Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-11-20
2004-09-21
Nguyen, Dave T. (Department: 1635)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C424S479000, C424S480000, C424S482000, C424S493000, C424S494000, C424S497000, C536S023100, C536S024500, C435S320100
Reexamination Certificate
active
06794367
ABSTRACT:
TECHNICAL FIELD
The invention relates to a solid preparation for oral administration of gene-related drugs.
A variety of gene-related drugs have been developed as useful pharmaceuticals, though in the case of producing them as a solid preparation for oral administration, there are problems such as that worsened fluidity of mixed powder due to wettability of a gene-related drug and viscosity after its moisture absorption causing a compressing problem, in the case of increase of the mixed amount, production of tablets with good disintegration becomes difficult, and, in addition that it is very difficult to keep stability of a gene-related drug during a production process. Furthermore, even if a solid preparation for oral administration can be produced, a gene-related drug is easily decomposed in digestive tracts due to the unusually high instability in it, and so on, therefore, it has been generally considered difficult to develop a solid preparation appropriate for oral administration.
BACKGROUND ART
On the other hand, in the development of a general solid preparation for oral administration, recently various attempts have been made to make a drug which easily loses its due to decomposition in small intestines to be absorbed in large intestines in which the enzyme activity of protein decomposition is remarkably low by delivering it to the organ. Illustrative of such examples are oral preparations by the inventors (International application WO, 94/10983, A) mainly for drugs of protein or polypeptide nature having a high specificity toward lower digestive tracts such as large intestines. However, as to a gene-related drug, a solid preparation for oral administration which is practical and effective has not been developed yet owing to the above reasons.
SUMMARY OF THE INVENTION
Consequently, the problem of the invention is to solve problems in the prior art described above in a gene-related drug and to provide a solid preparation for oral administration which is practical and effective. More specifically, it is to provide a solid preparation for oral administration of a gene-related drug in which compressing preparation is easy, preparation processes are stable, and it is effectively absorbed in the digestive tracts.
The inventors made extensive researches to solve the above problems and found out that the decomposition activity for a gene-related drug, as for drugs of peptide nature is remarkably low in large intestines compared with small intestines, and as the result of continuing further research based on such evidence the inventors accomplished the invention.
Namely, the invention relates to a solid preparation with a coating around the core containing a gene-related drug for oral administration with releasability in lower digestive tracts in small intestines is applied.
The invention also relates to a solid preparation for oral administration in which the core is formed by compressing mixed powder of a gene-related drug and additives appropriately containing a binder, a saccharide, a disintegrator, an excipient or the like, and its outside is coated with an inner layer comprising a cationic copolymer and with an outer layer comprising an anionic copolymer.
Further, the invention comprises the following embodiments.
The above solid preparation for oral administration wherein the mixed ratio of a gene-related drug and a binder is 1:0.2-1:5 or the mixed ratio of a gene-related drug, a binder and an excipient is 1:0.2:0.01-1:5:1.
The above solid preparation for oral administration wherein the mixed ratio of a saccharide contained in the core containing a gene-related drug is in the range of 20-60 wt. %.
The above solid preparation for oral administration wherein a disintegrator contained in the core containing a gene-related drug is in the range of 2-15 wt. %.
The above solid preparation for oral administration, characterized in that a disintegrator is mixed in the ratio of 1:0.05-1:10 against the mixed amount of a gene-related drug and produced.
The above solid preparation for oral administration wherein an excipient contained in the core containing a gene-related drug is in the range of 0.1-15 wt. %.
The above solid preparation for oral administration wherein a gene-related drug contained in the core of the gene-related drug is in the range of 0.1-50 wt. %.
The above solid preparation for oral administration wherein a binder contained in the core containing a gene-related drug is in the range of 5-40 wt. %.
The above solid preparations for oral administration wherein the disintegrators are crospovidone, alpha starch, sodium carboxymethyl starch, carmellose, calcium carmellose, sodium carmellose, agar powder, sodium croscarmellose, crystalline cellulose, low substituted hydroxypropyl cellulose, starch, dextrin, hydroxyethylmethyl cellulose, hydroxypropyl starch, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, macrogol and mannitol.
The above solid preparations for oral administration wherein the saccharide are monosaccharides and disaccharides such as lactose, fructose, sucrose, glucose, xylitol, maltose, mannitol and sorbitol, or polysaccharides and derivatives thereof such as cellulose, crystalline cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, ethyl cellulose, starch, dextrin, dextran, pectin and pullulan.
The above solid preparations for oral administration wherein the excipients are light anhydrous silicic acid, ethyl cellulose, carmelose, agar, magnesium aluminosilicate, calcium silicate, magnesium silicate, cyclodextrin, starch, synthetic aluminum silicate, synthetic hydrotalcite, titanium oxide, zinc oxide, magnesium oxide, alumina magnesium hydroxide, magnesium stearate, calcium stearate, aluminum silicate, talc, crystalline cellulose and lactose.
The above solid preparations for oral administration wherein the gene-related drugs are DNA, RNA and modified compounds thereof, and compounds thereof conjugated or bound to a carrier.
The above solid preparations for oral administration wherein the binders are crystalline cellulose, gumarabic, sodium alginate, ethyl cellulose, agar, carboxyvinyl polymer, carmelose, gelatin, low substituted hydroxypropyl cellulose, starch, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, pectin, polyvinylpyrrolidone, macrogol and methyl cellulose.
The above solid preparations for oral administration wherein the carriers comprise a cationic polymer, cationic lipid, virus vector and phage.
The above solid preparations for oral administration wherein the gene-related drugs comprise a nucleic acid, oligonucleotide, antisense, triple helix forming oligonucleotide (TFO), ribozyme, decoy, plasmid, cosmid, P
1
phage, YAC (yeast artificial chromosome), chromosome, aptamer and phage.
Thus, the above problems were solved once for all by the solid preparations for oral administration of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the invention, illustrative of available gene-related drugs are DNA, RNA and modified compounds thereof, and compounds thereof conjugated or bound to a carrier, nucleic acid, oligonucleotide, antisense, triple helix forming oligonucleotide (TFO), ribozyme, decoy and plasmid. Illustrative of the carriers used are cationic polymer, cationic lipid, virus vector and phage.
Specifically, in the case of aiming at the colitis therapy as a topical therapeutic use are illustrated suppressive type gene pharmaceuticals such as TNF-&agr; (Tumor necrosis factor &agr;), ICAM-1 (Intercellular adhesion molecule-1), COX-2 (Cyclooxygenase-2), IL-1 (Interleukin-1), IL-6 (Interleukin-6) and IL-8 (Interleukin-8), or expression type gene pharmaceuticals such as IL-2 (Interleukin-2) and IL-10 (Interleukin-10). In the case of aiming at the colon cancer are illustrated suppressive type gene pharmaceuticals such as ICAM-1, COX-2 and TGF-&bgr; (Transforming growth factor &bgr;), or expression type gene pharmaceuticals such as INF-&ggr; (Interferon-&ggr;), TNF-&agr;, APC (
Adenomatous Polyposis Coli
), p53, MCC (Mutated in Colorectal Carcinoma) and DCC (deleted in co
Aoki Jun
Goto Takeshi
Tanida Norifumi
Hisamitsu Pharmaceutical, Inc.
Nguyen Dave T.
Schnizer Richard
Wolf Greenfield & Sacks P.C.
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