CA2258965A1 - Useful formulations of acid addition salt drugs - Google Patents

Abstract

Methods of and formulations for administering acid addition salts of compounds of Formula (A) or Formula (B), wherein R1 comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula (A) or said quaternary ammonium ion of Formula (B), R2, R3 and R4 are alkyl or aryl groups, and X- is an anion. In the methods, a sterile injectable formulation of a liquid vehicle containing the acid addition salt in solution is adjusted in pH for reducing the development of undesirable side effects of the material or provided at a pH within a range of about 5.5 to 7.0, and administering these acid addition salts by intramuscular injection contain the salt at a concentration of at least about 50 mg/ml and are at a pH within a range of about 5.5 to 7Ø

Description

USEFUL FORl\IULATIONS OF ACID ADDITION
SALT DRUGS

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of copending U.S. patent application Serial No. 08/479,113 filed June 7, 1995, which is a division of copending U.S.
patent application Serial No. 08/218,072 filed March 25, 1994. The disclosures of both of these patent applications are incorporated herein by this reference.

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, 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 et al, Oncology 9(8):707-721, 1995, George and Singh. Indian J. Expt. Biol. 22:305-307, 1984, Kennedy et al, Int. J.

WO 98/OOlS9 PCTIUS97/10829 Radiat. Oncol. Biol. Phys. 12:1367-1370, 19~6). 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 34:571-5g7, 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 cytntoxicity 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, Kjellén 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

Reference is made hereinbelow to the following four papers, in all of which ~ applicant herein is a co-author: (1) 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 Neu-Sensamide," unpublished typescript, 1996, pp. 1-25 + 5 Figures (hereinafter "Pero et al unpublished 1996"), now published as Pharmacolo~y & Toxicolo~y 80:231-239~ 1997 (2) 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 et al unpublished 1996"),(3) H.H. Rotmensch, G.P. Mould~ J.A. Suttom S. Kilminster, C. Moller, R.W. Pero, "Comparative Central Nervous System Effectsand Phannacokinetics 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), (4) A. Schwartz and R.W. Pero, "Evidence for Conformational Mobility of Me~oclopramide as a Function of pH: Implications for Drug Design,"
unpu'nlished typescript, 1996, 18 pp. (unpaginated) (hereinafter "Schwartz et alunpublished 1996") .

One of the most popular chemical functionalities (i.e. structures, substitutions) used in drug design is a tertiary or a quarternary nitrogen usually introduced via an alkylaminodialkyl sidè chain, so that drugs such as the nicotinamides, ben~amides, calcium antagonists, antiemetics, antipsychotics and anaesthetics 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~ ("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 Sensamide~ ("acidic"
metoclopramide) (Schwartz et al unpublished 1996). Neu-Sensamiden' has a reduced extrapyramidal side effect profiie in rats and humans but the radiosensitizing properties remain unaltered compared to Sensamide~ at equimolar doses (Amiri et al unpublished 1996; Hua et al, Anti-Cancer Drugs 6:451-4~3, 1995, Pero et al, Biochimie 77:385-393, 1995; Pero et al unpublished 1996; Rotmensch et al unpublished 1996). Therefore, it is logical to extrapolatethese data to other drugs containing acid addition salt structures in the following way:
Compounds that can form acid salts of types A or B:

. H \X; X R2 R1-CH2)n-N~ R2 (A) R1-(CH2)n-N\ R3 (B) R, 4=aLkyl or aryl groups; X = any anion, normally Cl~ or Br~ or I-Wherein:

(1) 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 (2) R, comprises an aryl or alkyl group 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:

(1) Most drugs express their biological activity by binding receptors .

(2) Receptor affinities are determined l y conformation and charge-distribution of the ligand drugs.

(3) Altering the pH of acid addition salt drugs can alter their receptor affinity by either conformation or charge-distribution or both.

(4) Altering receptor affinity as has heen accomplished with SensamideT"/Neu-Sensamiden' 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 CA 022~896~ 1998-12-22 WO 98/00159 PCT/US97tlO829 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 radio-chemo-sensitizing and antiemetic properties of N-substituted aryl compounds such as the benzamides and nicotinamides (U.S. 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 3-chloro 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 hroad 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 CA 022~896~ 1998-12-22 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 methodof 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, andanaesthetics as identified and listed in Table 2 below, comprising the s~eps 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 - 7Ø

Intramuscular injection, to achieve a dose of I - 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 likedose 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 (U.S. Patent application No. 08/218,072, Pero et al unpublished 1996).

CA 022~896~ 1998-12-22 Further in accordance with the invention, a concentrated acid addition salt formulation (e.g. 100 - 7000 mg/ml) is advantageously provided at a pH of about S.S to 7.0, for intramuscular injection. At pH values within this range (which is substantially higher, i.e. Iess 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 above7.0 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 shownthat 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 - 7.0 a substantially reduced local tissue reaction was observed (U . S 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 ~o 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 identifiedand 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 (e.g. <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 CA 022~896~ 1998-12-22 Also surprisingly, it has been found that the administration of an acid additionsalt, 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 theextrapyramidal 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 fromthe 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 7Ø

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 (A) having a tertiary nitrogen present, acid addition salts of compounds that can form acid salts of CA 022~896~ 1998-12-22 Forrnula (B) having a quaterrlary ammoniurn ion present, and mixtures thereof, Formula (A) and Formula (B) being as fo}lows:

R1--(CH2)n--N~--R3 (A) ~2 X-R1--(CH2)n--N~--R3 (B) wherein R, comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with the tertiary nitrogen of Formula (A) or the quaternary ammonium ion of Formula (B), R2 and R, and R4 are alkyl or aryi groups, and X- is an anion. In specific embodiments, the hydrogen bond acceptor site is a carbonyl or carboxy}ic oxygen atom, and X~ is Cl-, F-, Br- or I-.
Advantageously or preferably, the material is selected from the group consistingof nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics and anaesthetics which are acid addition salts of compounds that can form acid salts of Formula (A) or Formula (B), 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 .

.

BRIEF DESCRIPI'ION 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 ,uM
solutions of metoclopramide pH adjusted between 4.8 and 6.0 with I N HCI or 1 N NaOH.

Fig. 2A is a graph on which the UV absorption intensity of 100 ~M 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 ~M 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 ~IM 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 ~LM 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 98100159 PCT/I)S97/10829 Fig. 2F is a graph on which the UV absorption intensity of 100 ~LM 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 ~M solutions of acidic (pH 2-3) chlorpromazine are plotted against the wavelength of UV
absorption between l9~ nm and 380 nm.

DETAILED DESCRIPIION

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~ andanaesthetics as identified and listed in Table 2 below, to reduce the development of undesirahle 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 preparingaqueous 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 effectsof the drug without affecting or improving the indicated clinically useful CA 022~896~ 1998-12-22 WO 98100159 ~CTIUS97/10829 pharmacological properties (e.g. erlhancement of radio- and chemo-therapies of cancer) .

In another aspect. the practice of this invention invol~es consideration of the pH
of acid addition salts of chemical or pharmacological structures such as nicotinamides, benzamides, calcium antagonists, antiemetics, antipsychotics, andanaesthetics 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 solutionsranging in pH from 2 to 6.5 depending on the initial drug concentration and formulation ingredients (American Society of Hospital Pharmacists, 1993, Sveriges Lakersmedels 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 6.5 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 thesite 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; Peroetalunpublished 1996). Hence.this CA 022~896~ 1998-12-22 invention embraces the feature that high concentrations of metoclopramide hydrochloride (e.g. 100 mg/m}), and by analogy other acid addition salt drugs because the drug itsel~ 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 cliniçally 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 dopamine2 (D2) receptor and the 5-hydroxytryptamine3 (5-HT3) 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 . 1): S8-Sll, 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

CA 022~896~ 1998-12-22 .

