Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-08-24
2002-12-03
Azpuru, Carlos (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424SDIG001, C514S772300, C514S966000
Reexamination Certificate
active
06488954
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a liquid suppository composition of diclofenac sodium.
BACKGROUND ART
Diclofenac sodium, 2-[(2,6-dichlorophenyl)amino] benzeneacetic acid, monosodium salt, (Voltaren®, CibaGeneva Pharmaceuticals, Summit, N.J., USA) is one of the nonsteroidal anti-inflammatory agents with analgesic, antipyretic and anti-inflammatory properties. The potency of its antipyretic effect is similar to that of indomethacin, phenylbutazone and acetylsalicylic acid, while having the effect of uterine contraction, antihypertension and the treatment for menstrual disorder. Although oral-administered diclofenac sodium is almost completely absorbed, its typical adverse reactions in the gastrointestinal tract include gastric ulcer, GI hemorrhage and perforation. To avoid the various adverse reactions associated with the oral administration of diclofenac sodium, its suppository form was already introduced. However, the said suppository form has another disadvantages, that is not only the general disadvantages of the suppository form, but also adverse effects due to sudden increasing of blood concentration of drug after its administration and due to the inconveniency of twice medication per day.
These disadvantages can be eliminated by a formulation of the sustained-release dosage form in such a manner to combine some appropriate base with the materials that can make a drug to be sustained-released. However, such materials for sustained-releasing of drug are not dissolved in the oily bases by heating, while being in dispersed state. Thus it is necessary that the sustained-release dosage form should be prepared in such a manner that each component is homogeneously dispersed in oily bases. For example, there are several methods of preparing the sustained-release dosage form in the following manner:
a method of changing the blending ratio of fatty acid ester (Japan Patent Pyung 2-73010, Pyung 1-11618, Pyung 7-138149, Sho 64-63512);
a method of adding hydrogen lecithin to the base of conventional suppository with a very high melting point (Japan Patent Sho 63-14716); and,
a method of adding polyglycerin fatty acid ester to the base of conventional suppository.
According to these methods, their drug application are limited due to the fact that the drug-release rate are controlled only by the contents of materials for sustained-release.
There is another method of controlling the drug-release rate by adding water-containing polymers to the conventional solid suppository [
Drug Develop. and Ind. Pharm.
16(10), 1675-1686, 1990]. However, the rectal mucosa may be irritated during administration of the preparation formulated by using this method.
Likewise the conventional suppositories, the sustained-release dosage forms prepared by the said methods are applicable easily and widely to patients including elderly people and children, and the absorption of drug from those is not affected by meals, due to their special route of administration. But they have still encountered the following problems, likewise the conventional suppositories: (1) inconvenience in manufacture and handling; (2) a feel of foreign matter and discomfort on the part of patients during administration, and (3) greater deviation of bioavailability due to the drug absorption via the large intestine, not via rectum, due to the movement of the preparation
Meantime, in recent years, there are many cases that poloxamer is selected as a base of suppository, because it is liquid at a low temperature but when temperature goes up, it can form gel. For example, a basic method of using poloxamer as a base for suppository composition is that the scope of gelation temperature of base is simply adjusted by modulating the concentrations of poloxamer and such poloxamer derivatives as Tetronic™(BASF Corp., Parsippany, N.J., USA), Tergitol™(Union Carbine, Danbury, Conn., USA), etc. (U.S. Pat. No. 4,188,373 and Canadian Patent 1,072,413). Another method of using poloxamer as a main base for suppository composition is that various kinds of additives are employed so as to adjust the gel strength and pH of suppository composition for applying it to the body cavity such as rectum, skin, etc. (U.S. Pat. No. 4,478,822, 4,474,951, 4,474,952, 4,474,752 and 4,474,753). However, since the said suppository compositions are in principle characterized by controlling the general properties of base only through the selection of proper poloxamer, their application to rectum are inappropriate; when these suppository compositions are administered to rectum, they are easily leaked out from the anus or shifted to the end of large intestine, thus a drug undergoes the first-pass effect.
In another method of using poloxamer for suppository composition, it is designed with the addition of polymers including carbomer to adjust the gelation temperature and gel strength that the composition can be applied to the body cavity such as skin, eye and rectum (Europe Patent Number 551626). Nevertheless, this composition has proven to be insufficient for its application to the suppository composition since the bioadhesive force and dissolution rate of the drug were not considered. Thereafter, another method of using sodium alginate, chitosan, etc., which are ionic polysaccharides, to be mixed with poloxamer has been disclosed so as to delivery drugs such as antipyretic to a body cavity (U.S. Pat. No. 5,346,703). However, this method has recognized some disadvantages in that (1) the physical properties of sodium alginate or chitosan is inappropriate to suppository form, (2) the irreversible base containing counter ion such as calcium ion (Ca
+2
) is inconvenient in use and handling of suppository, (3) the scope of gelation temperature cannot be widely controlled due to its use of one poloxamer, and (4) the damages of rectal mucosa, which must be considered carefully during rectal administration, are severe.
Besides, another method of using chitosan as a main gel-forming material has been disclosed (U.S. Pat. No. 4,946,870 and EPPatent 103995). This method has also encountered some drawbacks in that (1) the accurate gel temperature of suppository composition cannot be made available, (2) although poloxamer is used, the composition contains some absorption enhancers, while concentrating on the application of peptide drugs only. There is another method of using polysaccharide as the main ingredient (International Patent WO94/03157 and WO94/03186), but this method has proven to be disadvantageous in that the accurate adjustment of physical properties such as gelation temperature and gel strength may not be easily available.
There is another method of using poloxamer, sodium alginate or chitosan as a base for application to a drug that is inadequate as an oral administration due to the hepatic first-pass effect, the severe gastrointestinal disturbance or the disintegration by gastric juice (International Patent WO97/30693 and WO97/34580). However, the base cannot be employed to diclofenac sodium of the present invention.
The suppository composition of this invention is characterized in that: (1) it has the suitable gelation temperature at 30-36° C. to be a liquid form at room temperature and readily becomes a gel at body temperature after rectal administration, (2) it has the gel strength of more then 15 sec with no weight, and is not leaked out the anus, (3) and it has suitable bioadhesive force of more then 50 dyne/cm
2
and does not move up to the end of the colon from the rectum, and does not give any damage to the rectal mucosa.
Therefore, an object of the present invention is to provide a novel liquid suppository composition containing diclofenac sodium, being characterized in that: (1) the process for manufacturing the composition is easy and economical, (2) the composition has better gel strength and bioadhesive force, (3) a feel of foreign matter or discomfort does not occur during rectal administration, (4) the administration of the composition is easy and (5) the composition is neither leaked out from the anus nor shifted into
Cho Su Jin
Jung Jae Hee
Ryu Jei Man
Yoon Sung June
Azpuru Carlos
Clement, Esq. Candice J.
Dong Wha Pharm. Ind. Co. Ltd.
Heslin Rothenberg Farley and Mesiti P.C.
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