WO1998000159A1 - 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 7.0.

Description

USEFUL FORMULATIONS 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.

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: 1 141 - 1 144, 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 , Kjellen 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 Pharmacology & Toxicology 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. 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). (4) A. 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") .

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 side chain, so that drugs such as the nicotinamides, benzamides, 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-Sensamide™ has a reduced extrapyramidal side effect profile 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 6:451-453, 1995, Pero et al, Biochimie 77:385-393, 1995; Pero et al unpublished 1996; Rotmensch et al unpublished 1996) . Therefore, it is logical to extrapolate these data to other drugs containing acid addition salt structures in the following way: Compounds that can form acid salts of types A or B:

R₁_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) Ri 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 by 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 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 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 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 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 - 7.0.

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 (U . S . Patent application No. 08/218,072, Pero et al unpublished 1996) . 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 5.5 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 7.0 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 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 - 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 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 (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. 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 7.0.

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

Formula (B) having a quaternary ammonium ion present, and mixtures thereof, Formula (A) and Formula (B) being as follows:

R₄

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 R₃ and R₄ 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 , F , Br or T. 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 (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 DESCRIPTION OF DRAWINGS

Fig . l is a graph on which the UV absorption intensity is plotted against wavelength of UV absorption between 195 nm and 215 nm for 100 μM 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 μM 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 μM solutions of aqueous (pH 5-6) and acidic (pH 2-3) lidocaine are plotted against the wavelength of UV absoφtion between 195 nm and 380 nm.

Fig. 2C is a graph on which the UV absoφtion intensity of 100 μlM solutions of aqueous (pH 5-6) and acidic (pH 2-3) metoclopramide are plotted against the wavelength of UV absoφtion between 195 nm and 380 nm.

Fig. 2D is a graph on which the UV absorption intensity of 100 μM 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 μM 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. Fig. 2F is a graph on which the UV absoφtion intensity of 100 μM 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 μM 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 pharmacological properties (e.g. 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 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 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 invention embraces the feature that high concentrations of metoclopramide hydrochloride (e.g. 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 dopamine₂ (D2) receptor and the 5-hydroxytryptamine₃ (5-HT₃ ) receptor (Pharmacokinetic principles in the use drugs, in Medical Pharmacology, A. Goth ed. , CV. 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-S1 1 , 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 sensitive conformational changes observed for metoclopramide especially at A₂₀o (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 (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 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 μM 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 I N HC1 and IN NaOH to produce pH gradient solutions which were then subjected to scanning of the UV spectrum between A₁₉₅ and A₃₈₀. The UV spectra were corrected for absorption from appropriate solvent blanks .

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 6.0. 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.

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 A₂₀₀ 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 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 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 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:

Metoclopramide -HC1 "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^"

Neu-Sensamide™

"extended side chain conformation' 1 hydrogen bond defines structure poorer binding at d-2 receptor

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 D₂ 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 D₂ receptor. In a broader sense, Table 1 also shows that changes in UV absorption at A_20ϋ 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 A₂₀₀. 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 A₂₀₀ (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 A_20fl.

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 μM 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 (i.e. pH 5-6).

Drug/ Agent -.200- Comments

(1) 3 Amino benzamide No N-substitution of benzamide-

Acidic 1.150 no pH change at A₂₀₀

Aqueous 1.150

(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 A_20o

Aqueous 1.400

(4) 3-Chloro procainamide N-alkylaminodialkyl substituted

Acidic 0.200 benzamide-pH change at A₂₀₀

Aqueous 2.700

(5) Procainamide 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 A₂₀₀ Aqueous 2.800

(7) Lidocaine N-alkylaminodialkyl substituted

Acidic 0.180 benzamide-pH change at A₂₀₀ Aqueous 2.700

(8) Chlorpromazine N-alkylaminodialkyl substituted

Acidic 0.200 phenothiazine-pH change at A_20o Aqueous 2.600 Example 4

List of drugs capable of forming acid addition salts via the formation of a quaternized nitrogen (e.g. 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 (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 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.

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.

