229920002362 Tetronic® 1304 Polymers 0.000 claims 4
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims 4
- 239000001509 sodium citrate Substances 0.000 claims 4
- 239000011778 trisodium citrate Substances 0.000 claims 4
- 229940009662 edetate Drugs 0.000 claims 1
- 239000004599 antimicrobial Substances 0.000 abstract description 21
- 239000003755 preservative agent Substances 0.000 abstract description 7
- 230000002335 preservative Effects 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 239000007853 buffer solution Substances 0.000 abstract description 2
- 230000002708 enhancing Effects 0.000 abstract 1
- 230000000249 desinfective Effects 0.000 description 26
- 238000009472 formulation Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 11
- 241000607715 Serratia marcescens Species 0.000 description 10
- 230000000813 microbial Effects 0.000 description 10
- 238000004140 cleaning Methods 0.000 description 7
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 6
- 150000001642 boronic acid derivatives Chemical class 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000594 mannitol Substances 0.000 description 6
- 235000010355 mannitol Nutrition 0.000 description 6
- 235000000346 sugar Nutrition 0.000 description 6
- 241000222122 Candida albicans Species 0.000 description 5
- 238000011109 contamination Methods 0.000 description 5
- 230000001105 regulatory Effects 0.000 description 5
- 238000004659 sterilization and disinfection Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 230000000844 anti-bacterial Effects 0.000 description 4
- 239000002738 chelating agent Substances 0.000 description 4
- 201000009910 diseases by infectious agent Diseases 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 230000002110 toxicologic Effects 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 3
- 239000000645 desinfectant Substances 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 231100000759 toxicological effect Toxicity 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 241001225321 Aspergillus fumigatus Species 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 229960003260 Chlorhexidine Drugs 0.000 description 2
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Exidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 description 2
- 241000427940 Fusarium solani Species 0.000 description 2
- 241000192086 Staphylococcus warneri Species 0.000 description 2
- 229940033663 Thimerosal Drugs 0.000 description 2
- RTKIYNMVFMVABJ-UHFFFAOYSA-L Thiomersal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 2
- 229940035504 Tromethamine Drugs 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 229940058933 biguanide antimalarials Drugs 0.000 description 2
- 229940090145 biguanide blood glucose lower drugs Drugs 0.000 description 2
- 150000004283 biguanides Chemical class 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000002538 fungal Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000002195 synergetic Effects 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- DTOUUUZOYKYHEP-UHFFFAOYSA-N 1,3-bis(2-ethylhexyl)-5-methyl-1,3-diazinan-5-amine Chemical compound CCCCC(CC)CN1CN(CC(CC)CCCC)CC(C)(N)C1 DTOUUUZOYKYHEP-UHFFFAOYSA-N 0.000 description 1
- VARKIGWTYBUWNT-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanol Chemical compound OCCN1CCN(CCO)CC1 VARKIGWTYBUWNT-UHFFFAOYSA-N 0.000 description 1
- LFVVNPBBFUSSHL-UHFFFAOYSA-N Alexidine Chemical compound CCCCC(CC)CNC(=N)NC(=N)NCCCCCCNC(=N)NC(=N)NCC(CC)CCCC LFVVNPBBFUSSHL-UHFFFAOYSA-N 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 229940073464 BENZODODECINIUM BROMIDE Drugs 0.000 description 1
- 229960000686 Benzalkonium Chloride Drugs 0.000 description 1
- KHSLHYAUZSPBIU-UHFFFAOYSA-M Benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 1
- 210000004087 Cornea Anatomy 0.000 description 1
- 206010015946 Eye irritation Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- IFYDWYVPVAMGRO-UHFFFAOYSA-N N-[3-(dimethylamino)propyl]tetradecanamide Chemical group CCCCCCCCCCCCCC(=O)NCCCN(C)C IFYDWYVPVAMGRO-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002413 Polyhexanide Polymers 0.000 description 1
