JPH04243831A - Azaribine composition - Google Patents

Abstract

PURPOSE: To provide a method for treating an azaribine responding symptom for a patient showing an extreme pyridoxal phosphate deficiency after orally treated with azaribine, and a composition therefor. CONSTITUTION: This composition containing azaribine is obtained by coating the azaribine with a film forming material dissolvable selectively in a digestive liquid in an intestine. The coated azaribine is orally administered to a patient in an effective amount for the treatment of a disease, preferably the amount capable of supplying 1.5-15g azaribine per 1m<2> body surface area of the patient.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the treatment of azaribine reactions, particularly in patients who exhibit significant pyridoxal phosphate deficiency symptoms after oral administration of azaribine.

0002

[Prior Art] Oral administration of azarivine (2', 3', 5'-triacetate-6-azauridine) is effective against psoriasis, psoriatic arthritis, polycythemia vera, fungiform mycosis, and choriocarcinoma. It has been known. However, severe side effects, including life-threatening thromboembolism in 4% of treated patients, resulted in the Food and Drug Administration (FDA) issuing a recall order for the drug.

In rabbits as well as humans, oral administration of azarivine is known to result in severe pyridoxal phosphate deficiency and abnormally high homocysteine levels, which are thought to be related to the prothrombotic effects of this drug. . It has also been found that in rabbits, both severe pyridoxal phosphate deficiency and homocysteine increase can be prevented or at least alleviated by simultaneously administering pyridoxine.

[0004] The mechanism by which azarivine and pyridoxal phosphate interfere with each other is unknown, but it is believed that the cause is interference with the pyridoxal phosphate coenzyme necessary for the correct metabolism of accumulated amino acids. Experiments have shown that homocysteine accumulates in pigs fed diets lacking vitamin B6. The active drug formed by hydrolysis of azauribine after absorption is 6 - the catabolic metabolite of azauridine is 6
-It is thought to be due to cleavage of the triazine ring of azauridine. It has been hypothesized that this catabolite is a hydrazine or semicarbazide derivative that can react quickly and easily with pyridoxal phosphate.

It has been discovered that extreme pyridoxal phosphate deficiency does not result in homocysteine increases if azarivine is administered in a formulation that is poorly absorbed by the stomach. Therefore,
The present invention provides chemical agents for the treatment of azaaribine reactions, including psoriasis, psoriatic arthritis, polycythemia vera, mycosis, and choriocarcinoma in patients who exhibit symptoms of extreme pyridoxal phosphate deficiency after oral administration of azaaribine. and a method.

This chemical agent consists of a solid composition containing azarivine encapsulated with an enteric coating, ie, a film-forming substance that is selectively soluble in the digestive fluids within the intestinal tract. The drug can be administered orally in any suitable form such as tablets or capsules.

Preferably, the composition also includes a pyridoxine compound selected from pyridoxine, pyridoxal phosphate, pyridoxamine, pyridoxamine phosphate, pyridoxal, pyridoxine phosphate, and mixtures thereof. The pyridoxine compound is at least about 0.0005 moles per mole of azarivine administered, preferably at least about 0.000.
Preferably, the amount is sufficient to provide 0.001 mole, more preferably 0.025 mole, of the pyridoxine compound.

The treatment method of the present invention involves first encapsulating azaribine with an enteric coating, and then administering orally the uncoated azaribine in an amount effective for treating the disease to a patient exhibiting symptoms of extreme pyridoxal phosphate deficiency. The coated azarivine is administered orally. Azaribine is preferably administered in an amount sufficient to provide about 1.5 to about 15 g of azaribin per m 2 of body surface area per day, preferably in two or more equal doses.

[0009] In the method of the present invention, it is preferred that the pyridoxine compound be administered within 24 hours before and after administering azaaribine, preferably at the same time as administering azaaribine. Pyridoxal phosphate is at least 0.0005 moles per mole of azarivine administered, preferably at least about 0.
．． 001 mol, more preferably at least about 0.02 mol
Administer an amount sufficient to provide 5 moles of pyridoxine compound.

