US3501577A - Method of treating hypertension with alkali metal salts of zinc diethylenetriaminepentaacetate - Google Patents

Description

United States Patent METHOD OF TREATING HYPERTENSION WITH ALKALI METAL SALTS 0F ZINC DIETHYLENE- TRIAMINEPENTAACETATE Robert C. ONeill, Newark, N.J., assignor to Cooper Laboratories, Inc., Mystic, Conn., a corporation of Delaware No Drawing. Filed Nov. 21, 1967, Ser. No. 684,637

Int. Cl. A61k 27/00 US. Cl. 424-289 3 Claims ABSTRACT OF THE DISCLOSURE The sodium and potassium salts of the zinc chelate of diethylenetriaminepentaacetic acid (Na ZnDTPA and K ZnDTPA); therapeutic combinations containing Na Zn DTPA or K ZnDTPA or both; and methods of treating hypertension utilizing Na ZnDTPA or K ZnDTPA or both.

CHzCOO -M M- 000C112 GHQ-CH2 CHzCHzN i/ N C(z/iri nn 00 0 o o o where M represents sodium or potassium ions and n is a low number up to 6. The lower hydrates which are obtained, for example, when the compounds are evaporated to constant dryness are highly hygroscopic and tend to pick up moisture to form the hexahydrate which is stable. For the purpose of this invention there is no preference between the anhydrous salts and the various hydrates. As a matter of convenience their quantities are therefore better described by the amount of zinc present, i.e., the zinc equivalent.

Na ZnDTPA and K ZnDTPA can be used orally and parenterally in doses to provide the equivalent of as much as 40 mg. of zinc daily per kilogram of body weight. Generally lower levels are preferred. The preferred route of administration is intermuscularly.

According to this invention, the Na ZnDTPA and K ZnDTPA can be associated with a carrier which can be either a solid material or a sterile parenteral liquid. The compositions can take the form of tablets, powders, capsules, or other dosage forms which are particularly useful for oral ingestion. Liquid diluents are emplayed in sterile condition for parenteral use, that is, by injecttion. Such a medium can be a sterile solvent such as water. The compositions can take the form of active material, namely, Na ZnDTPA or K ZnDTPA or both, admixed with solid diluents, tableting adjuvants, such as cornstarch, lactose, talc, stearic acid, magnesium stearate, gums, or the like. Any of the tableting materials used in pharmaceutical practice can be employed where there is no incompatibility with the Na ZnDTPA and K ZnDPTA. The material can be tableted with or without adjuvants. Alternatively Na Zn-DTPA or K ZnDTPA or both with adjuvant material can be placed in the usual capsule or resorbable material such as the usual gelatine capsule and administered in that form. Na ZnDTPA and CHzCOO M -nHzO K ZnDTPA can also be put up into powder packets. Alternatively Na ZnDTPA or K3ZHDTPA or both can be prepared in the form of a suspension in a material in which Na Zn'DTPA and K ZnDTPA are not soluble.

EXAMPLE I To a stirred, externally cooled suspension of diethylenetriaminepentaacetic acid (400 g.; 1.0 mole) in 400 ml. distilled water was added 300 ml. of 10 N sodium hydroxide over a twenty minute period. To the resulting clear, pale yellow solution (pH 7.1) was added a solution of zinc acetate dihydrate (222 g.; 1.0 mole) in 600 ml. distilled water. The pH of this final solution was 5.8. After filtration to remove particulate matter, the final solution was diluted with 2 liters of ethanol and chilled overnight.

The product, which deposited as small colorless crystals, was collected by filtration, washed with ethanol, and dried to constant weight at room temperature in a vacuum desiccator. Yield: 459.6 g. of colorless crystalline product corresponding approximately to the hexahydrate of trisodium zinc diethlenetriaminepentaacetate (hereinafter referred to as the hexahydrate of Example I).

A sample of the hexahydrate of Example I was analyzed for carbon, hydrogen, nitrogen and zinc, as follows:

Calc. (as hexahydrate (percent): C, 26.6; H, 4.8; N, 6.7; Zn, 10.4. Found (percent): C, 26.5; H, 5.5; N, 6.6; Zn, 10.5.

The loss-on-drying at 110 C. was 18.2%. The hexahydrate of Example I is a colorless, free-flowing powder which appeared to be wholly crystalline when viewed under plane polarized light. It had no precise melting po nt; a sample showed shrinking and effervescence at 110 C. and then gradual sintering and decomposition above 300 C.

EXAMPLE II A suspension of diethylenetriaminepentaacetic acid monohydrate g., 98% pure, 0.25 mole) in 100* ml. of distilled water was prepared.

