US3076027A - Colchicine glycyrrhetinate - Google Patents
Colchicine glycyrrhetinate Download PDFInfo
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- US3076027A US3076027A US716658A US71665858A US3076027A US 3076027 A US3076027 A US 3076027A US 716658 A US716658 A US 716658A US 71665858 A US71665858 A US 71665858A US 3076027 A US3076027 A US 3076027A
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- colchicine
- glycyrrhetinate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
Definitions
- the present invention relates to a new therapeutic compound, colchicine glycyrrhetinate, the method of preparing the same, and dosage forms incorporating the compound.
- Colchicine has been widely employed both to diagnose and treat gout and gouty arthritis, and particularly the acute atoctis thereof. Unfortunately, the administration of this agent often causes severe gastric distress resulting from. the local irritation of the colchicine and its derivatives. The degree of local gastro-intestinal distress is proportional to the amounts of the drug ingested. It is well known that colchicine undergoes hydrolytic decomposition to form essentially inactive therapeutic compounds which, nevertheless, contribute to the noxious local effects. When a portion of a dose of colchicine is hydrolyzed, to an inactive form, a greater dosage is required to produce the desired therapeutic effect and consequently a higher index of local irritation results.
- this ratio of local irritation to quantity of drugingested is such as to preclude the use of the drug for these patients.
- glycyrrhetinic acid By combining the very large molecule, glycyrrhetinic acid, with the large colchicine molecule, an insoluble derivative results which is far less irritating than the smaller mobile molecule.
- colchicine glycyrrhetinate When colchicine glycyrrhetinate is subjected to a hydrolyzing medium of either water or dilute acid, less than one percent of the molecule is destroyed, whereas the hydrolytic destructive rate is increased by ten to fifty times when the smaller colchicine molecule is treated in a similar manner.
- the pH of the media is maintained to at least pH 3. virtually no destruction results and the fuil therapeutic effect of a given dose is achieved.
- colchicine-glycyrrhetinate makes available the colchicine moiety to patients who have previously been denied its beneficial effects because of an extreme sensitivity to the local irritation of colchicine and/ or colchiceine.
- Colchicine an alkaloid obtained from plants of various species of genus Colchicum, usually Colchicum autumnale Liane, and commonly called yellow saffron, has been used for centuries in the specific treatment of gout.
- Colchicine is an odorless alkaloidal base occurring as pale yellow amorphous scales or powder which darkens on exposure to light.
- One gram of colchicine is soluble in 25 ml. of water and in about 220 ml. of ether. It is freely soluble in alcohol and in chloroform. Its melting point is betweeen 153 and 157 C.
- Colchicine is readily decomposed by dilute acids to produce methyl alcohol and the demethylated derivative, colchiceine, which is virtually without therapeutic activity.
- the acid hydrolytic decomposition of colchicine may be postulated as follows:
- Colchiceine Hz Hg 0 colchicine Colchiceine has been shown to possess only a fraction of the biological activity of colchicine.
- the activity of orally administered colchicine is at least partially lost by the action of the acid medium of the gastric con-' are often taken as an index that the level of tolerance for the drug has been reached. This is based upon the supposition that the gastrointestinal toxicity is solely due to central nervous system origin. However, the fact that larger doses may be administered intravenously indicates that at least a portion of the gastrointestinal distress following oral administration must be due to local irritation in the stomach.
- colchicine has been called the sovereign remedy for gout and its specificity is such that a therapeutic trial with colchicine is frequently used to establish the diagnosis of gout, neither the pharmacodynamics of colcihicine nor the pathogenesis of gout, have been completely established. Since gout is related to abnormal uric acid metabolism, it has been assumed that colchicine in some way a-lfects the uric acid metabolism.
- Glycyrrhetinic acid (also known as glycyrrhetic acid) is a polyterpene with the following structural formula:
- Glycyrrhetinic acid is obtained by acid or alkaline hytdrolysis of glycyrrhizic acid which is extracted from the 'dried rhizome and roots of several varieties of Glycyrrhiza .glabra and occassionally firom other species of Glycyr- "rhiza. It has been found that two or more stereoisomers occur in the hydrolysate of the glycoside, glycyrrhizic acid. The melting point range for glycyrrhetinic acid has been reported as 270-298 C. This substance has been found to be soluble in alcohol, dioxane and chloroform, and practically insoluble in petroleum ether and water.
