Stabilized pharmaceutical preparation

Details Stabilized pharmaceutical preparation Stabilized pharmaceutical preparation

1998-09-09

2001-02-13

Williamson, Michael A. (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S475000, C424S451000, C424S463000, C424S490000, C424S464000

Reexamination Certificate

active

06187340

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to a pharmaceutical preparation which is stable to light (especially ultraviolet rays) or heat, and which has excellent storage-stability; and a coating agent which is a raw material of such a pharmaceutical preparation.
2. Background Art
It has been found that O
6
-benzylguanine is decomposed in an aqueous solution of polyethylene glycol 400 at room temperature by the reaction of formaldehyde (present as an impurity of polyethylene glycol 400 and probably produced by air oxidation of polyethylene glycol 400) with O
6
-benzylguanine [Pharmaceutical Research, 11 (7), 1060-1064 pp. (1994)].
JP-A-63-301816 (EP-A1-0277741) mentions an enteric coating using an enteric film-liquid including titanium oxide and polyethylene glycol 6000.
Chemical Abstracts 122:388853 mentions tablets containing vitamin C, Yinqiao extracts, acetaminophen, chlorphenramine, calcium carbonate, starch, dextran, peppermint oil and Yinqiao and jingfang volatile oils coated with a composition containing hydroxypropylmethyl cellulose, no.2 enteric vinyl resin, PEG 6000, sesame oil, Tween 80, titanium oxide, talc, Mg stearate, food color, 95% ethanol, and distilled water.
JP-A-63-166824 mentions soft capsules comprising oily solution containing pharmaceutically active ingredient unstable in light, coated with a coating agent containing fine particles of titanium oxide of at least 85% with particle size of 0.1 &mgr;m or less.
When a pharmaceutical preparation which is unstable to light is provided to consumers, the pharmaceutical preparation has to be wrapped or coated for protection from light. However, when storage conditions of a pharmaceutical preparation at a pharmacy in a hospital or at patients are considered, it is difficult to say that sufficient quality of the pharmaceutical preparation is guaranteed by wrapping for protection from light. Therefore, when a pharmaceutical preparation which is unstable to light is manufactured, coating for protection from light is desired.
However, in case of manufacturing a pharmaceutical preparation comprising a drug which is unstable to light, when a tablet comprising the drug was coated with a coating agent which comprises an agent for protection from light such as titanium oxide and a plasticizer such as polyethylene glycol, there was a problem that the obtained film-coated tablet was less stable to light than before coating.
SUMMARY OF THE INVENTION
In view of such a problem, when the stability of a drug in a film-coated tablet was studied, it was found that 1) titanium oxide in a coating agent produces free radicals when exposed to ultraviolet rays, 2) free radicals decompose an alcohol such as polyethylene glycol, etc., in a coating agent, or a drug, 3) decomposition products of an alcohol such as polyethylene glycol in a coating agent, for instance, an aldehyde such as formaldehyde, acetaldehyde, etc., an acid such as formic acid, etc., or a peroxide, also decomposes a drug.
As a result of further studies to remove the factors making the drugs unstable and to obtain various stabilized pharmaceutical preparations based on these findings, the present invention has been completed.
Therefore, the present invention relates to
(1) A stabilized pharmaceutical preparation which is coated with a coating agent comprising (i) an agent for the protection from light, said agent being capable of producing free radicals when exposed to ultraviolet rays, and (ii) a free radical scavenger;
(2) A pharmaceutical preparation as described in the above (1), wherein the coating agent further comprises an oily substance selected from the group consisting of an ester and an alcohol;
(3) A pharmaceutical preparation as described in the above (1), wherein the agent for the protection from light is a metal oxide;
(4) A pharmaceutical preparation as described in the above (3), wherein the metal oxide is a titanium oxide, ferric oxide or zinc oxide;
(5) A pharmaceutical preparation as described in the above (1), wherein the free radical scavenger is sulfites or vitamins;
(6) A pharmaceutical preparation as described in the above (5), wherein the vitamins are vitamin C or vitamin E;
(7) A pharmaceutical preparation as described in the above (2), wherein the oily substance is polyethylene glycol;
(8) A stabilized pharmaceutical preparation which is coated with a coating agent comprising (i) titanium oxide and (ii) sodium hydrogensulfite, ascorbic acid, sodium ascorbate, calcium ascorbate, dl-&agr;-tocopherol or dl-&agr;-tocopherol acetate;
(9) A pharmaceutical preparation as described in the above (2), wherein the coating agent further comprises a basic substance;
(10) A pharmaceutical preparation as described in the above (9), wherein the basic substance is a metal carbonate or a metal hydroxide;
(11) A stabilized pharmaceutical preparation which is coated with a coating agent comprising (i) an oily substance selected from the group consisting of an ester and an alcohol, and (ii) a free radical scavenger;
(12) A stabilized pharmaceutical preparation which is coated with a coating agent comprising (i) an oily substance selected from the group consisting of an ester and an alcohol, and (ii) a basic substance;
(13) A pharmaceutical preparation as described in the above (12), wherein the coating agent further comprises an agent for the protection from light, said agent being capable of producing free radicals when exposed to ultraviolet rays;
(14) A coating agent which comprises (i) an agent for the protection from light, said agent being capable of producing free radicals when exposed to ultraviolet rays, and (ii) a free radical scavenger;
(15) A method of stabilizing a pharmaceutical preparation which comprises coating a composition containing a drug with a coating agent comprising (i) an agent for the protection from light, said agent being capable of producing free radicals when exposed to ultraviolet rays, and (ii) a free radical scavenger;
(16) A method of stabilizing a pharmaceutical preparation which comprises coating a composition containing a drug with a coating agent comprising (i) an oily substance selected from the group consisting of an ester and an alcohol, and (ii) a free radical scavenger;
(17) A method of stabilizing a pharmaceutical preparation which comprises coating a composition containing a drug with a coating agent comprising (i) an oily substance selected from the group consisting of an ester and an alcohol, and (ii) a basic substance;
(18) Use of a coating agent which comprises (i) an agent for the protection from light, said agent being capable of producing free radicals when exposed to ultraviolet rays, and (ii) a free radical scavenger, for stabilizing a pharmaceutical preparation;
(19) Use of a coating agent which comprises (i) an oily substance selected from the group consisting of an ester and an alcohol, and (ii) a basic substance, for stabilizing a pharmaceutical preparation;
(20) Use of a coating agent which comprises (i) an oily substance selected from the group consisting of an ester and an alcohol, and (ii) a basic substance, for stabilizing a pharmaceutical preparation.
DETAILED DESCRIPTION OF THE INVENTION
“An agent for the protection from light, said agent being capable of producing free radicals when exposed to ultraviolet rays”, “a free radical scavenger”, “an oily substance selected from the group consisting of an ester and an alcohol”, “a basic substance”, “a coating agent” and “a pharmaceutical preparation” which are used in the present invention, are detailed hereafter.
“An agent for the protection from light, said agent being capable of producing free radicals when exposed to ultraviolet rays” means that the agent is added to a pharmaceutical preparation for the protection from light, and is capable of producing free radicals when exposed to ultraviolet rays. In general, the agent for the protection from light is a substance producing free radicals when exposed to light from a fluorescent lamp indoors or to sunlight outdoors, at normal temperatures. The free radic

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