- 229920001451 Polypropylene glycol Polymers 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 229940055023 Pseudomonas aeruginosa Drugs 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 229950010221 alexidine Drugs 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000843 anti-fungal Effects 0.000 description 1
- 239000000607 artificial tear Substances 0.000 description 1
- 239000003212 astringent agent Substances 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- UUXDVNFJAYOINB-UHFFFAOYSA-N boron;manganese(2+);oxygen(2-) Chemical compound [B].[O-2].[Mn+2] UUXDVNFJAYOINB-UHFFFAOYSA-N 0.000 description 1
- 230000003139 buffering Effects 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 230000001332 colony forming Effects 0.000 description 1
- 230000000295 complement Effects 0.000 description 1
- 230000003750 conditioning Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 230000001627 detrimental Effects 0.000 description 1
- 231100000013 eye irritation Toxicity 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229960004867 hexetidine Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003522 irritant Effects 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 230000001050 lubricating Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000003641 microbiacidal Effects 0.000 description 1
- 230000003472 neutralizing Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920001987 poloxamine Polymers 0.000 description 1
- 229920005903 polyol mixture Polymers 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000012487 rinsing solution Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- VLCLHFYFMCKBRP-UHFFFAOYSA-N tricalcium;diborate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]B([O-])[O-].[O-]B([O-])[O-] VLCLHFYFMCKBRP-UHFFFAOYSA-N 0.000 description 1
- NFMWFGXCDDYTEG-UHFFFAOYSA-N trimagnesium;diborate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]B([O-])[O-].[O-]B([O-])[O-] NFMWFGXCDDYTEG-UHFFFAOYSA-N 0.000 description 1
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- SOBHUZYZLFQYFK-UHFFFAOYSA-K trisodium;hydroxy-[[phosphonatomethyl(phosphonomethyl)amino]methyl]phosphinate Chemical class [Na+].[Na+].[Na+].OP(O)(=O)CN(CP(O)([O-])=O)CP([O-])([O-])=O SOBHUZYZLFQYFK-UHFFFAOYSA-K 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 230000004382 visual function Effects 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Abstract
The use of low molecular weight amino alcohols in ophthalmic compositions is described. These compounds have been found to enhance the efficacy of anti-microbial preservatives. Particularly preferred amino alcohols are 2-amino-2-methyl-1-propanol (AMP), 2-dimethylamino-2-methyl-1-propanediol (DMAMP), 2-amino-2-ethyl-1,3-propanediol (AEPD), 2-amino-2-methyl-1,3-propanediol (AMPD), and 2-amino-1-butanol (AB). The ophthalmic compositions further optionally comprise a borate/polyol buffer system and an alkylamine.
Description
»" I- i -, h.
U§0 PE AMINOALCOHOLÉS WITH MOLECULAR WEIGHT LOW IN CO OFTLMIC POSTS? », H '" ^
iANTECEDEÑTES DE LA INVENCIÓN i fe - J- A. -f antimicrobial functions). This balance of antimicrobial efficacy and potential toxicological activity of antimicrobial agents is sometimes difficult to achieve. More specifically, the concentration of the antimicrobial agent necessary for the useful preservation of ophthalmic formation or the disinfection of contact lenses may create the potential for toxicological effects on the cornea and / or other ophthalmic tissues. Using low concentrations of antimicrobial agents generally helps reduce the potential for such toxicological effects, but low concentrations may be less effective for the biocidal efficacy of the ophthalmic compositions. This weak activity can create the potential for microbial contamination of the compositions and ophthalmic infections that result from such contaminations. This is also a serious problem, since ophthalmic infections involving Pseudomonas aeruginosa or other virulent microorganisms can lead to loss of visual