Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ortho-hydroxybenzoic acid or derivative doai
Reexamination Certificate
2001-11-27
2002-11-19
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ortho-hydroxybenzoic acid or derivative doai
Reexamination Certificate
active
06482811
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel compositions and kits comprising (a) a bretylium cation, and (b) a facilitating anion and/or a &bgr;-receptor blocker. This invention also relates to the use of such compositions and kits to prevent and/or treat cardiovascular conditions.
BACKGROUND OF THE INVENTION
Bretylium tosylate 1 (also known as o-bromobenzylethyldimethylammonium p-toluenesulfonate) has the structure:
It is a known Class III antiarrhythmic agent and an adrenergic blocking agent. The bretylium cation of this compound is reported to directly modify the electrical properties of the myocardium. It also is reported to depress adrenergic neural transmission by blocking neuronal norepinephrine release and re-uptake. Bretylium tosylate consequently has been used worldwide to suppress life-threatening ventricular tachyarrhythmias, such as ventricular tachycardia and fibrillation. Bacaner (in U.S. Reissue Pat. No. 29,618) discloses suppressing cardiac ventricular fibrillation and cardiac arrhythmias generally by administering bretylium tosylate. Similarly, Bacaner (in U.S. Pat. No. 3,911,125) discloses treating angina pectoris, treating coronary insufficiency, and preventing myocardial infarction by administering bretylium tosylate.
Unformulated bretylium tosylate exhibits poor and unpredictable absorption when orally ingested. Thus, oral administration of bretylium tosylate alone is generally unsuitable for treating heart conditions and has not been approved by the FDA. Accordingly, bretylium tosylate is instead usually administered parenterally in the form of an injectable solution. This mode of administration, however, is both inconvenient and painful, particularly for chronic administration.
Administration of bretylium tosylate also can result in severely reduced ambulation in a recipient due to a sharp drop in blood pressure on assuming the upright position, resulting in dizziness and loss of consciousness. The severity of this side-effect, however, can be reduced (and the therapeutic effects of the bretylium cation can be enhanced) by administering a tricyclic anti-depressant agent (e.g., protriptyline, mazindol, amitriptyline, nortriptyline, or desipramine) with the bretylium tosylate, as disclosed by Bacaner in U.S. Pat. No. 5,036,106.
A number of studies on the bioavailability of bretylium tosylate have been described in the literature. Most these studies, however, have primarily focused on parenteral, rectal, and other non-ingested compositions comprising bretylium tosylate. Most also involve the administration of bretylium tosylate compositions under alkaline conditions.
Neubert et al. (in Ion Pair Approach of Bretylium,
Pharm. Ind.
54, Nr. 4 (1992)) disclose a series of experiments in which bretylium tosylate was studied in the presence of saccharin, dodecylsulfate, or hexylsalicylate anions. The partition coefficients for the bretylium ion were measured in the presence of these anions using an alkaline (pH=7.2) n-octanol/buffer system and using an alkaline (pH=7.2) absorption model system employing an artificial lipid membrane. Bretylium absorption in vivo was also measured in rabbits receiving the bretylium tosylate in combination with these anions by i.v. injection (an i.v. injection of bretylium tosylate in Sorensen phosphate buffer (pH=7.2), together with an i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphate buffer (pH=7.2)) or rectal administration.
Neubert et al. (in Influence of Lipophilic Counter Ions on the Transport of Ionizable Hydrophilic Drugs,
J. Pharm. Pharmacol.
1991, 43: 204-206) disclose a series of experiments on the influence of the counterions hydroxynaphthoate, naphthylsulphonate, adamantoate, desoxycholate, dehydrocholate, octanoate, decanoate, dodecanoate, hexadecanoate, and hexylsalicylate on the transport of bretylium using an alkaline (pH=7.2) absorption model system. It was reported that the use of hydroxynaphthoate, adamantoate, desoxycholate, or dehydrocholate counterions resulted in minimal or no increase in bretylium transport across the membrane. No therapeutic or electrophysiologic action is disclosed.
