CA2193405C - Eyewash intended in particular for the treatment of the dry eye syndrome - Google Patents
Eyewash intended in particular for the treatment of the dry eye syndrome Download PDFInfo
- Publication number
- CA2193405C CA2193405C CA002193405A CA2193405A CA2193405C CA 2193405 C CA2193405 C CA 2193405C CA 002193405 A CA002193405 A CA 002193405A CA 2193405 A CA2193405 A CA 2193405A CA 2193405 C CA2193405 C CA 2193405C
- Authority
- CA
- Canada
- Prior art keywords
- eyewash
- viscosity
- polyvinylpyrrolidone
- buffer
- carbopol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000011282 treatment Methods 0.000 title claims abstract description 9
- 208000003556 Dry Eye Syndromes Diseases 0.000 title claims abstract description 6
- 206010013774 Dry eye Diseases 0.000 title claims abstract description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 22
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 20
- 239000000872 buffer Substances 0.000 claims abstract description 16
- 229920000447 polyanionic polymer Polymers 0.000 claims abstract description 11
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 11
- 239000007864 aqueous solution Substances 0.000 claims abstract description 5
- 229920002125 Sokalan® Polymers 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 24
- 239000012064 sodium phosphate buffer Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims description 3
- 239000008057 potassium phosphate buffer Substances 0.000 claims description 2
- 238000009877 rendering Methods 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 10
- 239000011734 sodium Substances 0.000 description 10
- 229910052708 sodium Inorganic materials 0.000 description 10
- 241001465754 Metazoa Species 0.000 description 9
- 239000000499 gel Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 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 description 7
- 210000001508 eye Anatomy 0.000 description 7
- 239000000600 sorbitol Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 210000000744 eyelid Anatomy 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000002688 persistence Effects 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229940086737 allyl sucrose Drugs 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 150000004683 dihydrates Chemical class 0.000 description 2
- 210000003717 douglas' pouch Anatomy 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 238000009434 installation Methods 0.000 description 2
- 230000010494 opalescence Effects 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- RFIMISVNSAUMBU-UHFFFAOYSA-N 2-(hydroxymethyl)-2-(prop-2-enoxymethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)COCC=C RFIMISVNSAUMBU-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- 238000000585 Mann–Whitney U test Methods 0.000 description 1
- 241000271569 Rhea Species 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000001949 anaesthesia Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000004397 blinking Effects 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 230000005499 meniscus Effects 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- CKRORYDHXIRZCH-UHFFFAOYSA-N phosphoric acid;dihydrate Chemical compound O.O.OP(O)(O)=O CKRORYDHXIRZCH-UHFFFAOYSA-N 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940037001 sodium edetate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Ophthalmology & Optometry (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to a ready-for-use eyewash intended in particular for the treatment of the dry eye syndrome comprising, in aqueous solution:
- a gelifying polyanionic polymer - a buffer in an amount sufficient to reduce the viscosity of the eyewash to a value of 10 to 60 mPa.cndot.s and - a polyvinylpyrrolidone in an amount sufficient for the eyewash to be clear.
- a gelifying polyanionic polymer - a buffer in an amount sufficient to reduce the viscosity of the eyewash to a value of 10 to 60 mPa.cndot.s and - a polyvinylpyrrolidone in an amount sufficient for the eyewash to be clear.
Description
EYEWASH INTENDED IN PARTICULAR FOR THE TREATMENT
OF THE DRY EYE SYNDROME
The present invention relates to an eyewash intended in particular for the treatment of the dry aye syndrome.
Compositions intended for the treatment of the dry .eye syndrome have already been described is WO 84/04 680 and WO 84/04 681. These compositions are composed of Qels or very viscous solutions containing polyanioaic polymers, such as products sold wader the trade mark Carbopol~ which are acrylic acid polymers crossliaked by allyl sucrose or allylpeataerythritol.
Thus, WO 84/04 681 describes, for example, a flowable gel which comprises 0.2% by weight of Carbopol~ 940. This gel has a viscosity of 12,400-12,600 mPa~s.
Such gels are, however, difficult to use and can result in feelings of stricking of the eyelids.
Moreover, it is known (BF Goodrich, Carbopol~ - Resins soluble in aqueous medium, 1981, bulletin GC-67) that the addition of soluble salts, such as sodium chloride or calcium chloride, to media containing Carbopols decreases the viscosity of these media.
Moreover, WO 95/05 804 has provided ophthalmic compositions containing 0.1 to 10% by weight of polyanionic polymers, such as acrylic acid polymers and in particular Carbopols, and from 0.01 to 1.0% by weight of electrolytes supplying cations, such as Na+, Zn2+ or AI3+.
These compositions have lower viscosities which allow instillation to be carried out.
The Applicant has, however, found that such compositions are opalescent and can obscure the vision during installation.
Moreover, it has been asserted, in a communication of Oechsver and Keipert, Proc. 1 st Wold Meeting APGI/APV, Budapest 9-11 May 1995, p.
OF THE DRY EYE SYNDROME
The present invention relates to an eyewash intended in particular for the treatment of the dry aye syndrome.
Compositions intended for the treatment of the dry .eye syndrome have already been described is WO 84/04 680 and WO 84/04 681. These compositions are composed of Qels or very viscous solutions containing polyanioaic polymers, such as products sold wader the trade mark Carbopol~ which are acrylic acid polymers crossliaked by allyl sucrose or allylpeataerythritol.
Thus, WO 84/04 681 describes, for example, a flowable gel which comprises 0.2% by weight of Carbopol~ 940. This gel has a viscosity of 12,400-12,600 mPa~s.
Such gels are, however, difficult to use and can result in feelings of stricking of the eyelids.
Moreover, it is known (BF Goodrich, Carbopol~ - Resins soluble in aqueous medium, 1981, bulletin GC-67) that the addition of soluble salts, such as sodium chloride or calcium chloride, to media containing Carbopols decreases the viscosity of these media.
