US4474751A
Expired / Lapsed
US
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Ophthalmic drug delivery system utilizing thermosetting gels
Assignee: Merck and Co Inc
•
Filing: 1983-05-16
•
Granted: 1984-10-02
•
Expires: 2003-05-16
Abstract
Abstract This invention describes the application of selected polymers as novel drug delivery systems which use the body temperature and pH to induce a liquid to gel transition of the polymer which contains a drug or therapeutic agent therein. The goal of such a delivery system is to achieve a greater degree of bioavailability or sustained concentration of a drug.
Inventors
- 👤 John L. Haslam
- 👤 Takeru Higuchi
- 👤 Arthur R. Mlodozeniec
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 17:27
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/0012; A61K9/0048; A61K47/00; A61K47/06; A61K47/16; A61K47/18
Claims Analysis
Total Claims: 68
Claim 1
Independent Claim
115 words
An aqueous pharmaceutical composition for treating an eye condition requiring pharmacological treatment comprising a. 10% to 50% by weight of a polymer of the formula ##STR2## wherein w is an integer from 2 to 6 containing approximately 40% to 80% poly(oxyethylene) and approximately 20 to 60% poly(oxypropylene) and having a molecular weight of 7,000 to 50,000; and x and y are any integers within the above constraints, b. a pharmacologically effective amount of a pharmaceutical or diagnostic agent; and, c. a pharmaceutically acceptable acid or base being in sufficient quantity to adjust the pH of the composition to range from 2 to 9 and wherein the composition is liquid at about room temperature or below.
Claim 2
Dependent Claim
115 words
An aqueous pharmaceutical composition for treating an eye condition requiring pharmacological treatment comprising a. 10% to 50% by weight of a polymer of the formula ##STR2## wherein w is an integer from 2 to 6 containing approximately 40% to 80% poly(oxyethylene) and approximately 20 to 60% poly(oxypropylene) and having a molecular weight of 7,000 to 50,000; and x and y are any integers within the above constraints, b. a pharmacologically effective amount of a pharmaceutical or diagnostic agent; and, c. a pharmaceutically acceptable acid or base being in sufficient quantity to adjust the pH of the composition to range from 2 to 9 and wherein the composition is liquid at about room temperature or below.
Claim 3
Dependent Claim
163 words
An aqueous pharmaceutical composition for treating an eye condition requiring pharmacological treatment comprising a. 10% to 50% by weight of a polymer of the formula ##STR3## wherein w is an integer of from 2 to 6 containing approximately 40% to 80% poly(oxyethylene) and approximately 20 to 60% poly(oxypropylene) and having a molecular weight of 7,000 to 50,000; and x and y are any integers within the above constraints, b. a pharmacologically effective amount of a drug selected from the group consisting of antibacterial substances, antihistamines and decongestants, anti-inflammatories, miotics and anticholinergics, mydriatics, antiglaucoma drugs, antiparasitics, antiviral effective compounds, carbonic anhydrase inhibitors, anesthetic agents, ophthalmic diagnostic agents, ophthalmic agents used as adjuvants in surgery, chelating agents, immunosuppressive agents and anti-metabolites or combinations of any of the above; and, c. a pharmaceutically acceptable acid or base being in sufficient quantity to adjust the pH of the composition to range from 2 to 9 and wherein the composition is liquid at about room temperature or below.
Claim 4
Dependent Claim
163 words
An aqueous pharmaceutical composition for treating an eye condition requiring pharmacological treatment comprising a. 10% to 50% by weight of a polymer of the formula ##STR3## wherein w is an integer of from 2 to 6 containing approximately 40% to 80% poly(oxyethylene) and approximately 20 to 60% poly(oxypropylene) and having a molecular weight of 7,000 to 50,000; and x and y are any integers within the above constraints, b. a pharmacologically effective amount of a drug selected from the group consisting of antibacterial substances, antihistamines and decongestants, anti-inflammatories, miotics and anticholinergics, mydriatics, antiglaucoma drugs, antiparasitics, antiviral effective compounds, carbonic anhydrase inhibitors, anesthetic agents, ophthalmic diagnostic agents, ophthalmic agents used as adjuvants in surgery, chelating agents, immunosuppressive agents and anti-metabolites or combinations of any of the above; and, c. a pharmaceutically acceptable acid or base being in sufficient quantity to adjust the pH of the composition to range from 2 to 9 and wherein the composition is liquid at about room temperature or below.
Claim 5
Dependent Claim
14 words
The composition of claim 2 wherein the polymer is one where w is 2.