function or loss of the eye. Therefore, there is a need for means to increase the activity of antimicrobial agents so that very low concentrations of these agents can be used without increasing the potential for toxicological effects or increasing the risk of microbial contamination and resulting in ophthalmic infections. Numerous antimicrobial agents have been used or have been suggested in the art for preserving ophthalmic compositions or disinfecting contact lenses. Such agents include: benzaniconium chloride (BAC), thimerosal, chlorhexidine, polymeric biguanides, such as polyhexylmethylbiguanides (PHMB) and polymeric quaternary ammonium agents, such as polyquatemium-1. Other agents have included aikilamines, such as the amidoamines which are described in the Patent of
E.U.A. Nos. 5,393,491 (Dassanayake et al.) And 5,573,776 (Dassanayake et al.). Although all these agents have offered some level of utility, their use has also led to certain limitations or disadvantages. For example, thimerosal, which contains mercury, has caused severe eye irritation resulting from the disinfection of contact lenses; BAC tends to be complicated in a detrimental manner with typical negative ionic species in ophthalmic compositions and polymeric biguanides and quaternary ammonium agents, although less irritant / ophthalmically toxic, have limited antimicrobial efficacy against certain fungal species, including Aspergillus. fumigatus and Aspergillus niger. In addition, new disinfectant requirements of the FDA are now being implemented, which still require a greater amount of microbial destruction against a greater number of microorganisms. Therefore, there is a need to increase the effectiveness of these otherwise useful antimicrobial agents. Compositions for treating contact lenses and other types of ophthalmic compositions are generally formulated as isotonic, pH regulating solutions. One approach to increasing the antimicrobial activity of said compositions is to include multiple functional components in the compositions. In addition to develop their primary functions, such as cleaning and wetting the surface of contact lenses (for example, surfactants), regulating the pH of the compositions (for example, borate), or chelating undesirable ions (for example, example, EDTA), these multi-function components also serve to increase all the antimicrobial activity of the compositions. For example, ethylenediaminetetraacetic acid and monosodium, disodium and trisodium salts thereof (collectively referred to herein as "EDTA") have been widely used for many years in ophthalmic products, particularly in products for treating contact lenses. They have been used in these products for several reasons, but particularly for their complementary antimicrobial activity and as a chelating agent. The inclusion of EDTA in products for the care of contact lenses and other ophthalmic compositions increases the antimicrobial efficacy of the chemical preservatives contained in said compositions, particularly the efficacy of those preservatives against gram-negative bacteria. Borate pH regulator systems are used in various types of ophthalmic compositions. For example, two commercial solutions for disinfecting contact lenses, OPTI-SOFT® (0.001% polyquatemium-1) Disinfectant Solution marketed by Alcon Laboratories, Inc. and ReNu® Multi Purpose Solution (0.00005% polyhexamethylenebiguanide) distributed by Bausch & Lomb, Inc., contain borate pH regulatory systems which contributes to the effective disinfection of the solutions. An improved borate pH regulator system for ophthalmic compositions is described in the U.S. Patent. Nos. 5,342,620
(Chowhan) and 5,505,953 (Chowhan). That system uses borate in combination with one or more polyols, such as mannitol. This combination increases the antimicrobial activity of the compositions, beyond the increase that was obtained with the borate alone. However, the inventors of the present have found that the water-soluble complex that was formed by the borate / polyol also significantly reduces the pH of the compositions.