WO 98/001~9 PCTIUS97/10829 sensitive conformational changes observed for metoclopramide especially at A200 (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 siteof intramuscular injection to receptors in the brain in order to mediate an enhanced efficacy or side effect (e.g. sedation).

The UV spectra of the Examples below were run using a Beckman scanning UV-visible spectrophotometer with a quartz cell having a l cm path length. The spectra were produced by scanning the UVbsorption produced between lgS
nm and 380 nm (379 nm in Fig. 1) at a bandwidth of 5 nm. 100 ~M 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 lN HCl and lN
NaOH to produce pH gradient solutions which were then subjected to scanning of the UV spectrum between A,95 and A380. The UV spectra were corrected for absorption from appropriate solvent blanks.

.. ..

.
WO 98/OOlS9 PCT/VS97110829 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. l report the result of a detailed UV spectral analysis of metoclopramide solutions carefully adjusted in pH between 4.8 and 6Ø The UV absorption spectra recorded between 195 nm and 215 nm show a very sharp change in maximal absorption in metoclopramide solutions around pH 5Ø These UV spectra changes around 5.0 were taken as strong supportive evidence for the shifting of equilibrium between the two conformational forms ofmetoclopramide, 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.
l 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.

F,Y~mple 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 shiftedand 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 A20(, for all the drugs containing alkylaminodialkyl substitutions.

Example 3 UV spectral evidence indicating alterations in A200 resulting from proposed pH sensitive conformational changes in the structure of N-alkylaminodialkyl substituted drugs.

The data in Table l 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 a~ueous solutions (presented in Example 1). 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 l99~). 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:

.. . . . , ... . ~

.

.

"H~

C~'~ N, ~ N/~CI

H2N '~- H heat H2N o- H
H C energy Metoclopramide HCI "extended hydrochloride conformation"
"highly structured, coplanar form" proton away from carbonyl 2 hydrogen bonds define structure 2nd hydrogen bond cannot form d-2 receptor antagonist base H Cl H2N~¢~N~

Neu-Sensamide~' "extended side chain conforrnation"
1 hydrogen bond defines structure poorer binding at d-2 receptor g CA 022~896~ 1998-12-22 WO 98/00159 PCI'IUS97110829 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" wit}l the proton away from the carbonyl such that the second hydrogen bond (between the carbonyl oxygen and the proton of the side chain a~nmonium hydrogen) cannot form. The formula at the lower right, representing "Neu-SensamideT~"', athigher (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. receptor. In a broader sense, Table 1 also shows that changes in UV
absorption at A20(, 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 changein their UV spectra at A20(,. For example. 3-amino benzarnide and procaine do not contain either alkylaminodialkyl- or N- substitutions nor do they exhibit pHsensitive UV absorption changes at A20" (Table 1). 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 A20n ~ . . . ~ . .

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 ~M samples of these agents were acidified topH 2 and their UV spectra were recorded. These spectra in turn were compared with the UV spectra at ambient pH (i.e. pH 5-6).
Drl~p/A~ent A~ Comments (1) 3 Amino benzamide No N-substitution of bem~ e-Acidic 1.150 no pH change at A200 Aqueous l . 1 S0 (2) Procaine O-substituted alkylaminodialkyl Acidic 1.500 benzoic acid-no pH change at A200 Aqueous 1 . 500 (3) Metoclopramide N-alkylaminodialkyl substituted Acidic 0.200 benzamide-pH change at A200 Aqueous 1.400 (4) 3-Chloro proc~in~mide N-alkylaminodialkyl substituted Acidic 0.200 benzamide-pH change at A20"
Aqueous 2.700 (5) Proc~in~mide N-alkylaminodialkyl substituted Acidic 0.900 benzamide-pH change at A200 Aqueous 2 . 300 (6) Remoxipride N-alkylaminodialkyl substituted Acidic 0.200 benzamide-pH change at A2W
Aqueous 2.800 (7) Lidocaine N-alkylaminodialkyl substituted Acidic 0.180 benzamide-pH change at A200 Aqueous 2.700 (8) Chlorpro~n~7ine N-alkylaminodialkyl substituted Acidic 0.200 phenothiazine-pH change at A20, Aqueous 2.600 9 PCT/US97/~0829 Example 4 List of drugs capable of forming acid addition salts via the formation of a quaternized nitrogen (e.g. alkylaminodialkyl substitutions), and thereb~
undergoing pH sensitive alteratioos, 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 (i.e. usually hydrochloride acid salts) because they contain a tertiary nitrogen group (i. e . usually as alkylaminodialkyl substitutions) . Because Examples 1-3 establish that compounds containing alkylaminodialky]
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.

Table 2. List of clinically available acid addition salt drugs including their structures, chemical abstract numbers, trade marks, commercial suppliers and clinical uses. This da~a has been compiled from the 1992-1996 Sveriges Lakersmedels Information AB, (FASS) and the 1995 Merck Index.

1. MELPHALAN [148-82-3]
TRADE NAME: ALKERAN (GLAXO, H WELLcoME) CICH2CH2 t=\ CLINICAL USE: CYTOSTATIC
N~ /~cH2~c~cooH ALKYLATING AGENT
CICH2CH2 '~Y

2. AMILORIDE [260946-3]
TRADE NAME: AMILOFERM (NORDIC) AMILORID (NM PHARMA) Cl NCONHCNHNH2 MIDAMOR (MSD) MODURETIC (MSD) NORMORIX (NYCMED) ~ ~ ~ ~ SPARKAL (SELENA) H2N N NH2 CLINICAL USE: POTASSIUM-SPARING
DIURETIC

3 CLOMIPRAMINE [36349-1l TRADE NAME: ANAFRANIL (CIBA) / KLOMIPRAMIN
\~ (NM PHARMA) N Cl CLINICAL USE ANTIDEPRESSANT
, CH3 CH2CH2CH2N ~ CH

4. CHLORCYCLIZINE l82-93-9]

,~ TRADE NAME: ANERVAN (RECIP) Dl-PARALENE (ABBOTT) EXOLYT (ABIGO) CH--N N--CH3 CLINICAL USE: ANTIHISTAMINE

5. HYDRALAZINE [86-544]
TRADE NAME: APRESOLIN (CIBA) NHNH2 CLINICAL USE: ANTIHYPERTENSIVE
~N
~N

6. ALPRENOLOL [13655-52-2]

O - CH2CHOHCH2NHCH(CH3)2 CH2CH=CH2 TRADE NAME: APTIN (HAssLE) CLINICAL USE: ANTIHYPERTENSIVE
ANTIARRHYT~IMIC

7 DOPAMINE [51-61-6]

OH TRADE NAME: ABBODOP (ABBOTT) \'-- GILUDOP (MEDA) HO ~\~CH2CH2NH2 INTROPIN (HAssLE) CLINICAL USE: ADRENERGIC

8. QUINAPRIL [85441-61-8]

COOH

~3CH2CH2--C--NI I C CO-N
H H

TRADE NAME: ACCUPRO (PARKE DAVIS) CLINICAL USE: ANTIHYPERTENSIVE

9. TETRACYCLINE ~60-54-8l -OH O OH O TRADE NAME: ACHROMYCIN (LEDERLE) OH I ACTISITE (MEDA) \/ \~ CONH2 TETRACYKLIN
r T¦ ll (NM PHARMA) ~CR3 CLINICAL USE ANTIBACTERIAL

