CA2149657A1 - Compositions containing growth factors and antiplastic agents - Google Patents
Compositions containing growth factors and antiplastic agentsInfo
- Publication number
- CA2149657A1 CA2149657A1 CA002149657A CA2149657A CA2149657A1 CA 2149657 A1 CA2149657 A1 CA 2149657A1 CA 002149657 A CA002149657 A CA 002149657A CA 2149657 A CA2149657 A CA 2149657A CA 2149657 A1 CA2149657 A1 CA 2149657A1
- Authority
- CA
- Canada
- Prior art keywords
- lens epithelial
- lens
- tgf
- composition according
- epithelial cell
- 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.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims description 48
- 239000003102 growth factor Substances 0.000 title claims description 18
- 239000003795 chemical substances by application Substances 0.000 title description 10
- 210000001542 lens epithelial cell Anatomy 0.000 claims abstract description 51
- 230000000340 anti-metabolite Effects 0.000 claims abstract description 31
- 229940100197 antimetabolite Drugs 0.000 claims abstract description 31
- 239000002256 antimetabolite Substances 0.000 claims abstract description 31
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims abstract description 20
- 230000010261 cell growth Effects 0.000 claims abstract description 16
- 239000003324 growth hormone secretagogue Substances 0.000 claims abstract description 13
- 238000001356 surgical procedure Methods 0.000 claims abstract description 13
- 208000008516 Capsule Opacification Diseases 0.000 claims abstract description 11
- 208000002177 Cataract Diseases 0.000 claims abstract description 10
- 229960004857 mitomycin Drugs 0.000 claims abstract description 10
- 230000006820 DNA synthesis Effects 0.000 claims abstract description 8
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 8
- 230000035755 proliferation Effects 0.000 claims abstract description 8
- 230000004936 stimulating effect Effects 0.000 claims description 7
- 229960002949 fluorouracil Drugs 0.000 claims description 4
- 108010081589 Becaplermin Proteins 0.000 claims description 3
- 230000000977 initiatory effect Effects 0.000 claims description 3
- QCXJFISCRQIYID-IAEPZHFASA-N 2-amino-1-n-[(3s,6s,7r,10s,16s)-3-[(2s)-butan-2-yl]-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-10-propan-2-yl-8-oxa-1,4,11,14-tetrazabicyclo[14.3.0]nonadecan-6-yl]-4,6-dimethyl-3-oxo-9-n-[(3s,6s,7r,10s,16s)-7,11,14-trimethyl-2,5,9,12,15-pentaoxo-3,10-di(propa Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N=C2C(C(=O)N[C@@H]3C(=O)N[C@H](C(N4CCC[C@H]4C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]3C)=O)[C@@H](C)CC)=C(N)C(=O)C(C)=C2O2)C2=C(C)C=C1 QCXJFISCRQIYID-IAEPZHFASA-N 0.000 claims description 2
- -1 5'-fluorouracil Chemical compound 0.000 claims description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
- 229930012538 Paclitaxel Natural products 0.000 claims description 2
- 108700002839 cactinomycin Proteins 0.000 claims description 2
- 229960000684 cytarabine Drugs 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- 229960001592 paclitaxel Drugs 0.000 claims description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 210000004027 cell Anatomy 0.000 abstract description 17
- 239000002775 capsule Substances 0.000 abstract description 10
- 230000012010 growth Effects 0.000 abstract description 4
- 230000006872 improvement Effects 0.000 abstract description 2
- 230000001629 suppression Effects 0.000 abstract description 2
- 239000002207 metabolite Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 10
- 229920001184 polypeptide Polymers 0.000 description 8
- 102000004196 processed proteins & peptides Human genes 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 230000002297 mitogenic effect Effects 0.000 description 7
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 4
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003855 balanced salt solution Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 230000002262 irrigation Effects 0.000 description 3
- 238000003973 irrigation Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 3
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- NMWKYTGJWUAZPZ-WWHBDHEGSA-N (4S)-4-[[(4R,7S,10S,16S,19S,25S,28S,31R)-31-[[(2S)-2-[[(1R,6R,9S,12S,18S,21S,24S,27S,30S,33S,36S,39S,42R,47R,53S,56S,59S,62S,65S,68S,71S,76S,79S,85S)-47-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-18-(4-aminobutyl)-27,68-bis(3-amino-3-oxopropyl)-36,71,76-tribenzyl-39-(3-carbamimidamidopropyl)-24-(2-carboxyethyl)-21,56-bis(carboxymethyl)-65,85-bis[(1R)-1-hydroxyethyl]-59-(hydroxymethyl)-62,79-bis(1H-imidazol-4-ylmethyl)-9-methyl-33-(2-methylpropyl)-8,11,17,20,23,26,29,32,35,38,41,48,54,57,60,63,66,69,72,74,77,80,83,86-tetracosaoxo-30-propan-2-yl-3,4,44,45-tetrathia-7,10,16,19,22,25,28,31,34,37,40,49,55,58,61,64,67,70,73,75,78,81,84,87-tetracosazatetracyclo[40.31.14.012,16.049,53]heptaoctacontane-6-carbonyl]amino]-3-methylbutanoyl]amino]-7-(3-carbamimidamidopropyl)-25-(hydroxymethyl)-19-[(4-hydroxyphenyl)methyl]-28-(1H-imidazol-4-ylmethyl)-10-methyl-6,9,12,15,18,21,24,27,30-nonaoxo-16-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29-nonazacyclodotriacontane-4-carbonyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CSSC[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](Cc4ccccc4)NC3=O)[C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N3CCC[C@H]3C(=O)N[C@@H](C)C(=O)N2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)C(C)C)C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1)C(=O)N[C@@H](C)C(O)=O NMWKYTGJWUAZPZ-WWHBDHEGSA-N 0.000 description 2
- IQFYYKKMVGJFEH-OFKYTIFKSA-N 1-[(2r,4s,5r)-4-hydroxy-5-(tritiooxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound C1[C@H](O)[C@@H](CO[3H])O[C@H]1N1C(=O)NC(=O)C(C)=C1 IQFYYKKMVGJFEH-OFKYTIFKSA-N 0.000 description 2
- 102400001368 Epidermal growth factor Human genes 0.000 description 2
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- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
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- 210000002966 serum Anatomy 0.000 description 1