1. MELPHALAN [148-82-3]

TRADE NAME ALKERAN (GLAXO, WELLCOME)

H CLINICAL USE. CYTOSTATIC, ALKYLATING AGENT

2. AMILORIDE [2609-46-3]

TRADE NAME AMILOFERM (NORDIC) AMILORID (NM PHARMA) MIDAMOR (MSD) MODURETIC (MSD) NORMORIX (NYCMED) SPARKAL (SELENA)

CLINICAL USE POTASSIUM-SPARING DIURETIC

3 CLOMIPRAMINE .363-49-11

TRADE NAME ANAFRANIL (CIBA) KLOMIPRAMIN (NM PHARMA)

CLINICAL USE ANTIDEPRESSANT

4 CHLORCYCUZINE 182-93-91

TRADE NAME ANERVAN (RECIP) DI-PARALENE (ABBOTT) EXOLYT (ABIGO) H -N N -CH₃ CLINICAL USE ANTIHISTAMINE

5. HYDRALAZINE [86-54-4]

TRADE NAME APRESOLIN (CIBA) CLINICAL USE: ANTIHYPERTENSIVE

6. ALPRENOLOL [13655-52-2]

TRADE NAME: APTIN (HASSLE)

CLINICAL USE ANTIHYPERTENSIVE ANTIARRHYTHMIC

7 DOPAMINE [51-61-6]

TRADE NAME. ABBODOP (ABBOTT) GILUDOP (MEDA) INTROPIN (HASSLE)

CLINICAL USE ADRENERGIC

8. QUINAPRIL [85441-61-8]

TRADE NAME. ACCUPRO (PARKE DAVIS) CLINICAL USE: ANTIHYPERTENSIVE TETRACYCLINE [60-54-81

TRADE NAME ACHROMYCIN (LEDERLE) ACTISITE (MEDA) TETRACYKLIN (NM PHARMA)

CLINICAL USE ANTIBACTERIAL

CIMETIDINE [51481-61-91

TRADE NAME ACILOC (ORION)

ACINIL (SELENA)

CIMETIDIN (SELENA)

TAGAMET (SMITH KLINE BEECHA) CLINICAL USE HISTAMINE 2 RECEPTOR ANTAGONIST, ESPECIALLY IN THE TREATMENT OF DUODENAL AND GASTRIC ULCERS

1 DOXORUBICIN [23214-92-81

TRADE NAME ADRIAMYCIN

(PHARMACIA & UPJOHN) DOXORUBICIN (NYCOMED)

CLINICAL USE ANTINEOPLASTIC

2 BIPERIDEN [514-65-81

TRADE NAME AKINETON (MEDA) CLINICAL USE ANTICHOLINERGIC ANTIPARKINSON

13. CARTEOLOL [51781-06-7]

TRADE NAME: ARTEOPTIC (CIBA VISION)

CLINICAL USE: β-RECEPTOR BLOCKER

H₂NHC(CH₃)₃

14. RANITIDINE [66357-35-5]

TRADE NAME: ARTONIL (SELENA)

ZANTAC (GLAXO WELLCOME)

CLINICAL USE: ANTIULCERATIVE

15. HYDROXYZINE [68-88-2]

TRADE NAME: ATARAX (UCB) HISTILOS (UCB) VISTARIL (ROERIG)

CLINICAL USE: TRANQUILIZER

16. CHLORTETRACYCUNE [57-62-5]

TRADE NAME: AUREOMYCIN (LEDERLE)

CLINICAL USE: ANTIBIOTIC

BAMBUTEROL

TRADE NAME BAMBEC (DRACO)

H₃CNCOO

CH₃

CH₃ - CLINICAL USE BRONCHODIALATOR

-CHOHCH₂NHCCH₃ CH₃

H₃CNCOO

CH₃

DIPHENHYDRAMINE [482-05-31

TRADE NAME BENYLAN (PARK-DAVIS) DESENTOL (PHARMACIA & UPJOHN)

CLINICAL USE ANTIHISTAMINE ANTI-MOTIONSICKNESS

BETAXOLOL [63659-18-71

TRADE NAME BETOPTIC (ALCON) KERLON (SEARLE)

CLINICAL USE ANTI-GLAUCOMA

ANTIHYPERTENSIVE

BROMHEXINE .3572-43-8]

TRADE NAME BISOLVON (BOEHRINGER)

Br BROMHEXIN (ACO) MOLLIPECT (TIKA)

CH₂NCH₃ CLINICAL USE MUCOLYTIC EXPECTORANT

Br NH₂ PHENYLEPHRINE HYDROCHLORIDE [61-76-71

TRADE NAME BLEFCON (ALLERGAN) METAOXEDRIN (MEDA) NEOSYNEPHRINE

CH₂NH-CH₃ (SANOFI WINTHROP) ZINCFRIN (ALCON)

CLINICAL USE ADRENERGIC

BUPIVACAINE [2180-92-91

TRADE NAME BUPIVAKAIN (NORCOX) MARCAIN (ASTRA)

