US4983586A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Pharmaceutical formulations for parenteral use
Assignee: University of Florida
•
Filing: 1988-03-29
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Granted: 1991-01-08
•
Expires: 2008-03-29
Abstract
Abstract Aqueous parenteral solutions of drugs which are insoluble or only sparingly soluble in water and/or which are unstable in water, combined with hydroxypropyl-β-cyclodextrin, provide a means for alleviating problems associated with drug precipitation at the injection site and/or in the lungs or other organs following parenteral administration.
Inventors
- 👤 Nicholas S. Bodor
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-26 03:47
CPC Classifications
C; C07; C07D; C07D401/00; C07D401/14; A; A61; A61K; A61K31/00; A61K31/33; A61K31/395; A61K31/41; A61K31/425; A61K31/429; A61K31/43; A61K47/00; A61K47/50; A61K47/51; A61K47/54; A61K47/559; A61K47/69; A61K47/6949; A61K47/6951; A61P; A61P43/00; B; B82; B82Y; B82Y5/00; C07C; C07C219/00; C07C219/26; C07C219/28; C07C229/00; C07C229/02; C07C229/04; C07C229/06; C07C229/08; C07C233/00; C07C233/01; C07C233/16; C07C233/17; C07C233/18; C07C271/00; C07C271/06; C07C271/08; C07C271/10; C07C271/16; C07D211/00; C07D211/04; C07D211/80; C07D211/84; C07D211/90; C07D213/00; C07D213/02; C07D213/04; C07D213/60; C07D213/78; C07D213/79; C07D213/80; C07D213/81; C07D213/82; C07D223/00; C07D223/14; C07D223/18; C07D223/22; C07D223/24; C07D223/28; C07D233/00; C07D233/54; C07D233/66; C07D233/72; C07D233/74; C07D233/76; C07D233/78; C07D243/00; C07D243/06; C07D243/10; C07D243/38; C07D401/02; C07D401/12; C07D473/00; C07D499/00; C07H; C07H19/00; C07H19/02; C07H19/04; C07H19/06; C07J; C07J43/00; C07J43/003; C08; C08B; C08B37/00; C08B37/0006; C08B37/0009; C08B37/0012; C08B37/0015; C07C2601/00; C07C2601/12; C07C2601/14
Claims Analysis
Total Claims: 42
Claim 1
Independent Claim
50 words
A method for decreasing the incidence of precipitation of a lipophilic and/or water-labile drug occurring at or near the injection site and/or in the lungs or other organs following parenteral administration, said method comprising parenterally administering said drug in an aqueous solution containing from about 20% to about 50% hydroxypropyl-β-cyclodextrin.
Claim 2
Independent Claim
50 words
A method for decreasing the incidence of precipitation of a lipophilic and/or water-labile drug occurring at or near the injection site and/or in the lungs or other organs following parenteral administration, said method comprising parenterally administering said drug in an aqueous solution containing from about 20% to about 50% hydroxypropyl-β-cyclodextrin.
Claim 3
Dependent Claim
13 words
A method according to claim 1, wherein the aqueous solution is approximately isotonic.
Claim 4
Dependent Claim
12 words
A method according to claim 1, wherein said drug is an antineoplastic.
Claim 5
Dependent Claim
20 words
A method according to claim 1, wherein said drug is a sedative, tranquilizer, anticonvulsant, antidepressant, hypnotic, muscle relaxant or antispasmodic.
Claim 6
Dependent Claim
21 words
A method according to claim 1, wherein said drug is an androgen, estrogen, progestin, anti-inflammatory steroid or steroidal hypnotic or anesthetic.
Claim 7
Dependent Claim
19 words
A method according to claim 1, wherein said drug is an anticoagulant, cardiotonic, vasodilator, vasoconstrictor, platelet inhibitor or anti-arrhythmic.
Claim 8
Dependent Claim
17 words
A method according to claim 1, wherein said drug is an antifungal, antiprotozoal, antibacterial, antibiotic or antiviral.