Moreover, WO 95/05 804 has provided ophthalmic compositions containing 0.1 to 10% by weight of polyanionic polymers, such as acrylic acid polymers and in particular Carbopols, and from 0.01 to 1.0% by weight of electrolytes supplying cations, such as Na+, Zn2+ or AI3+.
These compositions have lower viscosities which allow instillation to be carried out.
The Applicant has, however, found that such compositions are opalescent and can obscure the vision during installation.
Moreover, it has been asserted, in a communication of Oechsver and Keipert, Proc. 1 st Wold Meeting APGI/APV, Budapest 9-11 May 1995, p.
16-17, that the addition of polyvinylpyrrolidone decresed the viscosity of aqueous formulations based on Carbopol 980 and that the addition of sodium hydroxide rendered these formulations clear.
As will be shown subsequently, these results cannot be reproduced.
The present invention is targeted at providing ophthalmic compositions intended in particular for the treatment of dry eyes which exhibit low viscosities and which are clear.
The present invention relates to a ready-for use eyewash intended in particular for the treatment of the dry eye syndrome comprising, in aqueous solution - a gelifying polyanionic polymer, - a buffer in an amount sufficient to reduce the viscosity of the eyewash to a value of 10 to 60 mPa~s, preferably of 10 to 30 mPa~s, and - a water soluble polyvinylpyrrolidone in an amount sufficient for the eyewash to be clear.
The present invention relates also to is a process for rendering clear as opalescent composition containing a gelifyinQ polyanionic polymer and a buffer in an amount sufficient to reduce the viscosity of the composition to a value of 10 to 60 mPa~ s, which comprises the addition of a sufficient amount of polyvinyl-pyrrolidone to render the composition clear.
The gelifying polyanionic polymer can be in particular a crosslinked acrylic acid polymer and in particular a crosslinked acrylic acid homopolymer. These polymers are in particular those sold under the trade mark Carbopol~ and which are crosslinked by allyl sucrose or allylpentaerythritol, such as Carbopol 934, Carbopol 940 or Carbopol 980. These polymers can be present in particular at concentrations of 0.1 to 1% by weight.
dye pH of the eyewash is advantageously from 6.0 to 8.0 and in particular in the region of 7Ø It can be adjusted with sodium hydroxide.
As will be shown subsequently, these results cannot be reproduced.
The present invention is targeted at providing ophthalmic compositions intended in particular for the treatment of dry eyes which exhibit low viscosities and which are clear.
The present invention relates to a ready-for use eyewash intended in particular for the treatment of the dry eye syndrome comprising, in aqueous solution - a gelifying polyanionic polymer, - a buffer in an amount sufficient to reduce the viscosity of the eyewash to a value of 10 to 60 mPa~s, preferably of 10 to 30 mPa~s, and - a water soluble polyvinylpyrrolidone in an amount sufficient for the eyewash to be clear.
The present invention relates also to is a process for rendering clear as opalescent composition containing a gelifyinQ polyanionic polymer and a buffer in an amount sufficient to reduce the viscosity of the composition to a value of 10 to 60 mPa~ s, which comprises the addition of a sufficient amount of polyvinyl-pyrrolidone to render the composition clear.
The gelifying polyanionic polymer can be in particular a crosslinked acrylic acid polymer and in particular a crosslinked acrylic acid homopolymer. These polymers are in particular those sold under the trade mark Carbopol~ and which are crosslinked by allyl sucrose or allylpentaerythritol, such as Carbopol 934, Carbopol 940 or Carbopol 980. These polymers can be present in particular at concentrations of 0.1 to 1% by weight.
dye pH of the eyewash is advantageously from 6.0 to 8.0 and in particular in the region of 7Ø It can be adjusted with sodium hydroxide.
The buffers which make it possible to reduce the eyewash viscosity can be buffers such as potassium phosphate buffer (pH 7.0), borate buffer (pH 7.0), citrate buffer (pH 7.0) aad sodium phosphate buffer tpH 7.0), the sodium or potassium phosphate buffers being preferred.
The amounts of buffer to be added increase with the concentration of polyanionic polymers.
The amounts of buffer to be added can be easily determined by viscosity measurements.
The viscosity shown is that measured by using a Haake.VT500*rotational viscometer with NV coaxial cylin-ders comprising an inner cylinder with radii of 17.85-20.1 mm and a height of 60 mm and an outer cylinder with radii of 17.5-20.5 ~ aad a width of 0.35 mm. The viscosity shown is that measured at 1200 s'1 at a tem-perature of 22°C t 1°C.
The polyvinylpyrrolidoaes used in the invention are water-soluble polyvinylpyrrolidones which advantage-ously have weight-average molecular masses of 25,000 to 100,000, such as the polyvidone PV'P Ii30 (weight-average molecular. mass 45,000).
~e ~nouats of polyvinylpyrrolidones to be added can easily be determined by estimations of the clarity.
Generally, the amounts of polyvinylpyrrolidones to be added increase with the amounts of polyanioaic polymer.
For percentages of polyanionic polymer of the order of 0.2% by weight, percentages of 1% by weight of polyvinyl-pyrrolidone are suitable.
A preferred eyewash comprises, in aqueous solution:
0.2% of Carbopol 980, 1% of polyvinylpyrrolidone K30, sodium phosphate buffer in an amount sufficient to produce a viscosity of 10 to 30 mPa~s.
* trademark 3a The eyewash according to the invention can in addition contain conventional eye~t~rash adjuvants, such as sodium edetate, which acts as preservative (and which partly contributes to decreasing the viscosity), anti-microbial preservatives, such as benzalkonium chloride or sodium mercurothiolate, and isotonicity agents, such as sorbitol or manaitol.
Examples of eyewashes according to the invention which simultaneously have a low viscosity and are clear will be given below.
