1~907 The present invention is an aqueous isotonic storing and rinsing solution for contact lenses, containing chloro-hexidine and thiomersal as preserving and disinfecting agents, and a water-soluble cellulose derivative as a protective polymer, in a buffered saline solution with a pH value of approximately 7.~.
Conventional storing and rinsing solution of this type can only be used for soft contact lenses. There is a series of known preparations for hard contact lenses, which contains bazalkonium chloride as a preservative. It has been found, however, that the effectiveness of bazalkonium chloride is reduced by proteins which are present in the lacrimal fluid, and may be deposited on the contact lenses during wear.
Further, no storing and rinsing solution has yet been developed which can also serve as a solvent for a protein remover, i.e., to remove deposits of protein from the lacrimal fluid, which build up on the contact lens during wear. The reason for this is that the storiny and rinsing solution loses ;ts disinEectant property when protein remover is added to it.
The aim of the inventors was therefore to develop a storing and rinsing solution which could be used for both soft and hard contact lenses, and could also serve as a solvent for a protein remover.
The present invention achieves this objective. An additional aspect, for example, a suitable protein remover can be dissolved in, or diluted with, the storing and rinsing solu tion of the present invention.
11 115C~J07 1 additional advantage is that the ~ubstance ~DTA ~resent
2 ¦in the storin~ and rinsing solution prevents the inactivation
3 ¦of the protein remover, due to its chelating action with heavy
4 ¦metal ions. The substances EDTA and sulflte also form activators
5 ¦for the protease mixture of papain and chymopapain present in
6 ¦the protein remover.
7 l
8 ¦ In additional aspect, the invention provides for an addi-
9 ¦tive, viz., sodium lactate, for increasing the solubility of
10 ¦chlorohexidine in the inventive compositions, to avoid the preci-
11 ¦pitation of chlorohexidine and, thereby, to improve the stability
12 ¦and efficacy of the compositions.
13
14 ¦ The addition of the sodium lactate renders the inventive
15 ¦compositions unexpectedly superior relative to conventional
16 ¦storage and rinsing solutions in a nurnber of respects: The
17 ¦solubility o chlorohexidine in the inventive composition is
18 ¦greater than 1%, whereas its solubil:ity in convelltional chloride
19 ¦and/or phosphate-containin~ buEEer systems of other solutions is
20 ¦only about 0.002%. The increased solubility oE the hexidine in
21 ¦ the inventive composition significantly improves tlle chemical and
22 ¦ stora~e stability o the inventiv~ solutions. I~ue to ~he improved
23 ¦ solubility of the disinfectant hexidine and it~s better .stability,
24 ¦ it is possible to work with lower concentrations of hexidine,
25 ¦ improvin~ the long term compatibility of the inventive composition .
26 ¦ Furthermore, the undesired absorption and retention of hexidine in
27 ¦ HEMA-based lenses is substantially reduced when using the inventiv
28 ¦ compositions.
29 ~ 15~ 07 2 ¦ The relatively small amount of hexidine contained in the 3 ¦ soft lenses treated with the inventive compositions improves 4 ¦ the wearing characteristics of the lenses, and the long term 5 ¦ compatibility of such lenses, i.e., their tolerability by -the 6 ¦ eye, is enhanced by use of the inventive compositions. For 7 ¦ instance, a HEMA-based lens of 35C/~ water content will absorb 8 ¦ up to 2 mg chlorohexidine when treated with conventional 9 ¦ chloride and/or phosphate-containing lens care systems. When 10 ¦ using the inventive solution, only about O.S mg will be absorbed 11 ¦ and held by the lens. In addition, the leaching of chloro-12 ¦ hexidine from lenses treated with the inventive compositions 13 ¦ is significantly improved.