- glycyrrhetinic acid is capable of exhibiting desoxycortico-steroid-like activity and of potentiating amounts of the cortiscosteroids which by themselves are inadequate to meet physiologic needs.
- glycyrrhetinic acid is useful not in direct substitution for corticosteroids, but for enhancement of the activity of circulating endogenous adrenocortical hormones.
- Col'chicine glycyrrhetinate is prepared through the interaction of equirnolecular portions of colchicine and glycyrrhetinie acid in anhydrous soluton at moderately elevated temperatures. It is essential that the reaction takes place in anhydrous medium or hydrolytic cleavage of the complex salt will occur. The lack of appreciation of the need for reaction in an anhydrous medium has previously led to the inaccurate opinion that colchicine is not basic and hence does not combine with acids to form salts. Purification may be achieved by recrystallization.
- the compound, colchicine glycyrrhetinate is obtained as a pale yellow crystalline powder with extremely bitter taste and a faint odor of licorice. It melts with decomposition at 185-190 C.
- the UV. absorption spectrum of the compound shows a peak absorption at 245 mu. See FIG. 1 which shows such a spectrum of a solution of 1 mg. of the compound per 100 ml. of 95% ethanol. At 25 C., it is less than 0.25% soluble in water; approximately 1% soluble in alcohol, 5% soluble in ether, less than 1% soluble in acetone and less than 0.2% soluble in petroleum ether.
- the empirical formula of colchicine glycyrrhetinate is c n No Elemental analysis of this compound shows the following percentage composition: carbon 71.78, hydrogen 8.24, oxygen 18.39, nitrogen 1.71.
- the molecular weight of colchicine glycyrrhetinate is 870.1, the percentage composition ofwhich is: cplchicine moiety 45.90 percent. and iycynherimc acid ms iiety 54.10 percent.
- Colchicine glycyrrhetinate is a new therapeutic agent, useful in relieving the symptoms of acute gouty arthralgia, in reducing the frequency of occurrence of acute attacks, and in preventing or modifying impending attacks.
- a typical pattern of symptoms usually precedes an acute attack fior each person afflicted with gout. As this pattern becomes known to the individual, he is able to recognize the prodromal symptoms of an impending attack.
- the prompt ingestion of from 1.00 to 2.25 mgm. of colchicine glycyrrhetinate every two hours for a total of 3 or 5 doses will usually abort the attack.
- the frequency of occurrence of acute attacks may be reduced by the ingestion of 1.00 to 2.25 mgm. of colchicine glycyrrhetinate once or twice a week or every other night before retiring, or even as frequently as every night, d pending upon the particular patients needs.
- colchicine glycyrrhetinate is further extended by its adsorption onto the antacid, buffering adsorptive agent aluminum hydroxide gel.
- the inclusion of the antacid buffering adsorptive agent serves to maintain the integrity of the colchicine moiety of this compound until absorption has occurred.
- the antacid adsorptive agent assures maximium therapeutic utilization of the administered dose.
- Example 1 To 400 cc. of anhydrous isopropanol is added 0.05 mole glycyrrhetinic acid and 0.05 mole of colchicine with thorough mixing. The solution is refluxed with heating for about /2 hour, then evaporated under reduced pres sure to syrupy consistency. The material is redissolved in cc. of anhydrous isopropanol and recrystallized by precipitation with anhydrous ether. The crystalline compound obtained exhibits the following properties: a pale yellow color with an extremely bitter taste and faint odor. It melts (with decomposition) at -190 C. A sharp absorption band at 245 millimicrons wavelength is exhibited by this compound in ultraviolet analysis in ethanol. At 25 it is less than 0.25% soluble in water, approximately 1% soluble in alcohol, 5% soluble in ether, less than 1% soluble in acetone and less than 0.2% soluble in petroleum ether.
- Example 2 In place of the isopropanol described in Example 1 may be substituted wholly or in part, any anhydrous alcohol of the class ROI-I, wherein R represents a straight or branched-chain alkyl group containing up to five atoms of carbon.