As a result of the efforts directed to solve this and other problems, the inventors of the present have discovered that certain amino alcohols can be used effectively and safely to provide pH regulation of the ophthalmic compositions and to further increase the antimicrobial activity of The compositions. The use of tromethamine in compositions and methods for disinfecting contact lenses is described in U.S. Pat. No. 5,422,073 (Mowrey-McKee, et al.). This publication indicates that a synergistic effect is obtained when tromethamine is combined with other known microbicides and chelating agents. EDTA is identified as the preferred chelating agent. In view of the above, there is a need for improved means to increase the activity of the antimicrobial agents as well as to preserve the ophthalmic compositions of the microbial contamination and to disinfect the contact lenses more effectively. The present invention is directed to satisfy this need.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is based on a new use of a specific group of low molecular weight amino alcohols. The present inventors have found that the amino alcohols described herein increase the activity of the antimicrobial agents, particularly when used in combination with borate or borate / polyol buffer systems. The increase is more than additive. Of this, although the mechanisms of action are not fully understood, it is believed that the low molecular weight amino alcohols of the present invention produce a synergistic increase in antimicrobial activity. The present inventors have also found that the amino alcohols of this invention are very effective in neutralizing the acidic pH of the borate / polyol complexes. This regulatory effect of the pH of aminoalcohols is important. Although conventional bases, such as those of sodium hydroxide, can be used to adjust the pH of acid solutions containing borate / polyol complexes, the amino alcohols described herein have a significantly high pH-regulating capacity. This increased buffering capacity is particularly important if the compositions contain antimicrobial agents which are pH dependent (eg, alkylamidoamines). If the pH of said compositions is not maintained within the required range during maximum antimicrobial activity, all the antimicrobial activity of the composition can be reduced. The use of the borate-polyol pH regulator system can also significantly reduce the amount of NaOH needed for pH adjustments, and therefore reduce the amount of ions in the compositions. This feature is particularly important when using ion-sensitive antimicrobial agents, such as polyquatemium-1. Amino alcohols can be used in various types of ophthalmic compositions, particularly compositions for treating contact lenses, such as disinfectants, cleansers, drops for comfort and rehumidifying drops. Low molecular weight amino alcohols are particularly useful in the compositions for disinfecting, rinsing, storing and / or cleaning contact lenses. When these compositions are combined with the borate pH regulator systems, the combination also helps to protect the products against microbial contamination. This antimicrobial effect of the aminoalcohol / borate combination reduces the amount of antimicrobial agent required for conservation purposes, and in some cases, can totally eliminate the need for a conventional antimicrobial preservative agent. The present invention is particularly directed to the provision of improved compositions for disinfecting contact lenses. The compositions have significantly increased the antimicrobial activity, related to the above compositions containing the same primary disinfecting agents (e.g., polyquatemium-1).
The increase is achieved by a combination of the formulation criteria, which include the use of the borate / polyol complex and one or more amino alcohols, which are described herein. This increase in antimicrobial activity is highly significant. Preferred disinfectant compositions also contain a relatively small amount of an alkylamine. In fact, in some countries new government regulations created a need for compositions that have significantly higher antimicrobial activity. More specifically, the new regulations require that the compositions for disinfecting contact lenses be capable of disinfection without the aid of other compositions (for example, cleaning compositions or saline rinsing solutions). The increase in antimicrobial activity achieved by means of the present invention allows contact lens disinfectant compositions to meet this standard.
BRIEF DESCRIPTION OF THE INVENTION
The molecular weight amino alcohols under which they can be used in the present invention are water soluble and have a molecular weight in the range of about 60 to about 200.
The following compounds are representative of the low molecular weight amino alcohols, which can be used in the present invention: 2-amino-2-methyl-1-propanol (AMP), 2-dimethylamino-methyl-1-propanediol
(DMAMP), 2-amino-2-ethyl-1,3-propanediol (AEPD), 2-amino-2-methyl-1,3-propanediol (AMPD), 2-amino-1-butanol (AB). "AMP-95", which refers to 95% pure AMP and 5% water, is the preferred low molecular weight amino alcohol of the present invention. These amino alcohols are commercially available from Angus Chemical Company (Buffalo Grove,
Illinois). The amount of amino alcohol used will depend on the molecular weight of the aminoalcohol selected, the other ingredients in the composition, i.e., other antimicrobial agents, chelating agents, pH regulating agents, tonicity agents, and the function of the antimicrobial agents contained in the compositions. ophthalmic (ie, preservation of compositions or disinfection of contact lenses). In general, one or more of the amino alcohols described above will be used at a concentration of from about 0.01 to about 2.0% w / v ("% w / v"), and preferably from 0.1 to 1.0% w / v. When the borate / polyol complexes are employed with the amino alcohol compositions of the present invention, they will generally be present in an amount necessary to neutralize the pH of the complex, or they will bring the composition to a desired pH. Therefore, this amount is a function of the particular borate / polyol mixture and the concentration.