15 ¦ The use of the water-soluble cellulose derivative in the 16 ¦ inventive compositions imparts significant improvement to the 17 ¦ compositions, viz., it reduces the sur:Eace tensioll o~ the 18 ¦ solution sufficiently for use, but does not dcle~-eriously 19 ¦ affect the stability of the solut iOtl as do conventionally 20 ¦ used surfactants. Furthermore, the use of the ccllulose deri-21 ¦ vative makes it poxsible to sterilize the xolutions through 22 ¦ sterile filtration, leading to an improved purity and micro-23 ¦ biological safety relative to other preparative techniques, such 24 ¦ as preparation in the absence of micro-organisms.
26 ¦ The additional optional use of a phosphate, citrate or 28 acetate in the inventive compositions, or of a hydroxyalkylamine, ll 1150907 1 ! such as ethanolamine, further supports and enhances the advan-2 ¦ tages set forth above in connection with the use of sodium 3 ¦ lactate or other acid salt, in that the improved solubility of 4 ¦ chlorohexidine in the inventive compositions is enhanced by S ¦ use of such buffer systems.
6 l 7 ¦ The total composition of the invention does not affect the 8 ¦ optical properties or the geometry of the contact lenses. The 9 ¦ preparation also helps to prevent oxidative, hydrolytic and 10 ¦ catalytic decomposition of the active components caused by, 11 ¦ e.g., metal ions, variations in the organoleptic properties 12 ¦ (color/clearness) due to oxidation, effects caused bv light 13 ¦ and microbial recontamination.
In addition, the tear stren~,th of soft lenses was improved 16 by treatment with the inventive compositions, i.e., the tear 17 strength of the lenses was not reduced over a periocl oE tillle 18 as much as after treatment witll conventional rinsirl~T all(l st-orage 19 systems.
21 The excellent comE~atib~ ity oE the ~storing and rinsi.n~
22 solution is due in large part to the fact that the pfl va1ue, 23 the specific weight, the refractivt-~ inclex, the free~in~ point 24 depression and the visco.sity correspond to the phvsiological values of the lacrimal fluid. Below, an exemplification is 26 cited of the composition of a storing and rinsing solution in 27 accordance with the present invention.
29 ~ ~
.
1 ¦ Example 1 ¦ 0.025 g Chlorohexidine gluconate solution 20%
3 ¦ 0.002 g Thiomersal-sodium 4 1 0.050 g Ethylenediaminetetra-acetic acid-di-sodium 5 1 chloride (EDTA) l 0.2 g Water soluble cellulose (m.w. about 10,000) 6 1 0.3 g Sodium acetate 87 l 1.4 g Sodium lactate 9 1 Acetic acid sufficlent to give a pH of 7.4 11 ~ ad 100.000 ~ Water for injection pur~oses 12 1 The storin~ and rinsing solution was tested in accordance 13 with the r,uildelines of the (~erman Association for ~Iygiene and 14 ¦ Microbiology, and the requirements for eye drops in the USP
16 (United States Pharmacopeia XIX).
17 ¦ The bactericidal and bacteriostatic eEf~ctiveness o:E ~he 18 ¦ preparation was tested uslnp, the prescribe(l :inocuLation rates 19 ¦ and the following microbes:
20 ¦ Pseudomonas aeruginosa AT('C 9n27 21 ¦ Eschericllin coli Arrcc ~i7.39 22 I Proteus vul~aris ATCC :L3:315 23 ¦ Staphyl~coccus aurells ATCC 6538 24 ¦ Aspergillus niger ATCC 16404 26 Candida albican~s ATCC 10?31 27 ¦ Fifteen minutes after addition of the microbes to the stor:in~
28 ¦ solution, no further growth was observed.
I A further test was also carried out under actual practical l conditions. Three contact lens types were stored in the storing ll 115D91)7 1 and rin ing solution, and the microhial effectiveness test was 2 ¦ carried out once again. The results showed that 2 ml storing 3 ¦solution protected all the lenses tested from microbial con-4 ¦tamination, and killed off any microbes present within a short 5 ¦ time.
6 I .
7 ¦ The storing solution was also submitted to a further bacteri-8 ¦ cidal and bacteriostatic effectiveness test in the presence of 9 ¦ the protein remover (a combination of papain and chymopapain).