- Example 3 Another method of preparing colchicine glycyrrhetinate is to proceed as in Example 1 or in Example 2, substituting in either instance petroleum benzin for the anhydrous ether used in the recrystallization procedure.
- Example 4 The product of Example 4 may be filled into capsules each of which contains 1.0 mg. of colchicine-glycyrrheti mate and 100 mg. of aluminum hydroxide gel.
- Example 6 To the product of Example 4 is added the conventional excipients necessary for tablet preparation and then compressed into tablets, the Weight of which is adjusted, so that each tablet contains 1.00 milligram of colchicine glycyrrhetinate and 100 milligrams of aluminum hydroxide gel.
- the method of preparing colchicine glycyrrhetinate which comprises dissolving colchicine and glycyrrhetinie acid in an anhydrous alkanol selected from the group consisting of those alkanols having from 1 through 5 carbon atoms, and recovering colchicine glycyrrhetinate therefrom.
Description
Jan. 29, 1963 A. HALPERN 3,076,027
COLCHICINE GLYCYRRHETINATE Filed Feb. 21, 1958 l l 260 200 mwni/vqm/mimm/zrom) INVENTOR Aaresp HALPER/V ATTOR NEY United States Patent Ofilice Patented Jan. 29, 1963 The present invention relates to a new therapeutic compound, colchicine glycyrrhetinate, the method of preparing the same, and dosage forms incorporating the compound.
Colchicine has been widely employed both to diagnose and treat gout and gouty arthritis, and particularly the acute atoctis thereof. Unfortunately, the administration of this agent often causes severe gastric distress resulting from. the local irritation of the colchicine and its derivatives. The degree of local gastro-intestinal distress is proportional to the amounts of the drug ingested. It is well known that colchicine undergoes hydrolytic decomposition to form essentially inactive therapeutic compounds which, nevertheless, contribute to the noxious local effects. When a portion of a dose of colchicine is hydrolyzed, to an inactive form, a greater dosage is required to produce the desired therapeutic effect and consequently a higher index of local irritation results. In some instances, this ratio of local irritation to quantity of drugingested is such as to preclude the use of the drug for these patients. By combining the very large molecule, glycyrrhetinic acid, with the large colchicine molecule, an insoluble derivative results which is far less irritating than the smaller mobile molecule. When colchicine glycyrrhetinate is subjected to a hydrolyzing medium of either water or dilute acid, less than one percent of the molecule is destroyed, whereas the hydrolytic destructive rate is increased by ten to fifty times when the smaller colchicine molecule is treated in a similar manner. Furthermore, if the pH of the media is maintained to at least pH 3. virtually no destruction results and the fuil therapeutic effect of a given dose is achieved.
It is an object of the present invention to provide a more sensitive control of therapy of the patient and to provide the means to minimize the incidence oh gastrointestinal distress resulting fromlocal irritation. Further, colchicine-glycyrrhetinate makes available the colchicine moiety to patients who have previously been denied its beneficial effects because of an extreme sensitivity to the local irritation of colchicine and/ or colchiceine.
it is a still further object of the present invention to provide means to simultaneously adduce the steroid potentiating properties of the glycyrrhetinic acid moiety to enhance the effectiveness of the colchicine moiety.
- Colchicine, an alkaloid obtained from plants of various species of genus Colchicum, usually Colchicum autumnale Liane, and commonly called yellow saffron, has been used for centuries in the specific treatment of gout.
It appears that the structural formula of colchicine is as follows:
Colchicine Colchicine is an odorless alkaloidal base occurring as pale yellow amorphous scales or powder which darkens on exposure to light. One gram of colchicine is soluble in 25 ml. of water and in about 220 ml. of ether. It is freely soluble in alcohol and in chloroform. Its melting point is betweeen 153 and 157 C. Colchicine is readily decomposed by dilute acids to produce methyl alcohol and the demethylated derivative, colchiceine, which is virtually without therapeutic activity.
The acid hydrolytic decomposition of colchicine may be postulated as follows:
Although colchicine has been called the sovereign remedy for gout and its specificity is such that a therapeutic trial with colchicine is frequently used to establish the diagnosis of gout, neither the pharmacodynamics of colcihicine nor the pathogenesis of gout, have been completely established. Since gout is related to abnormal uric acid metabolism, it has been assumed that colchicine in some way a-lfects the uric acid metabolism.