The low molecular weight amino alcohols described herein can be included in various types of ophthalmic compositions to increase the antimicrobial activity, or for the other purposes mentioned above. Examples of such compositions include: pharmaceutical ophthalmic compositions, such as topical compositions that are used in the treatment of glaucoma, infections, allergies or inflammation. Compositions for treating contact lenses, such as cleaning products and products for increasing the ocular comfort of patients using contact lenses; and other various types of compositions, such as lubricating eye products, artificial tears, astringents, among others. The compositions can be aqueous or non-aqueous, but will generally be aqueous. In addition to the low molecular weight amino alcohols described above, the compositions of the present invention may contain one or more antimicrobial agents to preserve the compositions against microbial contamination and / or disinfect contact lenses. For example, the compositions may contain the antimicrobial agent known as polyquaternium-1 or POLYQUAD® (registered trademark of Alcon Laboratories, Inc.); the use of this agent as a preservative in ophthalmic compositions is described in U.S. Pat. No. 4,525,346 (Stark). All of the contents of the Stark Patent 346 are incorporated herein by reference herein. Additional examples of the antimicrobial agents include chlorhexidine, alexidine, hexetidine, polyhexamethylenebiguamide, benzalkonium chloride, benzododecinium bromide, alkylamines, alkyldiamines, alkyltriamines and other antimicrobial agents used as antimicrobial preservatives or disinfecting agents in ophthalmic compositions. The inclusion of one or more of the low molecular weight amino alcohols described above in the ophthalmic compositions containing said antimicrobial agents increases the total antimicrobial activity of the compositions. This increase is particularly evident when the compositions include a pH borate or borate-polyol buffer system. As indicated above, the low molecular weight amino alcohols described above are preferably used in combination with the borate or borate / polyol buffer systems. As used herein, the term borate should refer to boric acid, boric acid salts and other pharmaceutically acceptable borates, or combinations thereof. The following borates are particularly preferred: boric acid, sodium borate, potassium borate, calcium borate, magnesium borate, manganese borate, and others such as the borate salts. As used herein, and only if indicated otherwise, the term "polyol" should refer to any compound having at least two adjacent OH groups which are not in a trans-related configuration. The polyols can be linear or cyclic, substituted or unsubstituted, or mixtures thereof, until the resulting complex is water soluble and pharmaceutically acceptable. Examples of such compounds include: sugars, sugar alcohols, sugar acids, and uranic acids. Preferred polyols are sugars, sugar alcohols and sugar acids, including but not limited to: mannitol, glycerin, xylital, and sorbitol. Particularly preferred polyols are mannitol and sorbitol; the most preferred is sorbitol. The use of borate-polyol complexes in ophthalmic compositions is described in
Patent of E.U.A. No. 5,342,620 (Chowhan) and 5,505,953 (Chowhan) commonly assigned; the contents of these are incorporated in the present specification by reference in its entirety. The compositions of the present invention preferably contain one or more borates in an amount of from about 0.01 to about 2.0% w / v, more preferably from about 0.3 to 1.2% w / v, and one or more polyols in an amount of about 0.01 at 5.0% w / v, preferably from approximately 0.6 to 2.0% w / v. As stated above, the current disinfectant compositions 1 are capable of meeting the new requirements of the FDA for the disinfecting efficacy of contact lens disinfectant compositions. The compositions of the present invention improve with respect to prior art compositions with the inclusion of aminoalcohols in the compositions. The preferred disinfecting compositions of the contact lenses of the present invention comprise one or more low molecular weight amino alcohols, borate-polyol pH regulators, an antimicrobial agent, as described above, and an alkylamine. The alkylamines have been described in the Patents of E.U.A. Us.
