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AU738165B2 - Useful formulations of acid addition salt drugs - Google Patents

Useful formulations of acid addition salt drugs Download PDF

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Publication number
AU738165B2
AU738165B2 AU34075/97A AU3407597A AU738165B2 AU 738165 B2 AU738165 B2 AU 738165B2 AU 34075/97 A AU34075/97 A AU 34075/97A AU 3407597 A AU3407597 A AU 3407597A AU 738165 B2 AU738165 B2 AU 738165B2
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Prior art keywords
formulation
formula
acid addition
addition salts
patient
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AU3407597A (en
Inventor
Ronald W. Pero
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Oxi Gene Inc
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Oxi Gene Inc
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    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/541—Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

Useful Formulations of Acid Addition Salt Drugs Background of the Invention This invention relates to acid addition salt drugs having utility in the treatment of human patients. More particularly it relates to new and improved formulations and methods of administration of such acid addition salt drugs.
Nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and anaesthetics represent a wide range of diverse chemical and pharmacological structures, but they share a common property of modifying the tumor response to radiation or chemotherapy. A variety of chemical structures including the nitroimidazoles, to phenothiazines, butyrophenones, halopyrimidines, benzamides and nicotinamides are known to possess radio- and chemosensitizing properties (Horsman et al, Acta Oncologica 34:571-587, 1995: Brown et al, Cancer Treatment Symposia 1, 85-101, 1984, Pu el al, Oncology 9(8):707-721, 1995, George and Singh, Indian J. Expt. Biol. 22:305- 307, 1984, Kennedy et al, Int. J.
a *ooeo oO° °ooo *oo WO 98/00159 PCTIUS97/10829 Radiat. Oncol. Biol. Phys. 12:1367-1370, 1986). These various classes of agents are believed to accomplish this mechanistic action either by altering tumor blood supply to overcome hypoxia, inhibiting DNA repair, imbalancing calcium homeostasis or combinations thereof (Horsman et al, Acta Oncologica 34:571- 587, 1995, Hirst et al, Br. J. Cancer 67:1-6, 1993, Wood and Hirst, J. Radiat.
Oncol. Biol. Phys. 16:1141-1144, 1989; Menke and Vaupel, Radiation Res.
114:64-76, 1988; Rosenthal and Hait, Yale J. Biol. Med. 61: 39-49, 1988, Lybak and Pero, Carcinogenesis 12: 1613-1617, 1991, Olsson et al, Carcinogenesis 16: 1029-1035, 1995; Olsson, et al, Br. J. Cancer, In Press, 1996).
Regardless of the precise mechanism(s) the ultimate result is accumulation of DNA damage and an increase in tumor cytotoxicity either by necrosis or apoptosis (Kerr and Winterford, Cancer 73:2013-2026, 1993). As a result, these agents are all potential cancer therapy drugs even though they may have other well defined clinical uses. For example, metoclopramide, an N-substituted benzamide, has been used as an antiemetic for over 30 years (Harrington et al, Drugs 25: 451-494, 1983) but recently it has been shown to be an effective radio- and chemo-sensitizer (Pero et al, Biochimie 77:385-391, 1995, Kjell6n et al, Eur. J. Cancer 31A(13/ 14):2196-2202, 1995). Furthermore, most drugs having well established clinical uses are known to mediate their effects by antagonizing high affinity receptors capable of initiating physiological responses relating to many disease processes. Conformation and charge of these chemical structures, in turn, determine their abilities to antagonize receptors and mediate drug related efficacious responses.
Summary of the Invention According to a first aspect, the present invention consists in a method of administering to a human patient material selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula having a tertiary nitrogen present, acid addition salts of compounds that can form acid salts of Formula (B) having a quaternary ammonium ion present, and mixtures thereof, other than nimorazole salts and other than dibucaine hydrochloride when admixed with other actives, said Formula and Formula being as follows: H X- RI--(CH2)n N--R2 R3
R
3 (A) R2
X-
RI-- (CH2)n-- N+ R3 R4
(B)
wherein R, comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula or said quaternary ammonium ion of Formula R 2
R
3 and R 4 are alkyl or aryl groups, n is an integer of 1 S or more and X- is an anion, said method comprising the steps of 5 providing a sterile injectable formulation comprising a liquid vehicle containing the material in solution, at a pH within a range of about 5.5 to 7.0, and injecting the formulation into the patient in an amount for delivering to the patient a dose of about one to 100mg/kg of the material while the pH of the formulation is within said range.
o 20 According to a second aspect, the present invention consists in a sterile injectable oooo formulation for intramuscular administration to a human patient, comprising a material selected from the group consisting of acid addition salts of oo :compounds that can form acid salts of Formula having a tertiary nitrogen present, acid addition salts of compounds that can form acid salts of Formula having a quaternary ammonium ion present, and mixtures thereof, other than dibucaine hydrochloride when admixed with other active's, said Formula and Formula (B) being as follows: [R:\LIBFF]0912 lspeci.doc:njc 3a H X- R1-(CH2)n R2 R3
(A)
R
2
X-
Rl-(CH2)n-N--R3
R(B)
wherein Ri comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula or said quaternary ammonium ion of Formula R 2
R
3 and R 4 are alkyl or aryl groups, n is an integer of 1 or more and X- is an anion; a liquid vehicle in which said material is in solution; said material being present in said formulation in a concentration of at least about 50mg/ml, and to the formulation being at a pH within a range of about 5.5 to According to a third aspect, the present invention consists in a method of administering to a human patient material selected from the group consisting of acid 1: addition salts of compounds that can form acid salts of Formula having a tertiary nitrogen present, acid addition salts of compounds that can form acid salts of Formula (B) S 15 having a quaternary ammonium ion present, and mixtures thereof, other than nimorazole salts and other than dibucaine hydrochloride when mixed with other actives, said Formula 0.
and Formula being as follows: H X-
R
1
-(CH
2
R
2 R3
(A)
R
2
X-
R1-(CH2)n R3
(B)
wherein Ri comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula or said quaternary ammonium ion of Formula R 2
R
3 and R 4 are alkyl or aryl groups, n is an integer of 1 or more, and X' is an anion, said method comprising the steps of [R:\LIBFF]9613.doc:mef 3b providing a sterile formulation, comprising a liquid vehicle containing the material in solution, adjusting the pH of said formulation for reducing the development of undesirable side effects of the material, and administering the formulation having the adjusted pH to the patient.
According to a fourth aspect, the present invention consists in a method of administering to a human patient material selected from the group consisting of acid addition salts of maiphalan, amiloride, clomipramine, chlorcyclizine, hydralazine, alprenolol, dopamine, quinapril, tetracycline, cimetidine, doxorubicin, biperiden, o carteoloI, ranitidine, hydroxyzine, chlortetracycline, bambuterol, diphenhydramine, betaxolol, bromhexine, phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diItiazem, clonidine, succinyicholine, daunorubicin, ciprofloxacine, clopenthixol, prilocaine, ethylmorphine, tacrine, protripty line, amiodarone, cyclopentolate, clindamycin, propoxyphene, hydromorphone, orphenadrine, dobutamine, dopexamine, doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, deprenyl, ,epirubicin, fH upentixol, benoxinate, fluoxetin, gemcitabine, adrenaline, metformin, chloropromazine, prenalterol, terazosine, oxymetazoline, loperamide, propanolol, lidocaine, apraclonidine, veraparnil, pilocarpine, procyclidine, ketamine, ketobemidon, quinidine, granisetron, mie floqtu in, prommethazine, remoxipride, 1incorycin, levocabastin, arnorolfine, maprotiline, benserazide, thioridazine, cyclizine, cephepime, methadone, mexiletine, m ianserin, pivmecillinam, phenylpropanolamine, morphine, ethambutol, ambenonium, naloxone, xylometazoline, procarbazine, tropisetrone, phenylephrine, thiamine, tramadol, hydrochlorotiazid, quinagolide, noscapine, mitoxantrone, dipivefrin, oxytetracycline, flupheenazine, chlorguanide, trihexyphenidyl, bacampicillin, cyproheptadine, prazosin, meperidine, meclizine, metoclopramide, procainamide, pyridoxine, alfentanil, si naphazoline, inethacycline, roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol, buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, methixene, spectiniomycin, dorzolamide, chloroprothixene, lefepramine, valaciklovir, vancomycin, amantadine, alfiuzosine, 31 idarubicin, ondansetron, cetirizine, 3-chloro procainamide, N-(2-diethylamino-ethyl) nicotinamide, nimorazole and 2,3-dimethyl(dimethylaminoethyl)-5H-indolo-2,3 -b) guinoxline and mixtures thereof, said method comprising the steps of providing a sterile injectable formulation comprising a liquid vehicle -RAC&- \conraining the material in solution, at a pH within a range of about 5.5 to 7.0, and [R:\LIBFF]091 2 Ispeci.doc:njc 3c injecting the formulation intramuscularly into the patient in an amount for delivering to the patient a dose of about one to 100mg/kg of the material while the pH of the formulation is within said range.
According to a fifth aspect, the present invention consists in a sterile injectable formulation for intramuscular administration to a human patient, comprising a material selected from the group consisting of acid addition salts of malpphalan, amiloride, clomipramine, chlorcyclizine, hydralazine, alprenolol, dopamine, cuinapril, tetracycline, cimetidine, doxorubicin, biperiden, carteolol, ranitidine, hydroxyzine, chlortetracycline, bambuterol, diphenhydramine, betaxolol, bromhexine, phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem, clonidine, succinylcholine, daunorubicin, ciprofloxacine, clopenthixol, prilocaine, ethylmorphine, tacrine, protriptyline, amiodarone, cyclopentolate, ciindamycin, propoxyphene, hydromorphone, orphenadrine, dobutamine, dopexamine, doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, deprenyl, epirubicin, flupentixol, benoxinate, fluoxetin, I 5 gecitabine, adrenaline, metformin, chioropromazine, prenalterol, terazosine, oxymnetazoline, loperamide, propanolol, lidocaine, apraclonidine, verapamil, pilocarpine, procyclidine, ketamine, ketobemidon, quinidine, granisetron, meftoquin, prommethazine, remoxipride, lincomycin, levocabastin, amorolfine, maprotiline, benserazide, thioridazine, cyclizine, cephepime, methadone, mexiletine, mianserin, pivmecillinam, 20 phenylpropanolamine, morphine, ethambutol, ambenonium, naloxone, xylometazoline, 0:00 procarbazine, tropisetrone, phenylephrine; thiamine, tramadol, hydrochlorotiazid, qUinagolide, noscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, chlorguanide, trihexyphenidyl, bacampicillin, cyproheptadine, prazosin, meperidine, mcieclizine, metoclopramide, procainamide, pyridoxine, alfentanil, naphazoline, 25 iriethacyclne, roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol, buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, methixene, spectinomycin, dorzolamide, chloroprothixene, lefepramine, valacikiovir, Soo& vancomycin, amantadine, alfiuzosine, idarubicin, ondansetron, cetirizine, 3-chloro procainamide, N-(2-diethylamino-ethyl) nicotinamide, nimorazole and 2,3-dimethyl- (direthylaminoethyl)-5H-indolo-2,-b) guinoxline and mixtures thereof, a liquid vehicle in which said material is in solution, said material being present in said formulation in a concentration of at least about 50mg/mi, and the formulation being at a pH within a range of about 5.5 to 12 lspcci.doc:njc 3d According to a sixth aspect, the present invention consists in a method of administering to a human patient material selected from the group consisting of acid addition salts of maiphalan, amiloride, clomipramine, chlorcyclizine, hydralazine, alprenolol, dopamine, quinapril, tetracycline, cimetidine, doxorubicin, biperiden, ca rteolol, ranitidine, hydroxyzine, chlortetracycline, bambuterol, diphenhydramine, betaxolol, bromhexine, phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem, clonidine, succinyicholine, daunorubicin, ciprofloxacine, clopenthixol, prilocaine, ethylmorphine, tacrine, protriptyline, amiodarone, cyclopentolate, clindamycin, propoxyphene, hydromorphone, orphenadrine, dobutamine, dopexamine, I0 doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, deprenyl, epirubicin, fiupentixoI, benoxinate, fluoxetin, gemcitabine, adrenaline, metformin, chioropromazine, prenaltero1, terazosine, oxymetazoline, loperamide, propanolol, lidocaine, apraclonidine, verapamil, pilocarpine, procyclidine, ketamine, ketobemidon, quinidine, granisetron, mefloquin, prommethazine, remoxipride, lincomycin, levocabastin, anorolfine, maprotiline, benserazide, thioridazine, cyclizine, cephepime, methadone, mexiletine, i anserin, pivmecillinam, phenyipropanolamine, morphine, ethambutol, ambenonium, naloxone, xyloretazoline, procarbazine, tropisetrone, phenylephrine, thiamine, tramadol, hydrochlorotiazid, quinagolide, noscapine, mitoxantrone, dipivefrin, oxytetracycline, 1uphenazine, chiorguanide, trihexyphenidyI, bacampicillin, cyproheptadine, prazosin, a 20 meperidine, meclizine, metoclopramide, procainamide, pyridoxine, alfentanil, inaphazoline, methacycline, roxatidine, propafenone, aritriptyline, nortriptyline, paroxetine, clobutinol, sotalol, buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, methixene, spectinomycin, dorzolamide, ch loroprothixene, lefepramine, valaciklovir, vancomycin, amantadine, alfiuzosine, S2 5 idaruLibicin, ondansetron, cetirizine, 3-chloro procainamide, N-(2-diethylamino-ethyl) 4. nicotinamide and 2,3-dimethyl(dimethylaminoethyl)-5H-indolo-2,3-b) guinoxline and mixtures thereof, said method comprising the steps of 46*0 providing a sterile formulation, comprising a liquid vehicle containing the material in solution, adjusting the pH of said formulation for reducing the development of undesirable side effects of the material, and administering the formulation having the adjusted pH to the patient.
I 1 I1F]09 12 1 spci.doc:nic 3e According to a seventh aspect, the present invention consists in use of a material selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula having a tertiary nitrogen present, acid addition salts of compounds that can form acid salts of Formula having a quaternary ammonium ion present, and S mixtures thereof, other than nimorazole salts and other than dibucaine hydrochloride when admixed with other actives, said Formula and Formula being as follows: H X- R1- (CH2)n N- R2 R3
(A)
R2 X" Rl- (CH 2
R
3 R4
(B)
wherein R, comprises an aryl or alkyl group with a hydrogen bond acceptor site to accessible to interaction with said tertiary nitrogen of Formula or said quaternary ammonium ion of Formula R 2
R
3 and R 4 are alkyl or aryl groups, n is an integer of 1 or more and X- is an anion, in the manufacture of a sterile injectable formulation comprising a liquid vehicle containing the material in solution at a pH within a range of S! about 5.5 to 7.0 for administration to a human patient by injecting the formulation into the 15 patient in an amount for delivering to the patient a dose of about one to 100mg/kg of the material while the pH of the formulation is within said range.