CLINICAL USE LOCAL ANAESTHETIC

MELPERONE [3575-80-2]

TRADE NAME BURONIL (LUNDBECK)

CLINICAL USE NEUROLEPTIC

BUSPIRONE [36505-84-7]

TRADE NAME BUSPAR

(BRISTOL-MEYERS SQUIBB)

CLINICAL USE ANXIOLYTIC 25. MEPIVACAINE [96-88-8]

TRADE NAME CARBOCAIN (ASTRA) CLINICAL USE LOCAL ANAESTHETIC

26 DILTIAZEM [42399-41-71

TRADE NAME: CARDIZEM

(PHARMACIA & UPJOHN) ENTRYDIL (ORION) TILDIEM (TIKA)

CLINICAL USE CALCIUM ANTAGONIST VASODILATOR

27 CLONIDINE [4205-90-7]

TRADE NAME CATAPRESAN

(BOEHRINGER INGELHEIM)

CLINICAL USE ANTIHYPERTENSIVE

28. SUCCINYLCHOLINE CHLORIDE [71-27-2]

CH₃ TRADE NAME. CELOCURIN

/ (PHARMACIA & UPJOHN)

COOCH₂CH₂N⁺CH₃

CLINICAL USE SKELETAL MUSCLE RELAXANT CH₂ ^XCH₃ (SHORT DURATION)

CH_{2 /} ^CH3

COOCH₂CH₂N⁺CH₃ ^N CH₃ DAUNORUBICIN [20830-81-3]

TRADE NAME CERUBIDIN (RHONE-POULENC RORER)

DAUNOXOME (SWEDISH ORPHAN)

CLINICAL USE CYTOSTATIC

CIPROFLOXACINE [85721-33-1. 86393-32-0(HCI)]

TRADE NAME CILOXAN (ALCON)

CIPROXIN (BAYER)

CLINICAL USE ANTIBACTERIAL

CLOPENTHIXOL [982-24-1]

TRADE NAME CISORDINOL (LUNDBECK) CLINICAL USE ANTIPSYCHOTIC

PRILOCAINE [721-50-61

TRADE NAME CITANEST (ASTRA) EMLA (ASTRA)

CLINICAL USE LOCAL ANAESTHETIC

FTHYLMORPHINE [76-58-4]

TRADE NAME COCILLANA - ETYFIN (PHARMACIA & UPJOHN) COSYLA (PARKE-DAVIS) LEPHETON (PHARMACIA & UPJOHN)

CLINICAL USE ANTITUSSIVE

TACRINE [321-64-2]

TRADE NAME COGNEX (PARKE-DAVIS) CLINICAL USE CHOLINERGIC

PROTRIPTYLINE [438-60-8]

TRADE NAME CONCORDIN (MSD) CLINICAL USE ANTIDEPRESSANT

AMIODARONE [1951-25-31

TRADE NAME CORDARONE

(SANOFI WINTHROP)

CLINICAL USE ANTIARRYHYTHMIC 7 CYCLOPENTOLATE [512-15-21

TRADE NAME CYCLOGYL (ALCON) CYCLOPENTOLAT (MEDA)

CLINICAL USE ANTICHOLINERGIC

8 CLINDAMYCIN [18323-44-91

TRADE NAME DALACIN

(PHARMACIA & UPJOHN)

CLINICAL USE ANTIBIOTIC

9 PROPOXYPHENE [469-62-5]

TRADE NAME DEXODON (TIKA) DEXOFEN (ASTRA) CH₃ CH₃ DISTALQESIC (LILLY) pHCH₂NCH₃ DOLERON (ASTRA)

/ DOLOTARD (NYCOMED) DOLOXENE (LILLY) PARAFLEX (ASTRA)

^ -CH₂ OOCCH₂CH₃

CLINICAL USE ANALGESIC

0 HYDROMORPHONE [466-99-9]

TRADE NAME DILAUDID (MEDA) CLINICAL USE ANALGESIC

41. ORPHENADRINE [83-98-7]

ΓΛ TRADE NAME. DISIPAL (YAMANOUCHI)

CH₃ NORFLEX (3M) NORGESIC (3M)

CH₃

CLINICAL USE: MUSCLE RELAXANT (SCELETETAL) ANTIPARKINSON

42. DOBUTAMINE [30468-04-2]

TRADE NAME: DOBUJECT (LEIRAS) DOBUTREX (LILLY)