,393,491 (Dassanayake et al.), And 5,573,726 (Dassanayake et al.), And the U.S. Patent Application. No. 08/381, 889. The above patents and the application of the patent are incorporated herein in the present specification by reference. These alkylamines possess both antibacterial and antifungal activity. The preferred alkylamines are the amidoamides, as described in the Dassanayake patents and others mentioned above. The most preferred amidoamine is myristamidopropyldimethylamine ("MAPDA"). The amount of alkylamine in the compositions of the present invention will vary, due to several factors such as: the antimicrobial potency and the potential toxicity of the particular alkylamine. However, the inventors of the present have found that the amount of alkylamines, particularly the amidoamines, useful in the compositions of the present invention is drastically lower when combined with compositions comprising borate pH regulators, than when the alkylamines are used. without borates. In general, alkylamines will be present in concentrations of about 0.00005 to about 0.01% w / v, when combined with borates. As will be recognized by those skilled in the art, the preservative or disinfectant compositions may also contain a wide variety of other ingredients, such as tonicity agents (e.g., sodium chloride or mannitol), surfactants (e.g., alkyl ethoxylates and polyoxyethylene / polyoxypropylene copolymers), and viscosity adjusting agents. The present invention is not limited in terms of the types of ophthalmic compositions in which the other low molecular weight amino alcohols described above are used. All of the compositions described above will be formulated so as to be compatible with the eye and / or contact lenses to be treated with the compositions. As will be known to those skilled in the art, ophthalmic compositions designed for direct application to the eye will be formulated so that they have a pH and tonicity that are compatible with the eye. This will usually require a pH regulator to maintain the pH of the composition at or near the physiological pH (i.e., 7.4) and may require a tonicity agent to bring the osmolality of the composition to a level that is on or near 210-320 milliosmoles per kilogram (mOsm / kg.). The formulation of the compositions for disinfecting and / or cleaning contact lenses will involve similar considerations as well as considerations that relate to the physical effect of the compositions on contact lens materials and the potential for bonding or absorption of the components of contact lenses. composition by means of lenses.
The following examples are presented to further illustrate the selected inclusions of the present invention.
EXAMPLE 1
The following salt solutions containing several amino alcohols at a concentration of 1.2% were prepared for comparative purposes. The composition of the solutions is presented later. The pH of the solutions was adjusted to 7.4 with hydrochloric acid. The amino alcohols consisting of 2-Amino-2-methyl-1-propanol (AMP), 2-dimethylamino-methyl-1-propanediol (DMAMP), 2-amino-2-ethyl-1,3-propanediol (AEPD), 2-amino-2-methyl-1,3-propanediol (AMPD) and 1,4-Bis (2-hydroxyethyl) -piperazine (BHP). The osmolalities of the solutions were 335,250,254,304 and 208 mOsm / kg, respectively.
The antibacterial activity of the saline solutions described above for S. marcescens was evaluated. The formulations were evaluated by inoculating 20 ml of each solution with 0.1 ml of a microbial suspension.
The final concentration was 106 colony forming units ("CFUs") per ml. At each time point, the casting plates were prepared
SCDA containing diluted aliquots of several test samples. Bacteria and yeast plates were incubated at 30 ° to 35 ° C for 2 to 3 days. The fungal plates were incubated at 20 to 25 ° C for 5 days. After the incubation period of the colonies, the number of CFUs was counted and the logarithmic reduction of CFUs related to the start amount was calculated. The results at 6 and 24 hours (in logarithmic reduction of survivors) is shown in Table 1 shown below:
TABLE 1
As indicated by the above information, all formulations showed minimal activity for S. marcescens.
EXAMPLE 2
The following is an example of a protection composition of the present invention (Formulation A) and a comparative composition (Formulation B). Both formulations contain a borate / polyol pH regulator system (ie, boric acid and mannitol), but differ in that Formulation A uses AMP-95 and Formulation B uses NaOH to adjust the pH. The formulations were prepared by first dissolving sequentially in 90 ml of purified water, boric acid, mannitol, poloxamine, and disodium edetate. AMP-95 was added to Formulation A and the volume was adjusted to 100 ml with purified water. The pH of Formulation A was 7.4. the pH of Formulation B was adjusted to 7.4 with 6N NaOH, and the volume of the solution was adjusted to 100 ml with purified water. Both formulations had an osmolality of approximately 200 mOsm / kg. The compositions of the two formulations are set out below:
The antimicrobial activity of the formulations for S. marcescens and P. aeruginosa was evaluated. A microbial protocol similar to the protocol of Example 1 was used. The results are shown in Table 2 shown below:
TABLE 2
Note: The underlined numbers represent non-survivors. As indicated by the above information, Formulation A showed significantly greater antibacterial activity than Formulation B, which does not contain an amino alcohol in accordance with the present invention. This example demonstrates that the effect of the aminoalcohol in a borate composition exceeds the antibacterial effect of EDTA only (Formulation B).