According to an eighth aspect, the present invention consists in a material selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula having a tertiary nitrogen present, acid addition salts of compounds that can o.o159 20 form acid salts of Formula having a quaternary ammonium ion present, and mixtures 1 thereof, other than nimorazole salts and other than dibucaine hydrochloride when admixed with other actives, said Formula and Formula being as follows: H X-
R--(CH
2 )n R2 R3
(A)
R2 X- R1-(CH2)n-N R3
(B)
[R:\LIBFF]0912 Ispeci.doc:njc 3f wherein RI comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula or said quaternary ammonium ion of Formula R 2
R
3 and R4 are alkyl or aryl groups, n is an integer of 1 or more and X- is an anion, when used in a sterile injectable formulation comprising a S liquid vehicle containing the material in solution at a pH within a range of about 5.5 to for administration to a human patient by injecting the formulation into the patient in an amount for delivering to the patient a dose of about one to 100mg/kg of the material while the pH of the formulation is within said range.
According to a ninth aspect, the present invention consists in use of a material 0o selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula having a tertiary nitrogen present, acid addition salts of compounds that can form acid salts of Formula having a quaternary anmmonium ion present, and mixtures thereof, other than dibucaine hydrochloride when mixed with other actives, said Formula and Formula being as follows: H X- R1--(CH2)n -N R2 R3
R(A)
Rl-(CH2)n-N-R3
(B)
S anmonium ion of Formula R 2
R
3 and R 4 are alkyl or aryl groups, n is an integer of 1 NT~ liquid vehicle containing the material in solution wherein the pH of the formulation is adjusted for reducing the development of undesirable side effects of the material for administration of the formulation having the adjusted pH to a human patient.
According to a tenth aspect, the present invention consists in a material selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula having a tertiary nitrogen present, acid addition salts of compounds that can form acid salts of Formula having a quaternary ammonium ion present, and mixtures thereof, other than dibucaine hydrochloride when mixed with other actives, said Formula and Formula being as follows: [R I FFO1:19121 speci.doc:nic 3g H X Ri -(CH2)n -N R2 R3
R
3 (A) R2 X- Rl-(CH2)n-N'-R3
R
4 (B) wherein RI comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula or said quaternary ammonium ion of Formula R 2
R
3 and R4 are alkyl or aryl groups, n is an integer of 1 oi more, and X- is an anion, when used in a sterile formulation comprising a liquid vehicle containing the material in solution wherein the pH of the formulation is adjusted for reducing the development of undesirable side effects of the material for administration of the formulation having the adjusted pH to a human patient.
I0 According to a eleventh aspect, the present invention consists in use of a material, selected from the group consisting of acid addition salts of malphalan, amiloride, clomipramine, chlorcyclizine, hydralazine, alprenolol, dopamine, quinapril, tetracycline, cimetidine, doxorubicin, biperiden, carteolol, ranitidine, hydroxyzine, chlortetracycline, bambuterol, diphenhydramine, betaxolol, bromnhexine, phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem, clonidine, succinylcholine, daunorubicin, ciprotloxacine, clopenthixol, prilocaine, ethylmorphine, tacrine, protriptyline, *amiodarone, cyclopentolate, clindamycin, propoxyphene, hydromorphone, orphenadrine, dobutamine, dopexamine, doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, deprenyl, epirubicin, flupentixol, benoxinate, fluoxetin, gemcitabine, adrenaline, 0 metformin, chloropromazine, prenalterol, terazosine, oxymetazoline, loperamide, propanolol, lidocaine, apraclonidine, verapamil, pilocarpine, procyclidine, ketamine, *.ketobemidon, quinidine, granisetron, mrefloquin, prommethazine, remoxipride, lincomycin, levocabastin, amorolfine, maprotiline, benserazide, thioridazine, cyclizine, cephepime, methadone, mexiletine, mianserin, pivmecillinam, phenylpropanolamine, morphine, ethambutol, ambenonium, naloxone, xylometazoline, procarbazine, tropisetrone, phenylephrine, thiamine, tramadol, hydrochlorotiazid, quinagolide, noscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, chlorguanide, tribhexyphenidyl, bacampicillin, cyproheptadine, prazosin, meperidine, meclizine, metoclopramide, procainamide, pyridoxine, alfentanil, naphazoline, methacycline, [R:\LIBFF09121 speci.doc:njc 3h roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, ciobutinol, sotalol, buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, methixene, spectinomycin, dorzolamide, chioroprothixene, lefepramine, valacikiovir, vancomycin, amantadine, alfiuzosine, idarubicin, ondansetron, cetirizine, 3-chioro p rocainamide, N-(2-diethylamino-ethyl) nicotinamide, nimorazole and 2,3 cli methyl(dimethylaminoethyl)-5H-indolo-2,3-b) guinoxline and mixtures thereof, in the manufacture of a sterile injectable formulation comprising a liquid vehicle containing the material in solution at a pH within a range of about 5.5 to 7.0 for administration to a human patient by injecting the formulation intramuscularly into the patient in an amount o [or delivering to the patient a dose of about one to 100mg/kg of the material while the pH of the formulation is within said range.
According to a twelfth aspect, the present invention consists in a material selected From the group consisting of acid addition salts of malphalan, amiloride, clomipramine, chilorcyclizine, hydralazine, alprenolol, dopamine, quinapril, tetracycline, cimetidine, i doxorubicin, biperiden, carteolol, ranitidine, hydroxyzine, chlortetracycline, bambuterol, diphenhydramine, betaxolol, bromhexine, phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem, clonidine, succinylcholine, daunorubicin, cipo tioxacine, clopenthixol, prilocaine, ethylmorphine, tacrine, protriptyline, 00.. amiodarone, cyclopentolate, clindamycin, propoxyphene, hydromorphone, orphenadrine, 0 20 clobutamine, dopexamine, doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, 0.0 cleprenyl, epirubicin, flupentixol, benoxinate, fluoxetin, gemcitabine, adrenaline, metformin. chloropromazine, prenalterol, terazosine, oxymetazoline, loperaride, propanolol, lidocaine, apraclonidine, verapamil, pilocarpine, procyclidine, ketamine, .0.00: ketobemidon, quinidine, granisetron, nefloquin, prommethazine, remoxipride, lincomycin, levocabastin, amorolfine, maprotiline, benserazide, thioridazine, cyclizine, cephepi me, methadone, mexiletine, mianserin, pivmeciliminam, phenylpropanolamine, Sorpphine, ethambutol, ambenonium, naloxone, xylometazoline, procarbazine, tropisetrone, phenylephrine, thiamine, tramadol, hydrochlorotiazid, quinagolide, 0 inoscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, chlorguanide, so tri hexyphenidyl, bacampicillin, cyproheptadine, prazosin, meperidine, meclizine, metoclopramide, procainamide, pyridoxine, alfentani1, naphazoline, methacycline, roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol, buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, Imeth ixene, spectinomycin, dorzolamide, chloroprothixene, lefepramine, valacikiovir, jncomycin, amantadine, alfiuzosine, idarubicin, ondansetron, cetirizine, 3-chloro v O R :\II BF]09121speci.docinjmc procainamide, N-(2-diethylamino-ethyl) nicotinamide, nimorazole and 2,3 cl i methyl(dimethylaminoethyl)-5H-indolo-2,3-b) guinoxline and mixtures thereof, when used in a sterile injectable formulation comprising a liquid vehicle containing the material in solution at a pH within a range of about 5.5 to 7.0 for administration to a human patient by administering the formulation intramuscularly by injection into the patient in an amount for delivering to the patient a dose of about one to 100mg/kg of the material while the pH of the formulation is within said range.
According to a thirteenth aspect, the present invention consists in use of a material selected from the group consisting of acid addition salts of malphalan, amiloride, I clomipramine, chlorcyclizine, hydralazine, aiprenolol, dopamine. quinapril, tetracycline, cimetidine, doxorubicin, biperiden, carteolol, ranitidine, hydroxyzine, chlortetracycline, bambuterol, diphenhydramine, betaxolol, bromhexine, phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem, clonidine, succinylcholine, daunorubicin, ciprofloxacine, clopenthixol, prilocaine, ethylmorphine, tacrine, protriptyline, a iniodarone, cyclopentolate, clindamycin, propoxyphene, hydromorphone, orphenadrine, dobutamine, dopexamine, doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, deprenyl, epirubicin, flupentixol, benoxinate, fluoxetin, gemcitabine, adrenaline, metforin, chloropronazine, prenalterol, terazosine, oxymetazoline, loperamide, pmopanolol, lidocaine, apraclonidine, verapamil, pilocarpine, procyclidine, ketamine, ketobemidon, quinidine, granisetron, metloquin, prommethazine, remoxipride, I incomycin, levocabastin, amorolfine, maprotiline, benserazide, thioridazine, cyclizine, cephiepime, methadone, mexiletine, mianserin, pivmecillinam, phenylpropanolamine, morphine, ethambutol, ambenonium, naloxone, xyloretazoline, procarbazine, tropisetrone, phenylephrine, thiamine, tramadol, hydrochlorotiazid, quinagolide, S 5 lnoscapinc. mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, chlorguanide, ti-ihexyphenidyl, bacampicillin, cyproheptadine, prazosin, meperidine, meclizine, i metoclopramide, procainamide, pyridoxine, alfentani1, naphazoline, methacycline, roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol, buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, o m eth ixene, spectinomycin, dorzolamide, chioroprothixene, lefepramine, valaciklovir, vancornycin, amantadine, alfiuzosine, idarubicin, ondansetron, cetirizine, 3-chloro procainamide, N-(2-diethylamino-ethyl) nicotinamide. and 2,3cim7ethyl(dimethylaminoethyl)-5H-indolo-2,3-b) guinoxline and mixtures thereof, in the manufacture of a sterile formulation comprising a liquid vehicle containing the material in solution wherein the pH of the formulation is adjusted for reducing the development of \RAIolc LJJ i :IIB F]0 121s.ec~docn. i 3j undesirable side effects of the material for administration of the formulation having the adjusted pH to a human patient.
According to a fourteenth aspect, the present invention consists in a material selected from the group consisting of acid addition salts of malphalan, ariloride, clomipramine, chiorcyclizine, hydralazine, alprenolol, dopamine, quinapril, tetracycline, cimetidine, doxorubicin, biperiden, carteolol, ranitidine, hydroxyzine, chlortetracycline, bambuterol, diphenhydramine, betaxolol, bromhexine, phenylephrine, bupivacaine, inelperone, buspirone, mepivacaine, diltiazem, clonidine, succinyicholine, daunorubicin, ciprofloxacine, clopenthixol, prilocaine, ethylmorphine, tacrine, protriptyline, Io amiodarone, cyclopentolate, clindamycin, propoxyphene, hydromorphone, orphenadrine, clobutamine, dopexamine, doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, deprenyl, epirubicin, flupentixol, benoxinate, fluoxetin, gercitabine, adrenaline, metfo rmin, chioropromazine, prenaltero1, terazosine, oxymetazoline, loperamide, propanolol, lidocaine, apraclonidine, verapamil, pilocarpine, procyclidine, ketamine, ketobemidon, quinidine, granisetron, mefloquin, prommethazine, remoxipride, lincomycin, levocabastin, amorolfine, maprotiline, benserazide, thioridazine, cyclizine, cephepime, methadone, mexiletine, mianserin, pivmecillinam, phenylpropanolamine, iimorphine, ethambutol, ambenonium, naloxone, xylometazoline, procarbazine, tro p i setrone, phenylephrine, thiamine, tramadol, hydrochlorotiazid, quinagolide, noscapine. mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, chlorguanide, tri hexyphenidyl, bacampicillin, cyproheptadine, prazosin, meperidine, meclizine, ii-netoclopraride, procainamide, pyridoxine, alfentanil, naphazoline, methacycline, roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol, Sbuprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, methixene, spectinomycin, dorzolamide, chloroprothixene, lefepramine, valaciklovir, van-icomycin, arantadine, alfiuzosine, idarubicin, ondansetron, cetirizine, 3-chloro procainamide, N-(2-diethylamino-ethyl) nicotinamide, and 2,3 cli methyl(dimethylaminoethyl)-5H-indolo-2,3-b) guinoxline and mixtures thereof, when used in a sterile formulation comprising a liquid vehicle containing the material in solution wherein the pH of the formulation is adjusted for reducing the development of undesirable side effects of the material for administration of the formulation having the adjusted pH to a human patient.
[R:\LIBF1092 1 specidoc:nje 3k Reference is made hereinbelow to the following four papers, in all of which inventor herein is a co-author: R. W. Pero, M. Simanaitis, A. Olsson, A. Amiri and I.
Andersen, "Pharmacokinetics, Toxicity, Side Effects, Receptor Affinities and In Vitro Radiosensitizing Effects of the Novel Metoclopramide Formulations, Sensamide and S Neu-Sensamide," unpublished typescript, 1996, pp. 1-25 5 Figures (hereinafter "Pero et al unpublished 1996"), now published as Pharmacology Toxicology 80:231-239, .1997 A. Amiri, A. R. Olsson, J. Hua and R. W. Pero, "Apoptosis in HL-60 Cells As A Model for Determining Sensitization of Radio- And Chemotherapies By N-Substituted Benzamides," unpublished typescript, 1996, 14 pp. (unpaginated) 6 Figures (hereinafter Amiri el al unpublished 1996"), H. H. Rotmensch, G. P. Mould, J. A. Sutton, S.
Kilminster, C. Moller, R. W. Pero, "Comparative Central Nervous System Effects and Pharmacokinetics of Neu-Sensamide and Metoclopramide in Healthy Volunteers," unpublished typescript, 1996, pp. 1-19 2 Figures (hereinafter "Rotmensch et al unpublished 1996"), now published as J. Clin Pharmacol 37:222-228 (1997), A.
s1 Schwartz and R. W. Pero, "Evidence for Conformational Mobility of Metoclopramide as a Function of pH: Implications for Drug Design," unpublished typescript, 1996, 18 pp.
(unpaginated) (hereinafter "Schwartz et al unpublished 1996").
i One of the most popular chemical functionalities structures, substitutions) used in drug design is a tertiary or a quaternary nitrogen usually introduced via an 20 alkylaminodialkyl side chain, so that drugs such as the nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and anaesthetics *oo *o° o*o*• ooo 311:1FF10912 Ispeci.doc:njc 4 could be converted to more water soluble formulations for clinical administration.
However, drug formulation research with the N-substituted benzamides (incident to the development of the present invention) has so far shown that this structure can dramatically alter the pharmacological properties of, for example, metoclopramide simply by changing the pH of the formulation. Molecular modeling experiments support that Neu-Sensamide'M ("neutral" metoclopramide) has been formulated without the presence of a hydrogen mediated-bond between the tertiary ammonium ion and the carboxamide oxygen atom, whereas this hydrogen mediated-bond is present in SensamideTM ("acidic" metoclopramide) (Schwartz el al unpublished 1996). Neu-Sensamide"M has a reduced extrapyramidal side effect profile in rats and humans but the radiosensitizing properties remain unaltered compared to SensamideTM at equimolar doses (Amiri el al unpublished 1996; Hua el al, Anti-Cancer Drugs 6:451-453, 1995, Pero el al, Biochimie 77:385-393, 1995; Pero et al unpublished 1996; Rotmensch el al unpublished 1996). Therefore, it is logical to extrapolate these data to other drugs containing acid addition slat structures in the following way: Compounds that can form acid salts of types A or B: H X
R
2
X-
R--(CH
2 )n R 2 R (C H N Ri-(CH2) n
-N-R
3 R3
R
4
(B)
RI-4 alkyl or aryl groups; X any anion, normally Cl or Br or I a *ao.