CLINICAL USE: CARDIOTONIC

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

TRADE NAME: DOPACARD (FISONS)

CLINICAL USE: CARDIOTONIC

44. DOXYCYCLINE [564-25-0]

TRADE NAME: DORYX (SCAND PHARM) DOXYCYKLIN (ENAPHARM) DOXYFERM (NORDIC) IDOCYKLIN (ROERIG) VIBRAMYCIN (PFIZER)

CLINICAL USE: ANTIBACTERIAL

NEOMYCIN [1404-04-2, FOR THE MIXTURE]

TRADE NAME ECOMYTRIN (LUNDBECK)

CELESTON (SCHERING-PLOUGH) DECARDRON (MSD) ISOPTO - BIOTIC (ALCON) NEBACETIN (LUNDBECK)

CLINICAL USE ANTIBACTERIAL

NEOMYCIN B R = H, R¹ = CH₂NH₂ NEOMYCIN C R = CH₂NH₂, R¹ = H

TRADE NAME EFEDRIN (NM PHARMA) LEPHETON (PHARMACIA & UPJOHN) LERGIQAN (RECIP) MOLLIPECT (TIKA)

CLINICAL USE ADRENERGIC

VENLAFAXINE fl

TRADE NAME EFEXOR (WYETH) CLINICAL USE ANTIDEPRESSANT

ETILEFRIN [709-55-71

HO TRADE NAME EFFORTIL

(BOEHRINGER INGELHEIM)

CLINICAL USE ADRENERGIC

DOPAMINERGIC

ANTIHYPERTENSIVE

DEPRENYL [2323-36-6]

TRADE NAME ELDEPRYL (ORION) SELEGILIN (NM PHARMA)

CLINICAL USE ANTIPARKINSON

EPIRUBICIN [56390-09-1 (HCI), 56420-45-2(BAS)]

TRADE NAME FARMORUBICIN

(PHARMACIA & UPJOHN)

CLINICAL USE ANTINEOPLASTIC ANTIBIOTIC

FLUPENTIXOL [2709-56-01

TRADE NAME FLUANXOL (LUNDBECK)

CLINICAL USE ANTIPSYCHOTIC

BENOXINATE 199-43-41

TRADE NAME FLURESS (ABIGO)

OXIBUPROKAIN (MEDA)

CLINICAL USE ANAESTHETIC (TOPICAL)

FLUOXETIN .54910-89-31

TRADE NAME FONTEX (LILLY) CLINICAL USE ANTIDEPRESSANT

GEMCITABINE fl

TRADE NAME GEMZAR (LILLY) CLINICAL USE ANTINEOPLASTIC

ADRENALINE/EPINEPHRINE [1

TRADE NAME CITANEST ADRENALIN

(ASTRA)

EPPY (ABIGO)

GLAUFRIN (ALLERGAN)

MARCAIN ADRENALIN

(ASTRA)

XYLOCAIN ADRENALIN

(ASTRA)

CLINICAL USE ADRENERGIC

METFORMIN [657-24-9]

TRADE NAME GLUCOPHAGE (MEDA)

NH ™ ii II CLINICAL USE ANTIDIABETIC (CH₃)₂N-C-NHCNH₂ CHLORPROMAZINE [50-53-31

TRADE NAME HIBERNAL (RHONE-POULENE RORER) CLINICAL USE ANTI-EMETIC

TRANQUILIZER

(CH₃)₂ SEDATIVE

PRENALTEROL [57526-81-51

TRADE NAME HYPRENAN (HASSLE) CLINICAL USE ADRENERGIC

TE R AZOSI N E.63590-64-7 , 70024-40-7(HYDROCHLORIDE)]

TRADE NAME HYTRINEX (ASTRA)

SINALFA (SINALFA ABBOTT)

CLINICAL USE ANTIHYPERTENSIVE

OXYMETAZOUNE [1491-59-41

TRADE NAME LLIADIN (MEDA)

NASIN (TIKA) NEZERIL (DRACO) ZOLIN (ACO)

CLINICAL USE ADRENERGIC 61 LOPERAMJDE [53179-11-6]

TRADE NAME IMODIUM

(JENSSEN-CILAG)

LOPERAMID

(SCAND PHARM)

PRIMODIUM

(JENSSEN-CILAG)

TRAVELLO

(PHARMACIA & UPJOHN)

CLINICAL USE ANTIDIARETIC

62 PROPRANOLOL ,525-66-61

TRADE NAME INDERAL (ZENECA) PROPRANOLOL (NM PHARMA)

