Drug – bio-affecting and body treating compositions – Designated organic nonactive ingredient containing other... – Peptide containing
Reexamination Certificate
1999-04-27
2004-06-01
Kemmerer, Elizabeth C. (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic nonactive ingredient containing other...
Peptide containing
C514S772000, C514S773000, C514S449000, C514S510000
Reexamination Certificate
active
06743826
ABSTRACT:
FIELD OF THE INVENTION
The present invention is related to a new method, products and formulations for delivery in therapeutic use of therapeutically active compounds having poor water solubility and substantial binding affinity to plasma proteins and processes for the preparations of such products and formulations.
More particularly first objects of the invention are products and pharmaceutical formulations in solid or liquid form mainly for parenteral use consisting of or comprising
a) a therapeutically active substance having low aqueous solubility and a substantial binding affinity to plasma proteins (in the following “active substance”) and
b) a plasma protein fraction in controlled aggregation state
whereby the said active substance and the said protein fraction are bound to each other by way of non-covalent bonds and
c) optionally further pharmaceutically acceptable and mainly parenterally acceptable formulation additive(s)—such as water, stabilizer(s), protein aggregation controller(s).
The homogeneous solid state products of the invention consisting of the said protein and the said substance are water-soluble and their aqueous solutions can be used parenterally or can be used to prepare parenteral pharmaceuticals.
It is well known in the art that some biologically active compounds possess potent therapeutic activity but could never demonstrate their benefit because of their poor solubility in aqueous media. Some of them were never ever formulated while a few did not reach but the stage of the “phase I” clinical development. Some of them appear in “hardly biocompatible” formulations of relatively high toxicity caused by the materials used for formulation. A typical example for this is represented by the groups of taxones specifically paclitaxel which is a potent cytostatic the application of which however is reduced because of the toxicity of its known formulation in Klucel: tween 80 or Klucel and diluent 12, a 1:1 mixture of Cremaphor EL: ethanol. [Cancer Chemotherapy and Pharmacology (1994) 34:465-471; Journal of the National Cancer Institute (1990) 1247-1259]. Cremaphor EL (polyoxyethylated castor oil) has inherent toxicity, causing vasodilatation, lethargy, hypotension etc. In order to decrease the toxic side-effect of the solvent and adjuvant, a series of special methods were suggested: application of very small doses over a long period of time, pre-medication before treatment etc. (U.S. Pat. No. 5,665,761; U.S. Pat. No. 5,621,001; U.S. Pat. No. 5,670,537 etc.) A further suggestion consisted in combination of the active substance with a dispersing agent contained within a protein walled shell (U.S. Pat. No. 5,560,933) which is formed by reacting the protein with oil such as soy bean oil—such formulations being proposed for paclitaxel and amphotericin. However even the latest literature comprises warnings on the course of application of e.g. paclitaxel (see e.g. “Guidance for Industry issued by the U.S. Department of Health and Human Service CDER September 1997, OGD-L-8) where—because of hypersensitivity reactions—all patients treated with paclitaxel should be premedicated with corticosteroids, diphenhydramine and H
2
antagonists.
It was further proposed to prepare parenteral formulations of certain water-insoluble dihydropyridins, by dissolving them in an organic solvent or in a mixture of an organic solvent with water and adding an aqueous HSP solution to said solution in order to minimise crystallisation of the insoluble active substance (Hungarian Patent N
o
198381; DE Appl. 37 02105). The resulting liquid however was still not a
BACKGROUND OF THE INVENTION
It is further known that some of the water-insoluble active substances possess a considerable affinity to protein or serum protein. Some literature is mentioned here for paclitaxel [Cancer Chem. and Pharm. (1994) 34: 465-471]; miconazole, fluconazole, amphotericin B [Infection, 23(5): 292-297 (1995) September ]; carbamazepine [J. Chromatogr. B Biomed. Appl. 669(2): 281 -288 (1995 Jul. 21]; azathioprine (Ann. N.Y. Acad. Sci, 685 (1993): 175-192), propofol [J. Chromatogr. Sci (1992): 164-166]. According to new literature [The Lancet vol. 352 (1998): 540-542] the drug Taxol® caused rouleaux formation of red cells and so did polyoxyethylated castor oil which served as the solvent of said drug. Some water-insoluble drugs were formulated using the toxic Cremaphor (cyclosporin, teniposide, paclitaxel, amphotericin B). To the best of our knowledge a series of highly active but water-insoluble drugs was not available so far on the market in parenteral, intravenous administration forms at all e.g. ritonavit, carbamazepine, camphotethine, azathiopine, miconazole, fluconazole etc.
Thus there is a need to solve the problem whereby therapeutically valuable water-insoluble substances can be administered in water-soluble form, preferably parenterally to a patient in need to be treated with said active ingredients.
BRIEF SUMMARY OF THE INVENTION
The aim of this invention is to meet this requirement concerning practically water-insoluble active ingredients having a substantial binding affinity to plasma proteins.
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Paál, et al, 2001, Eur. J. Biochem, 268: 2197-2191.*
“Guidance for Industry, Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations”,U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research(CDER) (Sep. 1997), 1-24.
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Eiseman et al., “Plasma pharmacokinetics and tissue distribution of paclitaxel in DC2F1mice”,Cancer Chemotherapy and Pharmacology(1994), 34: 465-471.
Guitton et al., “Quantitation of propofol in whole blood by gas chromatography-mass spectrometry”,Journal of Chromatography B: Biomedical Applications(Jul. 21, 1995), 669:358-365.
Hallbach et al., “Determination of Lamotrigine, Carbamazepine and Carbamazepine Epoxide in Human Serum by Gas Chromatography Mass Spectrometry”,European Journal of Clinical Chemistry and Clinical Biochemistry(Oct. 1997), 35(10):755-759.
Johansen et al., “Automated analysis of free and total concentrations of three antiepileptic drugs in plasma with on-line dialysis and high-performance liquid chromatography”,Journal of Chromatography B: Biomedical Applications(Jul. 21, 1995) 669: 281-288.
Olah et al., “Molecular Mechanisms in the Antiproliferative Action ofTaxol and Tiazofurin”,Anticancer Research—International Journal of Cancer Research and Treatment(Sep.-Oct. 1996), 16:2469-2477.
Pavan et al., “Monitoring Propofol Serum Levels by Rapid and Sensitive Reversed-Phase High-Performance Liquid Chromatography During Prolonged Sedation in ICU Patients”,Chromatographic Science(May 1992), 30(5):164-166.
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Rivory et al., “Identification and Properties of a Major Plasma Metabolite of Irinotecan (CPT-11) Isolated from the Plasma of Patient
Hegedus Lajos
Krempels Krisztina
Paal Krisztina
Petho Gabor
Human RT
Kemmerer Elizabeth C.
Kenyon & Kenyon
Wegert Sandra
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