IF1']09315SPECI.doc.njc WO 98/00159 PCT/US97/10829 Wherein: A tertiary nitrogen is present that can form an acid addition salt (Type A) or a quarternary ammonium ion is present (Type B) and/or R, comprises an aryl or alkyl gioup with a hydrogen bond acceptor site accessible to interaction with the tertiary/quarternary nitrogen, e.g.
a carbonyl or carboxylic oxygen atom.
Have the potential to become pharmacologically altered because: Most drugs express their biological activity by binding receptors.
Receptor affinities are determined by conformation and chargedistribution of the ligand drugs.
Altering the pH of acid addition salt drugs can alter their receptor affinity by either conformation or charge-distribution or both.
Altering receptor affinity as has been accomplished with Sensamide'"/Neu-Sensamide'" does not alter radiosensitizing potency (Hua et al, Anti Cancer Drugs 6:451-453, 1995; Pero et al unpublished 1996).
There are at least 143 clinically available drugs (listed in Table 2 below) having potential properties of radiosensitization, and altering their receptor affinities by pH adjusting their formulations that in turn contain acid addition salt WO 98/00159 PCTIUS97/10829 substitutions, could affect side effect profiles permitting higher doses to be used for radiosensitization or other pharmacological indications. This point is a novel discovery not obvious as previously known in the literature. Although the 143 clinically available drugs have been the subject of many patents and patent applications, including recent patents and applications concerned with the radiochemo-sensitizing and antiemetic properties of N-substituted aryl compounds such as the benzamides and nicotinamides provisional Patent Application No. 60/013,072, U.S. Patent No. 4,576,386, U.S. Patent No. 5,340,565, U.S.
Patent No. 5,215,738, U.S. Patent No. 5,032,617 and U.S. Patent No.
5,041,653), the latter citations do not disclose that the pH of acid addition salt drugs could alter chemical structure, and in turn change the pharmacological properties of the formulations. Examples of compounds that are not as yet clinically available but that are capable of forming acid addition salts with a potential for alteration of pharmacological properties by pH adjustment are 3chloro procainamide, N-(2-diethylamino-ethyl) nicotinamide, nimorazole and 2,3-dimethyl(dimethylaminoethyl)-5H-indolo-(2,3-b) guinoxline (procedures for synthesizing 3-chloro procainamide and N-(2-diethylamino-ethyl) nicotinamide are described in copending U.S. provisional patent application No. 60/013,072, filed March 8, 1996, the disclosure of which is incorporated herein by this reference). Hence in a broad sense this invention is not confined to the 143 clinically available drugs listed in Table 2, but embraces the use of all compounds formulated to possess water solubility by formation of a substituted amide acid addition salt structure. The aforementioned U.S. Patent Application Serial No.
08/218,072 discloses that metoclopramide, a N-substituted benzamide, can undergo pH-sensitive conformational changes. However, the claims of this application and its division, Serial No. 08/479,113, are respectively directed to WO 98/00159 PCT/US97/10829 the N-substituted benzamides and phenothiazines and do not include claims covering other acid addition salt drugs.
The present invention, in a first aspect, contemplates the provision of a method of administering to a human patient material selected from the group consisting of acid addition salts of chemical or pharmacological structures such as nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics, and anaesthetics.as identified and listed in Table 2 below, comprising the steps of providing a sterile injectable formulation comprising a liquid vehicle containing the material in solution and injecting the formulation into the patient in an amount for delivering to the patient a dose of about one to about 100 mg/kg of the material. In important embodiments of this method, the injection is intramuscular, also, conveniently or preferably, the material to be administered is in the acid addition salt form, pH adjusted to 5.5 Intramuscular injection, to achieve a dose of 1 100 mg/kg, requires a much more concentrated formulation than i.v. injection of a like dose, owing to the limited tolerance of muscle tissue for injected fluid. Whereas a solution at a 5 mg/ml concentration of metoclopramide hydrochloride is suitable for i.v. injection of a dose of 5 mg/kg, a concentration of at least about 50 mg/ml or even more (preferably, in many cases, as much as 100 mg/ml) is needed to administer a like dose by intramuscular injection. At these high concentrations, present-day commercial acid addition salt formulations tend to produce local tissue toxic reactions at the injectable site if not pH adjusted to 5.5 7.0 Patent application No. 08/218,072, Pero et al unpublished 1996).
WO 98/00159 PCT/US97/10829 Further in accordance with the invention, a concentrated acid addition salt formulation 100 7000 mg/ml) is advantageously provided at a pH of about to 7.0, for intramuscular injection. At pH values within this range (which is substantially higher, i.e. less acidic, than the pH of currently available formulations of equivalent concentration), local tissue toxic reactions are satisfactorily minimized or avoided, yet without adversely affecting the solubility of acid addition salt drugs or their therapeutic activity. A pH above would derogate from solubility, while values below about 5.5 are insufficient to achieve the desired reduction in local tissue side effects. It has been shown that this is the case because an acid addition salt formulation of metoclopramide at pH 2.5 3.5 caused local tissue irritation but when neutralized to pH 6.5 a substantially reduced local tissue reaction was observed Patent application No. 08/218,072, Pero et al unpublished 1996).
In a second aspect, the invention contemplates the provision of a sterile injectable formulation for intramuscular administration to a human patient, comprising a material selected from the group consisting of acid addition salts of chemical or pharmacological structures such as nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics, and anaesthetics as identified and listed in Table 2 below, a liquid vehicle in which the material is in solution being present in the formulation in a concentration of at least about 50 mg/ml; and the formulation being at a pH within a range of about 5.5 to 7.0. In these formulations, the solution pH, once established, may be stabilized to a less variable range <0.5 pH unit) by the inclusion of a phosphate or other buffer, or alternatively, by the inclusion of a preservative such as sodium metabisulfite to prevent auto-oxidation.
WO 98/00159 PCT/US97/10829 Also surprisingly, it has been found that the administration of an acid addition salt, metoclopramide hydrochloride, in otherwise conventional formulations (which contain Na' ions, present in the saline solution and/or introduced as sodium metabisulfite) but at a pH of about 5.5 to 7.0 substantially prevents the extrapyramidal side effects of known metoclopramide treatments (Pero et al, Biochimie 77:385-393, 1995, Pero et al unpublished 1996). In a third aspect, which is not limited to intramuscular injection, the invention contemplates the provision of a method of administering to a human patient material selected from the group consisting of acid addition salts of chemical or pharmacological structures such as nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics, and anaesthetics as identified and listed in Table 2 below, comprising a liquid vehicle containing the material in solution (and, in some instances, also containing Na' ions), adjusting the pH of the formulation for reducing the development of undesirable side effects or improving pharmacological indications of the material, and administering the formulation having the adjusted pH to the patient. A preferred or effective range of formulation pH for reduction or avoidance of extrapyramidal side effects is between about 5.5 and Stated in some respects more broadly, the invention in each of the above described aspects may be embodied in a method or formulation wherein the aforementioned material is selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula having a tertiary nitrogen present, acid addition salts of compounds that can form acid salts of It WO 98/00159 PCT/US97/10829 Formula having a quaternary ammonium ion present, and mixtures thereof, Formula and Formula being as follows: R2
R
1
(CH
2 )n-N-R3
(A)
R4 R2 X-
R
1
-(CH
2 R3 (B) R4 wherein R, comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with the tertiary nitrogen of Formula or the quaternary ammonium ion of Formula R 2 and R 3 and R 4 are alkyl or aryl groups, and X' is an anion. In specific embodiments, the hydrogen bond acceptor site is a carbonyl or carboxylic oxygen atom, and X- is Cl-, Br or P.
Advantageously or preferably, the material is selected from the group consisting of nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and anaesthetics which are acid addition salts of compounds that can form acid salts of Formula or Formula and mixtures thereof.
Further features and advantages of the invention will be apparent from the detailed description herein below set forth, together with the accompanying drawings.
WO 98/00159 PCT/US97/10829 BRIEF DESCRIPTION OF DRAWINGS Fig.1 is a graph on which the UV absorption intensity is plotted against wavelength of UV absorption between 195 nm and 215 nm for 100 AM solutions of metoclopramide pH adjusted between 4.8 and 6.0 with 1 N HCI or 1 N NaOH.
Fig. 2A is a graph on which the UV absorption intensity of 100 MM solutions of aqueous (pH 5-6) and acidic (pH 2-3) 3-chloroprocainamide are plotted against the wavelength of UV absorption between 195 nm and 380 nm.
Fig. 2B is a graph on which the UV absorption intensity of 100 MM solutions of aqueous (pH 5-6) and acidic (pH 2-3) lidocaine are plotted against the wavelength of UV absorption between 195 nm and 380 nm.
Fig. 2C is a graph on which the UV absorption intensity of 100 plM solutions of aqueous (pH 5-6) and acidic (pH 2-3) metoclopramide are plotted against the wavelength of UV absorption between 195 nm and 380 nm.
Fig. 2D is a graph on which the UV absorption intensity of 100 MM solutions of aqueous (pH 5-6) and acidic (pH 2-3) remoxipride are plotted against the wavelength of UV absorption between 195 nm and 380 nm.
Fig. 2E is a graph on which the UV absorption intensity of 100 /M solutions of aqueous (pH 5-6) and acidic (pH 2-3) procainamide are plotted against the wavelength of UV absorption between 195 nm and 380 nm.
WO 98/00159 PCT/US97/10829 Fig. 2F is a graph on which the UV absorption intensity of 100 AM solutions of aqueous (pH 5-6) chlorpromazine are plotted against the wavelength UV absorption between 195 nm and 380 nm.
Fig. 2G is a graph on which the UV absorption intensity of 100 AxM solutions of acidic (pH 2-3) chlorpromazine are plotted against the wavelength of UV absorption between 195 nm and 380 nm.
DETAILED DESCRIPTION The invention is embodied in methods involving the use of pH adjustment of acid addition salts of chemical or pharmacological structures such as nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics, and anaesthetics as identified and listed in Table 2 below, to reduce the development of undesirable side effects of the drug without affecting or enhancing the pharmacological properties such as antiemetics, antiarrhythmics, antidepressants, antipsychotics, antihypertensives, adrenergics, anaesthetics, or the enhancement of radio- and chemotherapies of cancer.
In addition, the invention is embodied in methods involving the use of preparing aqueous sterile injectable formulations of acid addition salts of chemical or pharmacological structures such as nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics, and anaesthetics as identified and listed in Table 2 below, with pH adjustment, in order to avoid undesirable side effects of the drug without affecting or improving the indicated clinically useful WO 98/00159 PCT/US97/10829 pharmacological properties enhancement of radio- and chemo-therapies of cancer).
In another aspect, the practice of this invention involves consideration of the pH of acid addition salts of chemical or pharmacological structures such as nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics, and anaesthetics as identified and listed in Table 2 below. The 1993 Physicians' Desk Reference lists over 145 hydrochloride salt formulations as available for clinical use. Most of these hydrochloride salt formulations are acidic solutions ranging in pH from 2 to 6.5 depending on the initial drug concentration and formulation ingredients (American Society of Hospital Pharmacists, 1993, Sveriges Likersmedels Information AB, FASS, 1993). In order to deliver doses of 1-100 mg/kg by intramuscular injection to patients, the injectable formulations would require initial drug concentrations of around 100 to 7000 mg/ml, which in most cases is a concentration having a pH range of 1 to 4.5 depending on its formulation (American Society of Hospital Phamacists, 1993, FASS, 1993).
Because commercial preparations of solutions of acid addition salt drugs drastically vary in pH, and because they can be pH adjusted from 2 to without regulatory restrictions, the prior art teaches that there is no difference in biological activity associated with changes in pH between 2 and 6.5. However, applicant herein has found that when acidic formulations of metoclopramide hydrochloride solutions within a pH range of 2 to 3.7 are compared to a neutralized formulation at around pH 7.0, the local tissue toxic reaction at the site of intra-muscular injection and the extrapyramidal side effect of sedation, are substantially reduced when the neutralized formulation is administered (Pero et al, Biochimie 77:385-393, 1995; Pero et al unpublished 1996). Hence, this WO 98/00159 PCT/US97/10829 invention embraces the feature that high concentrations of metoclopramide hydrochloride 100 mg/ml), and by analogy other acid addition salt drugs because the drug itself is acidic, which would be required for intramuscular administration of metoclopramide or other acid addition salt drugs as pharmacological agents, have fewer toxic side effects in the near neutral pH range than in the acidic form, which in turn are currently the clinically available forms of these drugs.
Metoclopramide and the other acid addition salt drugs listed in Table 2 below are known to bind to high affinity receptors such as both the dopamine 2 (D2) receptor and the 5-hydroxytryptamine 3 (5-HT 3 receptor (Pharmacokinetic principles in the use drugs, in Medical Pharmacology, A. Goth ed., C.V. Mosby Company, tenth edition, St. Louis, MO, pages 15-30, 1981; Harrington et al, Drugs 25:451-494, 1983, Blower, Eur. J. Cancer 26 (Suppl S8-S11, 1990).
The side effects of acid addition salt drugs are believed to be delivered from receptor binding; for example, extrapyramidal side effects generated from D2 binding (King and Sanger, Drugs of the Future 14(9):875-889, 1989). These data from the scientific literature support and are consistent with the altered systemic biological effects of acidic metoclopramide hydrochloride salt formulations described herein (Pero et al unpublished 1996). As already mentioned above, acidic metoclopramide has a conformation altering pH sensitive hydrogen mediated-bond which is lacking in neutralized metoclopramide (Pero et al, Biochimie 77:385-393, 1995; Schwartz et al unpublished 1996). This finding is supported by the data revealed in Examples 1-3 which establish that a wide variety of drugs containing tertiary nitrogen substitutions that can convert drugs to acid addition salts, have very similar UV spectra changes indicative of the pH WO 98/00159 PCT/US97/10829 sensitive conformational changes observed for metoclopramide especially at
A
200 (wavelength of 200 nm). In addition, it would have been an unexpected observation for one skilled in the art to have been able to predict that metoclopramide or other acid addition salt drugs could form a chemical interaction (e g. a hydrogen bond) stable enough to be transported from the site of intramuscular injection to receptors in the brain in order to mediate an enhanced efficacy or side effect sedation).
The UV spectra of the Examples below were run using a Beckman scanning UVvisible spectrophotometer with a quartz cell having a 1 cm path length. The spectra were produced by scanning the UVbsorption produced between 195 nm and 380 nm (379 nm in Fig. 1) at a bandwidth of 5 nm. 100 FtM samples of the drugs or model compounds were acidified to pH 2-3 and their UV spectra were recorded. These UV spectra were compared with the UV spectra determined at ambient (aqueous) pH which was normally between pH 5 and 6.
In some cases the ambient drug solutions were titrated with IN HCI and 1N NaOH to produce pH gradient solutions which were then subjected to scanning of the UV spectrum between A 195 and A 380 The UV spectra were corrected for absorption from appropriate solvent blanks.
WO 98/00159 PCTIUS97/10829 Example I UV spectral evidence for the pH sensitive conformation change in metoclopramide.
There is considerable analytical evidence supporting that a hydrogen bond is formed in acidic aqueous solutions of metoclopramide between the tertiary nitrogen of the N-ethylaminodiethyl substitution and the carbonyl of the carboxamide group of substituted benzamide (Reviewed by Schwanz et al unpublished 1996). The data in Fig. 1 report the result of a detailed UV spectral analysis of metoclopramide solutions carefully adjusted in pH between 4.8 and The UV absorption spectra recorded between 195 nm and 215 nm show a very sharp change in maximal absorption in metoclopramide solutions around pH 5.0. These UV spectra changes around 5.0 were taken as strong supportive evidence for the shifting of equilibrium between the two conformational forms of metoclopramide, namely, one with the pH sensitive hydrogen bond present and one without it. Because acidic metoclopramide induces extrapyramidal side effects whereas neutral metoclopramide does not (Pero et al, Biochimie 77:385- 393, 1995, Pero et al unpublished 1996, Rotmensch et al unpublished 1996), Fig.