10. CIMETIDINE ~51481-61-9l 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
H
~CH3 N-CN

11. DOXORUBICIN [23214-92-8]
~ OH
Il I COCH20H
~OH TRADE NAME: ADRIAMYCIN
(PHARMACIABl UPJOHN) o DOXORUBICI N ~NYCOMED) CLINICAL USE: ANTINEOPLASTIC
~r~~
I\CH3/
HO ~ H

12. BIPERIDEN [514-65-8]
TRADE NAME: AKINETON (MEDA) ~CH2~ CLINICAL USE: ANTICHOLINERGIC

r~
COHCH2CH2--N~ ~

.
WO 98/OOlS9 PCT/US97/10829 13. CARTEOLOL [51781-06-7]
TRADE NAME: ARTEOPTIC (CIBA VISION) N ~ CLINICAL USE: 13-RECEPTOR BLOCKER

OCH2CHOHCH2NHC(CH3)3 14. RANITIDINE 166357-35-5]

H3C ll ~NCH2~ ~ ~CH2SCH2CH2NHCNHCH3 TRADE NAME: ARTONIL (SELENA) ZANTAC (GLAXO WELLCOME) CLINICAL USE: ANTIULCERATIVE

15. HYDROXYZINE 168-88-2]
Cl TRADE NAME: ATARAX(UCB) HISTILOS (UCB) ~=\ VISTARIL (ROERIG) CLINICAL USE: TRANQUILIZER
CH--N N--CH2CH20CH2cH20H
/=< --/

16. CHLORTETRACYCLINE 157-62-5]
TRADE NAME: AUREOMYCIN

~"CONH2 CLINICAL USE: ANTIBIOTIC

~OH
cr CH31 1H INCH3 WO 98/OOlS9 PCT/US97/10829 17. BAMBUTEROL
TRADE NAME: BAMBEC (DRACO) CH3 CLINICAL USE: BRONCHODIALATOR
CH3 ~CHOHCH2NHCCH3 18. DIPHENHYDRAMINE [482-05-31 TRADE NAME: BENYLAN (PARK-DAVIS) DESENTOL
CH3 ~PHARMACIA~ UPJOHN) CHOCH2CHlNCH3 ANTI-MOTIONSICKNESS

19. BETAXOLOL [63659-18-7]
~=~ CH3 ~CH20CH2CH2~0CH2CHOHCH2NH-CHCH3 TRADE NAME: BETOPTIC (ALCON) KERLON (SEARLE) CLINICAL USE: ANTI-GLAUCOMA
ANTlH'~tK I tNSlVE

20. BROMHEXINE 1357243-8l TRADE NAME: BISOLVON (BOEHRINGER) Br BROMHEXIN (ACO) MOLLIPECT (TIKA) \~cH2NcH3 CLINICAL USE: MUCOLYTIC
~=( ,J~ EXPECTORANT
Br NH2 ~J

21. PHENYLEPHRINE HYDROCHLORIDE [61-76-71 TRADE NAME: BLEFCON (ALLERGAN) HO METAOXEDRIN (MEDA) OH NEOSYNEPHRINE
- (SANOFI WINTHROP) CH2NH--CH3 ZINCFRIN (ALCON) H CLINICAL USE: ADRENERGIC

22. BUPIVACAINE 12180-92-9]
TRADE NAME: BUPIVAKAIN (NORCOX) MARCAIN (ASTRA) CH3 I CLINICAL USE: LOCAL ANAESTHETIC
~=< N
~NHCO~

23. MELPERONE l3575-80-2 /=\ r~
F ~COCH2CH2CH2--N~CH3 TRADE NAME: BURONIL (LUNDBECK) CLINICAL USE: NEUROLEPTIC

24. BUSPIRONE [36505-84-7]
o (~N N-cH2cH2cH2cH2--N~:X

TRADE NAME: BUSPAR
(BRISTOL-MEYERS SQUIBB) CLINICAL USE: ANXIOLYTIC

WO 98100~59 PCTIUS97/10829 25. MEPIVACAINE [96-88-8]
TRADE NAME: CARBOCAIN (ASTRA) c~3 CH3 CLINICAL USE LOCALANAESTHETIC
N
~NHCO~

26. DILTIAZEM [4239941-7]
TRADE NAME: CARDIZEM
H3CNCH2cH2 tPHARMAClA & UPJOHN) ~,~ ENTRYDIL (ORION) N--S_OCOCH3 TILDIEM (TIKA) l~ ,1 ~ CLINICAL USE: CALCIUM ANTAGONIST
~v S ~ VASODILATOR
H ¢~
~<

27. CLONIDINE [4205-90-7]
H Cl TRADE NAME: CATAPRESAN
~=~ (BOEHRINGER INGELHEIM) CLINICAL USE: ANTIHYPERTENSIVE

H Cl 28. SUCCINYLCHOLINE CHLORIDE [71-27-2]

CH3 TRADE NAME: CELOCURIN
~ (PHARMACIA ~ UPJOHN) COOCH2CH2N+CH3 CLINICAL USE: SKELETAL MUSCLE RELAXANT
CH2 CH3 (SHORT DURATION) COOCH2CH2N+CH3 29. DAUNORUBICIN ~20830-81-3l -O OH TRADE NAME CERUBIDIN (RHONE-POULENC

OH DAUNOXOME (SWEDISH
CLINICAL USE: CYTOSTATIC
OCH3 O OH H ~
~r~~
f~CH3 ~
HO ~--H

30. CIPROFLOXACINE [85721-33-1, 86393-32-0(HCI)]
TRADE NAME- CILOXAN (ALCON) V CIPROXIN (BAYER) A I CLIN1CAL USE: ANTIBACTERIAL
H N N ~ N ~

F I'~COOH

31. CLOPENTHIXOL 1982-24-1]
S TRADE NAME: CISORDINOL
(LUNDBECK) CI CLINICAL USE: ANTIPSYCHOTIC
/ \ /--\
H CH2CH2--N~N--CH2CH2~H

32. PRILOCAINE l721-50-6l TRADE NAME: CITANEST (ASTRA) EMLA (ASTRA) ~/ ,\)--NtlCOCHNHCH2CH2CH3 CLINICAL USE: LOCAL ANAESTHETIC
'=<~ CH3 . , , WO 98/OOlS9 PCTIUS97/10829 33. ETHYLMORPHINE [76-58~3 CH3CH2~ TRADE NAME: COCILLANA - ETYFIN
(PHARMACIA & UPJOHN) ¦ ¦ COSYLA (PARKE-DAVIS) l LEPHETON
G<' ~ (PHARMACIA & UPJOIlN) H ~ N--CH3 CLINICAL USE: ANTITUSSIVE
HO

34. TACRINE [321-64-2]
TRADE NAME: COGNEX (PARKE-DAVIS) NH2 CLINICAL USE: CHOLINERGIC

35. PROTRIPTYLINE [43B-60-8]
TRADE NAME: CONCORDIN (MSD) CLINICAL USE: ANTIDEPRESSANT

36. AMIODARONE t1951-25-3]

o CH2cH2cH2cH3 ~1' CH2CH3 --\CO ~ OCH2CH2NCH2CH3 TRADE NAME: CORDARONE
(SANOFI WINTHROP) CLINICAL USE: ANTIARRYHYTHMIC

, ................ .