Claim 9
Dependent Claim
38 words
A method according to claim 1, wherein said drug is a vitamin/nutritional factor, emetic, antiemetic, diuretic, non-steroidal anti-inflammatory agent, anesthetic, hypoglycemic, radiodiagnostic, carbonic anhydrase inhibitor, narcotic antagonist, pharmaceutically active protein, dopaminergic/anti-Parkinsonism agent or agent for treating Alzheimer's disease.
Claim 10
Dependent Claim
31 words
A method according to claim 3, wherein said drug is chlorambucil, lomustine, melphalan, methotrexate, hexamethylmelamine, teniposide, etoposide, semustine, fazarabine, mercaptopurine, tubulazole, carmofur, carmustine, amsacrine, bruceantin, diaziquone, didemnin B, echinomycin or PCNU.
Claim 11
Dependent Claim
14 words
A method according to claim 4, wherein said drug is phenytoin, sulpiride or etomidate.
Claim 12
Dependent Claim
15 words
A method according to claim 4, wherein said drug is a barbiturate or a benzodiazepine.
Claim 13
Dependent Claim
19 words
A method according to claim 11, wherein said drug is pentobarbital, phenobarbital, secobarbital, chlordiazepoxide, diazepam, medazepham, oxazepam or lorazepam.
Claim 14
Dependent Claim
31 words
A method according to claim 5, wherein said drug is dexamethasone, hydrocortisone, prednisolone, 17β-estradiol, 17α-ethynylestradiol, ethynylestradiol 3-methyl ether, estriol, norethindrone, norethindrone acetates, norgestrel, ethisterone, medroxyprogesterone acetate, progesterone, 17-methyltestosterone, testosterone or alfaxalone.
Claim 15
Dependent Claim
18 words
A method according to claim 6, wherein said drug is dicumarol, digoxin, digitoxin, nitroglycerin, flunarizine, alprostadil or prostacylin.
Claim 16
Dependent Claim
21 words
A method according to claim 7, wherein said drug is ampicillin, penicillin G, ketoconazole, itraconazole, metronidazole benzoate, miconazole, flubendazole or co-trimoxazole.
Claim 17
Dependent Claim
35 words
A method according to claim 8, wherein said drug is retinol, vitamin A-acetate, cholecalciferol, retinal, an E, D or K vitamin, apomorphine, chlorthalidone, furosemide, spironolactone, indomethacin, piroxicam, flurbiprofen, acetazolamide, lidocaine, acetohexamide, dimenhydrinate, L-DOPA or THA.
Claim 18
Dependent Claim
29 words
A method according to claim 1, wherein said drug is the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal dihydropyridine form of a dihydropyridine⃡pyridinium salt redox system for brain-targeted drug delivery.
Claim 19
Dependent Claim
13 words
A method according to claim 17, wherein the aqueous solution is approximately isotonic.
Claim 20
Dependent Claim
42 words
A method according to claim 17, wherein said dihydropyridine form is a compound of the formula [D-DHC] wherein [D] is a centrally acting drug species and [DHC] is the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal form of a dihydropyridine⃡pyridinium salt redox carrier.
Claim 21
Dependent Claim
49 words
A method according to claim 19, wherein the centrally acting drug species is a dopaminergic agent, an androgenic agent, an anticonvulsant, an anxiolytic agent, a neurotransmitter, an antibiotic or antibacterial agent, an antidepressant, an antiviral agent, an anticancer or antitumor agent, an anti-inflammatory agent, an estrogen or a progestin.
Claim 22
Dependent Claim
54 words
A method according to claim 20, wherein the centrally acting drug species is dopamine, testosterone, phenytoin, GABA, valproic acid, tyrosine, methicillin, oxacillin, benzylpenicillin, cloxacillin, dicloxacillin, desipramine, acyclovir, trifluorothymidine, zidovudine, hydroxy-CCNU, chlorambucil, tryptamine, dexamethasone, hydrocortisone, ethinyl estradiol, norethindrone, estradiol, ethisterone, norgestrel, estrone, estradiol 3-methyl ether, estradiol benzoate, norethynodrel, mestranol, indomethacin, naproxen, FENU, HENU or 5-FU.