1 also clarifies that unpredictable but detectable pH sensitive UV absorption spectral changes reflect conformational structural changes in metoclopramide altering the receptor mediated side effects of this drug.
WO 98/00159 PCT[US97/10829 Example 2 UV spectral evidence for pH sensitive changes of drugs having alkylaminodialkyl substitutions that are capable of forming acid addition salts.
First, the data in Figs. 2A-2G show that drugs that contain alkylaminodialkyl substitutions can have very different UV absorption maxima in aqueous solution, and several areas of each of these UV absorption maxima can be shifted and varied in intensity due to acidic pH adjustment into the range pH 2. Second, the most striking change in UV absorption was associated with pH adjustment at A 200 for all the drugs containing alkylaminodialkyl substitutions.
WO 98/00159 PCTIUJS97/10829 Example 3 UV spectral evidence indicating alterations in A2o o resulting from proposed pH sensitive conformational changes in the structure of Nalkylaminodialkyl substituted drugs.
The data in Table 1 show that aryl N-alkylaminodialkyl substitutions contribute mainly to the pH adjusted UV spectra in the 200 nm range. This UV region has been identified as being of interest by comparison to the UV spectral changes associated with pH adjustment of metoclopramide aqueous solutions (presented in Example Molecular modeling, analytical chemical analyses, extrapyramidal biologic responses and the previous scientific literature have confirmed the existence of a hydrogen mediated-bond between the carbonyl of the carboxamide and the tertiary nitrogen present in the N-ethylaminodiethyl substituted benzamide ring of metoclopramide (Schwartz et al unpublished 1996; Pero et al, Biochimie 77: 385-393 1995). Hence, acidic metoclopramide has the conformational change imposed by the presence of this pH sensitive hydrogen mediated-bond whereas neutral metoclopramide has an extended conformation due to the lack of this hydrogen bond. The pH dependence of intramolecular hydrogen bonding in metoclopramide is represented in Schwartz et al unpublished 1996 as follows: WO 98/00159 PCT/US97/10829 0 N+CI Cl I N C N inversion
H
2 N H heat
H
3 energy H3C Metoclopramide HCl "highly structured, coplanar form" 2 hydrogen bonds define structure d-2 receptor antagonist
N-+C
'extended hydrochloride conformation" proton away from carbonyl 2nd hydrogen bond cannot form Sbase H CI
CI
H
2
N
N
H-3H 0H3C
H
3
C
Neu-Sensamide"' "extended side chain conformation" 1 hydrogen bond defines structure poorer binding at d-2 receptor WO 98/00159 PCT/US97/10829 The formula in the upper left is metoclopramide-HCI in the highly structured, "coplanar" form in which two hydrogen bonds define the structure, this form, dominant at lower (more acid) pH, is a D, receptor antagonist. The formula at the upper right represents the "extended hydrochloride conformation" with the proton away from the carbonyl such that the second hydrogen bond (between the carbonyl oxygen and the proton of the side chain ammonium hydrogen) cannot form. The formula at the lower right, representing "Neu-Sensamide"', at higher (less acid, approaching neutral) pH, has an extended side chain conformation, again with only one hydrogen bond (that between the oxygen of the methoxy group and the amide hydrogen), and exhibits poorer binding at the
D
2 receptor. In a broader sense, Table 1 also shows that changes in UV absorption at A 200 detects the conformational difference between acidic and neutral metoclopramide formulations, and as a result, other aryl compounds having N-alkylaminoalkyl substitutions capable of forming a quaternized nitrogen and hydrogen mediating-bonding site, will display a pH sensitive change in their UV spectra at A 200 For example, 3-amino benzarnide and procaine do not contain either alkylaminodialkyl- or N- substitutions nor do they exhibit pH sensitive UV absorption changes at A 200 (Table On the other hand, 3-chloro procainamide, procainamide, remoxipride, lidocaine and chlorpromazine all contain N-alkylaminodialkyl substitutions, and they also display UV absorption changes at A 200 WO 98/00159 PCT/US97/10829 Table 1. pH sensitive alterations in the UV spectra attributed to proposed conformational changes of the alkylaminodialkyl substructures of agents capable of forming acid addition salts. 100 AM samples of these agents were acidified to pH 2 and their UV spectra were recorded. These spectra in turn were compared with the UV spectra at ambient pH pH 5-6).
nrlrrn/ A nant A nmmmatc A rL rR In 20SAZ L3 3 Amino benzamide Acidic Aqueous Procaine Acidic Aqueous Metoclopramide Acidic Aqueous 3-Chloro procainamide Acidic Aqueous Procainamide Acidic Aqueous Remoxipride Acidic Aqueous Lidocaine Acidic Aqueous Chlorpromazine Acidic Aqueous 1.150 1.150 1.500 1.500 3.200 1.400 0.200 2.700 0.900 2.300 0.200 2.800 0.180 2.700 0.200 2.600 No N-substitution of benzamideno pH change at O-substituted alkylaminodialkyl benzoic acid-no pH change at N-alkylaminodialkyl substituted benzamide-pH change at N-alkylaminodialkyl substituted benzamide-pH change at N-alkylaminodialkyl substituted benzamide-pH change at N-alkylaminodialkyl substituted benzamide-pH change at A2oo N-alkylaminodialkyl substituted benzamide-pH change at A 2 oo N-alkylaminodialkyl substituted phenothiazine-pH change at WO 98/00159 PCTIUS97/10829 Example 4 List of drugs capable of forming acid addition salts via the formation of a quaternized nitrogen alkylaminodialkyl substitutions), and thereby undergoing pH sensitive alterations, that may consequentially alter drug efficacy or side effects.
The data for this example (obtained from literature, not actual experiment) are presented in Table 2. It lists 143 drugs that are available for clinical use in Sweden (FASS 1992-1996). The data show that the chemical structures and clinical uses of the drugs listed in Table 2 are extremely diverse, but they share a common chemical substitution; namely all have been formulated as acid addition salts usually hydrochloride acid salts) because they contain a tertiary nitrogen group usually as alkylaminodialkyl substitutions). Because Examples 1-3 establish that compounds containing alkylaminodialkyl substitutions can undergo conformational changes due to pH adjustment, together with the fact that conformation and charge can determine the degree of drug mediated receptor binding antagonism, then Table 2 also show that all the drugs listed are capable of pH modification leading to an altered receptor mediated efficacy or side effect profile.
WO 98/00159 PCT/US97/10829 Table 2. List of clinically available acid addition salt drugs including their structures, chemical abstract numbers, trade marks, commercial suppliers and clinical uses. This data has been compiled from the 1992-1996 Sveriges Lakersmedels Information AB, (FASS) and the 1995 Merck Index.
WO 98/00159 PCT/US97/10829 1. MELPHALAN [148-82-3] TRADE NAME: ALKERAN (GLAXO,
WELLCOME)
CLINICAL USE: CYTOSTATIC, ALKYLATING AGENT
CICH
2
CH
2 N CH 2
<CCOOH
CICH
2
CH
2
NH
2 2. AMILORIDE [2609-46-3] Cl N CONHCNHNH 2
H
2 N N NH 2 3. CLOMIPRAMINE [363-49-1] N Cl
,CH
3
CH
2
CH
2
CH
2
NCH
3
"CH
3 4. CHLORCYCLIZINE [82-93-9] CH-N N-CH 3 TRADE NAME: AMILOFERM (NORDIC) AMILORID (NM PHARMA) MIDAMOR (MSD) MODURETIC (MSD) NORMORIX (NYCMED) SPARKAL (SELENA) CLINICAL USE: POTASSIUM-SPARING
DIURETIC
TRADE NAME: ANAFRANIL (CIBA)
KLOMIPRAMIN
(NM PHARMA) CLINICAL USE: ANTIDEPRESSANT TRADE NAME: ANERVAN (RECIP) DI-PARALENE (ABBOTT) EXOLYT (ABIGO) CLINICAL USE: ANTIHISTAMINE WO 98/00159 HYDRALAZINE [86-54-4] PCT[US97/10829 TRADE NAME: APRESOLIN (CIBA)1 CLINICAL USE: ANTI HYPERTENSIVE 6. ALPRENOLOL [1 3655-52-21 0 -CH 2
CHOHCH
2
NHCHCH
3 2
CH
2
CH-CH
2 7. DOPAMINE [5 1-61-6]
OH
HO D CH 2
CH
2
NH
2 TRADE NAME: APTIN (HASSLE) CLINICAL USE: ANTI HYPERTENSIVE
ANTIARRHYTHMIC
TRADE NAME: ABBODOP (ABBOTT) GILUDOP (MEDA) INTROPIN (HASSLE) CLINICAL USE: ADRENERGIC 8. QUINAPRIL [85441-61-8]
COCH
H
COOCH
2
CH
3
CH
3
CH
2
CH
2 -oCv,-NH-uC-C0-N TRADE NAME: ACCUPRO (PARKE DAVIS) CLINICAL USE: ANTIHYPERTENSIVE WO 98/00159 PCT/US97/10829 9. TETRACYCLINE [60-54-8] OH O OH O
.CONH
2 TRADE NAME: ACHROMYCIN (LEDERLE) ACTISITE (MEDA)
TETRACYKLIN
(NM PHARMA) CLINICAL USE: ANTIBACTERIAL CIMETIDINE [51481-61-9] TRADE NAME: ACILOC (ORION) ACINIL (SELENA) CIMETIDIN (SELENA) TAGAMET (SMITH KLINE BEECHA) CLINICAL USE: HISTAMINE 2 RECEPTOR ANTIAGONIST, ESPECIALLY IN THE TREATMENT OF DUODENAL AND GASTRIC ULCERS N
CH
3 N
-CN
CH
2
SCH
2
CH
2
NHCNHCH
3 11. DOXORUBICIN [23214-92-8] 0 OH Jl,_ 1 .,COCH 2
OH
TRADE NAME: ADRIAMYCIN (PHARMACIA UPJOHN) DOXORUBICIN (NYCOMED) CLINICAL USE: ANTINEOPLASTIC
NH
2 12. BIPERIDEN [514-65-8]
CH
2
COHCH
2
CH
2
N\
TRADE NAME: AKINETON (MEDA) CLINICAL USE: ANTICHOLINERGIC
ANTIPARKINSON
WO 98/00159 13. CARTEOLOL [51781-06-7] PCTIUS97/10829 TRADE NAME: ARTEOPTIC (CIBA VISION) CLINICAL USE: B-RECEPTOR BLOCKER
N
OCH
2
CHOHCH
2
NHC(CH
3 3 14. RANITIDINE [66357-35-5]
CHNO
2
H
3
C
NHCH
2 0 CH 2
SCH
2
CH
2
NHCNHCH
3
H
3 C j TRADE NAME: ARTONIL (SELENA) ZANTAC (GLAXO WELLCOME) CLINICAL USE: ANTIULCERATIVE HYDROXYZINE [68-88-2]
CI
TRADE NAME: ATARAX (UCB) HISTILOS (UCB) VISTARIL (ROERIG) CLINICAL USE: TRANQUILIZER 16. CHLORTETRACYCLINE [57-62-5] TRADE NAME: AUREOMYCIN
(LEDERLE)
CLINICAL USE: ANTIBIOTIC WO 98/00159 WO 9800159PCTIUS97/10829 17. BAMBUTEROL
H
3
CNCOO
CH
3
\CHOHCH
2
NHCCH
3
H
3 CNCOO ?DCH 3
CH
3 TRADE NAME: BAMBEC (DRACO) CLINICAL USE: BRONCHODIALATOR 18. DIPHENHYDRAMINE [482-05-3] CH3 TRADE
NAME:
CHOCH
2 CH INCH 3 CLINICAL USE: 19. BETAXOLOL [63659-18-7]
CH
3
CH
2
OCH
2
CH
2
CH
2
CHOHCH
2
NH-CHCH
3 TRADE NAME CLINICAL USE BROMHEXINE [3572-43-8] Br TRADE NAME:
CH
2
NCH
3 CLINICAL USE: Br
NH
2 BENYLAN (PARK-DAVIS)
DESENTOL
(PHARMACIA UPJOHN)
ANTIHISTAMINE
ANTI-MOTIONSICKNESS
BETOPTIC (ALCON) KERLON (SEARLE)
ANTI-GLAUCOMA
ANTI HYPERTENSIVE BISOLVON (BOEHRINGER) BROMHEXIN (ACO) MOLLIPECT (TIKA) MU COLYT IC
EXPECTORANT
WO 98/00159 21. PHENYLEPHRINE HYDROCHLORIDE [61-76-7] PCTIUS97/10829
OH
CH
2
NH-CH
3 TRADE NAME: BLEFCON (ALLERGAN) METAOXEDRIN (MEDA)
NEOSYNEPHRINE
(SANOFI WINTHROP) ZINCFRIN (ALCON) CLINICAL USE: ADRENERGIC TRADE NAME: BUIPIVAKAIN (NORCOX) MARCAIN (ASTRA) CLINICAL USE: LOCAL ANAESTHETIC 22. BUPIVACAINE [2180-92-9]
CH
3
CH
2
CH
2
CH
2
CH
3 23. MELPERONE [3575-80-2] F COCH 2
CH
2
CH
2 -No CH 3 TRADE NAME: BURONIL. (LUNDBECK) CLINICAL USE: NEUROLEPTIC 24. BUISPIRONE [36505-84-7] N N- WO 98/00159 PCT/US97/10829 MEPIVACAINE [96-88-8] TRADE NAME: CARBOCAIN (ASTRA) CLINICAL USE: LOCAL ANAESTHETIC 26. DILTIAZEM [42399-41-7] o N
S.