WO 98/OOlS9 PCTIUS97/10829 37. CYCLOPENTOLATE [512-15-2]
TRADE NAME CYCLOGYL (ALCON) CYCLOPENTOLAT (MEDA) fH3 CLINICAL USE~ ANTICHOLINERGIC

OH

38 CLINDAMYCIN 11 832344-9l C~3 CH3 TRADE NAME: DALACIN
N H CH -Cl (PHARMACIA & UPJOHN) H~CONHCH CLINICAL USE~ ANTIBIOTIC

CH3CH2C 2 1~

OH

39. PROPOXYPHENE l469-62-5]
TRADE NAME DEXODON (TIKA) DEXOFEN (ASTRA) Cl H3 ICH3 DISTALQESIC (LILLY) \--/ CHCH NCH DOLERON (ASTRA) 2 3 DOLOTARD (NYCOMED) C DOLOXENE (LILLY) ~CH2 OOccH2CH3 PARAFLEX (ASTRA) \=/ CLINICAL USE: ANALGESIC

40 HYDROMORPHONE [466-99-9]

TRADE NAME: DILAUDID (MEDA) CLINICAL USE: ANALGESIC
,~' H H
H_~ ~N--CH3 0~

., 41. ORPHENADRINE 183-98-7]
TRADE NAME: DISIPAL (YAMANOUCHI) CH3 NORFLEX (3M) \=~ CH3 NORGESIC (3M) CH NCH CLINICAL USE: MUSCLE RELAXANT
CHO--CH2 2 3 (SCELETETAL) ANTIPARKINSON

42. DOBUTAMINE [30468-04-2]

HO ~ CH2CH2NHCHCH2cH2 ~OH

TRADE NAME: DOBUJECT (LEIRAS) DOBUTREX (LILLY) CLlNiCAL USE: CARDIOTONIC

43. DOPEXAMINE [86494-91-5(HYDROCHLORIDE)]
HO

HO ~CH2CH2NH(CH2)6NHCH2cH2 ~

TRADE NAME: DOPACARD
(FISONS) CLINICAL USE: CARDIOTONIC

44. DOXYCYCLINE [564-25-0]

OH O 10 TRADE NAME: DORYX (SCAND PHARM) CONH2 DOXYCYKLIN (ENAPHARM) / DOXYFERM (NORDIC) 1 IDOCYKLIN (ROERIG) ~= ~ OH VIBRAMYCIN (PFIZER) H \ H H\H H NCH3 CLINICAL USE: ANTIBACTERIAL

45. NEOMYCIN [1404-04-2 FOR THE MIXTURE]

~0 ~OH \
Ho\Ll/ TRADE NAME: ECOMYTRIN (LUNDBECK) CELESTON (SCHERING-PLOUGH) H2N DECARDRON (MSD) O ISOPTO- BIOTIC (ALCON) /~ NEBACETIN (LUNDBECK) H2 N~ CLINICAL USE: ANTIBACTERIAL

o o R~ NEOMYCIN B R = H, R = CH2NH2 ~ ~/ NEOMYCIN C R = CH2NH2, R' = H
HO O OH

46. EPHEDRINE l50-98-61 HO NHCH TRADE NAME EFEDRIN (NM PHARMA) ~\ 3 LEPHETON (PHARMACIA& UPJOHN) // \--C C--CH3 LERGIQAN (RECIP) H H MOLLIPECT (TIKA) CLINICAL USE: ADRENERGIC

47. VENLAFAXINE []

N(CH3)2 TRADE NAME: EFEXOR (WYETH) CH30~3 CH~ CLINICAL USE: ANTIDEPRESSANT

48 ETILEFRIN [709-55-7]

o TRADE NAME: EFFORTIL
H (BOEHRINGER INGELHEIM) CLINICAL USE: ADRENERGIC

OH ANTIHYPERTENSIVE

WO 981001S9 PCT/llS97110829 49. DEPRENYL l2323-36-6]
TRADE NAME: ELDEPRYL (ORION) ,~ CH3 SELEGILIN (NM PHARMA) ~CH2--C~--NCH2C--CH CLINICAL USE: ANTIPARKINSON

50. EPIRUBICIN [56390-09-1(HCI), 56420-45-2(BAS)~
O OH
Il I COCH20H
/~ ~ /~,/\~ TRADE NAME: FARMORUBICIN
'OH (PHARMACIA~ UPJOHN) \~ CLINICAL USE: ANTINEOPLASTIC
Jl ANTIBIOTIC
OCH3 O OH o HO O
~, 51. FLUPENTIXOL [2709-56-0l TRADE NAME: FLUANXOL
~CF3 (LUNDBECK) CLINICAL USE; ANTIPSYCHOTIC
CHCH2CH2--N hl -CH2CH20H

52. BENOXINATE [99-43 1]
TRADE NAME: FLURESS (ABIGO) OXIBUPROKAIN (MEDA) CLINICAL USE: ANAESTHETIC (TOPICAL) CH3CH2CH2cH20\

H2N ~ CoocH2cH2N(cH2cH3)2 WO 98/00159 I'CTfUS97110829 53. FLUOXETIN [54910-89-3]
TRADE NAME: FONTEX (LILLY) F3C~OCHCH2CH2NHCH3 CLINICAL USE. ANTIDEPRESSANT
~3 54. GEMCITABINE []
NH2 TRADE NAME: GEMZAR (LILLY~
CLINICAL USE: ANTINEOPLASTIC

l~N~o HO~H2 ~o~
;~
HO F

55. ADRENALINE/EPINEPHRINE l~

TRADE NAME: CITANEST ADRENALIN
OH (ASTRA) ~_ OH EPPY (ABIGO) // \\ GLAUFRIN (ALLERGAN) HO~/ '~C--CH2NHCH3 MARCAiN ADRENALIN
\=/ H (ASTRA) XYLOCAIN ADRENALIN
(ASTRA) CLINICAL USE: ADRENERGIC

56. METFORMIN [657-24-g]

NH TRADE NAME: GLUCOPHAGE (MEDA) NH ll CLINICAL USE: ANTIDIABETIC
(CH3)2N - C - NHCN~2 57. CHLORPROMAZINE [50-53-3]
S TRADE NAME. HIBERNAL
~/ ~ (RHONE-POULENE RORER) /~ CLINICAL USE: ANTI-EMETIC
N Cl TRANQUILIZER
CH2CH2CH2N(CH3)2 SEDATIVE

58. PRENALTEROL [57526-81-5]
OH
HO ~30CH2--C-CH2NHCH(cH3)2 H

TRADE NAME: HYPRENAN (HASSLE) CLINICAL U SE: ADRENERGIC

59. TERAZOSINE~63590-64-7, 70024-40-7(HYDROCHLORIDE)]

CH30~ N / \ 11 \

TRADE NAME: HYTRINEX (ASTRA) SINALFA (SINALFA ABBOTT) CLINICAL USE: ANTIHYPERTENSIVE

60. OXYMETAZOLINE 11491-594]

CH3 OH TRADE NAME: LLIADIN (MEDA) H ~ NASIN (TIKA) N CH2~/ \~C(CH3)3 NEZERIL (DRACO) ~=/ ZOLIN (ACO) N CH3 CLINICAL USE: ADRENERGIC

. ,. ~ .

.