0010

[Detailed explanation]

The present invention provides chemical agents useful in the treatment of mammals exhibiting azaribine reactions, ie, symptoms of extreme pyridoxal phosphate deficiency after oral administration of azaribine. Azaribin reactions include psoriasis, psoriatic arthritis, polycythemia vera, mycosis, and choriocarcinoma.

This chemical agent consists of a solid composition containing azarivine encapsulated with an enteric coating. When we refer to "azaribin" here, we refer to 6-azauridine triacetate or 2',3',5'-triacetyl-
6-Means azauridine. Preferably, the composition comprises powdered azaribine applied to a substrate, such as sugar beads. Administration may be performed by known methods. The substrate and azaribine are then encapsulated by applying an enteric coating to the azaribine-coated substrate.

The enteric coating may be formed from any suitable composition. Suitable enteric coatings are described, for example, in U.S. Pat. No. 4,311,8 to Namikoshi et al.
No. 33, Chopra U.S. Pat. No. 4,377,56
No. 8, U.S. Patent No. 4,385,078 to Onda et al., U.S. Patent No. 4,457,907 to Porter,
U.S. Patent No. 4,462,839 to McGinley et al.
No. 4,518,4 to McGinley et al.
No. 33, U.S. Pat. No. 4,556,5 to Porter et al.
No. 52, Bechgaard et al. U.S. Pat. No. 4,6
No. 06,909, U.S. Patent No. 4 to Nakagame et al.
, 615,885, and Tsuji U.S. Pat.
, 670, 287.

Preferred enteric coating compositions include alkyl and hydroxyalkylcelluloses and their aliphatic esters, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxyethylethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose. , hydroxypropylcellulose phthalate, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate; carboxyalkylcellulose and its salts, such as carboxymethylethylcellulose; cellulose acetate phthalate; polycarboxymethylene and its salts and derivatives;
Polyvinyl alcohol and its esters; polycarboxymethylene copolymers with sodium carboxylate formaldehyde; acrylic acid polymers and copolymers, such as methacrylic acid-methyl methacrylic acid copolymers and methacrylic acid-methyl acrylate copolymers; peanuts Edible oils such as oil, palm oil, olive oil and hydrogenated vegetable oils; polyvinylpyrrolidone; polyethylene glycol and its esters; and natural products such as shellac.

Other preferred enteric coatings include polyvinyl acetate esters, such as polyvinyl acetate phthalate, partial ethylene glycol monomethyl ether esters of ethyl acrylate-maleic anhydride copolymers, or methyl acrylate-maleic anhydride copolymers, alkylene glycol ether esters of copolymers such as diethylene glycol monomethyl ether ester of N-butyl acrylate-maleic anhydride copolymer, isobutyl acrylate-maleic anhydride copolymer or ethyl acrylate-maleic anhydride copolymer; and stomach Polypeptides that are difficult to degrade in the environment include polyarginine and polylysine.

If desired, it is also possible to use mixtures of two or more of the above-mentioned compounds. The presently preferred enteric coating is cellulose acetate phthalate.

The enteric coating material may contain various excipients such as triethyl citrate, acetyl triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, dibutyl tartrate, dibutyl maleate, dibutyl succinate and diethyl succinate. and inert fillers such as chalk or pigments.

[0017] The overall composition and thickness of the coating may be selected so that it dissolves immediately upon contact with the digestive fluids in the intestines. Alternatively, the composition and thickness may be selected to provide a time release coating that melts over a predetermined period of time, as is known in the art.

As a first step in preparing a particularly preferred composition, nu-pariel beads are wetted with an alcohol, preferably having 2 to 8 carbon atoms. The alcohol may be any one of primary, secondary, and tertiary alcohols. The surface of the beads is then sprinkled with a layer of azaribin, for example about 3 microns thick, re-wetted with alcohol and then sprinkled with azaribin again. This process step is repeated until the beads reach the desired total weight. Preferably, the total weight of the beads is about four times the weight of the original Nupaliel beads. The beads are then coated with a pharmaceutical or confectionery shellac, e.g.
About 0.1 to about 0.5 parts of confectionery shellac No. Apply 4 etc. Allow beads to partially dry until tacky.