.OCOCH
3
RH
TRADE NAME: CARDIZEM (PHARMACIA UPJOHN) ENTRYDIL (ORION) TILDIEM (TIKA) CLINICAL USE: CALCIUM ANTAGONIST
VASODILATOR
OCH
3 27. CLONIDINE [4205-90-7] H CI
N
H CI TRADE NAME: CATAPRESAN (BOEHRINGER INGELHEIM) CLINICAL USE: ANTIHYPERTENSIVE 28. SUCCINYLCHOLINE CHLORIDE [71-27-2] /CH3
COOCH
2
CH
2
N+CH
3
CH
2 CH 3 CH /CH 3
COOCH
2
CH
2
NCH
3
CH
3 TRADE NAME: CELOCURIN (PHARMACIA UPJOHN) CLINICAL USE: SKELETAL MUSCLE RELAXANT (SHORT DURATION) WO 98/00159 WO 9800159PCTIUS97/10829 29. DAUNORUBICIN [20830-81-31 TRADE NAME: CERUBIDIN (RHONE-POULENC
RORER)
DAUNOXOME (SWEDISH
ORPHAN)
CLINICAL USE: CYTOSTATIC
OCH
3 0 OH HO -H
NH
2 CIPROFLOXACINE [85721-33-1, 86393-32-O(HCI)] 7 HN N IF COOH TRADE NAME: CILOXAN (ALCON) CIPROXIN (BAYER) CLINICAL USE: ANTIBACTERIAL TRADE NAME: CISORDINOL
(LUNDBECK)
CLINICAL USE: ANTIPSYCHOTIC 31. CLOPENTHIXOL [982-24-1] H CH 2
CH
2 -N N-C H 2
CH
2 0H 32. PRILOCAINE [721-50-6)
NHCOCHNHCH
2
CH
2
CH
3
CH
3 CH TRADE NAME: CITANEST (ASTRA) EMLA (ASTRA) CLINICAL USE: LOCAL ANAESTHETIC WO 98/00159 33. ETHYLMORPHINE [76-58-4] PCTIUS97/10829
CH
3
CH
2 0,
N-CH
3 34. TACRINE [321-64-2]
NH
2
N
PROTRIPTYLINE [438-60-8] TRADE NAME: COCILLANA ETYFIN (PHARMACIA UPJOHN) COSYLA (PARKE-DAVIS)
LEPHETON
(PHARMACIA UPJOHN) CLINICAL USE: ANTITUSSIVE TRADE NAME: COGNEX (PARKE-DAVIS) CLINICAL USE: CHOLINERGIC TRADE NAME: CONCORDIN (MSD) CLINICAL USE: ANTIDEPRESSANT 36. AMIODARONE [1 951-25-3] o CH 2
CH
2
CH
2
CH
3 CF1 2
CH
3 co' OCH 2
CH
2
NCH
2
CH
3 TRADE NAME: CORDARONE (SANOFI WINTHROP) CLINICAL USE: ANTIARRYHYTHMIC WO 98/00159 37. CYCLOPENTOLATE [512-15-21 PCTLJS97/10829 TRADE NAME: CYCLOGYL (ALCON) CYCLOPENTOLAT (MEDA) CLINICAL USE: ANTICHOLINERGIC
CH
3 C H C O O C H 2 C Hl 2 Nl C H 3
L"OH
38. CLINDAMYCIN [18323-44-9]
CH
3 CH 3 N H~ CHt-CI H
COUNHCH~
HO
I
CH
3
CH
2
CH
2
OH
SCH
3
OH
39. PROPOXYPHENE [469-62-5] CH3 CH3
CHCH
2
NCH
3
CH
2
OOCCH
2
CH
3 TRADE NAME: DEXODON (TIKA) DEXOFEN (ASTRA) DISTALQESIC (LILLY) DOLERON (ASTRA) DOLOT.ARD (NYCOMED) DOLOXENE (LILLY) PARAFLEX (ASTRA) CLINICAL USE: ANALGESIC HYDROMORPHONE [466-99-9] TRADE NAME. DILAUDID (MEDA) CLINICAL USE: ANALGESIC
H
N-CH
3 WO 98/00159 41. ORPHENADRINE [83-98-7] /\CH3 CH3 CHO -CH 2
CH
2
NCH
3 42. DOBUTAMINE [30468-04-2]
HO
CH
3 HO/ CHqcHqNHCHC PCTIUS97/10829 TRADE NAME: DISIPAL (YAMANOUCHI) NORFLEX (3M) NORGESIC (3M) CLINICAL USE: MUSCLE RELAXANT
(SCELETETAL)
ANTIPARKINSONI
TRADE NAME: DOBUIJECT (LEIRAS) DOBUTREX (LILLY) CLINICAL USE: CARDIOTONIC 43. DOPEXAMINE [864 94-91 -5(HYD ROC HLORI DE)] TRADE NAME: DOPACARD
(FISONS)
CLINICAL USE: CARDIOTONIC 44. DOXYCYCLINE [564-25-0]
CONH
2 TRADE NAME: DORYX (SCAND PHARM) DOXYCYKLIN (ENAPHARM) DOXYFERM (NORDIC) IDOCYKLIN (ROERIG) VIBRAMYCIN (PFIZER) CLINICAL USE: ANTIBACTERIAL WO 98/00159 NEOMYCIN [1404-04-2, FOR THE MIXTURE] PCTIUS97/10829
CH
2
NH
2 0
OH
HO)
0H 2
N
0
OH
IH2N/ R 2 q0 R" 0 0
OH
HONH
2 0O TRADE NAME: ECOMYTRIN (LUNDBECK) CELESTON (SCHERING-PLOUGH) DECARORON (MSD) ISOPTO BIOTIC (ALCON) NEBACETIN (LUNDBECK) CLINICAL USE: ANTIBACTERIAL NEOMYCIN B R H, R' CH 2
NH
2 NEOMYCINC R =CH 2 N H 2 R H 46. EPHEDRINE [50-98-61 HO NHCH 3
C-C-CH
3 H H TRADE NAME: EFEDRIN (NM PHARMA) LEPHETON (PHARMACIA UPJOHN) LERGIQAN (RECIP) MOLLIPECT (TIKA) CLINICAL USE: ADRENERGIC 47. VENLAFAXINE
N(CH
3 2 CH 2
CH
3 0 C H 7
HO
48. ETILEFRIN [709-55-7]
HO
CHCH 2 NHCH 2
CH
3
OH
TRADE NAME:- EFEXOR (WYETH) CLINICAL USE: ANTIDEPRESSANT TRADE NAME: EFFORTIL (BOEHRINGER INGELHEIM) CLINICAL UISE:- ADRENERGIC
DOPAMINERGIC
ANTI HYPERTENSIVE WO 98/00159 49. DEPRENYL [2323-36-6]
CH
3
CH
2
-C-NCH
2
C=ECH
HCH
3 PCT[US97/10829 TRADE NAME: ELDEPRYL (ORION) SELEGILIN (NM PHARMA) CLINICAL.USE: ANTIPARKINSON EPIRUBICIN [56390-09-1 (HCI), 56420-45-2(BAS)] O OH
COCH
2 0H I I -OH TRADE NAME: FARMORUBICIN (PHARMACIA UPJOHN) CLINICAL USE. ANTINEOPLASTIC
ANTIBIOTIC
NH
2 51. FLUPENTIXOL [2709-56-0] TRADE NAME: FLUANXOL
(LUNDBECK)
CLINICAL USE. ANTIPSYCHOTIC
CHCH
2
CH
2 52. BENOXINATE TRADE NAME: FLURESS (ABIGO) I OXIBUPROKAIN (MEDA) CLINICAL USE: ANAESTHETIC (TOPICAL)
CH
3
CH
2
CH
2
CH
2
O
H
2 N COOCH 2
CH
2
N(CH
2
CH
3 2 WO 98/00159 53. FLUOXETIN [54910-89-3] PCTIUS97/10829 TRADE NAME: FONTEX (LILLY) CLINICAL USE: ANTIDEPRESSANT
F
3
C
54. GEMCITABINE TRADE NAME: GEMZAR (LILLY) CLINICAL USE: ANTINEOPLASTIC
N
ADRENALINE/EPINEPHRINE
OH
OH
HO C-CH 2
NHCH
3 56. METFORMIN [657-24-9] NH
NH
II II
(CH
3 2 N-C-NHCNH 2 TRADE NAME: CITANEST ADRENALIN
(ASTRA)
EPPY (ABIGO) GLAUFRIN (ALLERGAN) MARCAIN ADRENALIN
(ASTRA)
XYLOCAIN ADRENALIN
(ASTRA)
CLINICAL USE: ADRENERGIC TRADE NAME: GLUCOPHAGE (MEDA) CLINICAL USE: ANTIDIABETIC WO 98/00 159 57. CHLORPROMAZINE [50-53-3] PCT/US97/10829
C;H
2
CH
2
CH
2
N(CH
3 2 58. PRENALTEROL [57526-81-5]
OH
HO CH 2
-C-CH
2
NHCH(CH
3 2
H
TRADE NAME: HYPRENAN (HASSLE) CLINICAL USE: ADRENERGIC 59. TERAZOSINE[63590-64-7, 70024-40-7 (HYDROCH LORI DE)] 0
CH
3 0 N 1 N N-C 0
CH
3 0 :1:Nr
NH
2 TRADE NAME: HYTRINEX (ASTRA) SINALFA (SINALFA ABBOTT) CLINICAL USE: ANTI HYPERTENSIVE OXYMETAZOLINE [1491-59-4]
HCH
3
OH
I
N CH 2
C(CH
3 3 N CH 3 TRADE NAME: LLIADIN (MEDA) NASIN (TIKA) NEZERIL (DRACO) ZOLIN (ACO) CLINICAL USE: ADRENERGIC WO 98/00159 61. LOPERAMIDE [53179-11-6] PCTIUS97/10829 62. PROPRANOLOL [525-66-6]
OCH
2
CHCH
2
NHCH(CH
3 2
OH
63. LIDOCAINE [137-58-6]
CH
3
NHCOCH
2
N(CH
2
CH
3 2
CH
3 TRADE NAME: IMODIUM
(JENSSEN-CILAG)
LOPERAMID
(SCAND PHARM)
PRIMODIUM
(JENSSEN-CILAG)
TRAVELLO
(PHARMACIA UPJOHN) CLINICAL USE: ANTIDIARETIC TRADE NAME: INDERAL (ZENECA)
PROPRANOLOL
(NM PHARMA) CLINICAL USE: Il-ADRENERGIC BLOCKER
ANTIARRHYTHMIC
TRADE NAME: DEPO MEDROL (PHARMACIA UPJOHN)
EMLA(ASTRA)
INSTILLAGEL (ELLEM) LEDERSPAN (LEDERLE) XYLOCAIN (ASTRA)
XYLOCARD(ASTRA)
XYLOPROCT(ASTRA)
CLINICAL USE: LOCAL ANAESTHETIC 64. APRACLONIDINE [66711-21-5]
N-H
TRADE NAME: LOPIDINE (ALCON) CLINICAL USE: TREATMENT OF POSTSURGICAL ELEVATED INTRAOCULAR PRESSURE WO 98/00159 VERAPAMIL [52-53-9] PCTIUS97/10829 TRADE NAME: ISOPTIN (MEDA) VERALOC (ORION) VERAPAMIL (NM PHARMA) CLINICAL USE: ANTIARRHYTHMIC
VASODILATOR
OCH
3 66. PILOCARPINE [92-13-7]
CH
3
CH
2
CH
3
N
TRADE NAME: FOTIL (LEIRAS) ISOPTO PILOKARPIN (ALCON) LICARPIN (ALLERGAN)
PILKARIN(MEDA)
SPERSACARPINE (CIBA) TIMPILO (MSD) CLINICAL USE: ANTIGLAUCOMA
CHOLINERGIC
TRADE NAME: KEMADRIN (GLAXO WELLCOME) CLINICAL USE: ANTIPARKINSON 67. PROCYCLIDINE [77-37-2] H
O-CH
2 CH 2 -N
J
68. KETAMINE [6740-88-11
CI
C NHCHC2 0 TRADE NAME: KETALAR (PARKE-DAVIS) CLINICAL USE: GENERAL ANAESTHETIC WO 98/00159 69. KETOBEMIDON PCTIUS97/10829 TRADE NAME: KETOGAN (NOVUM-LU NDBECK) CLINICAL USE: ANALGETIC
SPASMOLYTIC
COCH
2
CH
3 QUINIDINE 130-95-0, 60-93-5(HYDROC HLORI DE)]
N
I
CH
3 0
H
HO C N H 1fH TRADE NAME: KININ (NM PHARMA) CLINICAL USE: ANITIMALARIAL 71. GRANISETRONE [109889-09-0, 1 07007-99-8(HYDROCH LORI DE)]
CH
3 TRADE NAME: KYTRIL (SMITH KLINE BEECHAM) CLINICAL USE: ANTIEMETIC lHC0 72. MEFLOQUIN [51773-92-3(HYDROCH LORI DE)]
CF
3 'N ,CF 3 TRADE NAME: LARIAM (ROCHE) CLINICAL USE: ANTIMALARIAL WO 98/00159 73. PROMETHAZINE [7440-12-12] PCT[US97/10829 CHt 2
C;HN(CH
3 2
CH
3 74. REMOXIPRIDE [a Br
CH
3 0H
CH
2
CH
3
N
CH
3
H
TRADE NAME: LERGIGAN (RECIP) CLINICAL USE: ANTIHISTAMINE TRADE NAME: ROXIAM (ASTRA) CLINICAL USE: NEUROLEPTIC TRADE NAME: LINCOCIN
(UPJOHN)
CLINICAL USE: ANTIBIOTIC TRADE NAME: LIVOSTIN
(JENSSEN-CILAG)
CLINICAL USE: H 1
-ANTAGONIST
LINCOMYCIN [154-21-2]
CH
3 H
C-H-CHCH
OH
SCH
3
OH
76. LEVOCABASTIN H
CH
3 CN N \lC00H
F
WO 98/00159 77. AMOROLFINE [78613-35-1, 7861 3-38-4(HYDROCHLORIDE)] PCTIUS97/10829
CH
3 78. MAPROTILINE [10260-69-8]
CH
2
CH
2
CH
2 N HCH 3 79. BENSERAZIDE [322-35-0] OH OH HO CH 2
NHNHCOCHCH
2
OH
NH
2 THIORIDAZINE [50-52-2] S C N
SCH
3 tC H 2
CH
2
N
C;H
3 TRADE NAME: LOCERYL (ROCHE) CLINICAL USE: ANTIMYCOTIC TRADE NAME: LUDIOMIL (CIBA)
MAPROTILIN
(NMV PHARMVA) CLINICAL USE: ANTIDEPRESSANT TRADE NAME: MADOPARK (ROCHE) CLINICAL USE: ANTIPARKINSON
DOPAMINERGIC
TRADE NAME: MALLOROL (SANDOZ) CLINICAL USE: NEUROLEPTIC WO 98/00159 81. CYCLIZINE [82-92-8] PCT[US97/10829 CH-N N-CH 3 82. CEPHEPIME TRADE NAME: MARZINE (GLAXO WELLCOME) CLINICAL USE: ANITHISTAMINE
ANTIEMETIC
H2NjS N
I
N
CH
3
COO
83. METHADONE [1095-90-5] TRADE NAME: METADON (PHARMACIA UPJOHN) CLINICAL USE: NARCOTIC ANALGETIC 84. MEXILETINE [31828-71-4]
CH
3 TRADE NAME: MEXITIL (BOEHRINGER INGELHEIM) CLINICAL USE: ANTIARRHYTHMIC
CH
3 WO 98/00159 MIANSERIN [24219-97-4] PCT/US97/10829 TRADE NAME: MIANSERIN (NM PHARMA) TOLVON (ORGANON) CLINICAL USE: ANTIDEPRESSANT
CH
3 86. PIVMECILLINAM TRADE NAME: MIRAXID (LOVENS) CLINICAL USE: ANTIBACTERIAL H H H S CH 3 N-CH=N c I N
CH
3 0 I COOCH 2 0COC(CH 3 3
H
87. PHENYLPROPANOLAMINE [154-41-61] TRADE NI CHCHNH2 H
CH
3
CLINICAL
88. MORPHINE [52-27-2] AME: LUNERIN (TIKA) MONYDRIN (TIKA) RINEXIN (RECIP) RINOMAR (RECIP) USE: VASOCONSTRICTOR
ADRENERGIC
TRADE NAME: DOLCONTIN (PHARMACIA UPJOHN) LOCEPTIN (NYCOMED) MAXIDON (ASTRA)
MORFIN
(PHARMACIA UPJOHN) SPASMOFEN (ABIGO) CLINICAL USE: NARCOTIC
ANALGESIC
-CH
3 WO 98/00159 89. ETHAMBUTOL [304-84-7]
CH
3
CH
2
CHNHCH
2
CH
2
NHCHCH
2
CH
HOH
2 C CH 2 0H PCTIUS97/10829 TRADE NAME: MYAMBUTOL
(LEDERLE)
CLINICAL USE: TUBERCULOSTATIC AMBENONIUM CHLORIDE [115-79-7]
CI
ICH
2
CH
3
CONHCH
2 CI-1N+CH 2
CH
2
CH
3 CH 2 CH 3 c cONHCH 2 CHjN+CH 2
CH
2
CH
3 91. NALOXONE [46 5-65-6]
HO
OHH
H
N-CH
2
CH=CH
2 0 92. XYLOMETAZOLINE [526-36-31 TRADE NAME: MYTELASE (SANOFI WINTHROP) CLINICAL USE: CHOLINESTERASE
INHIBITOR
TRADE NAME: NARCANTI (MEDA) CLINICAL USE: ANTAGONIST (TO NARCOTICS) TRADE NAME: NASOFERM (NORDIC) OTRIVIN (CIBA) CLINICAL USE: ADRENERGIC
VASOCONSTRICTOR
CH
3
C(H
3 3 WO 98/00159 93. PROCARBAZINE [671-16-9]
CH
3
NHNHCH
2
\CONHCH(CH
3 2 PCTIUS97/10829 TRADE NAME: NATULANAR (ROCHE)1 CLINICAL USE: ANTINEOPALSTIC TRADE NAME: NAVOBAN (SANDOZ) CLINICAL USE: ANTIEMETIC 94. TROPISETRONE
H
N
0-CO PHENYLEPHRINE [61 -76-7(HYDROCHLORIDE)] O1HO
C-CH
2
NHCH
3
H
96. THIAMINE [67-03-8]
H
3 C N NHI:S CH 2
CH
2
OH
H
2 C .1CH 3 TRADE NAME: BLEFCON (ALLERGAN) ISOPTO-BIOTIC (ALCON) METAOXEDRIN (MEDA) N EOSYN EPH RINE (SANOFI WINTHROP) ZINCFRIN (ALCON) CLINICAL USE: ADRENERGIC TRADE NAME: ASTRATONIL FORTE (ASTRA) BETABION (MEDA) CLINICAL USE: ENZYME CO-FACTOR-VITAMIN 81 WO 98/00159 97. TRAMADOL [27203-92-5, 22204-88-2( HYDRC H CH 2
N(CH
3 2 -HO0,
CH
3 0 98. HYDROCHLOROTIAZID [58-93-5] PCTIUS97/10829
)CHLORIDE)]
TRADE NAME: NOBLIGAN (SEARLE) CLINICAL USE: ANALGESIC TRADE NAME: SPARKAL (SELENA) TRIATEC COMP (HOECHST) AMILOFERM (NORDIC) CLINICAL USE: DIURETIC
H
2 N 0 "0 ,is 99. QUINAGOLIDE H H
~N-SO
2
-N(CH
2
CH
3 2 TRADE NAME: NORPROLAC (SANDOZ) CLINICAL USE: PROLACTIN ANTAGONIST 100. NOSCAPINE [128-62-1, 912-60-7(HYDROCHL 0 rHH TRADE NAME:- NIPAXON (PHARMACIA
UPJOHN)
NOSKAPIN (ACO) SPAMOFEN (ABIGO) CLINICAL USE: ANTITUSSIVE
OCH
3 WO 98/00159 101. MITOXANTRON E [65271-80-90, 76476-82-3(HYDROCH LORIDE)] PCTIUS97/10829 OH 0 NHCH 2
CH
2
NHCH
2
CH
2
OH
OH 0 NHCH 2
CH
2
NHCH
2
CH
2
OH
DIPIVEFRI N [52365-63-6, 64019-93-8( HYDROC
(CH
3 3
CCOO
(CH
3 3 CCOO CHCH 2
NHCH
3 3. OXYTETRACYCLIN E [79-57-2, 2055-46-0(HYD
CH
2
C
2
CH
2 N N-H 2
C(
TRADE NAME: NOVANTRONE
(LEDERLE)
CLINICAL USE: ANTINEOPALSTIC ;HLORIDE)i TRADE NAMI CLINICAL US
'ROCHLORIDE)]
TRADE NAME: CLINICAL USE.