WO 98~00159 PCTIUS97110829 61. LOPERAMIDE t53179~ 6]
Cl TRADE NAME: IMODIUM
~1 ~ (JENSSEN-CILAG) // \\ LOPERAMID
~/ ~ ~ (SCAND PHARM) /--\ >=' PRIMODIUM
(CH3)2NCO--C--CH2CH2--N~OH TRAVELLO
,~ ( PHARMACIA ~ U PJ OH N ) IJ CLINICAL USE: ANTIDIARETIC

62. PROPRANOLOL ~25-66-6l ~, TRADE NAME: INDERAL (ZEN ECA) PROPRANOLOL
~\~ (NM PHARMA) T CLINICAL USE: 13-ADRENERGIC BLOCKER
ocJ-l2fHcH2NHcH(cH3)2 ANTIARRHYTHMIC
OH

63. LIDOCAINE [137-58-6~
TRADE NAME: DEPO - MEDROL
(PHARMACIA & UPJOHN
CH3 EMLA ~ASTRA) _~ INSTILLAGEL (ELLEM) // \\ LEDERSPAN (LEDERLE) ~/ \~NHCOCH2N(CH2cH3)2 XYLOCAIN (ASTRA) \=~ XYLOCARD (ASTRA) \CH3 XYLOPROCT (ASTRA) CLINICAL USE: LOCAL ANAESTHETIC

64 APRACLONIDINE [66711-21-5]

H ~ TRADE NAME: LOPIDINE (ALCON) N N~/ \\) NH2 CLINICAL USE: TREATMENT OF POSTSURGICAL
~=/ ELEVATED INTRAOCULAR PRESSURE
N--H C

65. VERAPAMIL 152-53-9l TRADE NAME: ISOPTIN (MEDA) VERALOC (ORION) VERAPAMIL (NM PHARMA) CLINICAL US~: ANTlARRHYTtlMlC
VASODILATOR

CH30 ~3CCH2CH2CH2NCH2CH2~ocH3 66. PILOCARPINE 192-13-7l TRADE NAME: FOTIL (LEIRAS) O o ISOPTO - PILOKARPIN (ALCON) ~ ~. H LICARPIN (ALLERGAN) CH3CH2 1 ¦ -H Cl 3 PILOKARPIN (MEDA) J N SPERSACARPINE (CIBA) H CH2~ 1 TIMPILO (MSD) N CLINICAL USE: ANTIGLAUCOMA
CHOLINERGIC

67. PROCYCLIDINE [77-37-2]
TRADE NAME: KEMADRIN
(GLAXO WELLCOME) CLINICALUSE: ANTIPARKINSON
HO -~ CH2cH2--N

68. KETAMINE [6740-88-1]
TRADE NAME: KETALAR (PARKE-DAVIS) ¢~ CLINICAL USE: GENERAL ANAESTHETIC
r~cl \~ NHCH3 WO 98/00159 PCT/US9~/10829 69. KETOBEMIDON 1]
TRADE NAME: KETOGAN
(NOVUM-LUNDBECK) CLINICAL USE: ANAL(~ETIC
~/ \~OH SPASMOLYTIC

CH3N~ COCH2CH3 70. QUINIDINE [130-95-0, 60-93-5(~1YDROCHLORIDE)]
~N TRADE NAME: KININ (NM PHARMA) ~,~ CLINICAL USE: ANTIMALARIAL

HO I C y N~, H ~H
CH=CH2 71. GRANISETRONE [109889-09-0, 107007-99-8(HYDROCHLORIDE)]
~CH3 TRADE NAME: KYTRIL
N (SMITH KLINE BEECHAM) CLINICAL USE: ANTIEMETIC

l\ HCO

72. MEFLOQUIN [51773-92-3(HYDROCHLORIDE) l~yN~CF3 TRADE NAME: LARIAM (ROCHE) b~ CLINICAL USE: ANTIMALARIAL
HC--OH
~H

WO 981001~9 PCTIUS97110829 73. PROIAETHAZINE ~7440-12-12]
TRADE NAME: LERGIGAN (RECIP) CLINICAL USE: ANTIHISTAMINE

CH2CHN(Ctl3)2 74. REMOXIPRIDE 11 Br CH3 TRADE NAME: ROXIAM (ASTRA) CH3 --~2CH3 CLINICAL USE: NEUROLEPTIC

75. LINCOMYCIN 1154-21-2]
ICH3 TRADE NAME: LINCOCIN
N H HO~CHCH3 (UPJOHN) H ~CO--NH--CH CLINICAL USE: ANTIBIOTIC
CH3CH2CH2 HO~o ~&~SCH3 OH

76. LEVOCABASTIN l]
TRADE NAME: LIVOSTIN
H CH3 (JENSSEN-CILAG) CN~O,N~COOH CLINICAL USE: H,-ANTAGONIST

H ~

, WO 98/OOlS9 PCTIUS97/10829 77. AMOROLFINE ~78613-35-1, 78613-38-4(HYDROCHLORIDE)]

C~N--Ctl2CHCH2 ~ C(CH3)2CH2CH3 TRADE NAME: LOCERYL (ROCHE) CLINICAL USE: ANTIMYCOTIC

78. MAPROTILINE [10260~9-8]
TRADE NAME: LUDIOMIL tC113A) ~ ~ r\ ,~ MAPROTILIN
'' 'I ' 1l ~NM PHARMA) ~/ ~/) CLINICAL USE: ANTIDEPRESSANT

79. BENSERAZIDE l322-35-0]
TRADE NAME: MADOPARK (ROCHE) OH OH CLINICAL USE: ANTIPARKINSON
DOPAMINERGIC
HO ~ CH2NHNHCOCHCH2OH

80. THIORIDAZINE [50-52-21 TRADE NAME: MALLOROL (SANDOZ) ~¢ ~3~ CLINICAL USE. NEUROLEPTIC

CH
CH
N

, _ .. ..

WO 98/00159 PCI'IUS97/10829 81. CYCLIZINE [82-92-8]
TRADE NAME: MARZINE
~9 (GLAXO WELLCOME) \=( A CLINICAL USE: ANITHISTAMINE

82. CEPHEPIME []
TRADE NAME: MAXIPIME
(BRISTOL-MEYERS SQUIBB~
CLINICAL USE: ANTIBIOTIC

NOCH3 H H, S

83. METHADONE [1095-90-53 TRADE NAME: METADON
J (PHARMACIA & UPJOHN) ~ CH3 CLINICAL USE: NARCOTIC ANALGETIC
CH3CH2CO- lC--CH2CHN(CH3)2 84. MEXILETINE 131828-71-4]
TRADE NAME: MEXITIL
CH3 (BOEHRINGER INGELHEIM) /=~ CLINICAL USE: ANTIARRHYTHMIC
~OCH2CH-NH2 85. MIANSERIN [24219-974]
TRADE NAME: MIANSERIN ~NM PHARMA) /~ TOLVON (ORGANON) N ~d CLINICAL USE ANTIDEPRESSANT
<~N
~ CH3 86. PIVMECILLINAM []
TRADE NAME: MIRAXID (LOVENS) CLINICAL USE: ANTIBACTERIAL

~ H COOCH20COC(CH3)3 87. PHENYLPROPANOLAMINE [154-41-61]
TRADE NAME: LUNERIN (TIKA) /=\ MONYDRIN (TIKA) (~ ~CHCHNH2 RINEXIN (RECIP) '~b I I RINOMAR (RECIP) HO I H CLINICAL USE: VASOCONSTRICTOR

88. MORPHINE [52-27-2]
TRADE NAME: DOLCONTIN
HO (PHARMACIA & UPJOHN) LOCEPTIN (NYCOMED) MAXIDON (ASTRA) ~ ~\ MORFIN
o _, H (PHARMACIA ~ UPJOHN) H _~ SPASMOFEN (ABIGO) N--CH3 CLINICAL USE: NARCOTIC
HO, \~ ANALGESIC

, WO 98/OOlS9 PCT/US97/10829 89. ETHAMBUTOL [304-84-7]
CH3CH2CHNHCH2--CH2NHCHCH2CH TRADE NAME: MYAMBUTOL

CLINICAL USE: TUBERCULOSTATIC

90. AMBENONIUM CHLORIDE [115-79-7]
Cl TRADE NAME: MYTELASE
CH2CH3 \~ (SANOFI WINTHROP) CONHCH2CH~N CH2~ ~ CLINICAL USE: CHOLINESTERASE
~ INHIBITOR

CONHCH2CH2N I C~2 ~3 91. NALOXONE [465-65-6]

HO TRADE NAME: NARCANTI (MEDA) ~ ~ CLINICAL USE: ANTAGONIST
C~/ ~ (TO NARCOTICS) H--~N--CH2CH=CH2 ~ 0~--92. XYLOMETAZOLINE [526-36-33 TRADE NAME: NASOFERM (NORDIC) H CH3 OTRIVIN (CIBA) \ ~ CLINICAL USE: ADRENERGIC
H2C ~ ~ C(H3)3 VASOCONSTRICTOR

._ ... , . .. .~.. ..

