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Oral compositions having increased bioavailability and methods of using the same

a technology of oral compositions and retinoids, which is applied in the directions of drug compositions, dispersed delivery, biocides, etc., can solve the problem of limited bioavailability of oral fenretinide compositions

Inactive Publication Date: 2005-12-08
MAURER BARRY J +5
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides an edible composition for oral delivery of an active agent such as a retinide. The composition comprises an active agent, a lipid matrix composition, a sweetener, flour, and optionally a humectant. The lipid matrix composition comprises at least one non-esterified fatty acid, at least one monoglyceride, and lysophosphatidylcholine. The composition can be packaged in bulk or unit dosage form and can be administered per se or mixed with a solid or liquid food carrier. The composition can be used to treat disorders such as proliferative diseases in a subject in need thereof. The use of an active agent in the composition is also described."

Problems solved by technology

However, the bioavailability of this oral fenretinide composition is limited and greater anticancer effects might be obtained if fenretinide could be delivered intravenously to achieve higher drug plasma levels.

Method used

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  • Oral compositions having increased bioavailability and methods of using the same
  • Oral compositions having increased bioavailability and methods of using the same
  • Oral compositions having increased bioavailability and methods of using the same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Oral Compositions of 4-HPR

[0063] The actual dose of 4-HPR to be delivered to patients will ultimately define the resulting mixture volume, once it is determined. These arbitrary values present 4-HPR doses of 0.5 to 2.5 grams per mixture volume.

[0064] A concentrated LXS-HPR mixture would be >1000 mg HPR per 10 cc. As awkward as this may be for typical dosage calculations, we usually describe [drug]-LXS ratios in terms of moles. This is because our prior work suggests that 1 mole of drug successfully interacts within the inclusion space of 1 mole of LXS. So, if we use a mole ratio of 0.8 (0.8 moles of drug per mole of LXS), the maximum concentrated dosage would be 397*0.8 / 2429, or 131 mg HPR per gram of LXS.

[0065] In reading Table 1, then, with a mole ratio of 0.8, 2.5 g of 4-HPR would complex with 19.09 g LXS with a resulting total volume of 17.18 ml, or approximately 1400 mg per 10 cc. The calculations for lower mole ratios are included.

[0066] Preferably, the LXS composition (in...

example 2

Improved Bioavailability of Oral 4-HPR Using LYM-X-SORB™ Lipid Matrix

[0067] LYM-X-SORB™ (Lymphatic Xenobiotic Absorbability) lipid matrix (also referred to as LXS™ herein) is a patented and proprietary technology of LYM-DRUG PRODUCTS, LLC and BioMolecular Products, Inc., Byfield, Mass., useful for increasing the oral bioavailability of water insoluble compounds. LXS™ is a non-liposomal, lipid-based, drug delivery system composed of FDA-accepted GRAS (Generally Regarded As Safe) lipids (lysophosphatidylcholine (LPC), monoglycerides (MG), and fatty acids (FA)). LXS™ acts as a “lipid-fingered glove” which wraps around the drug of interest in a 1:1 molar ratio. In the presence of sodium bicarbonate and bile salts, the LXS / drug matrix forms <10 nm size particles that are readily absorbed. Neither the LXS™ monomer, nor the LXS / drug matrix, damage intestinal villae. LXS™ has been demonstrated safe in a one-year double blind oral feeding trial in Cystic Fibrosis (CF) children (Lepage, et a...

example 3

Powder Formulation Process

[0074] A 1:0.8 Mole ratio combination of LYM-X-SORB™ drug matrix compostition was combined with fenretinide in accordance with known techniques and as described in Example 1 above in a 1:0.8 Mole ratio to form an LXS / 4-HPR complex. The lipid matrix is not acidified or significantly hydrated to form a protonated aqueous lipid matrix of predominantly hexagonal or inverse hexagonal phase. Rather, the lipid matrix is basic, minimally-hydrated, and of predominantly lamellar phase. The LXS / 4-HPR is blended to anoil and stored at −20° C. The oil is ˜88.8% (wt) LXS and 11.2% (wt) 4-HPR (1:0.8 mole ratio).

[0075] A food processor is used for the blending to a powder but this may be replaced by a much larger reactor vessel with internal chopper blades or other mixing device to process multiple kilos simultaneously. Either way, the flour and sugar are loaded into the blending vessel and mixed for ˜1 minute or more at room temperature. The LXS / 4-HPR is then loaded at ...

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Abstract

The present invention provides an edible composition for oral delivery of an active agent such as paclitaxel or a retinide. The composition comprises, in the form of a dry flowable powder: (a) an active agent such as a retinide; (b) lipid matrix composition; (c) optionally sweetener; (d) flour. Compositions of the invention may be administered per se or mixed with a solid or liquid food carrier, for direct oral consumption by a subject or administration through a feeding tube.

Description

RELATED APPLICATIONS [0001] This application is a continuation of U.S. patent application Ser. No. 10 / 767,352, filed Jan. 30, 2004, which in turn claims the benefit of provisional application Ser. No. 60 / 444,530, filed Jan. 31, 2003, the disclosures of both of which are incorporated by reference herein in their entirety.FIELD OF THE INVENTION [0002] The present invention concerns pharmaceutical compositions for oral delivery of a retinide such as fenretinide. BACKGROUND OF THE INVENTION [0003] Fenretinide [HPR; all-trans-N-(4-hydroxyphenyl)retinamide; CAS Registry number 65646-68-6] is a synthetic retinoic acid derivative having the structure: Fenretinide is minimally soluble in aqueous solution. U.S. Pat. No. 4,665,098 by Gibbs describes an oral pharmaceutical composition of fenretinide as useful for the treatment of breast and bladder cancer. However, the bioavailability of this oral fenretinide composition is limited and greater anticancer effects might be obtained if fenretini...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A23L1/30A23L23/00A61K9/00A61K31/167
CPCA23V2002/00A61K9/0095A61K9/1617A61K9/1664A61K31/167A23V2250/30A23V2250/186A23V2250/192A23V2250/1846A23L33/10A61P35/00
Inventor MAURER, BARRY J.REYNOLDS, CHARLES PATRICKYESAIR, DAVID W.MCKEE, ROBERT TRAVISBURGESS, STEPHEN W.SHAW, WALTER A.
Owner MAURER BARRY J
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