Oral drug delivery compositions and methods
AssigneeEmisphere Technologies, Inc.
InventorsSam J. Milstein, Evgueni N. Barantsevitch, Donald J. Sarubbi, Andrea Leone-Bay, Duncan R. Paton
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Abstract
The present invention relates to an oral drug delivery system, and in particular to modified amino acids and modified amino acid derivatives for use as a delivery system of sensitive agents such as bioactive peptides. The modified amino acids and derivatives can form non-covalent mixtures with active biological agents and in an alternate embodiment can releasably carry active agents. Modified amino acids can also form drug containing microspheres. These mixtures are suitable for oral administration of biologically active agents to animals. Methods for the preparation of such amino acids are also disclosed.
Claims41
A composition comprising:
- (A) at least one biologically-active agent;
- and
- (B) at least one carrier comprising
- (a)
- (i) at least one acylated aldehyde of an amino acid,
- (ii) at least one acylated ketone of an amino acid,
- (iii) at least one acylated aldehyde of a peptide,
- (iv) at least one acylated ketone of a peptide, or
- (v) any combination of (a) (i), (a) (ii), (a) (iii) and (a) (iv);
- (b)
- (i) carboxymethyl-phenylalanine-leucine,
- (ii) 2-carboxy-3-phenylpropionyl-leucine,
- (iii) 2-benzylsuccinic acid, or
- (iv) an actinonin, or
- (v) a compound having the formula:
- Ar--Y--(R.sup.1).sub.n --OH
- wherein:
- Ar is a substituted or unsubstituted phenyl or naphthyl;
- R.sup.1 is ##STR9## wherein:
- R.sup.3 is C.sub.1 to C.sub.24 alkyl, C.sub.1 to C.sub.24 alkenyl, phenyl, naphthyl, (C.sub.1 to C.sub.10 alkyl) phenyl, (C.sub.1 to C.sub.10 alkenyl) phenyl, (C.sub.1 to C.sub.10 alkyl) naphthyl, (C.sub.1 to C.sub.10 alkenyl) naphthyl, phenyl (C.sub.1 to C.sub.10 alkyl), phenyl (C.sub.1 to C.sub.10 alkenyl), naphthyl (C.sub.1 to C.sub.10 alkyl) and naphthyl (C.sub.1 to C.sub.1 alkenyl)
- R.sup.3 is optionally substituted with C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkenyl, C.sub.1 to C.sub.4 alkoxy, --OH, --SH, --CO.sub.2 R.sup.5, cycloalkyl, cycloalkenyl, heterocyclic, aryl, alkaryl, heteroaryl or heteroalkaryl or any combination thereon;
- R.sup.5 is hydrogen, C.sub.1 to C.sub.4 alkyl or C.sub.1 to C.sub.4 alkenyl;
- R.sup.3 is optionally interrupted by oxygen, nitrogen, sulfur or any combination thereof;
- and
- R.sup.4 is hydrogen, C.sub.1 to C.sub.4 alkyl or C.sub.1 to C.sub.4 alkenyl;
- and n is from 1 to 5;
- (vi) any combination of (b) (i), (b) (ii), (b) (iii), (b) (iv) and (b) (v);
- or
- (c) a combination of (a) and (b).