Claim 6
Dependent Claim
11 words
The composition of claim 2 wherein the polymer is Tetronic 1307®.
Claim 7
Dependent Claim
26 words
The composition of claim 2 wherein the gel-sol transition temperature of the composition is room temperature or below and said composition is liquid at this temperature.
Claim 8
Dependent Claim
49 words
The composition of claim 2 wherein the antibacterial substances are selected from the group consisting of beta lactam antibiotics, tetracyclines, carbenicillin, colistin, penicillin G, polymyxin B, vancomycin, chloramphenicol, neomycin, gramicidin, bacitracin, cefazolin, cephaloridine, chibrorifamycin, sulfonamides, aminoglycoside antibiotics, tobramycin, nitrofurazone, nalidixic acid and norfloxacin and the antimicrobial combination of fludalanine/pentizidone.
Claim 9
Dependent Claim
22 words
The composition of claim 2 wherein the antihistaminics and decongestants are selected from the group consisting of perilamine, chlorpheniramine, tetrahydrazoline and antizoline.
Claim 10
Dependent Claim
40 words
The composition of claim 2 wherein the antiinflammatory drugs are selected from the group consisting of hydrocortisone acetate, cortisone, hydrocortisone, betamethasone, dexamethasone, fluocortolone, prednisolone, methyl prednisolone, medrysone, fluorometholone, prednisolone sodium phosphate, triamcinolone, indomethacin, sulindac and its salts and corresponding sulfide.
Claim 11
Dependent Claim
32 words
A composition of claim 2 wherein the miotics and anticholinergics are selected from the group consisting of echothiophate, pilocarpine, physostigmine salicylate, diisopropylfluorophosphate, carbachol, methacholine, bethanechol, epinephrine, dipivefrin, neostigmine, echothiopateiodide and demecium bromide.
Claim 12
Dependent Claim
27 words
The composition of claim 2 wherein the mydriatics are selected from the group consisting of atropine, homatropine, scopolamine, hydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine, cyclopentolate, oxyphenonium and eucatropine.
Claim 13
Dependent Claim
41 words
The composition of claim 2 wherein the antiglaucoma drugs are selected from the group consisting of timolol, R-timolol, the hydrogen maleate salt of timolol, the combination of timolol and R-timolol with pilocarpine, epinephrine and epinephrine complex or prodrugs and hyperosmotic agents.
Claim 14
Dependent Claim
19 words
A composition of claim 2 wherein the antiparasitic or antiprotozoal compound is ivermectin, pyrimethamine, trisulfapyrimidone, clindamycin and corticosteroid preparations.
Claim 15
Dependent Claim
24 words
The composition of claim 2 wherein the antiviral effective compounds are selected from the group consisting of acyclovir, interferon, 5-iodo-2'-deoxyuridine, adenosine, arabinoside and trifluorothymidine.
Claim 16
Dependent Claim
23 words
The composition of claim 2 wherein the carbonic anhydrase inhibitors are selected from the group consisting of 2-(p-hydroxyphenyl)thio-5-thiophenesulfonimide, 6-hydroxy-2-benzothiazolsulfonamide, 6-pivaloyloxy-2-benzothiazolesulfonamide, acetazolamide, and dichlorphenamide.
Claim 17
Dependent Claim
23 words
The composition of claim 2 wherein the antifungal agents are selected from the group consisting of amphoterium B, nystatin, flucytosine, natamycin and miconazole.
Claim 18
Dependent Claim
37 words
The composition of claim 2 wherein the anesthetic agent is selected from the group consisting of etidocaine, cocaine, benoxinate, dibucaine hydrochloride, dyclonine hydrochloride, naepaine, phenacaine hydrochloride, piperocaine, proparacaine hydrochloride, tetracaine hydrochloride, hexylcaine, bupivacaine, lidocaine, mepivacaine and prilocaine.
Claim 19
Dependent Claim
20 words
The composition of claim 2 wherein the chelating agent is selected from the group consisting of ethylenediamine tetra-acetate and deferoxamine.
Claim 20
Dependent Claim
23 words
The composition of claim 2 wherein the immunosuppressive agent and anti-metabolite is selected from the group consisting of methotrexate, cyclophosphamide, 6-mercaptopurine and azathioprine.
Claim 21
Dependent Claim
22 words
The composition of claim 2 which includes a buffering agent or salt of from 0 to 5% by weight of the composition.
Claim 22
Dependent Claim
32 words
The composition of claim 19 wherein the buffering agent or salt is selected from the group consisting of alkali or alkali earth carbonates, chlorides, sulfates, phosphates, bicarbonates, citrates, borates, acetates and succinates.