93. PROCARBAZINE [671-16-9]

CH3NHNHCH2 ~ coNHcH(cH3)2 TRADE NAME. NATULANAR (ROCHE) CLINICAL USE: ANTI N EOPALSTIC

94. TROPISETRONE []
TRADE NAME: NAVOBAN (SANDOZ) ~" H ¦
O-CO

95. PHENYLEPHRINE [61-76-7(HYDROCHLORIDE)l TRADE NAME: BLEFCON (ALLERGAN) ISOPTO-BIOTIC (ALCON) OH OH METAOXEDRIN (MEDA) '~=, NEOSYNEPHRINE
(SANOFI WINTHROP) C--CH2NHCH3 ZINCFRIN (ALCON) H CLINICAL USE: ADRENERGIC

96. THIAMINE [67-03-8~
TRADE NAME: ASTRATONIL FORTE (ASTRA) H3C N~ NH S ,CH2CH2OH BETABION (MEDA) \~ / 2~ ~ CLINICAL USE: ENZYME
N~ ~C~N ~CH3 CO-FACTOR-VITAMIN B1 .
WO 98/OOlS9 PCI/US97110829 97. TRAMADOL 127203-92-5, 22204-88-2(HYDFi OCHLORIDE)]
H CH2N(CH3)2 TRADE NAME: NOBLIGAN (SEARLE) ~3Hoh CLINICAL USE: ANALGESIC

- 98. HYDROCHLOROTIAZID [5~-93-5]
TRADE NAME: SPARKAL (SELENA) ~~ ,~ TRIATEC COMP (HOECHST) H2N--SO2 S AMILOFERM (NORDIC) C~NH~J H CLINICAL USE: DIURETIC

99. QUINAGOLIDE [
OH
H
\ NH - S~2--N(CH2CH3)2 --N TRADE NAME: NORPROLAC (SANDOZ) H I
CH2CH2CH3 CLINICAL USE: PROLACTIN ANTAGONIST

100. NOSCAPINE [128-62-1. 912-60-7(HYDROCHLORIDE)]
TRADE NAM~: NIPAXON (PHARMACIA &
O ~ ~ UPJOHN) / ~r rl H 1 NOSKAPIN (ACO) \o ~ N ~ CH SPAMOFEN (AE~IGO) CLINICAL USE: ANTITUSSIVE

H O

r OCH3 ... . , ~

..

101. MITOXANTRONE ~65271-80-90, 76476-82-3(HYDROCHLORIDE)]
OH O NHcH2cH2NHcH2cH2oH TRADE NAME: NOVANTRONE
(LEDERLE) CLINICAL USE: ANTINEOPALSTIC

OH O NHcH2cH2NHcH2cH2oH

102. DIPIVEFRIN l52365-63-6, 64019-93-8(HYDROCHLORIDE)I
TRADE NAME: OFTAPINEX (LEIRAS) PROPINE ~ALLERGAN) (CH3)3CCOo CLINICAL USE: ANTI-GLAUCOMA
(CH3)3CCOO~/ \~CHCH2NHCH3 ADRENERGIC
OH

103. OXYTETRACYCLINE [79-57-2, 2058-46-0(HYDROCHLORIDE)]

O OH O TRADE NAME: OXYTETRAL (DUMEX) ll I OHII TERRACORTRIL (PFIZER) ,~J~"r- CONH2 TERRAMYCIN (PFIZER) CLINICAL USE: ANTIBIOTIC
~/ ~ --OH
HO ' ~ H NCH3 t04. FLUPHENAZINE [69-23-8, 146-56-5(HYDROCHLORIDE)]
TRADE NAME: PACINOL (SCHERING-PLOUGH) SIQUALONE (BRISTOL
S ~ MEYER S-SQU IBB) CLINICAL USE: ANTIPSYCHOTIC
~/ ~N~ ~/ ~CF3~

105. CHLORGUANIDE [500-92-5]
TRADE NAME: PALUDRINE
NH NH (ZENECA) ClgNHCNHCNHCH(CH3)2 CLINICAL USE: ANTIMALARIAL

106. TRIHEXYPHENIDYL [52-49-31 TRADE NAME: PARGITAN (ABIGO) CLINICAL USE: ANTIPARKINSON
HO - C - CH2CH2--N~

107. BACAMPICILLIN [50972-17-3, 37661-08-8(HYDROCHLORIDE)l TRADE NAME: PENGLOBE (ASTRA) C - CONH ~ CH3 H CoocHocoocH2cH3 108. CYPROHEPTADINE [129-03-3, 41354-29-4(HYDROCHLORIDE)I
,~ ~ TRADE NAME: PERIACTIN (MSD) ANTIHISTAMINE

~N~

WO g8/00159 PCl/VS97/10829 109. PRAZOSIN [19216-56-9,19237-84-4(HYDROCHLORIDE)]
A o CH30~N~N N--CO~
CH30 ~ N

TRADE NAME: PERIPRESS (PFIZER) CLINICAL USE: o~ 1 -ADRENERGIC E~LOCKER
ANTIHYPERTENSIVE

110. MEPERIDINE [57~2-1, 50-13-5(HYDROCHLORIDE)]
TRADE NAME: PETIDIN
,~ (PHARMACIA & UPJOHN) /--\ / \=/ CLINICAL USE~ NARCOTIC
CH3--N ~)~ ANALGETIC

111. MECLIZINE [569-65-3, 31884-77-2(HYDROCHLORIDE)]
Cl TRADE NAME: HISTILOS (UCB) POSTAFEN (UCB) CLINICAL USE: ANTIEMETIC
C H--N N--CH2 ~9 112. METOCLOPRAMIDE [364-62-5, 54143-57-6(HYDROCHLORIDE) CONHCH2CH2N(CH2cH3)2 TRADE NAME: PRIMPERAN
~,OCH3 CLINICAL USE: ANTIEMETIC

Cl~

WO 98/OOlS9 PCT/US97/10829 113 PROCAINAMIDE [614-39-1]

H2N ~CONHCH2CH2N(CH2CH3)2 TRADE NAME: PROKAINAMID
(HASSLE) CLINICAL USE: ANTIARRYTHMIC

114. PYRIDOXINE 158-56-0]
TRADE NAME: ASTRANOI L FORTE
N CH3 (ASTRA) ~ CLINICAL USE: VITAMIN B6 HOCH2 ~r OH

1 15. ALFENTANIL [71 195-28-6. 70879-28-6(HYDROCHLORIDE)]

N N 2 2 ~ ~N--COCH.2CH3 N=N

3 TRADE NAME. RAPIFEN
(JENSSEN-CILAG) CLINICAL USE: NARCOTIC
ANALGESIC

1 16 NAPHAZOLINE [835-31-4, 550-29-2(HYDROCHLORIDE)]

~ TRADE NAME: ANTASTEN-PRIVIN (CIBAVISION) IH ~ RIMIDOL (UCB) N CH2 CLINICAL USE: ADRENERGIC (VASOCONSTRICTOR
~y DECONGESTANT
N

~ . .