A method for preparing a composition, said method comprising mixing:
- (A) at least one biologically-active agent;
- (B) a carrier comprising
- (a)
- (i) at least one acylated aldehyde of an amino acid,
- (ii) at least one acylated ketone of an amino acid,
- (iii) at least one acylated aldehyde of a peptide,
- (iv) at least one acylated ketone of a peptide, or
- (v) any combination of (a) (i), (a) (ii) (a) (iii) a (iv);
- (b)
- (i) carboxymethyl-phenylalanine-leucine,
- (ii) 2-carboxy-3-phenylpropionyl-leucine,
- (iii) 2-benzylsuccinic acid, or
- (iv) an actinonin, or
- (v) a compound having the formula:
- Ar--Y--(R.sup.1).sub.n --OH
- wherein:
- Ar is a substituted or unsubstituted phenyl or naphthyl;
- R.sup.1 is ##STR11## wherein:
- R.sup.3 is C.sub.1 to C.sub.24 alkyl, C.sub.1 to C.sub.24 alkenyl, phenyl, naphthyl, (C.sub.1 to C.sub.10 alkyl) phenyl, (C.sub.1 to C.sub.10 alkenyl) phenyl, (C.sub.1 to C.sub.10 alkyl) naphthyl, (C.sub.1 to C.sub.10 alkenyl) naphthyl, phenyl (C.sub.1 to C.sub.10 alkyl), phenyl (C.sub.1 to C.sub.10 alkenyl), naphthyl (C.sub.1 to C.sub.10 alkyl) and naphthyl (C.sub.1 to C.sub.10 alkenyl);
- R.sup.3 is optionally substituted with C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkenyl, C.sub.1 to C.sub.4 alkoxy, --OH, --SH --CO.sub.2 R.sup.5, cycloalkyl, cycloalkenyl, heterocyclic, aryl, alkaryl, heteroaryl or heteroalkaryl or any combination thereof;
- R.sup.5 is hydrogen, C.sub.1 to C.sub.4 alkyl or C.sub.1 to C.sub.4 alkenyl;
- R.sup.3 is optionally interrupted by oxygen, nitrogen, sulfur or any combination thereof;
- and
- R.sup.4 is hydrogen, C.sub.1 to C.sub.4 alkyl or C.sub.1 to C.sub.4 alkenyl;
- and n is from 1 to 5;
- (vi) or any combination of (b) (i), (b) (ii), (b) (iii), (b) (iv) and (b) (v);
- (c) a combination of (a) and (b);
- and
- (C) optionally a dosing vehicle.
A pharmacological composition comprising:
- (A) at least one biologically-active agent;
- and
- (B) at least one carrier comprising
- (a)
- (i) at least one acylated aldehyde of an amino acid,
- (ii) at least one acylated ketone of an amino acid,
- (iii) at least one acylated aldehyde of a peptide,
- (iv) at least one acylated ketone of a peptide, or
- (v) any combination of (a) (i), (a) (ii) (a) (iii) and (a) (iv);
- (b)
- (i) carboxymethyl-phenylalanine-leucine,
- (ii) 2-carboxy-3-phenylpropionyl-leucine,
- (iii) 2-benzylsuccinic acid, or
- (iv) 4-(phenylsulfonamido)-4-phenylbutyric acid,
- (v) or any combination of (b) (i), (b) (ii), (b) (iii) and (b) (iv);
- or
- (c) a combination of (a) and (b).
A method for preparing a pharmacological composition, said method comprising mixing:
- (A) at least one biologically-active agent;
- (B) a carrier comprising
- (a)
- (i) at least one acylated aldehyde of an amino acid,
- (ii) at least one acylated ketone of an amino acid,
- (iii) at least one acylated aldehyde of a peptide,
- (iv) at least one acylated ketone of a peptide, or
- (v) any combination of (a) (i), (a) (ii), (a) (iii) and (a) (iv);
- (b)
- (i) carboxymethyl-phenylalanine-leucine,
- (ii) 2-carboxy-3-phenylpropionyl-leucine,
- (iii) 2-benzylsuccinic acid, or
- (iv) 4-(phenylsulfonamido)-4-phenylbutyric acid,
- (v) or any combination of (b) (i), (b) (ii), (b) (iii) and (b) (iv);
- or
- (c) a combination of (a) and (b);
- and
- (C) optionally a dosing vehicle.
The compound N-cyclohexanoylphenylalanine aldehyde.
A composition comprising an active agent and one or more modified amino acids comprising an amino acid amide or sulfonamide.
A composition comprising an active agent encapsulated within a microsphere, said microsphere comprising a wall of at least one amino acid amide or sulfonamide.
A method for preparing a modified amino acid microsphere comprising the steps of:
- (a) incubating at least one or more amino acid amide or sulfonamide in a aqueous acid solution so as to form said modified amino acid microsphere;
- and
- (b) collecting said modified amino acid microsphere.
Dependencies are inferred from the claim text.