Carbopol 934 . 0.200 g Sodium edetata : 0.050 Q
Sbdium hydroxide : 0.078 Q
70% Crystallizable sorbitol : 6.630 g Polyvidone PVP R30 . 1.000 g Potassium dihydroQanphosphata . 0.074 g Potassium hydroQaaphosphate : 0.200 Q
Purified water, q.s. for : 100.000 Q
Viscosity (at 1200 s'1) : 11.4 mPa- s Carbopol 980 : 0.500 Q
Sodium hydroxide : 0.195 Q
Polyvidone PVP R30 : 2.000 g Sodium dihydroQanphosphata dihydrate : 0.540 g Sodium hydroQanphosphate dodecahydrate : 2.260 Q
Purified water, q.s. for : 100.000 Q
viscosity (at 1200 s'~) : 30. 0 mPa- s Carbopol 980 : 0.750 Q
Sodium hydroxide . 0.292 Q
Polyvidone PYP R30 : 2.550 g Sodium dihydroQenphosphata dihydrata : 1.250 Q
Sodium hydroQenphosphata dodecahydrate : 5.200 Q
Purified water, q.s. for : 100.000 g Viscosity (at 1200 s'1) : 27.7 mPa~ s EXAMPL$ 4 Carbopol 980 : 0.200 Q
Benzalkonium chloride solution for ophthalmic use : 0.010 Q
Sodium edstats s 0.050 g Polyvidone PVP R30 : 1.000 Q
Sodium hydroxide ; 0,078 Q
Sodium dihydroQenphosphate dihydrate : 0.052 Q
Sodium hydroQanphosphate dodecahydrate s 0.217 y 70% Crystallizable sorbitol s 6.360 g Purified water, q.s. for s 100.000 g Viscosity (at 1200 s'1) : 15. 0 mPa- s 21934p~
The amounts of buffer to be added increase with the concentration of polyanionic polymers.
The amounts of buffer to be added can be easily determined by viscosity measurements.
The viscosity shown is that measured by using a Haake.VT500*rotational viscometer with NV coaxial cylin-ders comprising an inner cylinder with radii of 17.85-20.1 mm and a height of 60 mm and an outer cylinder with radii of 17.5-20.5 ~ aad a width of 0.35 mm. The viscosity shown is that measured at 1200 s'1 at a tem-perature of 22°C t 1°C.
The polyvinylpyrrolidoaes used in the invention are water-soluble polyvinylpyrrolidones which advantage-ously have weight-average molecular masses of 25,000 to 100,000, such as the polyvidone PV'P Ii30 (weight-average molecular. mass 45,000).
~e ~nouats of polyvinylpyrrolidones to be added can easily be determined by estimations of the clarity.
Generally, the amounts of polyvinylpyrrolidones to be added increase with the amounts of polyanioaic polymer.
For percentages of polyanionic polymer of the order of 0.2% by weight, percentages of 1% by weight of polyvinyl-pyrrolidone are suitable.
A preferred eyewash comprises, in aqueous solution:
0.2% of Carbopol 980, 1% of polyvinylpyrrolidone K30, sodium phosphate buffer in an amount sufficient to produce a viscosity of 10 to 30 mPa~s.
* trademark 3a The eyewash according to the invention can in addition contain conventional eye~t~rash adjuvants, such as sodium edetate, which acts as preservative (and which partly contributes to decreasing the viscosity), anti-microbial preservatives, such as benzalkonium chloride or sodium mercurothiolate, and isotonicity agents, such as sorbitol or manaitol.
Examples of eyewashes according to the invention which simultaneously have a low viscosity and are clear will be given below.
Carbopol 934 . 0.200 g Sodium edetata : 0.050 Q
Sbdium hydroxide : 0.078 Q
70% Crystallizable sorbitol : 6.630 g Polyvidone PVP R30 . 1.000 g Potassium dihydroQanphosphata . 0.074 g Potassium hydroQaaphosphate : 0.200 Q
Purified water, q.s. for : 100.000 Q
Viscosity (at 1200 s'1) : 11.4 mPa- s Carbopol 980 : 0.500 Q
Sodium hydroxide : 0.195 Q
Polyvidone PVP R30 : 2.000 g Sodium dihydroQanphosphata dihydrate : 0.540 g Sodium hydroQanphosphate dodecahydrate : 2.260 Q
Purified water, q.s. for : 100.000 Q
viscosity (at 1200 s'~) : 30. 0 mPa- s Carbopol 980 : 0.750 Q
Sodium hydroxide . 0.292 Q
Polyvidone PYP R30 : 2.550 g Sodium dihydroQenphosphata dihydrata : 1.250 Q
Sodium hydroQenphosphata dodecahydrate : 5.200 Q
Purified water, q.s. for : 100.000 g Viscosity (at 1200 s'1) : 27.7 mPa~ s EXAMPL$ 4 Carbopol 980 : 0.200 Q
Benzalkonium chloride solution for ophthalmic use : 0.010 Q
Sodium edstats s 0.050 g Polyvidone PVP R30 : 1.000 Q
Sodium hydroxide ; 0,078 Q
Sodium dihydroQenphosphate dihydrate : 0.052 Q
Sodium hydroQanphosphate dodecahydrate s 0.217 y 70% Crystallizable sorbitol s 6.360 g Purified water, q.s. for s 100.000 g Viscosity (at 1200 s'1) : 15. 0 mPa- s 21934p~
The results of a study on rabbits of the persist ence of eyewashes according to the invention on the eye, compared with that of a gel containing the sam~ concen tration of Carbopol (0.2% by weight), will be given below.
The persistence of the compositions at the surface of the eye was determined by studying the kinetics of the artificially induced increase in the lacrimal volume, in comparison with the effect of an ophthalmic solution not containing polymers.
The experiments were carried out on male New Zealand albino rabbits weighing from 2.3 kg to 3.6 kg, sourced from the breeder Charles River France (St Aubin-les-8lbeuf, 76410, CLEON), acclimatized for a minimum of 5 days in the animal house (temperature 19t2~C, relative humidity: 55110%, lighting: 12 hours of artificial lighting - 12 hours of night).