CLINICAL USE β-ADRENERGIC BLOCKER

₂CHCH₂NHCH(CH₃)₂ ANTIARRHYTHMIC

OH

63 LIDOCAINE [137-58-6]

TRADE NAME DEPO - MEDROL (PHARMACIA & UPJOHN) EMLA (ASTRA) INSTILLAGEL (ELLEM) LEDERSPAN (LEDERLE) XYLOCAIN (ASTRA) XYLOCARD (ASTRA) XYLOPROCT (ASTRA)

CLINICAL USE LOCAL ANAESTHETIC

64 APR AC LON I DINE [66711-21 -51

TRADE NAME LOPIDINE (ALCON)

CLINICAL USE TREATMENT OF POSTSURGICAL

ELEVATED INTRAOCULAR PRESSURE

5. VERAPAMIL [52-53-9]

TRADE NAME: ISOPTIN (MEDA) VERALOC (ORION) VERAPAMIL (NM PHARMA)

CLINICAL USE: ANTIARRHYTHMIC VASODILATOR

66. PILOCARPINE [92-13-7]

TRADE NAME: FOTIL (LEIRAS)

V° ISOPTO - PILOKARPIN (ALCON)

CH₃ LICARPIN (ALLERGAN)

CH₃CH₂ H PILOKARPIN (MEDA) SPERSACARPINE (CIBA)

H CH₂- TIMPILO (MSD)

N CLINICAL USE: ANTIGLAUCOMA CHOLINERGIC

67. PROCYCUDINE [77-37-2]

TRADE NAME: KEMADRIN

(GLAXO WELLCOME) CLINICAL USE: ANTIPARKINSON

68. KETAMINE [6740-88-1]

TRADE NAME: KETALAR (PARKE-DAVIS) CLINICAL USE: GENERAL ANAESTHETIC

69. KFTOBEMIDON []

TRADE NAME: KETOGAN (NOVUM-LUNDBECK) CLINICAL USE. ANALGETIC SPASMOLYTIC

70. QUINIDINE [130-95-0, 60-93-5(HYDROCHLORIDE)]

TRADE NAME: KININ (NM PHARMA) CLINICAL USE ANTIMALARIAL

H

71 GRANISETRONE [109889-09-0, 107007-99-8(HYDROCHLORIDE)]

TRADE NAME. KYTRIL

(SMITH KLINE BEECHAM)

CLINICAL USE ANTIEMETIC

72. MEFLOQUIN [51773-92-3(HYDROCHLORIDE)]

TRADE NAME: LARIAM (ROCHE) CLINICAL USE. ANTIMALARIAL

73. PROMETHAZINE [7440-12-12]

TRADE NAME LERGIGAN (RECIP) CLINICAL USE. ANTIHISTAMINE

74 REMOXIPRIDE fl

TRADE NAME: ROXIAM (ASTRA) CLINICAL USE. NEUROLEPTIC

75 LINCOMYCIN [154-21-21

TRADE NAME: LINCOCIN (UPJOHN)

CLINICAL USE. ANTIBIOTIC

76. LEVOCABASTIN []

TRADE NAME: LIVOSTIN (JENSSEN-CILAG)

CLINICAL USE. H ANTAGONIST

77 AMORQLFINE 178613-35-1 , 78613-38-4(HYDROCHLORIDE)]

TRADE NAME. LOCERYL (ROCHE) CLINICAL USE ANTIMYCOTIC

78 MAPROTILINE [10260-69-81

TRADE NAME LUDIOMIL (CIBA) MAPROTILIN (NM PHARMA)

CLINICAL USE ANTIDEPRESSANT

79 BENSERAZIDE .322-35-01

TRADE NAME MADOPARK (ROCHE)

CLINICAL USE ANTIPARKINSON DOPAMINERGIC

80 THIORIDAZINE [50-52-2]

TRADE NAME MALLOROL (SANDOZ) CLINICAL USE NEUROLEPTIC

81 CYCUZjNE [82-92-8]

TRADE NAME MARZINE

(GLAXO WELLCOME)

CLINICAL USE ANITHISTAMINE -CH₃ ANTIEMETIC

82 CEPHEPIME I

TRADE NAME MAXIPIME

(BRISTOL-MEYERS SQUIBB)

CLINICAL USE ANTIBIOTIC

83 METHADONE [1095-90-51

TRADE NAME METADON

(PHARMACIA & UPJOHN)

CLINICAL USE NARCOTIC ANALGETIC

84 MEXILETINE [31828-71 -41

TRADE NAME MEXITIL

(BOEHRINGER INGELHEIM)