E: OFTAPINEX (LEIRAS) PROPINE (ALLERGAN) E: ANTI-GLAUCOMA
ADRENERGIC
OXYTETRAL (DUMEX) TERRACORTRIL (PFIZER) TERRAMYCIN (PFIZER)
ANTIBIOTIC
TRADE NAME: PACINOL (SCHERING-
PLOUGH)
SIQUALONE (BRISTOL MEYERS-SQ U IBB) CLINICAL USE: ANTIPSYCHOTIC WO 98/00159 105. CHLORGUANIDE [500-92-5] PCTIUS97/10829 NH NH ci- CNHCNHCH(CH 3 2 106. TRIHEXYPHENIDYL [52-49-3] HO -C -CH 2
CH
2 -No TRADE NAME: PALUDRINE
(ZENECA)
CLINICAL USE: ANTIMALARIAL TRADE NAME: PARGITAN (ABIGO) CLINICAL USE: ANTIPARKINSON .107. BACAMPICILLIN [50972-17-3, 37661 -08-8(HYDROCHLORIDE)] TRADE NAME: PENGLOBE (ASTRA) CLINICAL USE: ANTIBACTERIAL
NH
2 H H S
CH
3 H C-CONH
CH
3
H
0 108. CYPROHEPTADINE 129-03-3, 41 354-2 9-4 (HYDROC H LORI DE)] TRADE NAME: PERIACTIN (MVSD) CLINICAL USE: Hi ANTAGONIST co oI ANTIHISTAMINE WO 98/00159 109. PRAZOSIN [i 9216-56-9, 19237-84-4(HYDROCHLORIDE)] PCTIUS97/10829 0 N CO I3 TRADE NAME: PERIPRESS (PFIZER) CLINICAL USE: al-AIDRENERGIC BLOCKER ANTI HYPERTENSIVE 110. MEPERIDINE [57-42-1, 50-1 3-5(HYDROCH LORI DE)] TRADE NAME: PETIDIN (PHARMACIA UPJOHN) CLINICAL USE: NARCOTIC
ANALGETIC
CH
3
COOCH
2
CH
3 111. MECLIZINE [569-65-3, 31 884-77-2(HYDROCHLORIDE)] TRADE NAME: HISTILOS (UCB) POSTAFEN (UCB) CLINICAL USE: ANTIEMETIC C H 2
CH
3 112. METOCLOPRAMIDE [364-62-5, 541 43-57-6(HYDROCHLORIDE)
CONHCH
2
CH
2
N(CH
2
CH
3 2
OCH
3 cI
NH
2 TRADE NAME: PRIMPERAN (LU NDBECK) CLINICAL USE: ANTIEMETIC WO 98/00159 113. PROCAINAMIDE [614-39-1] PCTIUS97/10829
H
2 N
HCH
2
CH
2 N (CH 2
CH
3 2
TRD
CLINIC
114. PYRIDOXINE [58-56-01 N OH 3
TRADE
HOCH 2 I OH
CII
CH
2 0H 115. ALFENTANIL [71195-28-6, 70879-28-6(HYDROCHLORIDE)I 0
CH
2 0CH 3
CH
3
CH
2 1 N NCH 2
CH
2 N I N -COCH 2
CH
3 116. NAPHAZOLINE [835-31-4, 550-29-2(HYDROCH LORI DE)] TRADE NAME: AN] H RIM N OH 2 CLINICAL USE: ADf LA
DE(
NAME: PROKAINAMID
(HASSLE)
AL USE: ANTIARRYTHMIC NAME: ASTRANOIL FORTE
(ASTRA)
AL USE: VITAMIN B6 ADE NAME: RAPIFEN (J ENSSE N-Cl LAG) INICAL USE: NARCOTIC
ANALGESIC
FASTEN-PRIVIN (CIBA VISION) IDOL (UCB) RENERGIC (VASOCONSTRICTOR
DONGESTANT
WO 98/00159 117. METHACYCLINE [914-00-1, 3963-95-9(HYDROCHLORIDE)] PCTIUS97/10829
CONH-
2
NCH
3
CH
3 118. ROXATIDINE
OCH
2
CH
2
CH
2
NHCOCH
2
OH
CN-CH
2 TRADE NAME: RON DOMYCIN
(ROERIG)
CLINICAL USE: ANTIBACTERIAL TRADE NAME: ROXIT (HOECHST) CLINICAL USE: ANTI-ULCERATIVE 119. PROPAFENONE [54063-53-5, 341 83-22-7(HYDROCH LORI DE)]
CH
2
CH
2
-CO
OCH
2
CHCH
2
NHCH
2
CH
2
CH
3 I I
OH
TRADE NAME: RYTMONORM (MEDA) CLINICAL USE: ANTIARRHYTHMIC 120. AMITRIPTYLINE [50-48-6, 549-1 8-8(HYDROCHLORIDE)] TRADE NAME: SAROTEN (LUNDBECK) TRYPTIZOL (MSD) CLINICAL USE: ANTIDEPRESSANT
CHCH
2
CH
2
N(CH
3 2 WO 98/00159 121. NORTRIPTYLINE [72-69-5, 894-71 -3(HYDROCH LORI DE) PCT/US97/10829 TRADE NAME: SENSAVAL (LUNOBECK) CLINICAL USE: ANTIDEPRESANT TRADE NAME: SEROXAT (NOVO NORDISK) CLINICAL USE: ANTIDEPRESSANT 122. PAROXETINE [61869-08-7] 0 OCH 2
H
0 F NH 123. CLOBUTINOL [14860-49-2] 124. SOTALOL [3930-20-9, 959-24-0(HYDROC HLORI DE)]
OH
CH
3
SO
2 NH CHCHm 2 NHCiLH(CH 3 2 TRADE NAME: SOTACOR (BRISTOL-MEYERS SQUIBB) SOTALOL (NM PHARMA) CLINICAL USE: ANTIANGINAL
ANTIARRHYTHMIC
ANTI HYPERTENSIVE WO 98/00159 125. BUPRENORPHINE [52485-79-7, 53152-21 -9(HYDROC HLORI DE)] HO PCTIUS97/10829 N-JCH2-< TRADE NAME:- TEMGESIC
(MEDA)
CLINICAL USE: ANALGESIC 126. TETRACAINE [136-47-0]
CH
3
CH
2
CH
2
CH
2 NH COOCH 2
CH
2
N(CH
3 2 TRADE NAME: TETRACAIN (ALCON) CLINICAL USE: ANAESTHETIC (TOPICAL) 127. TICLOPIDINE [55142-85-3, 53885-31-1 (HYDROCHLORIDE)]
H
2
C"
128. TOCAINIDE (41708-72-9]
CH
3 NHCO CHNH 2
CH
3 CH TRADE NAME: TONOCARD (HASSLE) CLINICAL USE: ANTIARRHYTHMIC WO 98/00159 129. OBIDOXIME CHLORIDE [1 14-90-9] HON=CH-/
N+-CH
2 HO N =CH N-CH 2 PCTIUS97/10829 TRADE NAME: TOXOGONIN (MEDA) CLINICAL USE: CHOLINESTERASE
REACTIVATOR
130. IMIPRAMINE [50-49-7, 113-52-0(HYDROCHLORIDE)] TRADE NAME: TOFRANAL (CIBA) CLINICAL USE: ANTIDEPRESSANT
N
CHt- 2
CH
2
CH
2
N(CH
3 2 131. LABETALOL. [36894-69-6, 32780-64-6(HYDROCH LORI DE)
H
2 NCO OH
CH
3 HO
CCH
2
NHCHCH
2
CH
2 TRADE NAME: TRANDATE (GLAXO WELLCOME) CLINICAL USE: ANTI HYPERTENSIVE 132. METHIZENE [4969-02-2, 7081 -4-5(HYD ROC HLORI DE)] TRADE NAME: TREMOQUIL (ASTRA) CLINICAL USE: ANTICHOLINERGIC
ANTIPARKINSON
LN3 WO 98/00159 133. SPECTINOMYCIN [1695-77-8, 221 89-32-3(HYD ROCH LORI DE)]
HO
T H H PCTIUS97/10829
H
3 C CH 3 134. DORZOLAMIDE 0 if0
H
3 *s S SO 2
NH
2
H
H- NHCH 2
CH
3 135. CHLORPROTHIXENE [113-59-7] TRADE NAME: TROBICIN (PHARMACIA UPJOHN) CLINICAL USE. ANTIBIOTIC TRADE NAME: TRUSOPT (MSD) CLINICAL USE: ANTIGLAUCOMA, CARBONIC ANHYDRASE
ANTAGONIST
TRADE NAME: TRUXAL (LUNDBECK) CLINICAL USE. ANTIPSYCHOTIC 136. LOFEPRAMINE [23047-25-8, 26786-32-3(HYDROCHLORIDE)] TRADE NAME: TYMELYT (LU NDBECK) CLINICAL USE: ANTIDEPRESSANT WO 98/00159 137. VALACIKLOVIR 0
TRADEI
N HN IH
NH
2
CLINICA
N, N_
H
2 N- N 'CH 2
OCH
2
OCOCCH(CH
3 2 138. VANCOMYCIN [1404-90-6, 1404-93-09(HYDROCHLORIDE)] N H 2 PCTIUS97/10829 NJAME: VALTREX (GLAXO WELLCOME) .L USE: ANTIVIRAL AGENT TRADE NAME: VANCOCIN (LILLY) VANCOMYCIN
(DUMEX)
VANCOMYCIN
(NORCOX)
CLINICAL USE: ANTIBACTERIAL
H
2
NCO-CH
2 139. AMANTADINE [768-94-5,665-66-7(HYDROC HLORI DE)]
NH
2 TRADE NAME: VIROFRAL (FERROSAN) riL> CLINICAL USE: ANTIVIRAL (INFLUENZA A) 140. ALFLUZOSINE
CH
3 0,
CH
3 0'
NCH
2
CH
2
CH
2
NHC
0
C;H
3 n TRADE NAME: XATRAL (ASTRA) CLINICAL USE: al-RECEPTOR ANTAGONIST WO 98/00159 141. IDARUBICIN PCTIUS97/10829
'OH
NH1 2 142. ONDANSETRON [99614-02-5, 99614-01-4 (HYDROC HLORI DE)] 0 1 TRADE NAME:
UH
3 143. CETIRIZINE [83881-51-0, 83881-52-1 (HYDROCHLORIDE)] TRADE NAME: ZYRLEX (UCB) CLINICAL USE: ANTIHISTAMINE -N \-/N-CH 3 WO 98/00159 PCTIUS97/10829 It is to be understood that the invention is not limited to the features and embodiments hereinabove specifically set forth. but may be carried out in other ways without departure from its spirit.

Claims (39)

1. A method of administering to a human patient material selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula having a tertiary nitrogen present, acid addition salts of compounds that can form acid Ssalts of Formula having a quaternary ammonium ion present, and mixtures thereof, other than nimorazole salts and other than dibucaine hydrochloride when admixed with other actives, said Formula and Formula being as follows: H X- R1-(CH2)n R2 R3 (A) R2 X' R1--(CH2)n R3 R4 (B) I0 wherein R, comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula or said quaternary ammonium ion of Formula R 2 R 3 and R 4 are alkyl or aryl groups, n is an integer of I or more and X- is an anion, said method comprising the steps of providing a sterile injectable formulation comprising a liquid vehicle 1s containing the material in solution, at a pH within a range of about 5.5 to 7.0, and injecting the formulation into the patient in an amount for delivering to the patient a dose of about one to 100mg/kg of the material while the pH of the formulation is within said range. S2. A method according to claim 1, wherein said hydrogen bond acceptor site is a 20 carbonyl or carboxylic oxygen atom.