The eyewashes tested had the following composi-tion:
219~40~
.-carbopol seo o.so Q o.~o Q -Sodium ~d~tat~ 0.05 Q 0.05 Q 0.05 Q
Crystalli:able 6.85 Q 6.36 Q 6.36 y sorbitol (70~t) seasall~oaium o.oi Q 0.01 ~ 0.01 chloride Sodium dihydroQaa-0.016 Q O.OSZ Q 0.052 Q
phosphate dihydrat~
Bodittm hy~droQ~a-0.077 p O.Z17 Q O.Z17 Q
plsosphat~
dod~oahydrat~
polyvidot~a PYp 1.00 p 1.00 qr 1.00 sodism~ bydrouide 0.070 Q 0.078 Q Q.s. p8 7 Hscrifisd ~ratex. 100.0 p 100.0 Q 100.0 p e~.s. for p$ 7 The lacrimal volume ~rao measured accardiaQ to a technique fox dilutiaQ a lluorercein solution similar to the methods used by Mishima et al. (Invest. Ophthalmol., 5(3), z64-276, 1966) and 08bbels et al. (t3raefe~s Arch.
Clin. Sxa. Ophthal.alal., ZZ9, 147-it9, 1991) in man. The Qeaeral principle of this method is as follows: a fluoreacein solution of kaovrn concentration it instilled, is the smallest possible volume, is order to avoid the lacrimal reflex, and rhea immediately distributed homo-Qensously in the lacrimal film by successive bllakiaQs.
A sample of tears is taken immediately afterlvarda~ the fluorescence of this sample is deteratined by fluorimetry.
The lacrimal volume is calculated accordiaQ to the equation:
::-rV = -us' ~l - vi Qs _~ _ .
V :.lncrimal volume Vs : volume of the sample of tears taken Qi . amount of fluoresceia instilled Qe . amount of fluoresceia in the sample of tears taken Vi . voluiae of the fiuorssasin solution instilled.
The animals are anaesthsti:ed by intramusculax administration of a ketamine (35 mg/kQ)/xylaaias ( 5 mQ/kQ) mixture in order to facilitate the taking of the sample of tears and to reader the measurement' of the lacria~al volume mare reliable indeed. in the conscious animal, a great deal of blinking is observed on approach of the microcapillary.
Ten minutes after iajectian of the anaesthetic, 1 (tl of a ix aqueous fiuoresceia solution was instilled L5 in the lower canjuactival cul-de-sac using a miarocapil-lary. The eyelids were maauaily closed twice. rodhile nvoiding any pressure oa the eyeball. Five seconds after the fluoresceia installation, 1 )11 of tears was removed by capillarity frown the louver meniscus while avoiding any contact of the microcapillary with the lower .yslid cad the surface of the eye.
The sample of tears taken was diluted in 4 ml of p8 7.4 isotonic phosphate buffer (NaB=g0,s 3Z ml~i, Ha=HFO,: 104 mgt) . The fluorescence of these samples was measured at room te~perature with a spectrofluorimeter (excitation wavelength: 496 amp ssiesion wavelength:
506 am) in co~mparisoa with that of a reference solution containing 1.6 ~tg of fluoresceia in 4 ml of phosphate buffer (100~s fluorescence). The 0 was adjusted with the phosphate buffer alone.
The amount of fluotescein contained is the sample of tears taken (Qs) tsar calculated frown the relative percentage of fluoreeceaae of the sample (x) aacordiag to the formulas x ($) x 1..6 ug Qs (ug) - _ ~~
,.1. r,4~.,T
l .. 21934 0~
_8_ The lacrimal volume, expressed in ~1. was calcu-lated according to the equation given above in which:
vi = 1 ~.1 Qi ' 10 ~g Vs = 1 ~1 Prior coatrols made it possible to confirm that the quantitative determination method was linear in this range of concentrations of the samples tested in this study and that the addition of tears or of the formulae tested did not modify the intensity of fluorescence of reference fluorescein solutions.
The animals were treated in a siagle eye by an instillation in the lower conjunctival cul-de-sac of 25 ~.1 of the preparation tested, at different times before measuring the lacrimal volume. Ths eyelids were then manually closed once.
For each formula tested and each time, a batch of animals receiving, under the same conditions, 25 ~,1 of an isotonic sorbitol solution was included as control (70%
sorbitol at 7.5% w/w).
When different treatments (different formulations or pretreatment times) were tested in the same animals, a minimum interval of 3 days was complied with between the experiments.
The lacrimal volume is expressed in mean t standard deviation form.
=n very rare cases, insufficient anaesthesia or poor homogenization of the fluorescein solution after manually closing the eyelids was observed. The corre-sponding measurements were not taken into account in calculating the means.
The mean values obtained in each batch (control and treated) were compared using the Mann-Whitney U-test.
Statistical analysis was carried out using Statworks software. The difference is regarded as significant when p is less than or equal to 0.05.
Eyewashes A and 8 are eyewashes according to the invention whereas Eyewash C does not contain Carbopol.
The composition of the comparison gel was as follows:
_ g _ Carbopol 940 : 0.2000 g Beazalkonium chloride . 0.0100 g Sodium hydroxide . 0.0660 g 70% Crystallizable sorbitol . 5.7143 g Purified water, q.s: for . 100.0000 g The viscosities of the compositions were measured with a Carri-Med CSL 100* device ~ Rotor: stainless steel cone/plate for the gel with a diameter of 4 cm, angle . 2°, gap ~ 56 cone/plate for the other compositions with a diameter of 6 cm, angle . 2° and gap 67.
The rate gradient is from 0 to 1200 s'1 over 3 minutes at a temperature of 34.0 t 1°C.