Aluminum hy- Recent data suggest that colchicine may act as a stressmg agent causing a release of adrenal corticosteroids. Furthermore, numerous investigations have demonstrated the fact that there is a pituitary-adrenal defect in gouty persons manifested by adrenocortical hormone deficiency.
Glycyrrhetinic acid (also known as glycyrrhetic acid) is a polyterpene with the following structural formula:
C O OH H30/ CH3 Glycyrrhetinic acid is obtained by acid or alkaline hytdrolysis of glycyrrhizic acid which is extracted from the 'dried rhizome and roots of several varieties of Glycyrrhiza .glabra and occassionally firom other species of Glycyr- "rhiza. It has been found that two or more stereoisomers occur in the hydrolysate of the glycoside, glycyrrhizic acid. The melting point range for glycyrrhetinic acid has been reported as 270-298 C. This substance has been found to be soluble in alcohol, dioxane and chloroform, and practically insoluble in petroleum ether and water.
Considerable clinical data indicates that glycyrrhetinic acid is capable of exhibiting desoxycortico-steroid-like activity and of potentiating amounts of the cortiscosteroids which by themselves are inadequate to meet physiologic needs. Thus, glycyrrhetinic acid is useful not in direct substitution for corticosteroids, but for enhancement of the activity of circulating endogenous adrenocortical hormones.
Col'chicine glycyrrhetinate is prepared through the interaction of equirnolecular portions of colchicine and glycyrrhetinie acid in anhydrous soluton at moderately elevated temperatures. It is essential that the reaction takes place in anhydrous medium or hydrolytic cleavage of the complex salt will occur. The lack of appreciation of the need for reaction in an anhydrous medium has previously led to the inaccurate opinion that colchicine is not basic and hence does not combine with acids to form salts. Purification may be achieved by recrystallization.
The compound, colchicine glycyrrhetinate, is obtained as a pale yellow crystalline powder with extremely bitter taste and a faint odor of licorice. It melts with decomposition at 185-190 C. In ethanol, the UV. absorption spectrum of the compound shows a peak absorption at 245 mu. See FIG. 1 which shows such a spectrum of a solution of 1 mg. of the compound per 100 ml. of 95% ethanol. At 25 C., it is less than 0.25% soluble in water; approximately 1% soluble in alcohol, 5% soluble in ether, less than 1% soluble in acetone and less than 0.2% soluble in petroleum ether.
The empirical formula of colchicine glycyrrhetinate is c n No Elemental analysis of this compound shows the following percentage composition: carbon 71.78, hydrogen 8.24, oxygen 18.39, nitrogen 1.71. The molecular weight of colchicine glycyrrhetinate is 870.1, the percentage composition ofwhich is: cplchicine moiety 45.90 percent. and iycynherimc acid ms iiety 54.10 percent.
4. Its structural formula may be postulated as follows:
mo on;
Colchicine glycyrrhetinate is a new therapeutic agent, useful in relieving the symptoms of acute gouty arthralgia, in reducing the frequency of occurrence of acute attacks, and in preventing or modifying impending attacks.
In treatment of the acute attack, 1.00 mg. ofl colchicine glycyrrhetinate is administered every /2 to 1 hour until relief is obtained or gastrointestinal distress is manifested.
A typical pattern of symptoms usually precedes an acute attack fior each person afflicted with gout. As this pattern becomes known to the individual, he is able to recognize the prodromal symptoms of an impending attack. The prompt ingestion of from 1.00 to 2.25 mgm. of colchicine glycyrrhetinate every two hours for a total of 3 or 5 doses will usually abort the attack.
The frequency of occurrence of acute attacks may be reduced by the ingestion of 1.00 to 2.25 mgm. of colchicine glycyrrhetinate once or twice a week or every other night before retiring, or even as frequently as every night, d pending upon the particular patients needs.
The usefulness of colchicine glycyrrhetinate is further extended by its adsorption onto the antacid, buffering adsorptive agent aluminum hydroxide gel.
The inclusion of the antacid buffering adsorptive agent serves to maintain the integrity of the colchicine moiety of this compound until absorption has occurred. By suppressing the acid hydrolysis of colchicine to the practically therapeutically inert colchiceine, the antacid adsorptive agent assures maximium therapeutic utilization of the administered dose.