3. A method according to claim I or 2, wherein X- is Cl-, F, Br- or I. *00 4. A method according to any one of claims 1 to 3, wherein said material is selected from the group consisting of nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and anaesthetics which are acid addition salts of compounds that can form acid salts of Formula acid addition salts of compounds that can form acid salts of Formula and mixtures thereof. 3
5. A method according to any one of claims 1 to 4, wherein said formulation is lpr ided at a concentration of about 100 to 7000mg/ml. (R.\LIBFF]09121 speci.doc:njc 62
6. A method according to any one of claims 1 to 5, wherein the injecting step comprises injecting the formulation intramuscularly into the patient.
7. A method according to any one of claims 1 to 6 wherein n is an integer of from 1 to 6.
8. A sterile injectable formulation for intramuscular administration to a human patient, comprising a material selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula having a tertiary nitrogen present, acid addition salts of compounds that can form acid salts of Formula having a io quaternary ammonium ion present, and mixtures thereof, other than dibucaine hydrochloride when admixed with other actives, said Formula and Formula being as follows: H X- R1-(C H2)n R2 R3 (A) R2 X- R-(CH 2 )n -N R 3 R4 (B) 15i wherein RI comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula or said quaternary ammonium ion of Formula R 2 R 3 and R4 are alkyl or aryl groups, n is an integer of 1 or more and X- is an anion; a liquid vehicle in which said material is in solution; 2 said material being present in said formulation in a concentration of at least about 50mg/ml, and the formulation being at a pH within a range of about 5.5 to
9. A formulation as defined in claim 8, wherein said material is selected from the group consisting of nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and anaesthetics which are acid addition salts of compounds that can form acid salts of Formula acid addition salts of compounds that can form acid salts of ?i o -ormula and mixtures thereof. S 10. A formulation as defined in claim 8 or 9, also including an amount of a buffer -/reservative effective to stabilize the pH of the formulation. [R \LIBFF]09121speci.doc:njc 63
11. A formulation as defined in claim 10, including an amount of a phosphate buffer effective to stabilize the pH of the formulation to a range of less than 0.5 pH unit.
12. A formulation as defined in claim 10, including an amount of sodium metabisulfite effective to stabilize the pH of the formulation to a range of less than 0.5 pH unit.
13. A formulation as defined in any one of claims 8 to 12 wherein n is an integer of from 1 to 6.
14. A method of administering to a human patient material selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula having a tertiary nitrogen present, acid addition salts of compounds that can form acid salts of Formula having a quaternary ammonium ion present, and mixtures thereof, o* other than nimorazole salts and other than dibucaine hydrochloride when mixed with other actives, said Formula and Formula being as follows: H X' RI-(CH2)n N--R2 R3 (A) eat R2 X- R 1 -(CH 2 )n-N--R 3 Is (B) wherein Ri comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula or said quaternary ammonium ion of Formula R 2 R 3 and R 4 are alkyl or aryl groups, n is an integer of 1 or more, and X is an anion, said method comprising the steps of providing a sterile formulation, comprising a liquid vehicle containing the material in solution, adjusting the pH of said formulation for reducing the development of undesirable side effects of the material, and administering the formulation having the adjusted pH to the patient.
15. A method according to claim 14, wherein said material is selected from the group consisting of nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and anaesthetics which are acid addition salts of compounds that can form acid salts of Formula acid addition salts of compounds that can form acid salts of t Formula and mixtures thereof. [R:\LIBFF]9613.doc:mef 64
16. A method according to claim 14 or 15 wherein n is an integer of from 1 to 6.
17. A method of administering to a human patient material selected from the group consisting of acid addition salts of maiphalan, amiloride, clomipramine, chiorcyclizine, hydralazine, aiprenolol, dopamine, quinapril, tetracycline, cimetidine, doxorubicin, biperiden, carteolol, ranitidine, hydroxyzine, chlortetracycline, bambuterol, diphenhydramine, betaxolol, bromhexine, phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem, clonidine, succinyicholine, daunorubicin, ci profloxacine, clopenthixol, prilocaine, ethylmorphine, tacrine, protriptyline, amiodarone, cyclopentolate, clindamycin, propoxyphene, hydromorphone, orphenadrine, I1 dobutamine, dopexamine, doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, clepreny epirubicin, flupentixol, benoxinate, fluoxetin, gemcitabine, adrenaline, metformin, chioropromazine, prenalterol, terazosine, oxymetazoline, loperamide, propanolol, lidocaine, apraclonidine, verapamil, pilocarpine, procyclidine, ketarine, ketobemidon. quinidine, granisetron, rnefloquin, prommethazine, remoxipride, lincomrycin, levocabastin, amorolfine, maprotiline, benserazide, thioridazine, cyclizine, cephepine, methadone, mexiletine, mianserin, pivmeciIlinam, phenyipropanolamine, morphine, ethambutol, ambenonium, naloxone, xylometazoline, procarbazine, tropisetrone, phenylephrine, thiamine, tramadol, hydrochiorotiazid, quinagolide, noscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, chiorguanide, 2 2 trihexyphenidyl, bacampicillin, cyproheptadine, prazosin, mneperidine, meclizine, metoclopramide, procainamide, pyridoxine, alfentanil, naphazoline, nethacycline, roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol, buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, imethixene, spectinomycin, dorzolamide, chioroprothixene, lefepramine, valacikiovir, 25 vancomycin, amantadine, alfiuzosine, idarubicin, ondansetron, cetirizine, 3-chioro procainamide, N-(2-diethylamino-ethyl) nicotinaride, nimorazole and 2,3- di methyl (dimethylaminoethyl)-5H-indolo-2, guinoxline and mixtures thereof, said method comprising the steps of providing a sterile injectable formulation comprising a liquid vehicle containing the material in solution, at a pH within a range of about 5.5 to 7.0, and injecting the formulation intramuscularly into the patient in an amount I'or delivering to the patient a dose of about one to 1 00mg/kg of the material while the pH of the formulation is within said range.
18. A sterile injectable formulation for intramuscular administration to a human patient, comprising 1I1:\lI B F]09 121 speci.doc:njc a material selected from the group consisting of acid addition salts of maiphalan, amiloride, clomipramine, chiorcyclizine, hydralazine, aiprenolol, dopamine, quinapril, tetracycline, cimetidine, doxorubicin, biperiden, carteolol, ranitidine, hydroxyzine, chlortetracycline, bambuterol, diphenhydramine, betaxolol, bromhexine, pheny lephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem, clonidine, SUCC my Icholine, daunorubicin, ciprofloxacine, clopenthixol, pri locaine, ethylmorphine, tacri ne, protriptyline, amiodarone, cyclopentolate, clindamnycin, propoxyphene, hydromorphone, orphenadrine, dobutamine, dopexamine, doxycyci me, neomycin, ephedrine, venlafaxine, etilefrin, deprenyl, epiruibicin, flupentixol, benoxinate, fluoxetin, I gemcitabine, adrenaline, metformin, chioropromazine, prenalterol, terazosine, oxymetazoline, loperamide, propanolol, lidocaine, apraclonidine, verapamil, pilocarpine, procyci idine, ketamine, ketobemnidon, quinidine, granisetron, mefloquin, prommethazine, rem-oxi pride, lincomycin, levocabastin, amorolfine, maproti line, benserazide, thioridazine, cyclizine, cephepirne, methadone, mexiletine, mianserin, pivmecillinam, phenylIpropanolIamine, morphine, ethambutol, am benoni ur, naloxone, xylometazoline, procarbazine, tropisetrone, phenylephrine; thiamine, trarnadol, hydrochlorotiazid, quinagolide, noscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, chiorguianide, trihexyphenidyl, bacampicillin, cyproheptadine, prazosin, meperidine, mcl izi ne, mnetoclopramide, procainamide, pyridoxine, alfentanil, naphazoline, 20 methacycline, roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol, buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, mnethixene, spectinomycin, dorzolamide, chioroprothixene, lefiepramine, valaciklovir, vancom-ycin, arnantadine, alfiuzosine, idarubicin, ondansetron, cetirizine, 3-chloro procainamide, N-(2-diethylamino-ethyl) nicotinamide, nirnorazole and 2,3 -dirnethyl- 25 (dimiethiylaminoethyl)-51--indolo-2,3'-b) guinoxline and mixtures thereof, a liquid vehicle in which said material isin solution, said material being present in said formulation in a concentration of at least about S5rng/ml, and the formulation being at a pH within a range of about 5.5 to 1 9. A method of administering to a human patient material selected from the g-rOLIP consisting of acid addition salts of maiphalan, amiloride, clornipramine, chlorcyclizine, hydralazine, alprenolol, doparnine, quinapril, tetracycline, cimetidine, doxorubicin, biperiden, carteolol, ranitidine, hydroxyzine, chlortetracycline, bambuterol, .diphienhydramine, betaxolol, bromhexine, phenylephrine, bupivacaine, melperone, uspirone, mnepivacaine, diltiazem, clonidine, succinyicholine, daunorubicin, S 0 A iiirrjo1m I speci.docmic 66 ciprofloxacine, clopenthixol, prilocaine, ethylmorphine, tacrine, protriptyline, ain odarone, cyclopentolate, clindamycin, propoxyphene, hydrororphone, orphenadrine, diobutamine, dopexamine, doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, deprenyl, epirubicin, flupentixol, benoxinate, fluoxetin, gemeitabine, adrenaline, metformin, chioropromazine, prenalterol, terazosine, oxymetazoline, loperamide, priopanolol, lidocaine, apraclonidine, verapamil, pilocarpine, procyclidine, ketamine, ketobemidon, quinidine, granisetron, mefloquin, prommethazine, remoxipride, lincomycin, levocabastin, amorolfine, maprotiline, benserazide, thioridazine, cyclizine, cephepime, methadone, mexiletine, mianserin, pivmecillinam, phenyipropanolamine, Iu morphine, ethambutol, ambenonium, naloxone, xylonetazoline, procarbazine, nropisetrone, phenylephrine, thiamine, tramadoI, hydrochiorotiazid, quinagolide, noscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, chlorguanide, trihexyphenidyl, bacampicillin, cyproheptadine, prazosin, meperidine, meclizine, metoclopraride, procainamide, pyridoxine, alfentanil, naphazoline, methacycline, roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol, bijprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, methixene, spectinomycin, dorzolarnide, chioroprothixene, lefepramine, valacikiovir, *9 :.00 \'ancomycin, amrantadine, alfiuzosine, idarubicin, ondansetron, cetirizine, 3-chloro 0. procainamide, N-(2-diethylanino-ethyl) nicotinamide and 2,3- 0. diimethyl(dimethylaminoethyl)-5H-indolo-2,3 guinoxtine and mixtures thereof, said method comprising the steps of providing a sterile formulation, comprising a liquid vehicle containing the material in solution, adjusting the pH of said formulation for reducing the development of undesirable side effects of the material, and administering the formulation having the adjusted pH to the patient.
20. Use of a material selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula having a tertiary nitrogen present, *:see: acid addition salts of compounds that can form acid salts of Formula having a quaternary ammonium ion present, and mixtures thereof, other than nimorazole salts and other than dibucaine hydrochloride when admixed with other actives, said Formula (A) and Formula being as follows: I R:\AI.113 F1) 21 specidociljc 67 H X" R1--(CH2)n R2 R3 R (A) R 2 X- R1--(CH2)n-N--R3 R4 (B) wherein R, comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula or said quaternary Sammonium ion of Formula R 2 R 3 and R 4 are alkyl or aryl groups, n is an integer of 1 or more and X is an anion, in the manufacture of a sterile injectable formulation comprising a liquid vehicle containing the material in solution at a pH within a range of about 5.5 to 7.0 for administration to a human patient by injecting the formulation into the patient in an amount for delivering to the patient a dose of about one to 100mg/kg of the to material while the pH of the formulation is within said range.
21. Use according to claim 20 wherein the hydrogen bond acceptor site is a carbonyl or carboxylic oxygen atom.
22. Use according to claim 20 or 21 wherein X- is Cl-, Br- or I-.
23. Use according to any one of claims 20 to 23 wherein said material is selected t is from the group consisting of nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and anaesthetics which are acid addition salts of compounds that can form acid salts of Formula acid addition salts of compounds that can form acid salts of Formula and mixtures thereof.
24. Use according to any one of claims 20 to 23 wherein the formulation is 2 provided at a concentration of about 100 to 7000mg/ml.
25. Use according to any one of claims 20 to 24 wherein the formulation is injected intramuscularly into the patent.
26. Use according to any one of claims 20 to 25 wherein n is an integer of from 1 to 6.
27. A material selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula having a tertiary nitrogen present, acid addition salts of compounds that can form acid salts of Formula having a quaternary ammonium ion present, and mixtures thereof, other than nimorazole salts and SR \LI BFF]09121 speci.doc:nic 68 other than dibucaine hydrochloride when admixed with other actives, said Formula (A) and Formula being as follows: H X- Rl--(CH2)n R2 R3 (A) R2 X- R- (CH 2 R 3 (B) wherein R, comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula or said quaternary ammonium ion of Formula R 2 R 3 and R 4 are alkyl or aryl groups, n is an integer of 1 or more and X- is an anion, when used in a sterile injectable formulation comprising a liquid vehicle containing the material in solution at a pH within a range of about 5.5 to for administration to a human patient by injecting the formulation into the patient in an amount for delivering to the patient a dose of about one to 100mg/kg of the material while the pl-I of the formulation is within said range.
28. Material when used according to claim 27, wherein said hydrogen bond acceptor site is a carbonyl or carboxylic oxygen atom. 0 i5 29. Material when used according to claim 27 or 28, wherein X- is ClI, Br- or *r.
30. Material when used according to any one of claims 27 to 29, wherein said material is selected from the group consisting of nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and anaesthetics which are acid addition salts of 20_ compounds that can form acid salts of Formula acid addition salts of compounds that can form acid salts of Formula and mixtures thereof.
31. Material when used according to any one of claims 27 to 30, wherein said o *0* formulation is provided at a concentration of about 100 to 7000mg/ml.
32. Material when used according to any one of claims 27 to 31 wherein the formulation is injected intramuscularly into the patient.
33. Material when used according to any one of claims 27 to 32 wherein n is an integer of from 1 to 6.
34. Use of a material selected from the group consisting of acid addition salts of Iil,mpounds that can form acid salts of Formula having a tertiary nitrogen present, IFFI109121 spcci.doc.nic 69 acid addition salts of compounds that can form acid salts of Formula having a quaternary ammonium ion present, and mixtures thereof, other than dibucaine hydrochloride when mixed with other actives, said Formula and Formula being as follows: H X- R1- (CH2)n N R2 R3 (A) R 2 X RI-(CH 2 )n-N--R 3 R4 (B) wherein RI comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula or said quaternary ammonium ion of Formula R 2 R 3 and R 4 are alkyl or aryl groups, n is an integer of 1 It or more, and X- is an anion, in the manufacture of a sterile formulation comprising a liquid vehicle containing the material in solution wherein the pH of the formulation is adjusted for reducing the development of undesirable side effects of the material for administration of the formulation having the adjusted pH to a human patient. Use according to claim 34, wherein said material is selected from the group 15 consisting of nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and anaesthetics which are acid addition salts of compounds that can form acid salts of Formula acid addition salts of compounds that can form acid salts of Formula and mixtures thereof.