Composition Appareat viscosity*
(mPa- s ) .A 30.4 t 0.3**
H 15.0 t 0.1 Gel 256.5 t 3.4 * Shear rate: 1200 s'1 ** Mean t standard deviation (3 measurements) The results obtained With the gal are as follows:
* trademark 9a Time Lacrimal volume (~,l) (min) Control Gel 4.82 t 0.23 (4) 13.45 t 5.28**
(il) 4.59 t 0.96 (4) 9.69 2.62** (12) t 40 3.77 t 0.26 (4) 7.47 2.28** (il) *
60 4.09 f 0.78 (4) 5.92 1.43* (12) t 10 120 4.46 t 0.37 (4) 5.03 I.06 (12) t * p < 0.05; ** p < 0.01 in comparison with the control batch Number of animals in brackets The results obtained With Eyewash A according to the invention are as follows:
Time Lacrimal volume (min) (~.l) Control Eyewash A
4.16 t 0.52 (5) 13.59 t 6.22** (11) 4.07 t 0.68 (5) 10.04 t 2.06** (11) 40 4:64 t 0.56 (5) 7.52 t 1.90** (11) 60 4.25 t 0.38 (5) 4.92 ~t 0.82 (8) 10 120 5.16 * 0.78 (5) 5.18 t 0.60 (10) ** p < 0.01 in comparison With the control batch Number of animals in brackets The results obtained with Eyewash B (according to the invention) are as follows:
15 Time Lacrimal volume (~,l) (min) Control Eyewash 8 10 4.56 t 0.84 (5) 12.42 t 3.40** (11) 20 4.72 t 0.64 (4) 10.51 t 2.46** (11) 40 4.84 * 0.75 (5) 7.80 t 1.91** (11) 20 60 4.33 t 1.06 (5) 5.54 t 1.63 (11) 120 4.98 * 1.12 (5) 5.28 t 1.03 (7) ** p < 0.01 is comparison with the control batch Ntunber of animals is brackets The results obtained with Eyewash C (comparative example) are as follows:
Time Lacrimal volume (mia) ( ~,l ) Coatrol Eyewash C
8.08 t 1.75 (6) 12.51 t 3.16** (10) 5.85 t 1.36 (6) 7.12 t 2.53 (9) 5 20 5.30 t 1.22 (6) 6.Oa t 1.47 (10) I
** p < 0.01 is coa~parisoa with the control batch Number of aaimals is brackets These results demonstrate a persistence on the eye with Eyewashes A and H accordiaQ to the invention 10 which is virtually comparable with that of the gel. Oa the other hand, Eyewash C, which contains polyviayl-pyrrolidone but which does not contain Carbopol, only has an effect of very limited duration.
moreover, results intea8ed to show the influence of the addition of polyvinylpyrrolidone and buffers to aqueous Carbopol-based compositions oa the viscosity and clarity will be Qiven below. These results are combined in the followiaQ table:
loz~la rosaula losmzla :ormala aormala 1 I 3 a s Carbopol 0.3 q Id. Id. Id. Id.
EDT11 0.05 Q Id. Id. Id. Id.
sodius q.r. D8.7Id. id. Id. Id.
hydroxide ' 8orbitol q.r. iro-Id. Id. Id. Id.
toaicity PV? l~ 30 - 1 Q g Q - 1 rraa,po,sa,o- _ - o.o5i Q o.osa Q
rrag,ro,-izx,o- - - o.zl~ Q a.sl~
Q
water q.s. !or id. Id. id. Id.
100 ml ~DDearaace clear clear opalescentoDalerceatclear vircority 100 130 95 16 19 3 is mpar (at 1400 r'1) These results shorn that, is contrast to what was anrtouaced is the article of Oechsver and Keipert mentioned above, the addition of polyvinylpyrrolidone does not significantly modify the viscosity of Carbopol-base compositions, either at concentrations of 1% or of 6%, and that, moreover, the addition of 6% of polyviayl-pyrrolidone induces an opalescence (which cannot be masked by the addition of sodium hydroxide since neutra-lity cannot be exceeded). Only the addition of buffer makes it possible to decrease the viscosity (Formulae 4 and 5) and the opalescence is removed by addition of polyvinylpyrrolidoas (Formula 5). The addition of a polyviaylpyrrolidone RZ5, as taught is the communication, instead of polyviaylpyrrolidone K30 gives the same results.
Finally, results showing that it is easy toy determine the amount of buf f er to be added is order to achieve the desired viscosity will be given.
Increasing amounts of sodium phosphate buffer were added to a composition identical to that of Example 4 but without buffer and without preservative, the sodium phosphate buffer having the campositioa:
NaHzPO,- 2H,o o . a~ Q
NaH=POD- l2FIs0 3 . s2 Q
HzO, q.s. for 100 ml.
The viscosities as a function of the amounts of buffer are as follows:
volum.
o=
bar:.=
D=~mat 0 0.15 0.5 1 Z 4 6 8 10 ml ml ml ml ml ml ml ml 3 is th.
formula vis-cosity 100 53 41 3S Z9 36 11 18 16 (m8at)
The persistence of the compositions at the surface of the eye was determined by studying the kinetics of the artificially induced increase in the lacrimal volume, in comparison with the effect of an ophthalmic solution not containing polymers.
The experiments were carried out on male New Zealand albino rabbits weighing from 2.3 kg to 3.6 kg, sourced from the breeder Charles River France (St Aubin-les-8lbeuf, 76410, CLEON), acclimatized for a minimum of 5 days in the animal house (temperature 19t2~C, relative humidity: 55110%, lighting: 12 hours of artificial lighting - 12 hours of night).
The eyewashes tested had the following composi-tion:
219~40~
.-carbopol seo o.so Q o.~o Q -Sodium ~d~tat~ 0.05 Q 0.05 Q 0.05 Q
Crystalli:able 6.85 Q 6.36 Q 6.36 y sorbitol (70~t) seasall~oaium o.oi Q 0.01 ~ 0.01 chloride Sodium dihydroQaa-0.016 Q O.OSZ Q 0.052 Q
phosphate dihydrat~
Bodittm hy~droQ~a-0.077 p O.Z17 Q O.Z17 Q
plsosphat~
dod~oahydrat~
polyvidot~a PYp 1.00 p 1.00 qr 1.00 sodism~ bydrouide 0.070 Q 0.078 Q Q.s. p8 7 Hscrifisd ~ratex. 100.0 p 100.0 Q 100.0 p e~.s. for p$ 7 The lacrimal volume ~rao measured accardiaQ to a technique fox dilutiaQ a lluorercein solution similar to the methods used by Mishima et al. (Invest. Ophthalmol., 5(3), z64-276, 1966) and 08bbels et al. (t3raefe~s Arch.