- 239000004017 serum-free culture medium Substances 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229940042596 viscoat Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1808—Epidermal growth factor [EGF] urogastrone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1825—Fibroblast growth factor [FGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1841—Transforming growth factor [TGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1858—Platelet-derived growth factor [PDGF]
-
- 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
-
- 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
- A61P27/12—Ophthalmic agents for cataracts
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/415—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from plants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
Abstract
The intraocular use of combinations of lens epithelial cell growth stimulators (e.g., TGF-.beta.) and antimetabolites (e.g., mitomycin C) is described. The combination is applied to the capsular bag to prevent or retard the formation of secondary cataracts following cataract surgery. The lens epithelial cell stimulators activate DNA synthesis in dormant lens epithelial cells, and thereby make those cells susceptible to the antimetabolites. This enables the antimetabolites to suppress the proliferation of lens epithelial cells to a much greater extent, relative to the proliferation observed when the metabolites alone are utilized. The increased suppression of the growth of lens epithelial cells results in a significant improvement in the ability to prevent or retard the formation of opacities on the lens capsule (i.e., secondary cataracts).
Description
. 2 1 ~ 9 6 ,:-COMP~SITIONS CONTAINING GROWTH FACTORS AND ANTIPLASTIC AGENTS
Background of the Invention:
The present invention relates to the field of ophthalmology. More specifically, the invention relates to the field of cataract surgery, wherein the natural crystallin lens of the human eye is surgically removed and an artificial lens is implanted.
Modern cataract surgery typically involves implantation of an artificial lens, referred to as an "intraocular lens" or "IOL", in the posterior chamber of the eye. The lo preferred site of irnplantation is within the capsule which surrounds the natural crystallin lens. When the natural crystallin lens is surgically removed, a portion of the anterior face of the lens capsule is also removed. This provides an opening which allows the artificial lens to be placed within the remaining portion of the lens capsule, which is also referred to as the "capsular bag". The capsular bag is considered to be the ideal location for s implantation of an intraocular lens. Unfortunately, there is a significant problem associated with implantation of intraocular lenses in the capsular bag.
The capsular bag is normally cleaned or "polished" by the ophthalmic surgeon to remove lens epithelial cells and other tissue remnants. This helps to ensure that deposits in the lens capsule do not impair the vision of the patient. However, il is generally not ?~O possible for the surgeon to remove all of the lens epithelial cells, particularly in the outer perimeter of the capsular bag. The remaining lens epithelial cells rnay eventually cause opacifications which impair the vision of the patient. Such impairment is referred to as "secondary cataract". The formation of a secondary cataract may require further medical treatment, such as use of a YAG laser to break up the opacifications, or further surgery.
In the past, the use of antimetabolites, such as 5'-fluorouracil or mitomycin C, has ; ~ -been sug~,ested as a means of preventing secondary cataract formation. Although antimetabolites can prevent the growth and proliferation of active lens epithelial cells, this approach has not proved to be effective. It is believed that the effectiveness of ~s WO 95/09004 PCT/US9'1/11091 ~s~
214965~7 ;`
antimetabolites in preventing lens epithelial cell growth is severely limited by the fact that these agents only target cells that are actively dividing. Since the antimetabolites are .
normally applied to the lens capsule in a single dose at the time of surgery, itis not possible for these agents to prevent the subsequent proliferation of lens epithelial cells ~ .
5 which are dorrnant (i.e., not actively dividing) at the time of surgery. A significant number of lens epithelial cells may therefore evade the action of the antimetabolite and proliferate at a later time. This lens epithelial cell proliferation ultimately contributes to the forrnation of lens opacifications or secondary cataracts.
Thus, there is a need for an improved method of preventing or retarding the 10 formation of secondary cataracts. The present invention is directed to satisfying this need.
Summarv of the Invention:
The present invention provides an improved method of preventing or retarding secondary cataract formation. The method is based on the application of a composition which contains a combination of one or more lens epithelial cell growth stimulators and 15 an antimetabolite to the lens capsule at the time of surgery. Various lens epithelial cell growth stimulators or combinations thereof may be utilized for this purpose, but the most preferred approach is to utilize a combination which includes transforming growth factor-beta ("TGF-~"). The lens epithelial cell stimulator component of the composition stimulates lens epithelial cells which are dormant at the time of surgery, so as to cause 20 these cells to initiate DNA synthesis. This mitogenic activation of the lens epithelial cells enhances their susceptability to the action of the antimetabolite component of the composition.
The above-described metnod results in a much greater suppression of lens epithelial cell growth, compared to that achieved with an antimetabolite alone. As a result, the 25 method provides a significant improvement in the ability to prevent or retard the fomlation of secondary cataracts. I
~ .