36. Use according to claim 34 or 35 wherein n is an integer from 1 to 6. 20 37. A material selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula having a tertiary nitrogen present, acid addition salts of compounds that can form acid salts of Formula having a quaternary ammonium ion present, and mixtures thereof, other than dibucaine hydrochloride when mixed with other actives, said Formula and Formula being as follows: H X- R1- (C H2)n R2 R3 R2 X- R 1 -(CH 2 Nt- R 3 R4 (B) wherein R, comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula or said quaternary ammonium ion of Formula R 2 R 3 and R 4 are alkyl or aryl groups, n is an integer of 1 or mnore, and X- is an anion, when used in a sterile formulation comprising a liquid vehicle containing the material in solution wherein the pH of the formulation is adjusted Ior reducing the development of undesirable side effects of the material for administration of the formulation having the adjusted pH to a human patient.
38. A material when used according to claim 37, wherein said material is selected i lifrom the group consisting of nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and anaesthetics which are acid addition salts of compounds that can form acid salts of Formula acid addition salts of compounds that can form acid salts of Formula and mixtures thereof.
39. A material when used according to claim 37 or 38, wherein n is an integer of from 1 to 6. Use of a material, selected from the group consisting of acid addition salts of mnalphalan, amiloride, clomipramine, chlorcyclizine, hydralazine, alprenolol, dopamine, f: cluinapril, tetracycline, cimetidine, doxorubicin, biperiden, carteolol, ranitidine, hydroxyzine, chlortetracycline, bambuterol, diphenhydramine, betaxolol, bromhexine, phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem, clonidine, succinycholine, daunorubicin, ciprofloxacine, clopenthixol, prilocaine, ethylmorphine, tacrine, protriptyline, amiodarone, cyclopentolate, clindamycin, propoxyphene, hydromorphone, orphenadrine, dobutamine, dopexamine, doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, deprenyl, epirubicin, flupentixol, benoxinate, fluoxetin, gemcitabine, adrenaline, metformin, chloropromazine, prenalterol, terazosine, oxymetazoline, loperamide, propanolol, lidocaine, apraclonidine, verapamil, pilocarpine, procyclidine, ketamine, ketobemidon, quinidine, granisetron, mefloquin, prommethazine, remoxipride, lincomycin, levocabastin, amorolfine, minaprotiline, benserazide, thioridazine, cyclizine, cephepime, methadone, mexiletine, mianserin, pivmecillinam, phenylpropanolamine, morphine, ethambutol, ambenonium, naloxone, xylometazoline, procarbazine, tropisetrone, phenylephrine, thiamine, tramadol, hydrochlorotiazid, SR uinagolide, noscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, 7:\LI 0 12 spci.do:i c IR\L 113 F FO9I s.p~c i. doc: n ic cliorguanide, trihexyphenidyl, bacamnpicillin, cyproheptadine, prazosin, meperidine, mcecl izine, metoclopramide, procainarnide, pyridoxine, alfentanil, naphazoline, methacycline, roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol. buprenorphin, tetracaine, ticlopidine, tocainide, obidoxim-e, imipramine, labetalol, rneth ixenie, spectinomycin, dorzolamide, chioroprothixene, lefepramine, valacikiovir, vancomyci n, amantadine, alfiuzosine, idarubicin, ondansetron, cetirizine, 3 -chioro procainarnide, N-(2-diethylamino-ethyl) nicotinarnide, nimorazole and 2,3 dim--ethiyl(dimethylaminoethyl)-5H-indolo-2,3)-b) guinoxline and mixtures thereof, in the manufacture of a sterile injectable formulation comprising a liquid vehicle containing the I material in solution at a pH within a range of about 5.5 to 7.0 for administration to a human patient by injecting the formulation intramuscularly into the patient in an amnount ['or delivering to the patient a dose of about one to 1 00mg/kg of the material while the pH of- the formulation is within said range.
41. A material selected from the group consisting of acid addition salts of miial phalan, amniloride, clomnipramine, chiorcyclizine, hydralazine, aiprenol dopamnine, q Uirnapri 1, tetracycline, cimetidine, doxorubicin, biperiden, carteolol, ranitidine, hyd roxyzine, chlortetracycline, bambuterol, diphenhydramine, betaxo lol, bromhexine, phenylephrine, bupivacaine, melperone, buspirone, niepivacaine, diltiazem, clonidine, SUCiciylcholine, daunorubicin, ciprofloxacine, clopenthixol, prilocaine, ethylmorphine, tacrinie, protriptyline, amniodarone, cyclopentolate, clindamycin, propoxyphene, hydromnorphone, orphenadrine, dobutam-ine, dopexamine, doxycycline, neomycin, e phedrine, venlafaxine, etilefrin, deprenyl, epirubicin, flupentixol, benoxinate, fluoxetin, geincitabi iie, adrenaline, metformin, chioroprornazine, prenalterol, terazosine, oxyrmetazoline, loperamide, propanolol, lidocaine, apraclonidine, verapamil, pilocarpine, pr-ocyclidine, ketamine, ketobemidon, quinidine, granisetroni, mrefioquin, prommethazine, remnoxipride, lincomycin, levocabastin, amorolfine, maprotiline, benserazide, thioridazine, cyci izine, cephepime, methadone, mexiletine, mianserin, pivmecillinam, phenyl propanolamnine, morphine, ethambuto I, ambenoniurn. naloxone, xylometazoline, procarbazi ne, tropisetrone, phenylephrine, thiamine, tramradol, hydrochlorotiazid, Ci L InoIde noscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, chlorguanide, trihexyphenidyl, bacampicillin, cyproheptadine, prazosin, meperidine, mcecl izi ne, rnetoci opramnide, procainamide, pyridoxi ne, alfentani I, naphazoline, methacycline, roxatidine, propafenone, arnitriptyline, nortriptyline, paroxetine, clobutinol, R;,tll buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, hikxene, spectinomycin, dorzolamnide, chloroprothixene, lefeprarnine, valaciklovir, A\I IFF10') 2I speci.doc:nje vanconycin, amantadine, alfiuzosine, idarubicin, ondansetron, cetirizine, 3-chloro procainamide, N-(2-diethylamino-ethyl) nicotinamide, nimorazole and 2,3- di methyl (dimethylaminoethyl)-5H-indolo-2 ,3 guinoxline and mixtures thereof, when used in a sterile injectable formulation comprising a liquid vehicle containing the material in solution at a pH within a range of about 5.5 to 7.0 for administration to a human patient by administering the formulation intramuscularly by injection into the patient in an amount for delivering to the patient a dose of about one to 100mg/kg of the material while the p1 of the formulation is within said range. 41. Use of a material selected from the group consisting of acid addition salts of I maiphalan, amiloride, clornipramine, chlorcyclizine, hydralazine, aiprenolol, dopamine, Cq1inapril. tetracycline, cimetidine, doxorubicin, biperiden, carteolol, ranitidine, hydroxyzine, chlortetracycline, bambuterol, diphenhydramine, betaxolol, bromhexine, phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem, clonidine, succinylcholine, daunorubicin, ciprofloxacine, clopenthixol, prilocaine, ethylmorphine, tacrine, protriptyline, amiodarone, cyclopentolate, clindamycin, propoxyphene, hyd romorphone, orphenadrine, dobutamine, dopexamine, doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, deprenyl, epirubicin, flupentixol, benoxinate, fluoxetin, nemcitabine, adrenaline, metformin, chioropromazine. prenalterol, terazosine, oxymetazoline, loperamide, propanolol, lidocaine, apraclonidine, verapamil, pilocarpine, t pocyclidine, ketamine, ketobemidon, quinidine, granisetron, n-efloquin, prommethazine, remoxipride, Iincomycin, levocabastin, amorolfine, maprotiline, benserazide, thioridazine, cyclizine, cephepime, methadone, mexiletine, mianserin, pivmecillinam, phenylpropanolamine, morphine, ethambutol, ambenonium, naloxone, xylometazoline, procarbazine, tropisetrone, phenylephrine, thiamine, tramadol, hydrochlorotiazid, 1i quinagolide, noscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, chilorguanide, trihexyphenidyl, bacampicillin, cyproheptadine, prazosin, neperidine, mcclizine, metoclopramide, procainamide, pyridoxine, alfentanil. naphazoline, methacycline, roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol, buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, o methixene, spectinomycin, dorzolamide, chloroprothixene. lefepramine, valaciklovir, vancomycin, amantadine, alfiuzosine, idarubicin, ondansetron, cetirizine, 3-chloro procainamide, N-(2-diethylamino-ethyl) nicotinamide, and 2,3- diimethyl(dimethylaminoethyl)-5H-indolo-2,3-b) guinoxline and mixtures thereof, in the manufacture of a sterile formulation comprising a liquid vehicle containing the material in 5i ss olution wherein the pH of the formulation is adjusted for reducing the development of g~ [RA:\LIBFFJ0912 Ilspeci.doc:jc 73 undesirable side effects of the material for administration of the formulation having the adusted pH to a human patient.
42. A material selected from the group consisting of acid addition salts of maiphalan, amiloride, clomipramine, chlorcyclizine, hydralazine, alprenolol, doparnine, q inapril, tetracycline, cimetidine, doxorubicin, biperiden, carteolol, ranitidine, hlydroxyzine, chlortetracycline, barbutero1, diphenhydramine, betaxolol, bromhexine, phenylephrine, bupivacaine, melperone, buspirone, mepivacaine diltiazem, clonidine, succinyicholine, daunorubicin, ciprofloxacine, clopenthixol. prilocaine, ethylmorphine, tacrine, protriptyline, amiodarone, cyclopentolate, clindamycin, propoxyphene, I0 hydromorphone, orphenadrine, dobutamine, dopexamine, doxycycline, neomycin, ephedrine, venlafaxine, etilefrin, deprenyl, epirubicin, flupentixol, benoxinate, fluoxetin, gemcitabine, adrenaline, metformin, chioropromazine, prenalterol, terazosine, oxymetazoline, loperamide, propanolol, lidocaine, apraclonidine, verapamil, pilocarpine, procyclidine, ketamine, ketobemidon, quinidine, granisetron, mefloquin, prommethazine, remoxipride, lincomycin, levocabastin, amorolfine, maprotiline, benserazide, thioridazine, cyclizine, cephepime, methadone, mexiletine, mianserin, pivmecillinam, l:pheny I propanolamine, morphine, ethambutol, ambenonium, naloxone, xylometazoline, procarbazine, tropisetrone, phenylephrine, thiamine, tramadol, hydrochlorotiazid, q uinagolide, noscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, ch lorguanide, trihexyphenidyl, bacampicillin, cyproheptadine, prazosin, meperidine, imelizine, metoclopramide, procainamide, pyridoxine, alfentani1, naphazoline, nmethacycline, roxatidine, propafenone, arnitriptyline, nortriptyline, paroxetine, clobutinol, sotalol, buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, metixene, spectinomycin, dorzolamide, chioroprothixene, lefepramine, valaciklovir, 25 vancomycin, amantadine, alfiuzosine, idarubicin, ondansetron, cetirizine, 3-chioro procainamide, N-(2-diethylamino-ethyl) nicotinamide, and 2,3- climethyl(dimethylaminoethyl)-5H-indolo-2,3-b) guinoxline and mixtures thereof, when used in a sterile formulation comprising a liquid vehicle containing the material in solution wherein the pH of the formulation is adjusted for reducing the development of 'M undesirable side effects of the material for administration of the formulation having the adjusted pH to a human patient.
43. A sterile injectable formulation for intramuscular administration to a human patient, substantially as hereinbefore described with reference to any one of the examples 7Iok any one of the accompanying drawings, but excluding any comparative examples. I :\lIJI I FF9121 speci.coc:nc
44. A method of administering to a human patient material, said method comprising providing a sterile injectable formulation according to claim 43 and injecting the formulation into the patient in an amount for delivering to the patient a dose of about one to 100mg/kg of the material while the pH of the formulation is within a range of bout 5.5 to Use of a material in the manufacture of a sterile injectable formulation comprising a liquid vehicle containing the material in solution at a pH within a range of about 5.5 to 7.0 for administration to a human patient by injecting the formulation into the patient in an amount for delivering to the patient a dose of about one to 100mg/kg of the 1I material while the pH of the formulation within said range, substantially as hereinbefore described with reference to any one of the examples or any one of the accompanying drawings, but excluding any comparative examples.
46. A material when used in a sterile injectable formulation comprising a liquid vehicle containing the material in solution at a pH within a range of about 5.5 to 7.0 for administration to a human patient by injecting the formulation into the patient in an amount for delivering to the patient a dose of about one to 100mg/kg of the material while the pl-I of the formulation is within said range, substantially as hereinbefore described with reference to any one of the examples or any one of the accompanying drawings, but excluding any comparative examples.
47. Use of a material in the manufacture of a sterile formulation comprising a liquid vehicle containing the material in solution wherein the pH of the formulation is adjusted for reducing the development of undesirable side effects of the material for administration of the formulation having the adjusted pH to a human patient, substantially as hereinbefore described with reference to any one of the examples or any one of the 25 accompanying drawings, but excluding any comparative examples.
48. A material when used in a sterile formulation comprising a liquid vehicle containing the material in solution wherein the pH of the formulation is adjusted for reducing the development of undesirable side effects of the material for administration of the formulation having the adjusted pH to a human patient, substantially as hereinbefore described with reference to any one of the examples or any one of the accompanying drawings, but excluding any comparative examples. Dated 8 March, 2001 OXiGENE, Inc. Patent Attorneys for the Applicant/Nominated Person I I SPRUSON FERGUSON \o
AU34075/97A 1996-06-28 1997-06-23 Useful formulations of acid addition salt drugs Ceased AU738165B2 (en)

Applications Claiming Priority (3)

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US67334196A 1996-06-28 1996-06-28
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IT1303671B1 (en) 1998-07-28 2001-02-23 Nicox Sa SALTS OF NITRIC ACID WITH ACTIVE DRUGS IN THE TREATMENT OF DISEASES OF THE RESPIRATORY SYSTEM
WO2002017921A2 (en) * 2000-08-28 2002-03-07 Synthon B.V. Paroxetine compositions and processes for making the same
JP2006028028A (en) * 2004-07-12 2006-02-02 Teikoku Medix Kk Oral medicinal composition
BRPI0503734A (en) * 2005-08-23 2007-04-27 Cristalia Prod Quimicos Farm pharmaceutical composition in ready-to-use morphine solution for injection and unit dosage form of morphine for epidural or intrathecal administration
US8513259B2 (en) 2009-07-03 2013-08-20 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US8263581B2 (en) 2009-07-03 2012-09-11 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
WO2014140095A1 (en) 2013-03-14 2014-09-18 Becton Dickinson France S.A.S. Injectable morphine formulations
PT2968729T (en) 2013-03-14 2018-11-06 Fresenius Kabi Deutschland Gmbh Packaging system for oxygen-sensitive drugs
CN118021718B (en) * 2024-04-12 2024-07-02 成都瑞尔医药科技有限公司 Propafenone hydrochloride injection and preparation method thereof

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EP0954327A1 (en) 1999-11-10
JP2000516204A (en) 2000-12-05

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