The following examples illustrate the method of preparation of the products of this invention:
Example 1 To 400 cc. of anhydrous isopropanol is added 0.05 mole glycyrrhetinic acid and 0.05 mole of colchicine with thorough mixing. The solution is refluxed with heating for about /2 hour, then evaporated under reduced pres sure to syrupy consistency. The material is redissolved in cc. of anhydrous isopropanol and recrystallized by precipitation with anhydrous ether. The crystalline compound obtained exhibits the following properties: a pale yellow color with an extremely bitter taste and faint odor. It melts (with decomposition) at -190 C. A sharp absorption band at 245 millimicrons wavelength is exhibited by this compound in ultraviolet analysis in ethanol. At 25 it is less than 0.25% soluble in water, approximately 1% soluble in alcohol, 5% soluble in ether, less than 1% soluble in acetone and less than 0.2% soluble in petroleum ether.
Example 2 In place of the isopropanol described in Example 1 may be substituted wholly or in part, any anhydrous alcohol of the class ROI-I, wherein R represents a straight or branched-chain alkyl group containing up to five atoms of carbon.
Example 3 Another method of preparing colchicine glycyrrhetinate is to proceed as in Example 1 or in Example 2, substituting in either instance petroleum benzin for the anhydrous ether used in the recrystallization procedure.
Example 4 Example 5 The product of Example 4 may be filled into capsules each of which contains 1.0 mg. of colchicine-glycyrrheti mate and 100 mg. of aluminum hydroxide gel.
Example 6 To the product of Example 4 is added the conventional excipients necessary for tablet preparation and then compressed into tablets, the Weight of which is adjusted, so that each tablet contains 1.00 milligram of colchicine glycyrrhetinate and 100 milligrams of aluminum hydroxide gel.
It is not desired to be limited except as set forth in the following claims, the above description being by way of illustration of the invention.
What is claimed is:
1. Colchicine glycyrrhetinate.
2. The method of preparing colchicine glycyrrhetinate which comprises dissolving colchicine and glycyrrhetinie acid in an anhydrous alkanol selected from the group consisting of those alkanols having from 1 through 5 carbon atoms, and recovering colchicine glycyrrhetinate therefrom.
3. The method of claim 2 and the step of purification of the resulting glycyrrhetinate by means of sequential redissolving in said anhydrous alkanol and crystallization therefrom by an anhydrous crystallizing agent selected from the group consisting of anhydrous ether and petroleum benzin.
References Cited in the file of this patent UNITED STATES PATENTS 1,954,432 Stuart Apr. 10, 1934 1,988,374 Craig Jan. 15, 1935 2,476,082 Burke et al July 12, 1949 2,817,623 Schneider Dec. 24, 1957
Claims (1)
1. COLCHICINE GLYCYRRHETINATE.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1954432A (en) * | 1933-11-04 | 1934-04-10 | Lilly Co Eli | Ephedrine ethyl mercurithiosalicylate |
US1988374A (en) * | 1932-05-25 | 1935-01-15 | William E Craig | Quinine mercuric compound and process of making it |
US2476082A (en) * | 1946-10-01 | 1949-07-12 | Squibb & Sons Inc | Prolonged-action preparations of d-tubocurarine salts and methods of preparing same |
US2817623A (en) * | 1956-03-22 | 1957-12-24 | Ciba Pharm Prod Inc | Tabernanthine, ibogaine containing analgesic compositions |
-
1958
- 1958-02-21 US US716658A patent/US3076027A/en not_active Expired - Lifetime
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1988374A (en) * | 1932-05-25 | 1935-01-15 | William E Craig | Quinine mercuric compound and process of making it |
US1954432A (en) * | 1933-11-04 | 1934-04-10 | Lilly Co Eli | Ephedrine ethyl mercurithiosalicylate |
US2476082A (en) * | 1946-10-01 | 1949-07-12 | Squibb & Sons Inc | Prolonged-action preparations of d-tubocurarine salts and methods of preparing same |
US2817623A (en) * | 1956-03-22 | 1957-12-24 | Ciba Pharm Prod Inc | Tabernanthine, ibogaine containing analgesic compositions |
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