CLINICAL USE ANTIARRHYTHMIC

85 MIANSERIN [24219-97-41

TRADE NAME MIANSERIN (NM PHARMA) TOLVON (ORGANON)

CLINICAL USE ANTIDEPRESSANT

CH -

86 PIVMECILLINAM fl

TRADE NAME MIRAXID (LOVENS)

CLINICAL USE ANTIBACTERIAL

87 PHENYLPROPANOLAMINE [154-41-611

TRADE NAME LUNERIN (TIKA) MONYDRIN (TIKA) RINEXIN (RECIP) RINOMAR (RECIP)

CLINICAL USE VASOCONSTRICTOR

ADRENERGIC

88 MORPHINE [52-27-2]

TRADE NAME DOLCONTIN

(PHARMACIA & UPJOHN) LOCEPTIN (NYCOMED) MAXIDON (ASTRA) MORFIN

(PHARMACIA & UPJOHN) SPASMOFEN (ABIGO)

CLINICAL USE NARCOTIC ANALGESIC

89. FTHAMBUTOL [304-84-7]

TRADE NAME: MYAMBUTOL

CH3CH2CHNHCH2-CH2NHCHCH2CH (LEDERLE)

CLINICAL USE: TUBERCULOSTATIC

HOH₂C CH₂OH

90. AMBENONIUM CHLORIDE [115-79-7]

TRADE NAME: MYTELASE

(SANOFI WINTHROP)

CLINICAL USE: CHOLINESTERASE INHIBITOR

91. NALOXONE [465-65-6]

TRADE NAME: NARCANTI (MEDA) CLINICAL USE: ANTAGONIST (TO NARCOTICS)

92. XYLOMETAZOLINE [526-36-3]

TRADE NAME: NASOFERM (NORDIC) OTRIVIN (CIBA)

CLINICAL USE: ADRENERGIC VASOCONSTRICTOR

93. PRQCARBAZINE [671-16-9]

TRADE NAME. NATULANAR (ROCHE)

CLINICAL USE. ANTINEOPALSTIC

94. TROPISETRONE []

TRADE NAME NAVOBAN (SANDOZ) CLINICAL USE ANTIEMETIC

95 PHENYLEPHRINE .61-76-7. HYDROCHLORIDE.1

TRADE NAME: BLEFCON (ALLERGAN) ISOPTO-BIOTIC (ALCON) METAOXEDRIN (MEDA) NEOSYNEPHRINE (SANOFI WINTHROP) ZINCFRIN (ALCON)

CLINICAL USE: ADRENERGIC

96. THIAMINE [67-03-8]

TRADE NAME: ASTRATONIL FORTE (ASTRA) BETABION (MEDA)

CLINICAL USE ENZYME

CO-FACTOR-VITAMIN B1

97 TRAMADOL [27203-92-5, 22204-88-2(HYDROCHLORIDE)]

TRADE NAME NOBLIGAN (SEARLE) CLINICAL USE. ANALGESIC

98 HYDROCHLOROTIAZID [58-93-5]

TRADE NAME. SPARKAL (SELENA)

TRIATEC COMP (HOECHST) AMILOFERM (NORDIC)

CLINICAL USE DIURETIC

99 QUINAGOUDE r

TRADE NAME NORPROLAC (SANDOZ)

CLINICAL USE PROLACTIN ANTAGONIST

100 NOSCAPINE [128-62-1. 912-60-7(HYDROCHLORIDE)]

TRADE NAME NIPAXON (PHARMACIA & UPJOHN) NOSKAPIN (ACO) SPAMOFEN (ABIGO)

CLINICAL USE ANTITUSSIVE

101 MITOXANTRONE 165271-80-90. 76476-82-3( HYDROCHLORIDE)]

TRADE NAME NOVANTRONE

(LEDERLE)

CLINICAL USE ANTINEOPALSTIC

102 DIPIVEFRIN [52365-63-6. 64019-93-8(HYDROCHLORIDE)]

TRADE NAME OFTAPINEX (LEIRAS) PROPINE (ALLERGAN)

(CH₃)₃CCOO_v

CLINICAL USE ANTI-GLAUCOMA ADRENERGIC (CH₃)₃CCOO- V-9^HCH2^NHCH3

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

TRADE NAME OXYTETRAL (DUMEX)

TERRACORTRIL (PFIZER) TERRAMYCIN (PFIZER)