Clin. Sxa. Ophthal.alal., ZZ9, 147-it9, 1991) in man. The Qeaeral principle of this method is as follows: a fluoreacein solution of kaovrn concentration it instilled, is the smallest possible volume, is order to avoid the lacrimal reflex, and rhea immediately distributed homo-Qensously in the lacrimal film by successive bllakiaQs.
A sample of tears is taken immediately afterlvarda~ the fluorescence of this sample is deteratined by fluorimetry.
The lacrimal volume is calculated accordiaQ to the equation:
::-rV = -us' ~l - vi Qs _~ _ .
V :.lncrimal volume Vs : volume of the sample of tears taken Qi . amount of fluoresceia instilled Qe . amount of fluoresceia in the sample of tears taken Vi . voluiae of the fiuorssasin solution instilled.
The animals are anaesthsti:ed by intramusculax administration of a ketamine (35 mg/kQ)/xylaaias ( 5 mQ/kQ) mixture in order to facilitate the taking of the sample of tears and to reader the measurement' of the lacria~al volume mare reliable indeed. in the conscious animal, a great deal of blinking is observed on approach of the microcapillary.
Ten minutes after iajectian of the anaesthetic, 1 (tl of a ix aqueous fiuoresceia solution was instilled L5 in the lower canjuactival cul-de-sac using a miarocapil-lary. The eyelids were maauaily closed twice. rodhile nvoiding any pressure oa the eyeball. Five seconds after the fluoresceia installation, 1 )11 of tears was removed by capillarity frown the louver meniscus while avoiding any contact of the microcapillary with the lower .yslid cad the surface of the eye.
The sample of tears taken was diluted in 4 ml of p8 7.4 isotonic phosphate buffer (NaB=g0,s 3Z ml~i, Ha=HFO,: 104 mgt) . The fluorescence of these samples was measured at room te~perature with a spectrofluorimeter (excitation wavelength: 496 amp ssiesion wavelength:
506 am) in co~mparisoa with that of a reference solution containing 1.6 ~tg of fluoresceia in 4 ml of phosphate buffer (100~s fluorescence). The 0 was adjusted with the phosphate buffer alone.
The amount of fluotescein contained is the sample of tears taken (Qs) tsar calculated frown the relative percentage of fluoreeceaae of the sample (x) aacordiag to the formulas x ($) x 1..6 ug Qs (ug) - _ ~~
,.1. r,4~.,T
l .. 21934 0~
_8_ The lacrimal volume, expressed in ~1. was calcu-lated according to the equation given above in which:
vi = 1 ~.1 Qi ' 10 ~g Vs = 1 ~1 Prior coatrols made it possible to confirm that the quantitative determination method was linear in this range of concentrations of the samples tested in this study and that the addition of tears or of the formulae tested did not modify the intensity of fluorescence of reference fluorescein solutions.
The animals were treated in a siagle eye by an instillation in the lower conjunctival cul-de-sac of 25 ~.1 of the preparation tested, at different times before measuring the lacrimal volume. Ths eyelids were then manually closed once.
For each formula tested and each time, a batch of animals receiving, under the same conditions, 25 ~,1 of an isotonic sorbitol solution was included as control (70%
sorbitol at 7.5% w/w).
When different treatments (different formulations or pretreatment times) were tested in the same animals, a minimum interval of 3 days was complied with between the experiments.
The lacrimal volume is expressed in mean t standard deviation form.
=n very rare cases, insufficient anaesthesia or poor homogenization of the fluorescein solution after manually closing the eyelids was observed. The corre-sponding measurements were not taken into account in calculating the means.
The mean values obtained in each batch (control and treated) were compared using the Mann-Whitney U-test.
Statistical analysis was carried out using Statworks software. The difference is regarded as significant when p is less than or equal to 0.05.
Eyewashes A and 8 are eyewashes according to the invention whereas Eyewash C does not contain Carbopol.
The composition of the comparison gel was as follows:
_ g _ Carbopol 940 : 0.2000 g Beazalkonium chloride . 0.0100 g Sodium hydroxide . 0.0660 g 70% Crystallizable sorbitol . 5.7143 g Purified water, q.s: for . 100.0000 g The viscosities of the compositions were measured with a Carri-Med CSL 100* device ~ Rotor: stainless steel cone/plate for the gel with a diameter of 4 cm, angle . 2°, gap ~ 56 cone/plate for the other compositions with a diameter of 6 cm, angle . 2° and gap 67.
The rate gradient is from 0 to 1200 s'1 over 3 minutes at a temperature of 34.0 t 1°C.