Neubert et al. (in Drug Permeation Through Artificial Lipoid Membranes,
Pharmazie
42 (1987), H. 5) evaluated the effect of alkylated derivatives of salicylic acid, particularly hexylsalicylic acid, on the partition and transport of ionized basic drugs including bretylium tosylate using lipophilic membranes in alkaline (pH=7.2) lipoid membrane models.
Hartl et al. (in Influence of the Ion-Pair-Formation of Bretylium and Hexylsalicylic Acid on Their Influence on Blood Plasma Levels in Dogs,
Pharmazie
45 (1990), H. 4) report an improvement in biological bretylium levels in dog plasma when a bretylium-tosylate/hexylsalicylic-acid combination was administered to dogs by i.v. injection (an i.v. injection of bretylium tosylate in Sorensen phosphate buffer (pH=7.2), together with an i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphate buffer (pH=7.2)). Hartl et al., however, do not discuss how to improve the bretylium level in the myocardium of the heart or the therapeutic effects of doing so.
Neubert et al. (in Influence of the Ion-Pair-Formation on the Pharmacokinetic Properties of Drugs (Part 4),
Pharmazie
43 (1988), H. 12) report a series of experiments to determine the pharmocokinetic parameters of bretylium tosylate administered in combination with hexylsalicylic acid in rabbits by i.v. injection or rectally. No therapeutic or electrophysiologic action is disclosed.
Amlacher et al. (in Influence of Ion-Pair Formation on the Pharmacokinetic Properties of Drugs,
J. Pharm. Pharmacol.
1991, 43: 794-797) disclose a series of experiments to measure the partition coefficients for the bretylium ion in the presence of salicylic acid using an alkaline (pH=7.2) n-octanol/buffer system. Bretylium absorption in vivo was also measured in rabbits receiving an i.v. injection of bretylium tosylate in Sorensen phosphate buffer (pH=7.2), together with an i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphate buffer (pH 7.2).
Neubert et al. (in Influence of the Ion-Pair-Formation on the Pharmacokinetic Properties of Drugs (Part 5),
Pharmazie
44 (1989), H. 9) disclose a series of experiments on the effect of ion-pair formation on the elimination of bretylium and hexylsalicylic acid in rats. In these experiments, the rats received an i.v. injection of bretylium tosylate in Sorensen phosphate buffer (pH=7.2), together with an i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphate buffer (pH=7.2) and, in some instances, an oral dose of cholestyramine. Neubert et al. concluded that the pharmacokinetic parameters of bretylium were not influenced by hexylsalicylic acid.
Cho (in WO 87/05505) discloses compositions comprising particles consisting essentially of a solid emulsifying agent and a surfactant, a biologically active proteinaceous material bound to the surface of the particles, and a lipid coating surrounding such particles. While Cho is primarily directed to pharmaceutical compositions comprising insulin, he does state generally that other pharmaceutical agents, such as bretylium tosylate, could be employed. Additional ingredients in the composition are described to include, among others, sodium lauryl sulfate (as a surfactant), sodium bicarbonate, and citric acid.
Stanley et al. (in U.S. Pat. Nos. 5,288,497 and 5,288,498) disclose a dissolvable or non-dissolvable drug containing matrix form for administering a drug for absorption through the mucosal tissues of the mouth, pharynx, and esophagus. Stanley et al. identify a large group of active drugs that can be administered buccally in accordance with the invention. These references further disclose a variety of additional ingredients that can be included in the matrix including, among others, sodium lauryl sulfate and sodium dodecyl sulfate (as “permeation enhancers”) and buffering systems (to adjust salival pH). Although the Stanl
Bacaner Marvin B.
Kreevoy Maurice M.
Henley III Raymond
Senniger Powers Leavitt & Roedel
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