CLINICAL USE ANTIBIOTIC

104 FLUPHENAZ1NE [69-23-8. 146-56-5(HYDROCHLORIDE)]

TRADE NAME PACINOL (SCHERING- PLOUGH)

SIQUALONE (BRISTOL MEYERS-SQUIBB)

CLINICAL USE ANTIPSYCHOTIC

-CH₂CH₂OH

105 CHLORGUANIDE [500-92-5]

TRADE NAME PALUDRINE

(ZENECA)

CLINICAL USE. ANTIMALARIAL

106. TRIHEXYPHENIDYL [52-49-3]

TRADE NAME PARGITAN (ABIGO)

CLINICAL USE ANTIPARKINSON

107 BACAMPICILLIN [50972-17-3. 37661 -08-8(HYDROCHLORIDE)]

TRADE NAME PENGLOBE (ASTRA)

CLINICAL USE ANTIBACTERIAL

108. CYPROHEPTADINE [129-03-3, 41354-29-4(HYDROCHLORIDE)]

TRADE NAME PERIACTIN (MSD) CLINICAL USE H1 ANTAGONIST ANTIHISTAMINE

109 PRAZOSIN [19216-56-9, 19237-84-4(HYDR0CHLORIDE)]

TRADE NAME PERIPRESS (PFIZER)

CLINICAL USE α1-ADRENERGIC BLOCKER ANTIHYPERTENSIVE

110 MEPERIDINE [57-42-1. 50-13-5(HYDROCHLORIDE)]

TRADE NAME PETIDIN

(PHARMACIA & UPJOHN) CLINICAL USE NARCOTIC ANALGETIC

111 MECLIZINE [569-65-3, 31884-77-2(HYDROCHLORIDE)] ' TRADE NAME HISTILOS (UCB) POSTAFEN (UCB) CLINICAL USE ANTIEMETIC

112 METOCLOPRAMIDE [364-62-5, 54143-57-6(HYDROCHLORIDE)

TRADE NAME PRIMPERAN

(LUNDBECK)

CLINICAL USE ANTIEMETIC

113 PROCAINAMIDE .614-39-1]

TRADE NAME PROKAINAMID (HASSLE)

CLINICAL USE ANTIARRYTHMIC

114 PYRIDOXINE [58-56-01

TRADE NAME ASTRANOIL FORTE (ASTRA)

CLINICAL USE VITAMIN B6

115 ALFENTANIL [71195-28-6 70879-28-6(HYDROCHLORIDE)]

TRADE NAME RAPIFEN

(JENSSEN-CILAG)

CLINICAL USE NARCOTIC ANALGESIC

116 NAPHAZOLINE .835-31-4. 550-29-2(HYDROCHLORIDE)]

TRADE NAME ANTASTEN-PRIVIN (CIBA VISION) RIMIDOL (UCB)

CLINICAL USE ADRENERGIC (VASOCONSTRICTOR DECONGESTANT

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

TRADE NAME RONDOMYCIN (ROERIG)

CLINICAL USE ANTIBACTERIAL

118 ROXATIDINE .1

TRADE NAME ROXIT (HOECHST) CLINICAL USE ANTI-ULCERATIVE

119 PROPAFENONE [54063-53-5, 34183-22-7(HYDROCHLORIDE)]

TRADE NAME RYTMONORM (MEDA)

CLINICAL USE ANTIARRHYTHMIC

120 AMITRIPTYLINE f50-48-6 549-18-8(HYDROCHLORIDE)]

TRADE NAME SAROTEN (LUNDBECK) TRYPTIZOL (MSD)

CLINICAL USE ANTIDEPRESSANT

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) CLINICAL USE. ANTIDEPRESSANT

123. CLOBUTINOL [14860-49-2]

TRADE NAME SILOMAT

(BOEHRINGER INGELHEIM)

CLINICAL USE. ANTITUSSIVE

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

TRADE NAME: SOTACOR

(BRISTOL-MEYERS SQUIBB) SOTALOL (NM PHARMA)

CLINICAL USE. ANTIANGINAL

ANTIARRHYTHMIC

ANTIHYPERTENSIVE 125 BUPRENORPHINE [52485-79-7. 53152-21-9(HYDROCHLORIDE)]

126 TETRACAINE [136-47-01

TRADE NAME TETRACAIN (ALCON) CLINICAL USE ANAESTHETIC (TOPICAL)

127 TICLOPIDINE [55142-85-3, 53885-31-1 (HYDROCHLORIDE)]

TRADE NAME TICLID (SANOFI WINTHROP)