Composition Appareat viscosity*
(mPa- s ) .A 30.4 t 0.3**
H 15.0 t 0.1 Gel 256.5 t 3.4 * Shear rate: 1200 s'1 ** Mean t standard deviation (3 measurements) The results obtained With the gal are as follows:
* trademark 9a Time Lacrimal volume (~,l) (min) Control Gel 4.82 t 0.23 (4) 13.45 t 5.28**
(il) 4.59 t 0.96 (4) 9.69 2.62** (12) t 40 3.77 t 0.26 (4) 7.47 2.28** (il) *
60 4.09 f 0.78 (4) 5.92 1.43* (12) t 10 120 4.46 t 0.37 (4) 5.03 I.06 (12) t * p < 0.05; ** p < 0.01 in comparison with the control batch Number of animals in brackets The results obtained With Eyewash A according to the invention are as follows:
Time Lacrimal volume (min) (~.l) Control Eyewash A
4.16 t 0.52 (5) 13.59 t 6.22** (11) 4.07 t 0.68 (5) 10.04 t 2.06** (11) 40 4:64 t 0.56 (5) 7.52 t 1.90** (11) 60 4.25 t 0.38 (5) 4.92 ~t 0.82 (8) 10 120 5.16 * 0.78 (5) 5.18 t 0.60 (10) ** p < 0.01 in comparison With the control batch Number of animals in brackets The results obtained with Eyewash B (according to the invention) are as follows:
15 Time Lacrimal volume (~,l) (min) Control Eyewash 8 10 4.56 t 0.84 (5) 12.42 t 3.40** (11) 20 4.72 t 0.64 (4) 10.51 t 2.46** (11) 40 4.84 * 0.75 (5) 7.80 t 1.91** (11) 20 60 4.33 t 1.06 (5) 5.54 t 1.63 (11) 120 4.98 * 1.12 (5) 5.28 t 1.03 (7) ** p < 0.01 is comparison with the control batch Ntunber of animals is brackets The results obtained with Eyewash C (comparative example) are as follows:
Time Lacrimal volume (mia) ( ~,l ) Coatrol Eyewash C
8.08 t 1.75 (6) 12.51 t 3.16** (10) 5.85 t 1.36 (6) 7.12 t 2.53 (9) 5 20 5.30 t 1.22 (6) 6.Oa t 1.47 (10) I
** p < 0.01 is coa~parisoa with the control batch Number of aaimals is brackets These results demonstrate a persistence on the eye with Eyewashes A and H accordiaQ to the invention 10 which is virtually comparable with that of the gel. Oa the other hand, Eyewash C, which contains polyviayl-pyrrolidone but which does not contain Carbopol, only has an effect of very limited duration.
moreover, results intea8ed to show the influence of the addition of polyvinylpyrrolidone and buffers to aqueous Carbopol-based compositions oa the viscosity and clarity will be Qiven below. These results are combined in the followiaQ table:
loz~la rosaula losmzla :ormala aormala 1 I 3 a s Carbopol 0.3 q Id. Id. Id. Id.
EDT11 0.05 Q Id. Id. Id. Id.
sodius q.r. D8.7Id. id. Id. Id.
hydroxide ' 8orbitol q.r. iro-Id. Id. Id. Id.
toaicity PV? l~ 30 - 1 Q g Q - 1 rraa,po,sa,o- _ - o.o5i Q o.osa Q
rrag,ro,-izx,o- - - o.zl~ Q a.sl~
Q
water q.s. !or id. Id. id. Id.
100 ml ~DDearaace clear clear opalescentoDalerceatclear vircority 100 130 95 16 19 3 is mpar (at 1400 r'1) These results shorn that, is contrast to what was anrtouaced is the article of Oechsver and Keipert mentioned above, the addition of polyvinylpyrrolidone does not significantly modify the viscosity of Carbopol-base compositions, either at concentrations of 1% or of 6%, and that, moreover, the addition of 6% of polyviayl-pyrrolidone induces an opalescence (which cannot be masked by the addition of sodium hydroxide since neutra-lity cannot be exceeded). Only the addition of buffer makes it possible to decrease the viscosity (Formulae 4 and 5) and the opalescence is removed by addition of polyvinylpyrrolidoas (Formula 5). The addition of a polyviaylpyrrolidone RZ5, as taught is the communication, instead of polyviaylpyrrolidone K30 gives the same results.
Finally, results showing that it is easy toy determine the amount of buf f er to be added is order to achieve the desired viscosity will be given.
Increasing amounts of sodium phosphate buffer were added to a composition identical to that of Example 4 but without buffer and without preservative, the sodium phosphate buffer having the campositioa:
NaHzPO,- 2H,o o . a~ Q
NaH=POD- l2FIs0 3 . s2 Q
HzO, q.s. for 100 ml.
The viscosities as a function of the amounts of buffer are as follows:
volum.
o=
bar:.=
D=~mat 0 0.15 0.5 1 Z 4 6 8 10 ml ml ml ml ml ml ml ml 3 is th.
formula vis-cosity 100 53 41 3S Z9 36 11 18 16 (m8at)
Claims (10)
1. Ready-for-use eyewash comprising, in aqueous solution:
- a gelifying polyanionic polymer - a buffer in an amount sufficient to reduce the viscosity of the eyewash to a value of 10 to 60 mPa.cndot.s and - a water-soluble polyvinylpyrrolidone in an amount sufficient for the eyewash to be clear.
- a gelifying polyanionic polymer - a buffer in an amount sufficient to reduce the viscosity of the eyewash to a value of 10 to 60 mPa.cndot.s and - a water-soluble polyvinylpyrrolidone in an amount sufficient for the eyewash to be clear.
2. Eyewash according to claim 1, in which the gelifying polyanionic polymer is a crosslinked acrylic acid polymer.
3. Eyewash according to claim 2, in which the crosslinked acrylic acid polymer is a Carbopol®
4. Eyewash according to claim 2 or 3, in which the crosslinked acrylic acid polymer is present at a concentration of 0.1 to 1% by weight.
5. Eyewash according to any one of claims 1 to 4, in which the buffer is selected from the group consisting of potassium phosphate buffer and sodium phosphate buffer.
6. Eyewash according to any one of claims 1 to 5, in which the polyvinylpyrrolidone is polyvinylpyrrolidone K30.
7. Eyewash according to any one of claims 1 to 6, comprising 0.2% by weight of the gelifying polyanionic polymer and 1% by weight of polyvinylpyrrolidone.
8. Eyewash according to any one of claims 1 to 7, comprising, in aqueous solution:
0.2% of Carbopol® 980, 1% of polyvinylpyrrolidone K30, sodium phosphate buffer in an amount sufficient to produce a viscosity of 10 to 30 mPa.cndot.s.
0.2% of Carbopol® 980, 1% of polyvinylpyrrolidone K30, sodium phosphate buffer in an amount sufficient to produce a viscosity of 10 to 30 mPa.cndot.s.