Claim 23
Dependent Claim
19 words
The composition of claim 2 which includes from 0.001% to 5% by weight of the composition of a preservative.
Claim 24
Dependent Claim
30 words
The composition of claim 21 wherein the preservatives are selected from the group consisting of sodium bisulfite, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric borate, parabens, benzylalcohol and phenylethanol.
Claim 25
Dependent Claim
22 words
The composition of claim 2 wherein the acid or base is selected from the group consisting of hydrochloric acid or sodium hydroxide.
Claim 26
Dependent Claim
26 words
An aqueous pharmaceutical composition for treating an eye condition requiring pharmacological treatment comprising a. 10% to 50% by weight of a polymer of the formula ##STR4##
Claim 27
Dependent Claim
26 words
An aqueous pharmaceutical composition for treating an eye condition requiring pharmacological treatment comprising a. 10% to 50% by weight of a polymer of the formula ##STR4##
Claim 28
Dependent Claim
65 words
wherein w is an integer of from 2 to 6 containing approximately 40% to 80% poly(oxyethylene) and approximately 20-60% poly(oxypropylene) and having a molecular weight of 7,000 to 50,000; and x and y are any integers within the above constraints; and, b. a pharmaceutically acceptable acid or base being in sufficient quantity to adjust the pH of the composition to range from 2 to 9.
Claim 29
Dependent Claim
65 words
wherein w is an integer of from 2 to 6 containing approximately 40% to 80% poly(oxyethylene) and approximately 20-60% poly(oxypropylene) and having a molecular weight of 7,000 to 50,000; and x and y are any integers within the above constraints; and, b. a pharmaceutically acceptable acid or base being in sufficient quantity to adjust the pH of the composition to range from 2 to 9.
Claim 30
Dependent Claim
22 words
A composition of claim 24 which includes a buffering agent or salt of from 0 to 5% by weight of the composition.
Claim 31
Dependent Claim
19 words
A composition of claim 24 which includes a preservative of from 0.001% to 5% by weight of the composition.
Claim 32
Independent Claim
41 words
A method of treating an eye condition requiring pharmacological treatment or administration of a diagnostic agent which comprises administering to the eye a liquid drug delivery vehicle comprising: a. 10% to 50% by weight of a polymer of the formula ##STR5##
Claim 33
Independent Claim
41 words
A method of treating an eye condition requiring pharmacological treatment or administration of a diagnostic agent which comprises administering to the eye a liquid drug delivery vehicle comprising: a. 10% to 50% by weight of a polymer of the formula ##STR5##
Claim 34
Dependent Claim
76 words
wherein w is an integer of from 2 to 6 containing approximately 40% to 80% poly(oxyethylene) and approximately 20-60% poly(oxypropylene) and having a molecular weight of 7,000 to 50,000; and x and y are any integers within the above constraints, b. a pharmacologically effective amount of a pharmaceutical or diagnostic agent; and, c. a pharmaceutically acceptable acid or base being in sufficient quantity to adjust the pH of the composition to range from 2 to 9.
Claim 35
Dependent Claim
76 words
wherein w is an integer of from 2 to 6 containing approximately 40% to 80% poly(oxyethylene) and approximately 20-60% poly(oxypropylene) and having a molecular weight of 7,000 to 50,000; and x and y are any integers within the above constraints, b. a pharmacologically effective amount of a pharmaceutical or diagnostic agent; and, c. a pharmaceutically acceptable acid or base being in sufficient quantity to adjust the pH of the composition to range from 2 to 9.
Claim 36
Independent Claim
41 words
A method of treating an eye condition requiring pharmacological treatment or administration of a diagnostic agent which comprises administering to the eye a liquid drug delivery vehicle comprising: a. 10% to 50% by weight of a polymer of the formula ##STR6##
Claim 37
Independent Claim
41 words
A method of treating an eye condition requiring pharmacological treatment or administration of a diagnostic agent which comprises administering to the eye a liquid drug delivery vehicle comprising: a. 10% to 50% by weight of a polymer of the formula ##STR6##
Claim 38
Dependent Claim
121 words
wherein w is an integer of from 2 to 6 containing approximately 40% to 80% poly(oxyethylene) and approximately 20-60% poly(oxypropylene) and having a molecular weight of 7,000 to 50,000; and x and y are any integers within the above constraints, b. a pharmacologically effective amount of a drug selected from the group consisting of antibacterial substances, antihistamines and decongestants, anti-inflammatories, miotics and anticholinergics, mydriatics, antiglaucoma drugs, antiparasitics, antiviral effective compounds, carbonic anhydrase inhibitors, anesthetic agents, opthalmic diagnostic agents, opthalmic agents used as adjuvants in surgery, chelating agents, immunosuppressive agents and antimetabolites or combinations of the above; and c. a pharmaceutically acceptable acid or base being in sufficient quantity to adjust the pH of the composition to range from 2 to 9.