117 METHACYCLINE [914-00-1 3963-95-9(HYDROCHLORIDE)]

~ ~ CONH2 ~OH TRADE NAME RONDOMYCIN
~ \ ~ ~ (ROERIG) - H OH CH CLINICAL USE ANTIBACTERIAL
118 ROXATIDINE [1 CN CH2~
TRADE NAME ROXIT (HOECHST) CLINICAL U SE ANTI-U LC ERATIVE
119 PROPAFENONE ~54063-53-5 34183-22-7(HYDROCHLORIDE)]

TRADE NAME RYTMONORM (MEDA) CLINICAL USE ANTIARRHYTHMIC
120 AMITRIPTYLINE [50-48-6 549-18-8(HYDROCHLORIDE)]
TRADE NAME
SAROTEN (LUNDBECK) / ~ TRYPTIZOL (MSD) CLINICAL USE
ANTIDEPRESSANT

CHCH2CH2N~CH3)2 Wo 98/00lS9 PCT/US97tlO829 121. NORTRIPTYLINE [72-69-5 894-71 -3(HYDROCHLORIDE)]
TRADE NAME: SENSAVAL (LUNDBECK) ~, ~ CLINICAL USE. ANTIDEPRESANT

122. PAROXETINE [61869-08-7~
TRADE NAME: SEROXAT
(NOVO NORDISK) O~O--CH2 H CLINICAL USE. ANTIDEPRESSANT

O F ~f \NH
H

123. CLOBUTINOL [14860-4g-23 TRADE NAME: SILOMAT
CI ~ CH2COHCHCH2N(cH3)2 (BOEHRINGER INGELHEIM) CLINICAL USE: ANTITUSSIVE

124. SOTALOL [3930-20-9, 959-24-0(HYDROCHLORIDE)]

CH3S~2NH' ~3CHCH2NHCH(CH3)2 TRADE NAME: SOTACOR
(BRISTOL-MEYERS SQUIBB) SOTALOL (NM PHARMA) CLINICAL USE: ANTIANGINAL
ANTIARRHYTHMIC
ANTIHYPERTENSIVE

WO 981001S9 PCTt~JS97/10829 125. BUPRENORPHINE [52485-79-7, 53152-21-9(HYDROCHLORIDE)]

Il 1 ~ I TRADE NAME: TEMGESIC
H ~ N--CH2 ~ (MEDA) ~ ~J CLINICAL USE: ANALGESIC
CH30 H ~
HO - C--C(CH3)3 126. TETRACAINE [136-47-0]

CH3CH2CH2CH2NH ~COOCH2CH2N(CH3)2 TRADE NAME: TETRACAIN (ALCON) CLINICAL USE: ANAESTHETIC (TOPICAL) 127. TICLOPIDINE [55142-a5-3, 53885-31-1(HYDROCHLORIDE)I
TRADE NAME: TICLID (SANOFI WINTHROP) ~/ S CLINICAL USE: PLATELETAGGREGATION
H2C ~L3 INHIBITOR

128 TOCAINIDE 141708-72-9]
CH3 TRADE NAME: TONOCARD (HASSLE~
CLINICAL USE: ANTIARRHYTHMIC

CH

_ . ... .

WO 98/001~9 rcTI~Jsg7/10829 129. OBIDOXIME CHLORIDE [114-90-9]
TRADE NAME: TOXOGONIN (MEDA) HON=CH~N+--CH2 CLINICAL USE: CHOLINESTERASE
,=, b REACTIVATOR
~ +
HON--CH~=~N --CH2 130. IMIPRAMINE [5049-7, 113-52-0(HYDROCHLORIDE)]
TRADE NAME: TOFRANAL (CIBA) CLINICAL USE: ANTIDEPRESSANT

CH2CH2CH2N(CH3)2 131. LABETALOL [36894-69-6, 32780-64-6(HYDROCHLORIDE)~

HO ~CHCH2NHCHCH2cH2 ~

TRADE NAME: TRANDATE
(GLAXO WELLCOME) CLINICAL USE: ANTIHYPERTENSIVE

132. METHIZENE[4969-02-2, 70814-5(HYDROCHLORIDE)l S TRADE NAME: TREMOQUIL (ASTRA) CLINICAL USE: ANTICHOLINERGIC
ANTIPARKINSON
I r\
H2C ~
N

WO 98tO0159 PCT/US97110829 133. SPECTINOMYCIN [1695-77-8. 22189-32-3(HYDROCHLORIDE)~
HO
H3C--HN ~ ~--~ ~ CH3 TRADE NAME: TROBICIN
~10 ~o ~ (PHARMACIA & UPJOHN) tl HO o CLINICAL USE: ANTIBIOTIC

134. DOR20LAMIDE []

o o TRADE NAME: TRUSOPT (MSD) H3C ~'S~ S S02NH2 CLINICAL USE~ ANTIGLAUCOMA
~ ~ / ~ ~ CARBONIC ANHYDRASE
H i~ _ ANTAGONIST

H NHcH2cH3 135 C H LOR PROTH IXE N E l 113-59-7]
,~,S~ TRADE NAME: TRUXAL (LUNDBECK) ~ CLINICAL USE ANTIPSYCHOTIC

H ' ' CH2CH2N(CH3)2 136. LOFEPRAMINE [23047-25-8 26786-32-3(HYDROCHLORIDE)]

~ ~ TRADE NAME: TYMELYT (LUNDE3ECK) bJ~ ~ CLINICAL USE: ANTIDEPRESSANT

CH2CH2CH2 INCH2C~~CI

-137. VALACIKLOVIR []
O TRADE NAME: VALTREX
(GLAXO WELLCOME) HN ~ N H NH2 CLINICAL USE: ANTIVIRAL AGENT
H2N N 'CH20CH20C0CcH(cH3)2 138. VANCOMYCIN 11404-90-6, 1404-93-09(HYDROCHLORIDE)]

HOAL ~ TRADE NAME: VANCOCIN (LILLY) H3 ~ VANCOMYCIN (DUMEX) ~3 'I VANCOMYCIN (NORCOX) o CLINICAL USE: ANTIBACTERIAL

H~Vr~
\OH 'I
~~1 ClHO~H2 ~ Cl HQ~ 1~ ~ 3 "G1H

~~ N ~ N ~ N J~ ~ NH
H~ H2NCO-CH2 C~O

139. AMANTADINE [768-94-5, 665-66-7(HYDROCHLORIDE)]
NH2 TRADE NAME: VIROFRAL (FERROSAN) CLINICAL USE: ANTIVIRAL (INFLUENZA A) 140. ALFLUZOSINE [] CH30~q, NCH2CH2CH2NHCO~

TRADE NAME: XATRAL (ASTRA) CLINICAL USE~ RECEPTOR ANTAGONIST

-141. IDARUBICIN []
TRADE NAME: ZAVEDOS
~ OH (PHARMACIA ~ UPJOHN) COCH3 CLINICAL USE: CYTOSTATIC

O OH O
- ~r~
~CH3 HO~--142 ONDANSETRON ~99614-02-5, 99614-01-4(HYDROCHLORIDE)]

o TRADE NAME ZOFRAN
Il /= (GLAXO WELLCOME) ~,H2C--N ~ CLINICAL USE ANTIEMETIC

143. CETIRIZINE [83881-51-0, 83881-52-1 (HYDROCHLORIDE)l TRADE NAME: ZYRLEX (UCB) Cl CLINICAL USE: ANTIHISTAMINE
/-\

... _ .. ....