[0019] Next, the concentration is about 0.1 to about 40.0%.
A known enteric coating material dissolved in alcohol, alcohol water, or alcohol solvent is sprayed onto the bead surface so as to give the following properties. The amount of enteric coating will depend on the particular enteric coating composition used, but is preferably sufficient to substantially prevent absorption of the azarivine in the stomach. The presently preferred amount is about one-sixth the amount of shellac. Hydroxyalkylcellulose and its aliphatic esters, carboxyalkylcellulose and its salts, polycarboxymethylene and its salts and derivatives, polyvinyl alcohol and its esters, polycarboxymethylene-sodium formaldehyde carboxylate copolymer, polyvinylpyrrolidone, polyethylene glycol and Enteric coatings can be formed by dissolving the ester in a minimum amount of water, then adding alcohol until the initial cloud point is reached, and applying the mixture in a known manner. To apply cellulose acetate phthalate, simply dissolve it in a minimum amount of alcohol and apply by known methods. In the case of hydrogenated vegetable oils, they may be first dissolved in a non-polymeric solvent such as methylene chloride, chloroform or carbon tetrachloride, then alcohol added to the initial cloud point and applied in a known manner.

[0020] In the method of the invention, azaribin is first encapsulated with an enteric coating, for example as described above, and then
Azaribine without enteric coating is administered orally to patients exhibiting symptoms of severe pyridoxal phosphate deficiency.

[0021] Psoriasis, psoriatic arthritis, polycythemia vera,
To be effective in the treatment of fungal mycosis and choriocarcinoma, about 1.5 g to about 15 g per m2 of body surface area per day.
g, preferably about 4.5 g of azarivine. This results in about 1 g to about 1 g of free 6-azauridine, the active substance formed by deacetylation of azaribine during or after absorption into the bloodstream.
0g will be supplied.

The mechanism by which enteric coating prevents extreme pyridoxal phosphate deficiency is not completely understood. Although it cannot be theorized, it is believed that the catabolic metabolites of the azauridine compound are involved in the decrease in serum pyridoxal levels. Since most of the drug and its metabolites are excreted in the urine within 6 hours after administration, the initial sharp decrease in serum pyridoxal phosphate levels may be explained by the rapid formation of catabolic metabolites. It will be done. It is therefore assumed that the enteric coating will prevent or at least reduce the formation of catabolites. Although the mechanism is unknown, it is certain that it is beneficial. Thus, while oral administration of azarivine has been shown to be effective in treating certain diseases, it cannot be used in patients who are susceptible to extremely low serum pyridoxal phosphate levels. However, the presence of an enteric coating alleviates, if not completely eliminates, this problem, making azarivine usable for patients such as those mentioned above.

It has been demonstrated that administration of a pyridoxine compound concomitantly with the administration of azaaribine can at least partially, if not completely, compensate for the reduction in serum pyridoxine phosphate levels caused by the administration of azaaribine. Therefore, the azarivine agent of the present invention preferably contains a pyridoxine compound. Incorporation of pyridoxine compounds provides two separate mechanisms to increase the safety of azarivine administration. First, the enteric coating substantially prevents rapid and extreme declines in serum pyridoxine phosphate levels. Second, if for any reason serum pyridoxine phosphate levels decrease, the administered pyridoxine compound will compensate for this decrease.

Preferably, the pyridoxine compound is selected from pyridoxine, pyridoxal phosphate, pyridoxamine, pyridoxamine phosphate, pyridoxal, pyridoxine phosphate, pyridoxine hydrochloride, and mixtures thereof. A presently preferred pyridoxine compound is pyridoxine hydrochloride.