Brief Descri~tion of the Drawings:
Figure 1, t'ne sole figure of drawings, is a bar graph presentation of the data discussed in Example 1.
WO 95/09004 PC'r~US94/11091 ~
~` 21~96S7 Description of Preferred Embodiments: ¦
The lens epithelial cell stimulators which may be utilized in the present invention include all agents which ~,vill activate dorrnant lens epithelial cells by stimulating the ' initiation of DNA synthesis. Such agents are collectively referred to herein as "lens s epithelial cell growth stimulators". The use of mixtures which include various isoforms of TGF-~, and modifications thereof, is preferred.
There are five known isoforms of TGF-,B. These forrns have been designated as TGF-~I, TGF-~2, TGF-~3, TGF-~4 and TGF-,B5, the first three being common to man.The physical properties of these growth factors, sources of same, and methods ofpurification are known. See, for example, United States Patent No. 5,108,989 (~nento, et al; Genentech, Inc.) and the references cited therein at lines 21-45 of colurnn 1. The entire contents of that patent relating to the various forms of TGF-~ are herebyincorporated by reference in the present specification. As utilized herein, the term "TGF-~" encompasses one or more polypeptides having lens epithelial cell stimulating 15 activity, such as mature and precursor forms of TGF-,BI, TGF-,B2~ TGF-~3, TGF-,B4 and TGF-,~5; hybrid TGF-~s; latent TGF-~ complexes; TGF-~ analogs (e.g., deletion variants and hybrids); and biologically active polypeptides based on transforming growth factor-beta sequences, such as those described in United States Patent No. 5,061,786 (Burnier, et al.; Genentech, Inc.).
The lens epithelial cell growth stimulators which may be utilized in the presentinvention also include transforming growth factor-alpha (TGF-~), keratinocyte growth factor (KGF), epidermal growth factor (EGF), platelet-derived growth factors (PDGF-BB, -AA, or -AB), basic fibroblast growth factor (b-FGF), acid fibroblast growth factor (a-FGF), angiogenin, nerve growth factor (NGF), insulin-like growth factor I and II (IGF-I
2s and IGF-II), and other proteins or polypeptides having mitogenic activity relative to lens epithelial cells. As used herein, the term "polypeptides'i encompasses natural, synthetic and recombinant polypeptides, including polypeptides having deleted, replaced or altered amino acid sequences in comparison with the full-length natural polypeptide or T
biologically active fragments thereof~
The lens epithelial cell growth stimulators utilized in the present invention are preferably human derived. As used herein, the term "human derived" encompasses agents WC~ 95/09004 PCT/US94/11091 ¦ .
rj~
. I
recovered from human tissues and agents produced from human cell lines by means of recombinant DN~ technology.
The mosl preferred lens epithelial cell growth stimulator of the present invention is a mixture which includes TGF-~, in combination with EGF, b-FGF, TGF-X and s PDGF-BB.
The compositions utilized in the present invention contain one or more of the above-described lens epithelial cell stimulators in an amount sufficient to achieve mitogenic activation of dorrnant lens epithelial cells. The amount of lens epithelial cell stimulator required for this purpose will vary depending on the particular agent(s) utilized, but will generally be from about 0.01 to about 10,000 nanograms/milliliter ("ngfml").
The compositions utilized in the present invention will also include one or moreantirnetabolites to suppress the proliferation of lens epithelial cells. Variousantirnetabolites may be utilized for this purpose. The antimetabolites which may be utilized can be generally characterized as be~ng structural analogs to metabolically active molecules, such as purines, pyrimidines and folic acid. These compounds interfere with normal DNA/RNA synthesis, and thereby terminate cell growth. The net effects of this action are reduced mitotic activity and impaired proliferation of lens epithelial cells.
Examples of antimetabolites which may be utilized in the present invention include mitomycin C, 5'-fluorouracil, arabinocytosine, taxol, actinomycin C and methotrexate.
The use of mitomycin C as the antimetabolite component of the present invention is preferred, because it is relatively less toxic to corneal endothelial cells than other antimetabolites, such as 5'-fluorouracil.
The compositions utilized in the present invention contain one or more of the above-described antimetabolites in an amount sufficient to suppress the growth of lens 25 epithelial cellsThe amount of antimetabolite required for this purpose will vary depending on the particular antimetabolite(s) selected, but will generally be from about 0.01 to about 500 micrograms/milliliter ("mcgfml").
The above-described combinations of lens epithelial cell stimulators and antimeta~olites can be included in various types of pharmaceutical vehicles suitable for intraocular use. The vehicles are preferably aqueous, and are formulated so as to be chemically and physically compatible with ophthalmic tissues. For example, viscoelastic .~....... . . . .
~'O ~5/09004 PCT/US94/11091 ~` .
- 2149~7 1``
formulations currently utilized in connection with intraocular surgical procedures, such as Healon~ (Pharmacia) or Viscoat(~ (Alcon Surgical, Inc.) may be utili~ed as a vehicle for the above-described combinations of growth factors and antimetabolites. Such viscous formulations are coherent and tend to adhere to tissue. These properties help to ensure s that the compositions will expose lens epithelial cells to the actions of the growth factor/antimetabolite combinations of the present invention. This is particularly true when the compositions are applied following removal of the natural crystallin lens, since at that point the capsular bag will be at least partially open and therefore prone to immediately losing any iluid which is applied to the interior of the bag by means of irrigation. The use of a viscous solution or semi-solid composition may therefore be preferable in some cases.