EXAMPLE 3
The following is a comparative example of a protection and / or disinfectant composition of the present invention (Formulation C) and a comparative composition (Formulation D). Two formulations similar to those described in Example 2 above were prepared, but containing an antimicrobial agent POLYQUAD®. The formulations were prepared by means of procedures similar to those described in Example 2, above.
POLYQUAD® was added before the final pH adjustment. The pH of the formulation
C was 7.4; the pH of Formulation D was adjusted to pH 7.4 with 6N NaOH. The composition of the formulations is presented below:
The antimicrobial activity of the formulations for S. marcescens, S aureus and P. aeruginosa was evaluated. Microbial protocols similar to the protocol of the Example were used. The results are presented in Table 3 shown below:
TABLE 3
Note: The underlined numbers represent non-survivors. These results demonstrate that the aminoalcohol contained in Formulation C significantly increased the antimicrobial activity of the composition.
EXAMPLE 4
The following is a multi-purpose composition that is preferred for cleaning, disinfecting, rinsing, and storing soft hydrophilic lenses:
The antimicrobial activity of the above compositions was evaluated for A. fumigatus, C. albicans, F. solani, P. aeruginosa, S. marcescens, S. aureus and S. warneri. Microbial protocols similar to those of the Example were used for most microorganisms. The results are illustrated in Table 4, which is shown below:
TABLE 4
Microorganism Time (hours) Logarithmic reduction
A. fumigatus 4 2.2 ATCC 10894 6 3.1 24 4.8 48 4.8 C. albicans 4 1.5 ATCC 10231 6 1.7 24 2.7 48 4.0 F. solani 4 3.8 ATCC 36031 6 4.3 24 5.6 48 5.8 P. aeruginosa 4 4.7 ATCC 9027 6 5.7 24 6.1 48 6.1 S. marcescens 4 3.3 ATCC 13880 6 4.1 24 6.0 48 4.7 S. marcescens 4 2.1 ATCC 14041 6 2.7 24 5.6 48 5.6 S. aureus 4 3.7 ATCC 6538 6 3.7 24 5.5 48 6.1 S. warneri 4 4.9 ATCC 17917 6 5.1 24 5.9 48 5.9
EXAMPLE 5
The following is a comparative example of a multi-purpose composition of the present invention (Formulation E) and a comparative composition (Formulation F). The two formulations are the same, however Formulation F does not contain EDTA.
The antimicrobial activity of the above compositions for P. aeruginosa, S. marcescens, S. aureus, and C. albicans was evaluated using a protocol similar to that of Example 1, above: The logarithmic reduction information is illustrated in FIG.
Table 5, shown below:
TABLE 5
Note: Underlined numbers indicate non-survivors.
EXAMPLE 6
The following composition is an example of a multi-purpose composition useful for cleaning, rinsing, disinfecting and conditioning rigid gas permeable (RGP) lenses:
The antimicrobial activity of the above composition was evaluated for S. marcescens, S. aureus, and C. albicans using a protocol similar to that of Example 1, above. The logarithmic reduction data are illustrated in Table 6, which is shown below:
TABLE 6
Note: Underlined numbers indicate non-survivors
EXAMPLE 7
The following is an example of a disinfectant composition useful for soft hydrophilic lenses.