10 ¦ This test also showed that the solution dislnfected as re~uired.
12 ¦ The same effectiveness test was repeated on the storing 13 ¦ solution after storage for one year in the commercial packaging.
14 ¦ It was found that the microbiologicallv re~uired induction time 15 ¦ coTr.plied with the directions for use.
17 ¦ As has already been mentioned, t:he newly- illVCIl ted .5 toring 18 ¦ and rinsing solution can be used as a dilu~ing medium ~or the 19 ¦ conc~ntrated protein remover. Tl~e .stal~i.li~,er in tlle protease preparation which makes up the protein removcr :i.s adiusted 21 to the storing solution in SUCIl a Wcly that it ac~ivate.s the 22 microbiological power o the stor-ing solution at the same t:i.me 23 as the protein remover is perforrlinp, its cleaning action. The 24 protease combination of papain and chymopapain, which makes up the protein remover, has an intensive biological cleaning 26 power in the pH range from 7 to 9. The storing solution and 27 the protein remover are formulated in the present invention in 28 such a way that a pH optimum of pH 7.2 is achieved when the 29 concentrated protein remover is admixed. By addition of the storing solution to the concentrated protein remover, in a ll ~15~07 l ¦container used for the care of the contact lens, an optimum 2 ¦mixture of SH activators and ~DTA is achieved, which prevents 3 ¦the inactivation of the protein remover throu~h its chelating 4 ¦action with heavy metal ions.
5 l 6 ¦ Enzyme protein removers in powder or tablet form may 7 ¦become damp during storage, e.g., because of imperfectly sealed 8 ¦packaging, so that their stability is considerably reduced. By 9 ¦contrast, the concentrated protein remover intended for use ~ith 10 ¦the present invention may be stored in, e.g., disposable pipettes.
ll ¦The stability of the preparation is thus increased, and the 12 ¦danger of abuse, e.g., by children, is y,reatly reduced.
13 l 14 ¦ The contact lens can be cleaned in the following simple way:
15 l 16 ¦ For each contact lens to be cleaned, the contents of one 17 ¦pipette (approximately 150 mg) are emptied into a suitable con-18 ¦tainer. The contact lens is removed Erom the eye, rinsed with, l9 le.g., the storing and rinsing solution, then placed in the 20 ¦ contai.ner. To dilute the concent]^ate(l ~rotei.n remover, approxi~
21 ¦ mately 2 to 2.5 ml storing and rinsing solution are added, up 22 ¦ to an appropriate index mar~, and mixed thorou~TIlly. The 23 ¦ cleaning process takes about 2 hours. ~iven ~hat thè mlxture 24 ¦ has a pH value of 7.2, the same degree of effectiveness is 25 ¦ maintained throughout this cleaning period. After a cleaning 26 ¦ period of 10 hours, the initial effectiveness is halved, given 27 ¦ a temperature of 35C. The recommended cleaning period is 28 ¦ approximately 2 hours.
115~907 The compositions of the protein remover is illustrated in Example 2, which can be used with the present invention.
Example 2
30.0 g Boerozyme F
10.0 g Sorbitol solution 70/O
0.2 g Sodium pyrosulfite 54.7 g Glycerol 0.1 g Komplexon (disodium ethylenediaminetetra-acetic acid) 5.0 g Water for injection purposes Boerozyme F is a solution of a protease mixturernade up of papain and chymopapain in glycerol and a sorbitol solution, and contains maximum 1.5% sulphur dioxide.
Aqueous enzyme solutions are highly subject to contamination by microbes, regardless of how they are prepared (e.g., tablets + solvent or concentrate + storing solution).
Tests were therefore carried out to determine whether mi.crobes are capable of reproduction in thc prescnce oL prot:ein remover and storing solution, or ~-~ether thoy ar.c kil~ecl off by the disinfectant action of thc~ ';U})';t`(lllCC` chlorotlexidine digluconate (in a specially forrnulatcd })rcs(.ription) in thc? solution.