In other cases, such as those where the growth factor/antimetabolite combinationis injected into the capsular bag prior to rernoval of the natural crystallin lens, the viscosity of the composition will not be a primary concern, since leakage of thecomposition from the capsular bag will be a less significant problem. The use of an aqueous solution as the vehicle for the growth factor/antimetabolite combination may therefore be preferred in such cases. The aqueous solutions which might be utilized must be compatible with intraocular tissues, and should preferably help to maintain the integrity and function of intraocular tissues during the surgical procedure. The aqueous solutions which might be utilized for the above-described purposes include balanced salinesolutions, such as BSS~) Balanced Salt Solution and BSS Plus(~) Balanced Salt Solution Enriched with Bicarbonate, Dextrose and Glutathione, both of which are available from Alcon Surgical, Inc., and Bion Tears~, which is available from Alcon Laboratories, Inc., Fort Worth, Texas.
As will be appreciated by those skilled in the art, the above-described compositions must be sterile and should not include any agents (e.g., antimicrobial preservatives) which will be toxic to sensitive intraocular tissues, particularly corneal endothelial cells. The above-described compositions can be forrnulated in accordance with techniques known to those skilled in the art. The following publications may be referred to for further details concerning the formulation of compositions containing polypeptides, such as TGF-~
United States Patent No. 4,717,717 (Finkenaur; Ethicon, Inc.); United States Patent 2 1 4 ~ ~ ~ 7 ! ~
., .
No. 4,962,091 (Eppstein, et al.; Syntex (U.S.A.) Inc.); and WO 92/15614 (Takruri; Chiron Ophthalmics, Inc.); and references cited in the foregoing patent publications. ,-The above-described compositions can be applied to the lens capsule by m~ans of various techniques. For example, the compositions can be applied to the interior of the 5 capsular bag by means of a syringe following removal of the crystallin lens, or can be injected into the lens capsule prior to removal of the crystallin lens by means of phacoemulsification or o~her methods. The only critical requirement with respect to how the compositions are applied is that the compositions be distributed throughout the lens capsule, and remain in contact with the dormant lens epithelial cells for a length of time lû sufficient to achieve mitogenic activation of those cells. The arnount of time required to achieve this purpose will vary somewhat depending on circumstances such a~s the lens epithelial cell stimulators and antimetabolites utilized, and the method by which the lens epithelial cell stimulator/antimetabolite combination is applied to the capsular bag (i.e., injection prior to phacoemulsification or irrigation following cataract removal). However, 15 the compositions will generally need to remain in contact with the interior of the capsular bag for approximately five to ten minutes or longer. The compositions may be removed by means of conventional irrigation and aspiration techniques.
The following example is provided to illustrate the e~fect of the above-described lens epithelial cell stimulators and antimetabolites on lens epithelial cells.
Example l Studies were conducted to examine the effects of a paI~icular antimetabolite, mitomycin C, on the mitogenic capability of cultured rabbit lens epithelial cells A
standard in vitro mitogenesis assay was utilized for these experiments. Normal rabbit lens epithelial cells (designation AG04676 from the Coriell Institute for Medical Research Cell Repository) between passage number six and thirteen were plated in a 96-well tissue culture plate. The cells were fed fresh MEM Eagle medium with Earle's salts supplemented with 10% normal rabbit serum, 2 mM l-glutamine, and 0.05 mg/ml gentamicin every three to four days until the cells were approximately 80% confluent.
The experiment was initiated three to five days after the last medium replacement to assure that the cells were at their maximum mitogenic potential.
WO 9~/09004 PCT/US94/11091 21 ~? 9 ~ -The tesl compounds (growth factor mixture and antimetabolite), forrnulated in serum-free culture medium, were exposed to cells in triplicate wells for ten minutes. The test substances were then aspirated off of the cells and replaced by serum-free c~ulture medium. After an eighteen hour incubation, tritiated thymidine was exposed to the cells for six hours. The DNA was then precipitated with trichloroacetic acid; thymidine not t incorporated into DNA was removed by washing, and the labeled DNA was solubilized with sodium dodecyl sulfate. The tritiated thymidine which was incorporated into the DNA of actively dividing cells was quantitated using a beta scintillation counter, and the mean and standard deviation were calculated for the t~plicate sets.
lo In these particular studies, a mixture of growth factors was used to maximally stimulate mitogenesis in these cells. The mixture consisted of 30 ng/ml of epidermal growth factor and 20 ng/ml each of platelet-derived growth factor (-BB homodimer), basic fibroblast growth factor, and transforming growth factor-alpha. As depicted in Figure 1, the addition of 2û ng/ml of transforming growth factor-beta significantly increased the stimulatory capability of the growth factor mixture. Mitomycin C was added to the cells in the presence of the growth factor mixture at various concentrations.
The results presented in Figure l indicate that the cells exposed to the growth factor mixture were more active in synthesizing DNA, when compared to control (i.e., unstimulated) cells. In addition, TGF-~I by itself has little or no effect on cell growth;
however, when added to the growth factor mixture, TGF-,BI enhances the DNA synthesis stimulatory effect. Thé mitogenic mixture which included TGF-~I maximized the stimulation of lens epithelial cell DNA synthesis. This stimulatory effect was effectively inhibited by mitomycin C (MIT C) at concentrations above 2.5 ug/ml (inhibition = 75.5%).
It is important to note that the growth factor mixture and mitomycin C were only exposed to the cells for a ten minute penod.
j;``
Background of the Invention:
The present invention relates to the field of ophthalmology. More specifically, the invention relates to the field of cataract surgery, wherein the natural crystallin lens of the human eye is surgically removed and an artificial lens is implanted.