The antimicrobial activity of the above compositions was evaluated for S. marcescens, S. aureus, and C. albicans using a protocol similar to that of Example 1, above. The logarithmic reduction data are illustrated in Table 7, which is shown below: TABLE 7
Note: Underlined numbers indicate non-survivors.
Claims (7)
1. A method for increasing the antimicrobial activity of an ophthalmic composition containing a borate compound, which includes adding to the composition an effective amount of a low molecular weight amino alcohol, characterized in that the amino alcohol has a molecular weight of 60 to 200.
2. A method according to claim 1, further characterized in that the composition includes a borate / polyol pH regulator system.
3. A method according to claim 1 or 2, further characterized in that the aminoalcohol is selected from the group comprising 2-amino-2-methyl-1-propanol (AMP), 2-dimethylamino-methyl-1-propanediol (DMAMP), 2-amino-2-ethyl-1,3-propanediol (AEPD), 2-amino-2-methyl-1,3-propanediol (AMPD), 2-amino-1-butanol (AB).
4. A method according to claim 1, 2 or 3, further characterized in that the composition includes an alkylamine.
5. A sterile multiple dose ophthalmic composition comprising an amount of a low molecular weight amino alcohol effective to increase the antimicrobial activity of a borate-containing composition, characterized in that the aminoalcohol has a molecular weight of 60 to 200.
6. A composition according to claim 5, further characterized in that the composition is adapted for the treatment of contact lenses. 7. A composition according to claim 5 or 6, further characterized in that the composition includes a borate / polyol pH regulator system. 8. A composition according to claim 5, 6 or 7, further characterized in that the aminoalcohol is selected from a group comprising 2-amino-2-methyl-1-propanol (AMP), 2-dimethylamino-methyl- 1-propanediol (DMAMP), 2-amino-2-ethyl-1,3-propanediol (AEPD), 2-amino-2-methyl-1,3-propanediol (AMPD), 2-amino-1-butanol (AB) ). 9. A composition according to claim 5, 6, 7 or 8, further characterized in that it includes an alkylamine. 10. A composition according to claim 5, 6, 7, 8 or 9, further characterized in that the alkylamine is an amidoamine. 11. A composition according to any of claims 5 to 10, further characterized in that the composition is a multi-purpose composition comprising: polyquaternium-1, boric acid, sorbitol, sodium chloride, sodium citrate, Tetronic 1304, edetate of disodium, sodium hydroxide, hydrochloric acid, purified water, 2-amino-2-methyl propanol and MAPDA. 12. - A composition according to any of claims 5 to 11, further characterized in that the composition comprises about 0.001% w / v polyquatemium-1; about 0.6% w / v boric acid; about 1.2% w / v of sorbitol; about 0.65% w / v sodium citrate; approximately 0. 1% w / v sodium chloride; approximately 0.05% w / v Tetronic 1304; about 0.05% w / v of disodium edetate; about 0.45% w / v AMP-95; approximately 0.0005% p / v of MAPDA; and further characterized in that the composition is adjusted to a pH of 7.8 with sodium hydroxide and hydrochloric acid. 13. A composition according to claim 11, further characterized in that the composition is a multi-purpose composition comprising: polyquatemium-1, boric acid, sorbitol, sodium chloride, sodium citrate, Tetronic 1304, disodium edetate, sodium hydroxide, hydrochloric acid, purified water, 2-amino-2-methyl propanol and MAPDA. 14. A composition according to claim 13, further characterized in that the composition comprises: about 0.001% w / v polyquatemium-1; about 0.6% w / v boric acid; about 1.2% w / v of sorbitol; about 0.65% w / v sodium citrate; about 0.1% w / v of sodium chloride; approximately 0.05% w / v Tetronic 1304; about 0.05% w / v of disodium edetate; about 0.45% w / v AMP-95; approximately 0.0005% p / v of MAPDA; and further characterized because the composition is adjusted to pH
7. 8 with sodium hydroxide and hydrochloric acid.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US60/033,079 | 1996-12-13 |
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MXPA99005481A true MXPA99005481A (en) | 2000-01-21 |
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