[0025] The amount of pyridoxine compound is arbitrary, but
Preferably, the amount is sufficient to provide at least about 0.0005 moles, preferably at least about 0.001 moles, and more preferably at least about 0.025 moles of pyridoxine compound per mole of azarivine. A preferred molar ratio of pyridoxine compound to azarivine is at least about 1:2000, preferably about 1:1000, and more preferably about 1:40.

The pyridoxine compound may be administered as part of an azarivine formulation in the form of a pill, capsule or powder. Additionally, apart from the azarivine agent, a pyridoxine compound may be administered in the form of a pill, capsule, powder, or droplet. If administered separately, the pyridoxine compound is preferably administered within 24 hours before or after administering the azarivine agent. However, in order to ensure that the patient enjoys the effects of both compositions, it is preferable to combine the pyridoxine compound and the enteric-coated azaribine agent into a single tablet or capsule.

[0027]

【Example】

[0028]

[Example 1] An enteric-coated azarivine drug was prepared according to the procedure described below. 125 mg of Nupariel beads were ethanol moistened in a pharmaceutical coating pan and the beads were sprinkled with azaribin to form a layer approximately 3 microns thick. The beads were again wetted with ethanol and sprinkled with azaribine. Approximately 475mg of Azaribin applied to beads
This was repeated until reaching . Next, at a temperature of about 50°C, the beads were mixed with about 70 mg of confectionery shellac No. 4. The beads were air dried until tacky. The beads were then sprayed with about 12 mg of cellulose acetate phthalate dissolved in ethanol and allowed to air dry.

Although the invention has been described above in connection with its preferred embodiments, it will be apparent to those skilled in the art that various modifications may be made to the compositions and methods described above without departing from the principle, spirit and scope of the invention. Changes can be made.

Accordingly, the foregoing description is not intended to limit the compositions and methods of the present invention, but rather to more particularly illustrate the scope of the appended claims.

Claims (32)