Modern cataract surgery typically involves implantation of an artificial lens, referred to as an "intraocular lens" or "IOL", in the posterior chamber of the eye. The lo preferred site of irnplantation is within the capsule which surrounds the natural crystallin lens. When the natural crystallin lens is surgically removed, a portion of the anterior face of the lens capsule is also removed. This provides an opening which allows the artificial lens to be placed within the remaining portion of the lens capsule, which is also referred to as the "capsular bag". The capsular bag is considered to be the ideal location for s implantation of an intraocular lens. Unfortunately, there is a significant problem associated with implantation of intraocular lenses in the capsular bag.
The capsular bag is normally cleaned or "polished" by the ophthalmic surgeon to remove lens epithelial cells and other tissue remnants. This helps to ensure that deposits in the lens capsule do not impair the vision of the patient. However, il is generally not ?~O possible for the surgeon to remove all of the lens epithelial cells, particularly in the outer perimeter of the capsular bag. The remaining lens epithelial cells rnay eventually cause opacifications which impair the vision of the patient. Such impairment is referred to as "secondary cataract". The formation of a secondary cataract may require further medical treatment, such as use of a YAG laser to break up the opacifications, or further surgery.
In the past, the use of antimetabolites, such as 5'-fluorouracil or mitomycin C, has ; ~ -been sug~,ested as a means of preventing secondary cataract formation. Although antimetabolites can prevent the growth and proliferation of active lens epithelial cells, this approach has not proved to be effective. It is believed that the effectiveness of ~s WO 95/09004 PCT/US9'1/11091 ~s~
214965~7 ;`
antimetabolites in preventing lens epithelial cell growth is severely limited by the fact that these agents only target cells that are actively dividing. Since the antimetabolites are .
normally applied to the lens capsule in a single dose at the time of surgery, itis not possible for these agents to prevent the subsequent proliferation of lens epithelial cells ~ .
5 which are dorrnant (i.e., not actively dividing) at the time of surgery. A significant number of lens epithelial cells may therefore evade the action of the antimetabolite and proliferate at a later time. This lens epithelial cell proliferation ultimately contributes to the forrnation of lens opacifications or secondary cataracts.
Thus, there is a need for an improved method of preventing or retarding the 10 formation of secondary cataracts. The present invention is directed to satisfying this need.
Summarv of the Invention:
The present invention provides an improved method of preventing or retarding secondary cataract formation. The method is based on the application of a composition which contains a combination of one or more lens epithelial cell growth stimulators and 15 an antimetabolite to the lens capsule at the time of surgery. Various lens epithelial cell growth stimulators or combinations thereof may be utilized for this purpose, but the most preferred approach is to utilize a combination which includes transforming growth factor-beta ("TGF-~"). The lens epithelial cell stimulator component of the composition stimulates lens epithelial cells which are dormant at the time of surgery, so as to cause 20 these cells to initiate DNA synthesis. This mitogenic activation of the lens epithelial cells enhances their susceptability to the action of the antimetabolite component of the composition.
The above-described metnod results in a much greater suppression of lens epithelial cell growth, compared to that achieved with an antimetabolite alone. As a result, the 25 method provides a significant improvement in the ability to prevent or retard the fomlation of secondary cataracts. I
~ .
Brief Descri~tion of the Drawings:
Figure 1, t'ne sole figure of drawings, is a bar graph presentation of the data discussed in Example 1.
WO 95/09004 PC'r~US94/11091 ~
~` 21~96S7 Description of Preferred Embodiments: ¦
The lens epithelial cell stimulators which may be utilized in the present invention include all agents which ~,vill activate dorrnant lens epithelial cells by stimulating the ' initiation of DNA synthesis. Such agents are collectively referred to herein as "lens s epithelial cell growth stimulators". The use of mixtures which include various isoforms of TGF-~, and modifications thereof, is preferred.
There are five known isoforms of TGF-,B. These forrns have been designated as TGF-~I, TGF-~2, TGF-~3, TGF-~4 and TGF-,B5, the first three being common to man.The physical properties of these growth factors, sources of same, and methods ofpurification are known. See, for example, United States Patent No. 5,108,989 (~nento, et al; Genentech, Inc.) and the references cited therein at lines 21-45 of colurnn 1. The entire contents of that patent relating to the various forms of TGF-~ are herebyincorporated by reference in the present specification. As utilized herein, the term "TGF-~" encompasses one or more polypeptides having lens epithelial cell stimulating 15 activity, such as mature and precursor forms of TGF-,BI, TGF-,B2~ TGF-~3, TGF-,B4 and TGF-,~5; hybrid TGF-~s; latent TGF-~ complexes; TGF-~ analogs (e.g., deletion variants and hybrids); and biologically active polypeptides based on transforming growth factor-beta sequences, such as those described in United States Patent No. 5,061,786 (Burnier, et al.; Genentech, Inc.).
The lens epithelial cell growth stimulators which may be utilized in the presentinvention also include transforming growth factor-alpha (TGF-~), keratinocyte growth factor (KGF), epidermal growth factor (EGF), platelet-derived growth factors (PDGF-BB, -AA, or -AB), basic fibroblast growth factor (b-FGF), acid fibroblast growth factor (a-FGF), angiogenin, nerve growth factor (NGF), insulin-like growth factor I and II (IGF-I
2s and IGF-II), and other proteins or polypeptides having mitogenic activity relative to lens epithelial cells. As used herein, the term "polypeptides'i encompasses natural, synthetic and recombinant polypeptides, including polypeptides having deleted, replaced or altered amino acid sequences in comparison with the full-length natural polypeptide or T
biologically active fragments thereof~
The lens epithelial cell growth stimulators utilized in the present invention are preferably human derived. As used herein, the term "human derived" encompasses agents WC~ 95/09004 PCT/US94/11091 ¦ .
rj~
. I
recovered from human tissues and agents produced from human cell lines by means of recombinant DN~ technology.
