US 4,308,257 AGrant
Accelerating Cellular Repair Composition for the Human Body and Method of Administering Same
Issue Date:1981-12-29
•3 Claims
Abstract
The present invention comprises a composition of matter and method for introducing the composition of matter into the human body to achieve cellular repair. The composition comprises as a first component a stable, pyrogen-free liquid mixture containing an amino acid metabolite, a thiamine salt, diphosphopyridine nucleotide, diaphorase flavin protein enzyme, and a carrier in select ratios, and as a second component an enteric coated tablet comprising nicotineamide, adenosine-5-monophosphate, diphosphopyridine nucleotide, and an inert carrier in select ratios. The first component is administered by subcutaneous injection, followed by ingestion of the second component. This invention is particularly useful in healing ulcers, burns, post-operative wounds, and various skin disruptions of diabetics.
Metadata
Inventor
- Saul Caspe
Application Information
Application Number:US 1561901
Filing Date:1980-06-03
Priority Date:1980-06-03
Art Unit:121
Classifications
IPC:
A61K 3144A61K 31465
Field of Search:
424180;177
Patent Drawings
This patent does not have any drawings.
Description
It has been found that certain enzyme components of the human body decrease in the body under various conditions, such as advanced age, internal ulcerations, shock, severe burns, and various metabolic diseases.
Specifically, respiratory enzymes such as diaphorase, diphosphopyridine nucleotide (coenzyme-1), and creatine are critical to the respiration mechanisms of cells. These enzymes have been found essential in the oxidation of the amino acids and the carbohydrates in cells. The resultant glycolysis and amino acid oxidation translates in vivo to cell proliferation.
In 1913 Carrel showed that muscle and gland tissue extracts stimulated the growth rate of homologous fibroblasts in vitro. Diaphorase was isolated by Straub in 1939, Biochem J., 33:787 (1939). Caspe described the stimulating effect upon cell proliferation including human fibroblasts and that the addition of coenzymes and creatine produced a synergistic effect, J. Cell and Comp. Physiol., V. 27, No. 1, pp. 43-52 (1946). Caspe in a series of reports established the reduction of coenzyme-1 in the blood of patients with ulcerative colitis and duodenal ulcers, that creatine levels were reduced in diabetes and muscular degeneration and that creatine was necessary for cell growth in chick, mouse, rat, and human tissue in tissue cultures, Clinical Chemistry, Vol. 4, No. 5, pp. 374-78 (1958); Amer. J. of Physiol., V. 159, No. 3, pp. 461-66 (1949).
It has now been discovered that abnormal metabolic conditions can be improved when the stable, pyrogen-free liquid mixture described below is periodically introduced into the body subcutaneously, followed by the periodic introduction into the body by ingestion of a tablet described in detail below. This two-part treatment has been found effective in stepping up various regenerative processes and healing in conditions such as peptic and duodenal ulcers, external ulcers, skin grafting, burns, and post-operative wounds. Of particular significance is the healing of diabetic wounds and skin ulcers which are generally recognized as slow healing. These results are listed in Tables 1 and 2 below.
Part 1 of the treatment method is the induction of initial healing by the subcutaneous injection of a stable, pyrogen-free liquid mixture comprising:
from 0.025 to 0.075% by wt. arginine or creatine (amino acid metabolite);
from 0.1 to 0.2% by wt. of a thiamine salt;
from 0.06 to 0.11% by wt. of coenzyme-1;
from 0.0001 to 0.0003% by wt. of diaphorase flavin protein enzyme;
with the balance an inert carrier,
wherein the weight ratios of--
(a) amino acid metabolite to thiamine salt is from between about 0.05:0.15 and about 0.075:0.2, and
(b) codehydrogenase (coenzyme-1) to diaphorase flavin protein enzyme is from between about 0.06:0.0001 and about 0.11:0.0003, and
the concentration of diaphorase flavin protein enzyme per ml. of tissue substrate is from between about 0.78 ug. and about 0.39 ug.
Part 2 of the treatment is the maintenance of the healing induced in Part 1 and comprises the subsequent periodic ingestion of tablets comprising nicotineamide, adenosine-5-monophosphate, codehydrogenase (coenzyme-1), and inert carrier, wherein the tablet is enteric coated with up to 20 coats of cellulose acetate phthalate. The two steps are repeated at various frequencies as described below. Specific examples of the two-step process are described in Tables 1 and 2 below.
The diaphorase used in the present invention is made according to the method of Straub, Biochem J., 33:787 (1939). The diphosphopyridine nucleotide (codehydrogenase) used in the invention is made according to the method of D. E. Green, J. Biol. Chem., 135:345 (1940).