To this was added a solution of 49 g. (0.75 mole) or potassium hydroxide pellets (85.9% assay) in 50 ml. of distilled water. A clear solution resulted. To this solution was added 55.4 g. (0.25 mole) of zinc acetate dihydrate (99% pure). After a brief period of stirring, a clear solution resulted. This was filtered and was then concentrated in vacuo to yield a crystalline residue. Recrystallization of this residue from a mixture of methanol and acetone gave 81 g. of colorless crystals. After having been dried to constant weight at room temperature under a vacuum of 0.1 mm., the compound was analyzed for zinc. The calculated zinc value, based on tripotassium zinc diethylenetriaminepentaacetate hexahydrate, is 9.6%. Found 9.4%. This free-flowing crystalline product, hereinafter referred to as the hexahydrate of Example II, readily dissolved in water yielding a clear colorless solution.

The compounds of the present invention are highly useful in solution form because of their high solubility in Water and because aqueous solutions of these compounds can be buffered to an essentially neutral pH without affecting their water solubility. These properties are illustrated in Example III.

EXAMPLE III Two grams of the hexahydrate of Example I were added to 10 ml. of distilled water, yielding a clear colorless solution. The pH was 4.2. The pH was adjusted to 6.5-7.0. The solution remained clear and colorless.

The following examples are illustrative of typical dosage forms for administering the compounds of this invention to animals in the treatment of hypertension. The formulations are made by the usual procedures for making tablets, enteric coated tablets, gelatine capsules, packets and oral and parenteral solutions.

EXAMPLE IV.ORAL TABJllilqTs) (EQUIVALENT TO 25 MG.

The above formulations are each mixed and tabletted to form 500 mg. tablets which are suitable for oral administration in treatment of hypertension to provide the equivalent of 25 mg. zinc per tablet.

EXAMPLE V When desired any of the tablets of Example IV can be coated with a solution of cellulose acetate phthalate to comply with U.S.P. specifications for enteric coated tablets.

EXAMPLE VI.GELATIN CAPSULES (EQUIVALENT TO 50 MG. ZINC) Parts by Weight Example VI(A) VI(B) VI(C) Hexahydrate of Example I 480 240 Hexahydrate of Example II 520 260 Corn starch 120 80 100 The above ingredients are mixed and dispensed in gelatine capsules, 600 mg. per capsule, to provide a suitable dosage form for oral administration in treatment of hypertension at a rate of 50 mg. zinc per capsule.

EXAMPLEWIL-O RAL SOLUTION Example VII(A) VII(B) VII(C) Hexahydrate of Example I, grams 9. 6 4. 8 Hexahydrate of Example II, grams 10. 4 5. 2 Sorbitol 70%, ml 10 10 10 Cyelamate, sodium, mg 100 100 100 Methyl paraben, mg.(0.18%) 138 180 18g Plropyl paraben, mg.(0.02%)

Distilled d onized water to make up to 4 The above ingredients are dissolved in water, as indicated, to form suitable solutions for oral administration in treatment of hypertension at a rate of mg. of zinc per 5 ml.

EXAMPLE VIIL-PARENTERAL SOLUTIONS Example VIII(A) VIII(B) VIII(O) Hexahydrate of Example I, mg- 240 Hexahydrate of Example II, mg 260 Benzyl alcohol, mg 5. 0 5. 0 5. 0 Sodium chloride, mg 5. 0 5. 0 Potassium chloride, mg 5. 0 Potassium biphthalate, mg 8. 0 8. 0 8. 0 Water for injection to make up to The above solutions are suitable for parenteral injection in 1 ml. dosages in treatment of hypertension and pro- Vides 25 mg. of zinc per ml.

What is claimed is:

1. A method of treating hypertension in animals which comprises administering to an animal afflicted with hypertension a hypotensive amount of a compound selected from the group consisting of the sodium salt of the zinc chelate of diethylenetriaminepentaacetic acid and the potassium salt of the zinc chelate of diethylenetriaminepentaacetic acid.

2. A method according to claim 1 in which said compound is administered orally.

3. A method according to claim 1 in which said compound is administered parenterally.

References Cited UNITED STATES PATENTS 2,781,291 2/1957 Rubin et a1. 167--68 3,172,898 3/1965 Wymore 260-439 3,240,701 3/1966 Furia 424-289 X OTHER REFERENCES Sollmann, Torald, A Manual of Pharmacology, 8th ed., p. 1304, W. B. Saunders Company, Philadelphia, Pa. (1957).

ALBERT T. MEYERS, Primary Examiner JAMES V. COSTIGAN, Assistant Examiner