The followillcl tests were carried out:
2.5 ml storing solution and 200 mg protcin remover were mixed in a sterile test tube, which was then inoculated wi.th microbe cultures. After induction periods of 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours and 8 hours, samples were removed and checked for growth. The results are shown in the following table:
~5~)7 l ¦ Microbiological Test of the Ready-for-Use Protein Remover I , 4 ¦ No l'est Microbe Type ATCC- Gul ture - Induction ~er d 5 ¦ . . Solution No.... count 10 130¦60¦2h¦4h l8h 6 1 . __ __ __ _ 7 ¦ 1) A Pseudomonas 9027 1.56 x 10 _ _ _ _ _ _ 8 ¦ aeruginosa 2) A Escherichia 5 9 coli 8739 ~.25 x 10 _ _ _ _ _ _ lO . 3) A Proteus vulga- 5 11 ris 13315 1,25 x 10 _ _ _ _ _ _ 12 4) A Staphylococcu 5 13 aureus 6538 1.44 x 10 _ _ _ _ _ _ 14 5) A Candida albi- 102313.37x 10 ~ + + _ _ _ 6) A Aspergillus 5 16 niger 16404 ~2,50x lO ~ _ _ L~
l8 _ _ ._ _ _ These result.s show that the 21 (1) protein remover i~5 not sub-jec~: ~o mi.crob:ial 22 contamination;
23 (2) s~oring solution i~s not inac~ivated by proteins;
24 (3) combination o:E storin~J solutlon and protein remover is Eully active, an o~timum ~alenical formulation 26 having been found.
28 The same test was carried out after the storing solution 29 had been stored for one year~ The results.confirm the above conclusions.
ll 1150907 1 ¦ The embodiment of the invention involving use of a protein 2 ¦remover, i.e., the provision o~ a rinsing and storage solution 3 ¦which is compatible with a protein remover, results in a mixed, 4 ¦ready-to-use protein remover-containing composition which is ¦hypertonic, i.e., having an osmolarity of 0.8 to 1.3 osmoles, ¦corresponding to a hypertonicity o~ 3 to 5 fold, to isotonicity.
7 ¦In general, the ratio of storage and rinsing solution to protein 8 ¦ remover solution is from 10 : 1 to 16 : 1, preferably about 9 ¦ 12.5 : 1, to result in a protease-concentrate content in the 10 ¦ ultimate ready-to-use composition of S to 9%.
12 ¦ The cellulose derivatives usable in the invention as pro-13 ¦ tective polymers, in addition to cellulose itself, are illus-14 ¦ trated by the hydroxypropylcellulose 22~8, 2906, and 2910, as 15 ¦ well as methylcellulose (see monographs thereon in the United 16 ¦ States Pharmacopeia XX).
18 ¦ The phosphates, citrates and acetates whlch are opti.onal 19 ¦ ingredients in certain embodiment~s o:~ the con)positions, include 20 ¦ sodium, potassium and ammoniulll ';.lLt~s of d.i.f~el'ellL water content.
21 ¦ Other usable salts are sodiulTI phosphate x ~1~(), potassi.~ hosphate 22 ¦ x H20, sodium acetate, ammoll:iulll aCetclte, sod:ium citrate, sodium 23 ¦ tartate, sodium salt o~ ~artronic ac:id, malic acid. ~11 salts 24 ¦ with dif.~erent water contents, as commercially available.
26 ¦ The mono-, di-, or tri-hydroxyalkylamines which are also 27 optional ingredients can include, in addition to ethanolamine, 28 methanolamine, dimethanolamine, propanolamine, and the like, 29 but preferably contain no more than 2 carbon atoms in each alkyl moiety.
1 ~15~907 ; l 1 ¦ It will be understood that the specification and examples 2 ¦ are lllustrative but not limitative of the present invention ¦ and that other embodiments within the spirit and scope of the 1 ¦ invent o will suggest themselves to those skilled in the art.
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