Claim 23
Dependent Claim
19 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 1-methyl-3-{{N-{β-[3,4-bis(pivalyloxy)phenyl]ethyl}carbamoyl}}-1,4-dihydropyridine, 1-methyl-3-{N-[[β-[3,4-bis(isobutyryloxy)phenyl]ethyl]]}carbamoyl-1,4-dihydropyridine or N-{β-[3,4-bis(pivalyloxy)phenyl]ethyl}aminocarbonyloxymethyl 1,4-dihydro-1-methyl-3-pyridinecarboxylate.
Claim 24
Dependent Claim
17 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 17β-[(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)oxy]androst-4-en-3-one or 17β-{[(3"-carbamoyl-1',4'-dihydropyridinyl)acetyl]oxy}androst-4-en-3-one.
Claim 25
Dependent Claim
18 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 5,5-diphenyl-3-[(1'-methyl-1',4'-dihydropyridin-3'-yl)carbonyloxymethyl]-2,4-imidazolidinedione, 3-[(3'-carbamoyl-1',4'-dihydropyridin-1'-yl)acetyloxymethyl]-5,5-diphenyl-2,4-imidazolidinedione or 3-[3'-(3"-carbamoyl-1",4"-dihydropyridin-1"-yl)propionyloxymethyl]-5,5-diphenyl-2,4-imidazolidinedione.
Claim 26
Dependent Claim
17 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 1-methyl-3-N-[3-(benzyloxycarbonyl)propyl]carbamoyl-1,4-dihydropyridine or 1-methyl-3-{N-[(3'-cyclohexylcarbonyl)propyl]}carbamoyl-1,4-dihydropyridine.
Claim 27
Dependent Claim
18 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 1-methyl-3-[2'-(2"-propyl)pentanoyloxy]ethylcarbamoyl-1,4-dihydropyridine, 1-methyl-3-[2'-(2"-propyl)pentanoyloxy]ethoxycarbonyl-1,4-dihydropyridine or 1-[2'-(2"-propyl)pentanoyloxy]ethyl-3-carboxamide-1,4-dihydropyridine.
Claim 28
Dependent Claim
17 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 1-methyl-3-{N-[(1'-ethoxycarbonyl)-2'-(4"-pivaloyloxyphenyl)ethyl]}carbamoyl-1,4-dihydropyridine or 1-methyl-3-{N-[(1'-ethoxycarbonyl)-2'-(4"-isobutyryloxyphenyl)ethyl]}carbamoyl-1,4-dihydropyridine.
Claim 29
Dependent Claim
25 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl]oxy]methyl [2S-(2α,5α,6β)]-3,3-dimethyl-7-oxo-6-[(2,6-dimethoxy)benzamido]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate, [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl]oxy]methyl [2S-(2α,5α,6β)-3,3-dimethyl-6-(5-methyl-3-phenyl-4-isoxazolecarboxamido)-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylate, [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl]oxy]methyl [2S-(2α,5α,6β)]-3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate, [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl]oxy]methyl [2S-(2α,5α,6β)]-6-[3-(2-chlorophenyl)-5-methyl-4-isoxazolecarboxamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate or [[(1,4-dihydro-1-methyl-3-pyridinyl)carbonyl]oxy]methyl [2S-(2α,5α,6β)]-6-[3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolecarboxamido]-3,3-dimethyl-7-oxo-4-thia-1azabicyclo[3.2.0]heptane-2-carboxylate.
Claim 30
Dependent Claim
19 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is [{N-[3-(10,11-dihydro-5H-dibenz(b,f]azepin-5-yl)]propyl-N-methylamino}carbonyloxy]methyl 1,4-dihydro-1-methyl-3-pyridinecarboxylate or [1-{N-[3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)]propyl-N-methylamino}carbonyloxy]ethyl 1,4-dihydro-1-methyl-3-pyridinecarboxylate.
Claim 31
Dependent Claim
15 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 1-methyl-3-{[2-(9-guanylmethoxy)ethoxy]carbonyl}-1,4-dihydropyridine.