To control various abnormal metabolic conditions and to stimulate recovery towards normal metabolic conditions, it has been observed that the concentration of certain proliferative elements must be routinely supplemented. Certain supplements are required at two levels, one mixture at a "peak level" obtained by periodic subcutaneous injection at a concentration of from about 0.5 to about 1.0 ml. at a frequency of from once every 24 hours to once every 96 hours; and the second mixture at a "minimal level" obtained by the oral ingestion of an enteric coated tablet having a composition and concentration different from the injectible. It is critical to the combined effect of the "peak" and "minimal" compositions that the latter pass to the intestine before the active agents are absorbed by the body. That is, the active agents must pass through the stomach encapsulated and enter the intestine intact in order to avoid the deactivating that would occur in the stomach.
Two specific examples of the injectible compositions of the invention and which are a stable, pyrogen-free mixture are as follows:
I.
50 mg. creatine
90 mg. DPN.4 H.sub.2 O (diphosphopyridine nucleotide)
150 mg. thiamin Hcl
0.1 mg. diaphorase flavin protein enzyme; and
Ii.
75 mg. creatine
108 mg. DPN.4 H.sub.2 O
200 mg. thiamin Hcl
0.2 mg. diaphorase flavin protein enzyme.
The concentrations of the above-stated components were added to 100 ml. of aqueous physiological saline (850 mg. Nacl) containing 300 mg. of phenol. This liquid medium was tested and found to be pyrogen free. To this solution was added 0.05 mg./ml. of riboflavin-5-phosphate which adds color to the solution and acts as an indicator. The solution is now ready for vialing to be used for subcutaneous injection when the proper dose is withdrawn into the chamber of the injection unit. The preparation is now ready for clinical testing.
An oral capsule suitable for the invention was prepared containing:
Coenzyme-1: 0.001 gm./per cap.
Nicotineamide: 0.1 gm./per cap.
Adenylic Acid (adenosine-5-mono phosphate): 0.025 gm./per cap.
Diluent: lactose 0.124 gm./per cap.
Indicator: riboflavin 0.0001 gm./per cap.,
and then was enteric coated with up to 20 coats cellulose acetate phthalate.
Claims
It is claimed:
1. A two-part system for accelerating cellular repair comprising an injectible liquid mixture formulated to produce an initial positive response to certain abnormal metabolic conditions comprising: (A) (a) an amino acid metabolite selected from the group consisting of arginine, creatine, and mixtures thereof in a concentration from between about 0.025% and about 0.075% by weight, (b) a thiamine salt in a concentration from between about 0.1% and about 0.2% by weight, (c) diphosphopyridine nucleotide in a concentration from between about 0.06% and about 0.11% by weight, (d) diaphorase flavin protein enzyme at an activity from between about 0.0001% and about 0.0003% by weight derived from animal muscles and characterized by the presence of a protein moiety that promotes respiratory activity on cells, and (e) the remainder an inert carrier; wherein: (1) the weight ratio of the amino acid metabolite to the thiamine salt is from between about 0.05:0.15 and about 0.075:0.2; (2) the weight ratio of diphosphopyridine nucleotide to diaphorase flavin protein enzyme is from between about 0.06:0.0001 and about 0.11:0.0003, and (3) the concentration of diaphroase flavin protein enzyme per ml. of tissue substrate is from between about 0.78 ug. and about 0.39 ug.; and (B) a respiratory enzyme booster tablet which will produce a maintenance response to abnormal metabolic conditions comprising an enteric coated substance containing a mixture of diphosphopyridine nucleotide, nicotineamide, adenosine-5-monophosphate, and an inert carrier wherein the enteric coating is cellulose acetate phthalate.
2. A method of treating abnormal metabolic conditions comprising: (A) periodically introducing subcutaneously a pyrogen-free, stabilized liquid mixture comprising: (a) an amino acid metabolite selected from the group consisting of arginine, creatine, and mixtures thereof in a concentration from between about 0.025% and about 0.075% by weight, (b) a thiamine salt in a concentration from between about 0.1% and about 0.2% by weight, (c) diphosphopyridine nucleotide in a concentration from between about 0.06% and about 0.11% by weight, (d) diaphorase flavin protein enzyme at an activity from between about 0.0001% and about 0.0003% by weight derived from animal muscles and characterized by the presence of a protein moiety that promotes respiratory activity on cells, and (e) the remainder an inert carrier; and (B) periodically introducing by ingestion an enteric control mixture comprising diphosphopyridine nucleotide, nicotineamide, adenosine-5-monophosphate, and an inert carrier.
3. A method of treating diabetic wounds and ulcers comprising: (A) periodically introducing subcutaneously a pyrogen-free, stabilized liquid mixture containing diphosphopyridine nucleotide, and (B) periodically introducing by ingestion a mixture comprising diphosphopyridine necleotide, nicotineamide, adenosine-5-monophosphate, and an inert carrier.
Non-Patent Literature (3)
- Straub, Biochem. J., vol. 33, pp. 787 et seq. (1939).
- Caspe, J. Cell and Comp. Physiol., vol. 27, No. 1, pp. 43-52, (1946).
- Green, J. Biol. Chem., vol. 135, p. 345 (1940).