9. Use of the eyewash according to any one of claims 1 to 8, for the treatment of the dry eye syndrome.
10. Process for rendering clear an opalescent composition containing a gelifying polyanionic polymer and a buffer in an amount sufficient to reduce the viscosity of the composition to a value of 10 to 60 mPa.cndot.s, which comprises the addition of a sufficient amount of polyvinylpyrrolidone to render the composition clear.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9515061 | 1995-12-19 | ||
| FR9515061A FR2742336B1 (en) | 1995-12-19 | 1995-12-19 | EYE DROPS INTENDED IN PARTICULAR FOR TREATING EYE DRY |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2193405A1 CA2193405A1 (en) | 1997-06-20 |
| CA2193405C true CA2193405C (en) | 2005-11-08 |
Family
ID=9485654
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002193405A Expired - Lifetime CA2193405C (en) | 1995-12-19 | 1996-12-18 | Eyewash intended in particular for the treatment of the dry eye syndrome |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0780121B1 (en) |
| JP (1) | JP4044165B2 (en) |
| AT (1) | ATE202924T1 (en) |
| CA (1) | CA2193405C (en) |
| DE (1) | DE69613803T2 (en) |
| DK (1) | DK0780121T3 (en) |
| ES (1) | ES2158267T3 (en) |
| FR (1) | FR2742336B1 (en) |
| GR (1) | GR3036822T3 (en) |
| PT (1) | PT780121E (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6261547B1 (en) | 1998-04-07 | 2001-07-17 | Alcon Manufacturing, Ltd. | Gelling ophthalmic compositions containing xanthan gum |
| US6174524B1 (en) | 1999-03-26 | 2001-01-16 | Alcon Laboratories, Inc. | Gelling ophthalmic compositions containing xanthan gum |
| PL354928A1 (en) | 1999-11-01 | 2004-03-22 | Alcon, Inc. | Pharmaceutical compositions containing a fluoroquinolone antibiotic drug and xanthan gum |
| EP1305033B1 (en) | 2000-07-28 | 2004-10-20 | Alcon, Inc | Pharmaceutical compositions containing tobramycin and xanthan gum |
| US20090286826A1 (en) * | 2008-05-19 | 2009-11-19 | Francisco Javier Galan | Pharmaceutical compositions having carboxyvinyl polymer and povidone polymer |
| FR3109524B1 (en) * | 2020-04-22 | 2022-04-08 | H4 Orphan Pharma | Use of a multifunctional ligand to treat dry eye and dysfunctions of the meibomian glands and lacrimal glands. |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE448544B (en) * | 1979-12-05 | 1987-03-02 | Kendall & Co | WATER ABSORPTION COMPOSITION AND USE THEREOF AS A CARRIER FOR A MEDICINE |
| WO1984004681A1 (en) | 1983-05-25 | 1984-12-06 | Alcon Lab Inc | Ophthalmic solution |
| EP0145714A1 (en) | 1983-05-25 | 1985-06-26 | Alcon Laboratories, Inc. | Ophthalmic gel |
| DE3440352A1 (en) * | 1984-11-05 | 1986-05-07 | Dr. Thilo & Co GmbH, 8029 Sauerlach | Dry-eye packing |
| US4744980A (en) * | 1986-04-28 | 1988-05-17 | Holly Frank J | Ophthalmic solution for treatment of dry eye syndrome |
| US5188826A (en) * | 1988-02-08 | 1993-02-23 | Insite Vision Incorporated | Topical ophthalmic suspensions |
| US5300296A (en) * | 1989-11-06 | 1994-04-05 | Frank J. Holly | Antimicrobial agent for opthalmic formulations |
| JP2873530B2 (en) * | 1991-12-13 | 1999-03-24 | 参天製薬株式会社 | Carboxyvinyl polymer-containing ophthalmic base showing Newtonian viscosity |
| WO1995005803A1 (en) * | 1993-08-20 | 1995-03-02 | Alcon Laboratories, Inc. | Topical ophthalmic pharmaceutical vehicles |
| IT1273011B (en) * | 1994-07-25 | 1997-07-01 | Trhecnopharma S A | OPHTHALMIC PREPARATION FOR USE AS ARTIFICIAL LACRIMA |
-
1995
- 1995-12-19 FR FR9515061A patent/FR2742336B1/en not_active Expired - Fee Related
-
1996
- 1996-12-17 DE DE69613803T patent/DE69613803T2/en not_active Expired - Lifetime
- 1996-12-17 PT PT96402770T patent/PT780121E/en unknown
- 1996-12-17 DK DK96402770T patent/DK0780121T3/en active
- 1996-12-17 ES ES96402770T patent/ES2158267T3/en not_active Expired - Lifetime
- 1996-12-17 EP EP96402770A patent/EP0780121B1/en not_active Expired - Lifetime
- 1996-12-17 JP JP33718796A patent/JP4044165B2/en not_active Expired - Lifetime
- 1996-12-17 AT AT96402770T patent/ATE202924T1/en active
- 1996-12-18 CA CA002193405A patent/CA2193405C/en not_active Expired - Lifetime
-
2001
- 2001-10-08 GR GR20010401683T patent/GR3036822T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CA2193405A1 (en) | 1997-06-20 |
| JP4044165B2 (en) | 2008-02-06 |
| DE69613803D1 (en) | 2001-08-16 |
| ES2158267T3 (en) | 2001-09-01 |
| DE69613803T2 (en) | 2001-10-25 |
| PT780121E (en) | 2001-10-31 |
| FR2742336B1 (en) | 1998-03-06 |
| FR2742336A1 (en) | 1997-06-20 |
| DK0780121T3 (en) | 2001-10-22 |
| ATE202924T1 (en) | 2001-07-15 |
| JPH09278649A (en) | 1997-10-28 |
| GR3036822T3 (en) | 2002-01-31 |
| EP0780121A1 (en) | 1997-06-25 |
| EP0780121B1 (en) | 2001-07-11 |
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