Claim 39
Dependent Claim
121 words
wherein w is an integer of from 2 to 6 containing approximately 40% to 80% poly(oxyethylene) and approximately 20-60% poly(oxypropylene) and having a molecular weight of 7,000 to 50,000; and x and y are any integers within the above constraints, b. a pharmacologically effective amount of a drug selected from the group consisting of antibacterial substances, antihistamines and decongestants, anti-inflammatories, miotics and anticholinergics, mydriatics, antiglaucoma drugs, antiparasitics, antiviral effective compounds, carbonic anhydrase inhibitors, anesthetic agents, opthalmic diagnostic agents, opthalmic agents used as adjuvants in surgery, chelating agents, immunosuppressive agents and antimetabolites or combinations of the above; and c. a pharmaceutically acceptable acid or base being in sufficient quantity to adjust the pH of the composition to range from 2 to 9.
Claim 40
Dependent Claim
15 words
A method of treatment according to claim 28 wherein the polymer is one wherein w=2.
Claim 41
Dependent Claim
14 words
A method of treatment according to claim 28 wherein the polymer is Tetronic 1307®.
Claim 42
Dependent Claim
29 words
A method of treatment according to claim 28 wherein the gel-sol transistion temperature of the composition is room temperature or below and said composition is liquid at this temperature.
Claim 43
Dependent Claim
51 words
A method of treatment according to claim 28 wherein the antibacterial substances are selected from the group consisting of beta-lactam antibiotics, tetracyclines, carbenicillin, colistin, penicillin G, polymyxin B, vancomycin, chloramphenicol, neomycin, gramicidin, bacitracin, cefazolin, cephaloridine, chibro-rifamycin, sulfonamides, aminoglycoside antibiotics, tobramycin, nitrofurazone, nalidixic acid and analogs and the antimicrobial combination of fludalanine/pentizidone.
Claim 44
Dependent Claim
25 words
A method of treatment according to claim 28 wherein the antihistaminics and decongestants are selected from the group consisting of perilamine, chlorpheneramine, tetrahydrazoline and antizoline.
Claim 45
Dependent Claim
43 words
A method of treatment according to claim 28 wherein the antiinflammatory drugs are selected from the group consisting of hydrocortisone acetate, cortisone, hydrocortisone, betamethasone, dexamethasone, fluocortolone, prednisolone, methyl prednisolone, medrysone, fluorometholone, prednisolone sodium phosphate, triamcinolone, indomethacin, sulindac and its salts and corresponding sulfide.
Claim 46
Dependent Claim
34 words
A method of treatment of claim 28 wherein the miotics and anticholinergics are selected from the group consisting of echothiophate, pilocarpine, physostigmine salicylate, diisopropylfluorophosphate, carbachol, methacholine, bethanechol, epinephrine, di-pivalylepinephrine, neostigmine, echothiopateiodide and demecium bromide.
Claim 47
Dependent Claim
30 words
A method of treatment according to claim 28 wherein the mydriatics are selected from the group consisting of atropine, homatropine, scopolamine, hydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine, cyclopentolate, oxyphenonium and eucatropine.
Claim 48
Dependent Claim
45 words
A method of treatment according to claim 28 wherein the antiglaucoma drugs are selected from the group consisting of timolol, R-timolol, the hydrogen maleate salt of timolol, the combination of timolol and R-timolol with pilocarpine, epinephrine, dipivefrin and epinephrine complex or prodrugs and hyperosmotic agents.
Claim 49
Dependent Claim
19 words
A composition of claim 28 wherein the antiparasitic or anti-protozoal compound is ivermectin, pyrimethaxine, trisulfapyrimidon, clindamycin and corticosteroid preparations.
Claim 50
Dependent Claim
28 words
A method of treatment according to claim 28 wherein the antiviral effective compounds are selected from the group consisting of acyclovir, interferon, 5-iodo-2'-deoxy uridine, adenosine, arabinoside and trifluorothymidine.