The mosl preferred lens epithelial cell growth stimulator of the present invention is a mixture which includes TGF-~, in combination with EGF, b-FGF, TGF-X and s PDGF-BB.
The compositions utilized in the present invention contain one or more of the above-described lens epithelial cell stimulators in an amount sufficient to achieve mitogenic activation of dorrnant lens epithelial cells. The amount of lens epithelial cell stimulator required for this purpose will vary depending on the particular agent(s) utilized, but will generally be from about 0.01 to about 10,000 nanograms/milliliter ("ngfml").
The compositions utilized in the present invention will also include one or moreantirnetabolites to suppress the proliferation of lens epithelial cells. Variousantirnetabolites may be utilized for this purpose. The antimetabolites which may be utilized can be generally characterized as be~ng structural analogs to metabolically active molecules, such as purines, pyrimidines and folic acid. These compounds interfere with normal DNA/RNA synthesis, and thereby terminate cell growth. The net effects of this action are reduced mitotic activity and impaired proliferation of lens epithelial cells.
Examples of antimetabolites which may be utilized in the present invention include mitomycin C, 5'-fluorouracil, arabinocytosine, taxol, actinomycin C and methotrexate.
The use of mitomycin C as the antimetabolite component of the present invention is preferred, because it is relatively less toxic to corneal endothelial cells than other antimetabolites, such as 5'-fluorouracil.
The compositions utilized in the present invention contain one or more of the above-described antimetabolites in an amount sufficient to suppress the growth of lens 25 epithelial cellsThe amount of antimetabolite required for this purpose will vary depending on the particular antimetabolite(s) selected, but will generally be from about 0.01 to about 500 micrograms/milliliter ("mcgfml").
The above-described combinations of lens epithelial cell stimulators and antimeta~olites can be included in various types of pharmaceutical vehicles suitable for intraocular use. The vehicles are preferably aqueous, and are formulated so as to be chemically and physically compatible with ophthalmic tissues. For example, viscoelastic .~....... . . . .
~'O ~5/09004 PCT/US94/11091 ~` .
- 2149~7 1``
formulations currently utilized in connection with intraocular surgical procedures, such as Healon~ (Pharmacia) or Viscoat(~ (Alcon Surgical, Inc.) may be utili~ed as a vehicle for the above-described combinations of growth factors and antimetabolites. Such viscous formulations are coherent and tend to adhere to tissue. These properties help to ensure s that the compositions will expose lens epithelial cells to the actions of the growth factor/antimetabolite combinations of the present invention. This is particularly true when the compositions are applied following removal of the natural crystallin lens, since at that point the capsular bag will be at least partially open and therefore prone to immediately losing any iluid which is applied to the interior of the bag by means of irrigation. The use of a viscous solution or semi-solid composition may therefore be preferable in some cases.
In other cases, such as those where the growth factor/antimetabolite combinationis injected into the capsular bag prior to rernoval of the natural crystallin lens, the viscosity of the composition will not be a primary concern, since leakage of thecomposition from the capsular bag will be a less significant problem. The use of an aqueous solution as the vehicle for the growth factor/antimetabolite combination may therefore be preferred in such cases. The aqueous solutions which might be utilized must be compatible with intraocular tissues, and should preferably help to maintain the integrity and function of intraocular tissues during the surgical procedure. The aqueous solutions which might be utilized for the above-described purposes include balanced salinesolutions, such as BSS~) Balanced Salt Solution and BSS Plus(~) Balanced Salt Solution Enriched with Bicarbonate, Dextrose and Glutathione, both of which are available from Alcon Surgical, Inc., and Bion Tears~, which is available from Alcon Laboratories, Inc., Fort Worth, Texas.
As will be appreciated by those skilled in the art, the above-described compositions must be sterile and should not include any agents (e.g., antimicrobial preservatives) which will be toxic to sensitive intraocular tissues, particularly corneal endothelial cells. The above-described compositions can be forrnulated in accordance with techniques known to those skilled in the art. The following publications may be referred to for further details concerning the formulation of compositions containing polypeptides, such as TGF-~
United States Patent No. 4,717,717 (Finkenaur; Ethicon, Inc.); United States Patent 2 1 4 ~ ~ ~ 7 ! ~
., .
No. 4,962,091 (Eppstein, et al.; Syntex (U.S.A.) Inc.); and WO 92/15614 (Takruri; Chiron Ophthalmics, Inc.); and references cited in the foregoing patent publications. ,-The above-described compositions can be applied to the lens capsule by m~ans of various techniques. For example, the compositions can be applied to the interior of the 5 capsular bag by means of a syringe following removal of the crystallin lens, or can be injected into the lens capsule prior to removal of the crystallin lens by means of phacoemulsification or o~her methods. The only critical requirement with respect to how the compositions are applied is that the compositions be distributed throughout the lens capsule, and remain in contact with the dormant lens epithelial cells for a length of time lû sufficient to achieve mitogenic activation of those cells. The arnount of time required to achieve this purpose will vary somewhat depending on circumstances such a~s the lens epithelial cell stimulators and antimetabolites utilized, and the method by which the lens epithelial cell stimulator/antimetabolite combination is applied to the capsular bag (i.e., injection prior to phacoemulsification or irrigation following cataract removal). However, 15 the compositions will generally need to remain in contact with the interior of the capsular bag for approximately five to ten minutes or longer. The compositions may be removed by means of conventional irrigation and aspiration techniques.