CLINICAL USE PLATELET AGGREGATION INHIBITOR

128 TOCAINIDE [41708-72-91

CH₃ TRADE NAME TONOCARD (HASSLE)

CLINICAL USE ANTIARRHYTHMIC

/ V_NHCOCHNH₂

CH CH₃ ³ 129 OBIDOXIME CHLORIDE [ 14-90-9]

TRADE NAME TOXOGONIN (MEDA) CLINICAL USE CHOLINESTERASE REACTIVATOR

130 IMIPRAMINE [50-49-7. 113-52-0(HYDROCHLORIDE)]

TRADE NAME TOFRANAL (CIBA)

CLINICAL USE ANTIDEPRESSANT

131 LABETALOL [36894-69-6. 32780-64-6(HYDROCHLORIDE)]

TRADE NAME TRANDATE

(GLAXO WELLCOME)

CLINICAL USE ANTIHYPERTENSIVE

132 METHIZENE [4969-02-2. 7081-4-5(HYDROCHLORIDE)J

TRADE NAME TREMOQUIL (ASTRA)

CLINICAL USE ANTICHOLINERGIC ANTIPARKINSON

133. SPECTINOMYCIN [1695-77-8. 22189-32-3(HYDROCHLORIDE)]

TRADE NAME: TROBICIN

(PHARMACIA & UPJOHN)

CLINICAL USE: ANTIBIOTIC

134. DORZOLAMIDE π

TRADE NAME: TRUSOPT (MSD)

CLINICAL USE: ANTIGLAUCOMA,

CARBONIC ANHYDRASE ANTAGONIST

135. CHLORPROTHIXENE [113-59-7]

TRADE NAME: TRUXAL (LUNDBECK)

CLINICAL USE. ANTIPSYCHOTIC

136. LOFEPRAMINE [23047-25-8, 26786-32-3(HYDROCHLORIDE)]

TRADE NAME. TYMELYT (LUNDBECK) CLINICAL USE: ANTIDEPRESSANT

137 VALACIKLOVIR fl

TRADE NAME VALTREX

(GLAXO WELLCOME)

CLINICAL USE ANTIVIRAL AGENT

139 AMANTADINE f768-94-5, 665-66-7(HYDROCHLORIDE)]

TRADE NAME VIROFRAL (FERROSAN) CLINICAL USE ANTIVIRAL (INFLUENZA A)

140 ALFLUZOSINE 11

141. IDARUBICIN .1

TRADE NAME ZAVEDOS

(PHARMACIA & UPJOHN)

CLINICAL USE CYTOSTATIC

142 ONDANSETRON [99614-02-5, 99614-01-4(HYDROCHLORIDE)]

TRADE NAME ZOFRAN

(GLAXO WELLCOME)

CLINICAL USE ANTIEMETIC

143 CETIRIZINE [83881-51-0, 83881-52-1 (HYDROCHLORIDE)]

TRADE NAME ZYRLEX (UCB)

CLINICAL USE ANTIHISTAMINE

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

CLAIMSWhat is claimed is:

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 (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:

H ¹ Y^"

\^x _{+ Rl} -(CH₂)_n-N — R₂ (A)

wherein R, 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. A method according to claim 1 , wherein said hydrogen bond acceptor site is a carbonyl or carboxylic oxygen atom.

3. A method according to claim 1 , wherein X is Cl ^', F ^', Br ^" or I -

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. A method according to claim 1 , wherein said formulation is provided at a concentration of about 100 to 7000 mg/ml.

6. A method according to claim 1 , wherein the injecting step comprises injecting the formulation intramuscularly into the patient.

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:

H

\^X ₊

^R1 -(^CH2)n-N — ^R2 (A)

X

+

Rl -(CH₂)_n- N — R₃ (B)

wherein R, 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 7.0.

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 . 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. 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.

1 1 . 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. 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:

^H Y^"

\^X ₊ ^R1 - (^C 2)n -^N — ^R2 (A)

wherein R, 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 R, 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. 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. 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, 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, 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. A method according to claim 14, wherein the injecting step comprises injecting the formulation intramuscularly into the patient.

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 , 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,

(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 7.0.

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, 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, clobutinol, sotalol, buprenorphin, tetracaine, ticlopidine, tocainide, obidoxime, imipramine, labetalol, methixene, spectinomycin, dorzolamide, chloroprothixene, lefepramine, valaciklovir, vancomycin, amantadine, alfluzosine, idarubicin, ondansetron, cetirizine, 3-chJoro 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 .