[Claims] Claim 1: A method for treating azaaribine reaction in humans and animals showing extreme decreases in serum pyridoxal phosphate after oral administration of azaaribine, the method comprising selectively coating azaribine with a film-forming substance that dissolves in digestive fluids in the intestinal tract. 1. A method for treating azarivine reaction, which comprises packaging the encapsulated azarivine and orally administering the encapsulated azaaribin to humans and animals. 2. A method according to claim 1, characterized in that the film-forming substance forms a time-release coating that dissolves in digestive fluids in the intestinal tract over a predetermined period of time. 3. The method of claim 1, wherein the encapsulated azaribine is administered in an amount sufficient to provide from about 1.5 to about 15 g of azaribine per square meter of human or animal body surface area at a time. 4. The method of claim 2, wherein the encapsulated azaribine is administered in an amount sufficient to provide about 4.5 g of azaribine per square meter of human or animal body surface area at a time. 5. Alkyl and hydroxyalkylcelluloses and their aliphatic esters; carboxylalkylcelluloses and their salts; cellulose acetate phthalate;
Polycarboxymethylene and its salts and derivatives; polyvinyl alcohol and its esters; polycarboxymethylene-sodium carboxylate formaldehyde copolymer; acrylic polymers and copolymers; edible oil; polyvinylpyrrolidone; polyethylene glycol and its salt; shellac; Polyvinyl acetate ester; copolymer alkylene glycol ether ester, such as partial ethylene glycol monomethyl ether ester of ethyl acrylate-maleic anhydride copolymer, and methyl acrylate-maleic anhydride copolymer, N-butyl acrylate-maleic anhydride. acid copolymers, diethylene glycol monomethyl ether esters of isobutyl acrylate-maleic anhydride copolymers and ethyl acrylate-maleic anhydride copolymers; polyarginene and polylysine;
A method according to claim 1, characterized in that the azaribine is encapsulated with a film-forming material consisting of a compound selected from the group consisting of: and mixtures thereof. 6. A method according to claim 5, characterized in that the azaribine is encapsulated in a film-forming material consisting of cellulose acetate phthalate. Claim 7: Before and after administration of the encapsulated azaaribine compound 24
2. The method of claim 1, further comprising administering the pyridoxine compound to the patient within a period of time. 8. The method of claim 7, wherein the pyridoxine compound is administered simultaneously with the encapsulated azaaribine compound. 9. The method of claim 7, wherein the pyridoxine compound is administered in an amount sufficient to provide at least about 0.0005 moles of pyridoxine compound per mole of azaribine. 10. The method of claim 6, wherein the pyridoxine compound is selected from pyridoxine, pyridoxal phosphate, pyridoxamine, pyridoxamine phosphate, pyridoxal, pyridoxine phosphate, pyridoxine hydrochloride, and mixtures thereof. 11. The method according to claim 10, wherein the pyridoxine compound is pyridoxine hydrochloride. 12. The method of claim 10, wherein the pyridoxine compound is pyridoxal phosphate. 13. The method according to claim 10, wherein the pyridoxine compound is pyridoxamine. 14. The method of claim 10, wherein the pyridoxine compound is pyridoxamine phosphate. 15. The method according to claim 10, wherein the pyridoxine compound is pyridoxal. 16. The method according to claim 10, wherein the pyridoxine compound is pyridoxine phosphate. 17. The method according to claim 10, wherein the pyridoxine compound is pyridoxine. 18. A method according to claim 1, characterized in that the azaribine is emulsified in oil so that it is selectively absorbed in the intestine. 19. An azaribine-containing composition for oral administration to humans and animals with azaribine reaction syndrome, which exhibits a severe decrease in serum pyridoxal phosphate levels after oral administration of azaribine, the composition comprising azaribine and the same. 1. An azaribine-containing composition comprising an enveloping enteric coating, said enteric coating being selectively soluble in digestive fluids within the intestinal tract. 20. The enteric coating comprises alkyl and hydroxyalkyl celluloses and their aliphatic esters; carboxyalkyl celluloses and their salts; cellulose acetate phthalate; polycarboxymethylene and its salts and derivatives; polyvinyl alcohol and its esters;
Polycarboxymethylene-sodium carboxylate formaldehyde copolymer; acrylic polymer and copolymer;
Edible oil; polyvinylpyrrolidone; polyethylene glycol and its salts; shellac; polyvinyl acetate ester; alkylene glycol ether ester of copolymers, such as partial ethylene glycol monomethyl ether ester of ethyl acrylate-maleic anhydride copolymer, and methyl acrylate- consisting of a compound selected from diethylene glycol monomethyl ether ester of maleic anhydride copolymer, N-butyl acrylate-maleic anhydride copolymer and ethyl acrylate-maleic anhydride copolymer; polyarginene and polylysine; and mixtures thereof. The composition according to claim 19, characterized in that: 21. The composition of claim 19, wherein the enteric coating is a time-release coating that is soluble in digestive fluids within the intestinal tract over a predetermined period of time. 22. The composition according to claim 19, further comprising a pyridoxine compound. 23. The content of the pyridoxine compound is at least about 0.000 per mole of azarivine in the composition.
23. A composition according to claim 22, characterized in that the amount is sufficient to provide 5 moles of pyridoxine compound. 24. The composition of claim 20, wherein the pyridoxine compound is selected from pyridoxine, pyridoxal phosphate, pyridoxamine, pyridoxamine phosphate, pyridoxal, pyridoxine phosphate, pyridoxine hydrochloride, and mixtures thereof. 25. The composition according to claim 24, wherein the pyridoxine compound is pyridoxine hydrochloride. 26. The composition according to claim 24, wherein the pyridoxine compound is pyridoxal phosphate. 27. The composition according to claim 24, wherein the pyridoxine compound is pyridoxamine. 28. The composition according to claim 24, wherein the pyridoxine compound is pyridoxamine phosphate. 29. The composition according to claim 24, wherein the pyridoxine compound is pyridoxal. 30. The composition of claim 24, wherein the pyridoxine compound is pyridoxine phosphate. 31. The composition according to claim 24, wherein the pyridoxine compound is pyridoxine. 32. The composition according to claim 19, wherein azaribin is emulsified in oil so that it is difficult to absorb in the stomach.