The following example is provided to illustrate the e~fect of the above-described lens epithelial cell stimulators and antimetabolites on lens epithelial cells.
Example l Studies were conducted to examine the effects of a paI~icular antimetabolite, mitomycin C, on the mitogenic capability of cultured rabbit lens epithelial cells A
standard in vitro mitogenesis assay was utilized for these experiments. Normal rabbit lens epithelial cells (designation AG04676 from the Coriell Institute for Medical Research Cell Repository) between passage number six and thirteen were plated in a 96-well tissue culture plate. The cells were fed fresh MEM Eagle medium with Earle's salts supplemented with 10% normal rabbit serum, 2 mM l-glutamine, and 0.05 mg/ml gentamicin every three to four days until the cells were approximately 80% confluent.
The experiment was initiated three to five days after the last medium replacement to assure that the cells were at their maximum mitogenic potential.
WO 9~/09004 PCT/US94/11091 21 ~? 9 ~ -The tesl compounds (growth factor mixture and antimetabolite), forrnulated in serum-free culture medium, were exposed to cells in triplicate wells for ten minutes. The test substances were then aspirated off of the cells and replaced by serum-free c~ulture medium. After an eighteen hour incubation, tritiated thymidine was exposed to the cells for six hours. The DNA was then precipitated with trichloroacetic acid; thymidine not t incorporated into DNA was removed by washing, and the labeled DNA was solubilized with sodium dodecyl sulfate. The tritiated thymidine which was incorporated into the DNA of actively dividing cells was quantitated using a beta scintillation counter, and the mean and standard deviation were calculated for the t~plicate sets.
lo In these particular studies, a mixture of growth factors was used to maximally stimulate mitogenesis in these cells. The mixture consisted of 30 ng/ml of epidermal growth factor and 20 ng/ml each of platelet-derived growth factor (-BB homodimer), basic fibroblast growth factor, and transforming growth factor-alpha. As depicted in Figure 1, the addition of 2û ng/ml of transforming growth factor-beta significantly increased the stimulatory capability of the growth factor mixture. Mitomycin C was added to the cells in the presence of the growth factor mixture at various concentrations.
The results presented in Figure l indicate that the cells exposed to the growth factor mixture were more active in synthesizing DNA, when compared to control (i.e., unstimulated) cells. In addition, TGF-~I by itself has little or no effect on cell growth;
however, when added to the growth factor mixture, TGF-,BI enhances the DNA synthesis stimulatory effect. Thé mitogenic mixture which included TGF-~I maximized the stimulation of lens epithelial cell DNA synthesis. This stimulatory effect was effectively inhibited by mitomycin C (MIT C) at concentrations above 2.5 ug/ml (inhibition = 75.5%).
It is important to note that the growth factor mixture and mitomycin C were only exposed to the cells for a ten minute penod.
j;``
Claims (11)
1. An ophthalmic pharmaceutical composition for reducing the formation of secondary cataracts following extracapsular cataract surgery, comprising: a lens epithelial cell growth stimulator in an amount sufficient to activate lens epithelial cells by stimulating the initiation of DNA synthesis; an antimetabolite in an amount sufficient to suppress the proliferation of lens epithelial cells; and a pharmaceutically acceptable vehicle therefor.
2. A composition according to Claim 1, wherein the lens epithelial cell growth stimulator comprises a growth factor.
3. A composition according to Claim 2, wherein the growth factor is human derived.
4. A composition according to Claim 1, wherein the lens epithelial cell growth stimulator comprises TGF-.beta..
5. A composition according to Claim 1, wherein the lens epithelial cell growth stimulator comprises a mixture of growth factors which includes TGF-.beta..
6. A composition according to Claim 5, wherein the mixture comprises TGF-.beta.1.
7. A composition according to Claim 6, wherein the mixture comprises TGF-.beta.1in combination with EGF, b-FGF, TGF-? and PDGF-BB.
8 A composition according to Claim 1, wherein the antimetabolite is selected from the group consisting mitomycin C, 5'-fluorouracil, arabinocytosine, taxol, actinomycin C, and methotrexate.
9. A composition according to Claim 8, wherein the antimetabolite comprises mitomycin C.
10. A composition according to Claim 1, wherein the composition comprises 0.01 to 10,000 ng/ml of the lens epithelial cell growth stimulator and 0.01 to 500 mcg/ml of the antimetabolite.
