Pharmaceutical formulations for parenteral use

• US 4,983,586 A
• Filed: 03/29/1988
• Issued: 01/08/1991
• Est. Priority Date: 12/30/1987
• Status: Expired due to Term

• Current Assignee: University of Florida (State University System of Florida)
• Original Assignee: University of Florida (State University System of Florida)
• Inventors: Bodor, Nicholas S.
• Primary Examiner(s): Griffin, Ronald W.
• Application Number:
  US07/174,945
• Time in Patent Office: 1,015 Days
• Field of Search: 536/103, 514/58, 514/777
• US Class Current: 514/58
• CPC Class Codes: A61K 31/43 Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula , e.g. penicillins, penems
• CPC Class Codes: A61K 47/559 Redox delivery systems, e.g. dihydropyridine pyridinium salt redox systems
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• CPC Class Codes: C07C 219/28 having amino groups bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07C 229/08 the nitrogen atom of the amino group being further bound to hydrogen atoms
• CPC Class Codes: C07C 233/18 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 271/16 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07D 211/90 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 213/80 in position 3
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 223/28 having a single bond between positions 10 and 11
• CPC Class Codes: C07D 233/74 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
• CPC Class Codes: C07D 233/78 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 243/38 [b, e]- or [b, f]-condensed with six-membered rings
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 473/00 Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 499/00 : Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula: , e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
• CPC Class Codes: C07H 19/06 : Pyrimidine radicals
• CPC Class Codes: C07J 43/003 : not condensed
• CPC Class Codes: C08B 37/0012 : Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
• CPC Class Codes: C08B 37/0015 : Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

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.

Claims

1. 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.

2. A method according to claim 1, wherein the aqueous solution is approximately isotonic.

3. A method according to claim 1, wherein said drug is an antineoplastic.

4. A method according to claim 1, wherein said drug is a sedative, tranquilizer, anticonvulsant, antidepressant, hypnotic, muscle relaxant or antispasmodic.

5. A method according to claim 1, wherein said drug is an androgen, estrogen, progestin, anti-inflammatory steroid or steroidal hypnotic or anesthetic.

6. A method according to claim 1, wherein said drug is an anticoagulant, cardiotonic, vasodilator, vasoconstrictor, platelet inhibitor or anti-arrhythmic.

7. A method according to claim 1, wherein said drug is an antifungal, antiprotozoal, antibacterial, antibiotic or antiviral.

8. 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.

9. 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.

10. A method according to claim 4, wherein said drug is phenytoin, sulpiride or etomidate.

11. A method according to claim 4, wherein said drug is a barbiturate or a benzodiazepine.

12. A method according to claim 11, wherein said drug is pentobarbital, phenobarbital, secobarbital, chlordiazepoxide, diazepam, medazepham, oxazepam or lorazepam.

13. 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.

14. A method according to claim 6, wherein said drug is dicumarol, digoxin, digitoxin, nitroglycerin, flunarizine, alprostadil or prostacylin.

15. A method according to claim 7, wherein said drug is ampicillin, penicillin G, ketoconazole, itraconazole, metronidazole benzoate, miconazole, flubendazole or co-trimoxazole.

16. 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.

17. A method according to claim 1, wherein said drug is the reduced, biooxidizable, blood-brain barrier penetrating, lipoidal dihydropyridine form of a dihydropyridine⃡

pyridinium salt redox system for brain-targeted drug delivery.

18. A method according to claim 17, wherein the aqueous solution is approximately isotonic.

19. A method according to claim 17, wherein said dihydropyridine form is a compound of the formula

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. 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.

32. 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.

33. 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.

34. 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.

35. 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.

36. 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.

37. 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.

38. 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.

39. 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.

40. 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.

41. 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.