..
WO 98/00159 PCTIIJS97~10829 It is to he 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 (17)

1. What is claimed is:
   l. 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 (A) 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, said Formula (A) and Formula (B) being as follows:
   
   wherein R1 comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula (A) or said quaternary ammonium ion of Formula (B), R2, R3 and R4 and alkyl or aryl groups, and X is an anion, said method comprising the steps of (a) 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 (b) injecting the formulation into the patient in an amount for delivering to the patient a dose of about one to 100 mg/kg of the material while the pH
   of the formulation is within said range.
2. 2. A method according to claim 1, wherein said hydrogen bond acceptor site is a carbonyl or carboxylic oxygen atom.
3. 3. A method according to claim 1, wherein X- is Cl-, F-, Br- or I :
4. 4. A method according to claim 1, 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 (A), acid addition salts of compounds that can form acid salts of Formula (B), and mixtures thereof.
5. 5. A method according to claim 1, wherein said formulation is provided at a concentration of about 100 to 7000 mg/ml.
6. 6. A method according to claim 1, wherein the injecting step comprises injecting the formulation intramuscularly into the patient.
7. 7. A sterile injectable formulation for intramuscular administration to a human patient, comprising (a) a material selected from the group consisting of acid addition salts of compounds that can form acid salts of Formula (A) 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, said Formula (A) and Formula (B) being as follows:
   
   wherein R1 comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula (A) or said quaternary ammonium ion of Formula (B), R2, R3 and R4 are alkyl or aryl groups, and X- is an anion;
   (b) a liquid vehicle in which said material is in solution;
   (c) said material being present in said formulation in a concentration of at least about 50 mg/ml, and (d) the formulation being at a pH within a range of about 5.5 to 7Ø
8. 8. A formulation as defined in claim 7, 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 (A), acid addition salts of compounds that can form acid salts of Formula (B), and mixtures thereof.
9. 9. A formulation as defined in claim 7, also including an amount of a buffer or preservative effective to stabilize the pH of the formulation.
10. 10. A formulation as defined in claim 9, including an amount of a phosphate buffer effective to stabilize the pH of the formulation to a range of less that 0.5 pH unit.
11. 11. A formulation as defined in claim 9, including an amount of sodium metabisulfite effective to stabilize the pH of the formulation to a range of less than 0.5 pH unit.
12. 12. 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 (A) 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. said Formula (A) and Formula (B) being as follows:
    
    wherein R1 comprises an aryl or alkyl group with a hydrogen bond acceptor site accessible to interaction with said tertiary nitrogen of Formula (A) or said quaternary ammonium ion of Formula (B), R2, R3 and R4 are alkyl or aryl groups, and X- is an anion, said method comprising the steps of (a) providing a sterile formulation, comprising a liquid vehicle containing the material in solution, (b) adjusting the pH of said formulation for reducing the development of undesirable side effects of the material, and (c) administering the formulation having the adjusted pH to the patient.
13. 13. A method according to claim 12, 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 (A), acid addition salts of compounds that can form acid salts of Formula (B), and mixtures thereof.
14. 14. A method of administering to a human patient 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, bromhexine, phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem, clonidine, succinylcholine, 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, Iidocaine, apraclonidine. verapamil, pilocarpine, procyclidine, ketamine, ketobemidon, yuinidine, granisetron, mefloquin, prommethazine, remoxipride, lincomycin, levocabastin, amorolfine, maprotiline, benserazide, thioridazine, cyclizine, cephepime, methadone, mexiletine, mianserin, pivmecillinam, phenylpropanolamine, morphine, ethambutol, ambenonium, naloxone, xylometazoline, procarbazine. tropisetrone, phenyiephrine, thiamine, tramadol, hydrochlorotiazid, quinagolide, noscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, chlorguanide, trihexyphenidyl, bacampicillin, cyproheptadine, prazosin, meperidine, meclizine, metoclopramide, procainamide, pyridoxine, alfentanil, naphazoline, methacycline, roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol, buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, methixene, spectinomycin, dorzolamide, chloroprothixene, lefepramine valaciklovir, vancomycin, amantadine, alfluzosine, 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 (a) 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 (b) injecting the formulation into the patient in an amount for delivering to the patient a dose of about one to 100 mg/kg of the material while the pH
    of the formulation is within said range.
15. 15. A method according to claim 14, wherein the injecting step comprises injecting the formulation intramuscularly into the patient.
16. 16. A sterile injectable formulation for intramuscular administration to a human patient, comprising (a) 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, bromhexine, phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem, clonidine, succinylcholine. 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, maprotiline, benserazide, thioridazine, cyclizine, cephepime, methadone, mexiletine, mianserin, pivmecillinam, phenylpropanolamine, morphine, ethambutol, ambenonium, naloxone, xylometazoline, procarbazine, tropisetrone, phenyiephrine; thiamine, tramadol, hydrochlorotiazid, quinagolide, noscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, chlorguanide, trihexyphenidyl, bacampicillin, cyproheptadine, prazosin, meperidine, meclizine, metoclopramide, procainamide, pyridoxine, alfentanil, naphazoline, methacycline, roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, clohutinol, sotalol, buprenorphin, tetracaine, ticlopidine. tocainide, obidoxime, imipramine, labetalol, methixene, spectinomycin, dorzolamide, chloroprothixene, lefepramine, valaciklovir, vancomycin, amantadine, alfluzosine, 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.
    (b) a liquid vehicle in which said material is in solution, (c) said material being present in said formulation in a concentration of at least about 50 mg/ml, and (d) the formulation being at a pH within a range of about 5.5 to 7Ø
17. 17. A method of administering to a human patient material selected from the group consisting of acid addition salts of malphalan, amiloride, clomipramine.
    chlorcyclizine, hydralazine, alprenolol, dopamine. quinapril, tetracycline, cimetidine, doxoruhicin, biperiden, carteolol, ranitidine, hydroxyzine, chlortetracycline. bambuterol, diphenhydramine, hetaxolol, bromhexine, phenylephrine, bupivacaine, melperone, buspirone, mepivacaine, diltiazem, clonidine. succinylcholine, daunoruhicin, 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, maprotiline, benserazide, thioridazine, cyclizine, cephepime, methadone, mexiletine, mianserin, pivmecillinam, phenylpropanolamine, morphine, ethambutol, ambenonium, naloxone, xylometazoline, procarbazine, tropisetrone, phenyiephrine, thi~mine, tramadol, hydrochlorotiazid. quinagolide, noscapine, mitoxantrone, dipivefrin, oxytetracycline, fluphenazine, chlorguanide, trihexyphenidyl, bacampicillin, cyproheptadine. prazosin, meperidine, meclizine, metoclopramide, procain~mide, pyridoxine, alfentanil. naphazoline, methacycline, roxatidine, propafenone, amitriptyline, nortriptyline, paroxetine, clobutinol, sotalol, buprenorphin, tetracaine, ticlopidine. tocainide, obidoxime, imipramine, labetaloh methixene, spectinomycin, dorzolamide, chloroprothixene, lefepramine, valaciklovir, vancomycin, amantadine, alfluzosine. 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 (a) providing a sterile formulation, comprising a liquid vehicle containing the material in solution, (b) adjusting the pH of said formulation for reducing the development of undesirable side effects of the material, and (c) administering the formulation having the adjusted pH to the patient.