Claim 32
Dependent Claim
15 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 3'-(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)-5'-pivaloyltrifluorothymidine.
Claim 33
Dependent Claim
15 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 3'-azido-3'-deoxy-5'-(1-methyl-1,4-dihydro-3-pyridinyl)carbonyl]thymidine.
Claim 34
Dependent Claim
18 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is N-(2-chloroethyl)-N'-[4-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy)cyclohexyl]-N-nitrosourea, N-(2-fluoroethyl)-N'-[2-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy)ethyl]-N-nitrosourea or N-(2-chloroethyl)-N'-[2-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxy)ethyl]-N-nitrosourea.
Claim 35
Dependent Claim
20 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 1-methyl-3-[(N-{2-[4-({4-[bis(2-chloroethyl)]amino}phenyl)butanoyloxy]ethyl})carbamoyl]-1,4-dihydropyridine, 1-methyl-3-(N-{4-[4-(4-{[bis(2-chloroethyl)]amino}phenyl)butanoyloxy]cyclohexyl}carbamoyl)-1,4-dihydropyridine, 1-methyl-3-[(N-{2-[4-({4-bis(2-chloroethyl)]amino}phenyl)butanoyloxy]propyl})carbamoyl]-1,4-dihydropyridine, 1-methyl-3-[(N-{2-phenyl-2-({4-[bis(2-chloroethyl)]amino}phenyl)butanoyloxy]}ethyl)carbamoyl]-1,4-dihydropyridine or 1-methyl-3-[N-({1-[4-(4-{[bis(2-chloroethyl)]amino}phenyl)butanoyloxy]cyclohexyl}methyl)carbamoyl]-1,4-dihydropyridine.
Claim 36
Dependent Claim
15 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 1-methyl-3-N-[2-(3-indolyl)ethyl]carbamoyl-1,4-dihydropyridine.
Claim 37
Dependent Claim
17 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 9-fluoro-11β,17-dihydroxy-16α-methyl-21-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy}pregna-1,4-diene-3,20-dione or 11β,17-dihydroxy-21-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy}pregn-4-ene-3,20-dione.
Claim 38
Dependent Claim
15 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 3-hydroxy-17β-[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxyestra-1,3,5(10)-triene.
Claim 39
Dependent Claim
23 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 3-hydroxy-17β-{[1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy}-19-nor-17α-pregna-1,3,5(10)-trien-20-yne, 3-[(1-methyl-1,4-dihydro-3-pyridinyl)carbonyloxy]estra-1,3,5(10)-trien-17-one, 17⊖-[(1-methyl-1,4-dihydro-3-pyridinyl)carbonyloxy]estra-1,3,5(10)-trien-3-ol 3-methyl ether, 3,17β-bis-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy}estra-1,3,5(10)-triene, 3-(phenylcarbonyloxy)-17β-{([(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy}estra-1,3,5(10-triene or 3-methoxy-17β-{[1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy}-19-nor-17α-pregna-1,3,5(10)-trien-20-yne.
Claim 40
Dependent Claim
19 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 17β-{([(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy}-19-norpregn-4-en-20-yn-3-one, 17β-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy}pregn-4-en-20-yn-3-one, 13-ethyl-17β-{[(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy}-18,19-dinorpregn-4-en-20-yn-3-one or 17β-{([(1-methyl-1,4-dihydropyridin-3-yl)carbonyl]oxy}-19-norpregn-5(10)-en-20-yn-3-one.
Claim 41
Dependent Claim
17 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 1-methyl-3-[N-(2-{1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl]acetoxy}ethyl)carbamoyl]-1,4-dihydropyridine or 1-methyl-3-{(N-[2-(6-methoxy-α-methyl-2-naphthalenylacetoxy)ethyl]carbamoyl-1,4-dihydropyridine.
Claim 42
Dependent Claim
17 words
A method according to claim 21, wherein the compound of the formula [D-DHC] is 3-(1,4-dihydro-1-methyl-3-pyridinylcarbonyloxymethyl)-5-fluorouracil or 1-(1,4-dihydro-1-methyl-3-pyridinecarbonyloxymethyl-5-fluorouracil.
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