Claim 51
Dependent Claim
26 words
A method of treatment according to claim 28 wherein the carbonic anhydrase inhibitors are selected from the group consisting of 2-(p-hydroxyphenyl)thio-5-thiophenesulfonimide, 6-hydroxy-2-benzothiazolesulfonamide, 6-pivaloyloxy-2-benzothiazolesulfonamide, acetazolamide and dichlorphenamide.
Claim 52
Dependent Claim
26 words
The method of treatment according to claim 28 wherein the antifungal agents are selected from the group consisting of amphoterium B, nystatin, flucytosine, natamycin and miconazole.
Claim 53
Dependent Claim
40 words
The method of treatment according to claim 28 wherein the anesthetic agent is selected from the group consisting of etidocaine, cocaine, benoxinate, dibucaine hydrochloride, dyclonine hydrochloride, naepaine, phenacaine hydrochloride, piperocaine, proparacaine hydrochloride, tetracaine hydrochloride, hexylcaine, bupivacaine, lidocaine, mepivacaine and prilocaine.
Claim 54
Dependent Claim
23 words
The method of treatment according to claim 28 wherein the chelating agent is selected from the group consisting of ethylenediamine tetra-acetate and deferoxamine.
Claim 55
Dependent Claim
26 words
The method of treatment according to claim 28 wherein the immunosuppressive agent and anti-metabolite is selected from the group consisting of methotrexate, cyclophosphamide, 6-mercaptopurine and azathioprine.
Claim 56
Dependent Claim
27 words
A method of treatment according to claim 28 wherein the composition includes a buffering agent or salt of from 0% to 5% by weight of the composition.
Claim 57
Dependent Claim
35 words
A method of treatment according to claim 45 wherein the buffering agent or salt is selected from the group consisting of alkali or alkali earth carbonates, chlorides, sulfates, phosphates, bicarbonates, citrates, borates, acetates and succinates.
Claim 58
Dependent Claim
24 words
A method of treatment according to claim 28 wherein the composition includes from 0.001% to 5% by weight of the composition of a preservative.
Claim 59
Dependent Claim
33 words
A method of treatment according to claim 47 wherein the preservatives are selected from the group consisting of sodium bisulfite, sodium thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric borate, parabens, benzylalcohol and phenylethanol.
Claim 60
Dependent Claim
25 words
A method of treatment according to claim 28 wherein the acid or base is selected from the group consisting of hydrochloric acid or sodium hydroxide.
Claim 61
Dependent Claim
32 words
A methou of treating a dry eye which comprises administering to the eye a liquid drug delivery device comprising a. 10% to 50% by weight of a polymer of the formula ##STR7##
Claim 62
Dependent Claim
32 words
A methou of treating a dry eye which comprises administering to the eye a liquid drug delivery device comprising a. 10% to 50% by weight of a polymer of the formula ##STR7##
Claim 63
Dependent Claim
65 words
wherein w is an integer of from 2 to 6 containing approximately 40% to 80% poly(oxyethylene) and approximately 20-60% poly(oxypropylene) and having a molecular weight of 7,000 to 50,000; and x and y are any integers within the above constraints; and, b. a pharmaceutically acceptable acid or base being in sufficient quantity to adjust the pH of the composition to range from 2 to 9.
Claim 64
Dependent Claim
65 words
wherein w is an integer of from 2 to 6 containing approximately 40% to 80% poly(oxyethylene) and approximately 20-60% poly(oxypropylene) and having a molecular weight of 7,000 to 50,000; and x and y are any integers within the above constraints; and, b. a pharmaceutically acceptable acid or base being in sufficient quantity to adjust the pH of the composition to range from 2 to 9.
Claim 65
Dependent Claim
26 words
A method of treatment of claim 50 wherein the composition includes a buffering agent or salt of from 0% to 5% by weight of the composition.
Claim 66
Dependent Claim
23 words
A method of treatment of claim 50 wherein the composition includes a preservative of from 0.001% to 5% by weight of the composition.
Claim 67
Dependent Claim
23 words
The composition of claim 6 wherein the β-lactam antibiotics are selected from the group consisting of cefoxitin, n-formamidoyl thienamycin and other thienamycin derivatives.
Claim 68
Dependent Claim
25 words
A method of treatment of claim 32 wherein the β-lactam antibiotics are selected from the group consisting of cefoxitin, n-formamidoyl thienamycin and other thienamycin derivatives.
References Cited (Backward Citations)
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1987-10-02 | 1988-04-02 | 1988-10-02 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1991-10-02 | 1992-04-02 | 1992-10-02 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1995-10-02 | 1996-04-02 | 1996-10-02 | $7700.00 | Window Closed / Lapsed |