11. Use of an ophthalmic pharmaceutical composition to reduce the formation of secondary cataracts following extracapsular cataract surgery by applying a therapeutically effective amount of the composition to the surgical site at the time of surgery, said composition comprising: a lens epithelial cell growth stimulator in an amount sufficient to activate lens epithelial cells by stimulating the initiation of DNA synthesis; an antimetabolite in an amount sufficient to suppress the proliferation of lens epithelial cells;
and a pharmaceutically acceptable vehicle therefor.
and a pharmaceutically acceptable vehicle therefor.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12862993A | 1993-09-29 | 1993-09-29 | |
| US08/128,629 | 1993-09-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2149657A1 true CA2149657A1 (en) | 1995-04-06 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002149657A Abandoned CA2149657A1 (en) | 1993-09-29 | 1994-09-29 | Compositions containing growth factors and antiplastic agents |
Country Status (6)
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| US (1) | US5696091A (en) |
| EP (1) | EP0670733A1 (en) |
| JP (1) | JPH08503969A (en) |
| AU (1) | AU7846894A (en) |
| CA (1) | CA2149657A1 (en) |
| WO (1) | WO1995009004A1 (en) |
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| JP4246795B2 (en) | 1995-07-25 | 2009-04-02 | ノバルティス アクチエンゲゼルシャフト | β-type transforming growth factor crystals |
| US6750052B1 (en) | 1997-07-23 | 2004-06-15 | The Brigham And Women's Hospital, Inc. | Lens epithelial cell derived growth factor |
| WO1999005278A1 (en) * | 1997-07-23 | 1999-02-04 | Brigham & Women's Hospital, Inc. | Lens epithelial cell derived growth factor |
| US7067144B2 (en) * | 1998-10-20 | 2006-06-27 | Omeros Corporation | Compositions and methods for systemic inhibition of cartilage degradation |
| US6383245B1 (en) | 2000-04-05 | 2002-05-07 | Thomas T. Yamashita | Aqueous mineral compositions and methods for their use |
| US6533769B2 (en) * | 2001-05-03 | 2003-03-18 | Holmen Joergen | Method for use in cataract surgery |
| WO2004010894A2 (en) * | 2002-07-30 | 2004-02-05 | Omeros Corporation | Ophthalmologic irrigation solutions and method |
| US20040143368A1 (en) * | 2003-01-21 | 2004-07-22 | May Robert E. | Operating utility devices in a master-agent network environment |
| US20050058730A1 (en) * | 2003-09-15 | 2005-03-17 | Xushan Wan | Compositions and methods for preventing or treating eyestrain |
| US20100087486A1 (en) * | 2008-05-30 | 2010-04-08 | Hiroshi Nakamura | Methods for using tgf-b receptor inhibitors or activin-like kinase (alk) 5 inhibitors a-83-01 and sb-431542 to treat eye disease and wound healing conditions |
| JP2012524073A (en) * | 2009-04-17 | 2012-10-11 | スムマ ヘルス システムズ エルエルシー | Use of transforming growth factor-beta receptor inhibitors to inhibit eye scarring |
| AU2013201465B2 (en) | 2012-10-24 | 2016-03-03 | Rayner Surgical (Ireland) Limited | Stable preservative-free mydriatic and anti-inflammatory solutions for injection |
| TWI809304B (en) | 2014-12-01 | 2023-07-21 | 奥默羅斯公司 | Anti-inflammatory and mydriatic intracameral solutions for inhibition of postoperative ocular inflammatory conditions |
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| CA1275922C (en) * | 1985-11-28 | 1990-11-06 | Harunobu Amagase | Treatment of cancer |
| US4962091A (en) * | 1986-05-23 | 1990-10-09 | Syntex (U.S.A.) Inc. | Controlled release of macromolecular polypeptides |
| US5055291A (en) * | 1986-11-04 | 1991-10-08 | Baylor College Of Medicine | Compositions for preventing secondary cataracts |
| US4717717A (en) * | 1986-11-05 | 1988-01-05 | Ethicon, Inc. | Stabilized compositions containing epidermal growth factor |
| US4966577A (en) * | 1988-03-16 | 1990-10-30 | Allergan, Inc. | Prevention of lens-related tissue growth in the eye |
| US5124392A (en) * | 1988-10-03 | 1992-06-23 | Alcon Laboratories, Inc. | Pharmaceutical compositions and methods of treatment to prevent and treat corneal scar formation produced by laser irradiation |
| US5061786A (en) * | 1989-05-25 | 1991-10-29 | Genentech, Inc. | Biologically active polypeptides based on transforming growth factor-β |
| GB8927546D0 (en) * | 1989-12-06 | 1990-02-07 | Ciba Geigy | Process for the production of biologically active tgf-beta |
| US5108989A (en) * | 1990-04-04 | 1992-04-28 | Genentech, Inc. | Method of predisposing mammals to accelerated tissue repair |
| US5272135A (en) * | 1991-03-01 | 1993-12-21 | Chiron Ophthalmics, Inc. | Method for the stabilization of methionine-containing polypeptides |
| GB9206861D0 (en) * | 1992-03-28 | 1992-05-13 | Univ Manchester | Wound healing and treatment of fibrotic disorders |
| AU4668193A (en) * | 1992-07-08 | 1994-01-31 | Celtrix Pharmaceuticals, Inc. | Method of treating ophthalmic disorders using tgf-beta |
-
1994
- 1994-09-29 WO PCT/US1994/011091 patent/WO1995009004A1/en not_active Application Discontinuation
- 1994-09-29 JP JP7510468A patent/JPH08503969A/en active Pending
- 1994-09-29 EP EP94929389A patent/EP0670733A1/en not_active Withdrawn
- 1994-09-29 CA CA002149657A patent/CA2149657A1/en not_active Abandoned
- 1994-09-29 AU AU78468/94A patent/AU7846894A/en not_active Abandoned
-
1996
- 1996-02-20 US US08/602,476 patent/US5696091A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US5696091A (en) | 1997-12-09 |
| WO1995009004A1 (en) | 1995-04-06 |
| EP0670733A1 (en) | 1995-09-13 |
| AU7846894A (en) | 1995-04-18 |
| JPH08503969A (en) | 1996-04-30 |
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