Transport system conjugates

• US 20020035243A1
• Filed: 05/29/2001
• Published: 03/21/2002
• Est. Priority Date: 11/26/1998
• Status: Abandoned Application

• Current Assignee: Pentapharm AG (DSM-Firmenich AG)
• Original Assignee: Pentapharm AG (DSM-Firmenich AG)
• Inventors: Imfeld, Dominik, Ludin, Christian, Schreier, Thomas
• Application Number:
  US09/866,824
• Publication Number:
  US 20020035243A1
• Time in Patent Office: Days
• US Class Current: 530/408
• CPC Class Codes: A61K 2800/57 Compounds covalently linked to a(n inert) carrier molecule, e.g. conjugates, pro-fragrances
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 8/4986 with sulfur as the only hetero atom
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin

Abstract

The present invention relates to transport system conjugates as transmembrane transport systems for topical and transdermal applications, especially in dermatology and cosmetics, and for pharmaceutically active ingredients with a systemic action. The transport system according to the invention can be used for peptide active ingredients as well as for non-peptide active ingredients, such as vitamins, hormones and antibiotics. There are numerous fields of application of the topical and transdermal use of the transport system conjugates according to the present invention, including the transport of active ingredients into and through the skin for healing wound, protecting the skin, and controlling various disorders including skin aging, inflammation, cellulitis, psoriasis, melanoma, arthritis, acne, neurodermatitis, eczema, paradontitis, burns, and so forth.

Claims

1. Transport system conjugate as a transmembrane transport system, characterized in that it consists of at least one pharmaceutically and/or cosmetically active compound, and in that this compound has been modified in such a way that it has at least one substituent of formula (I) and at least one substituent, bonded to Y, of formula (II) and/or (III):

2. Transport system conjugate according to claim 1, characterized in that Y is the radical of lysine (Lys), aspartic acid (Asp), glutamic acid (Glu), omithine, D,L-α

β

-diaminopropionic acid, D,L-α

,γ

-butyrylamino acid, citrulline, homocitrulline, D,L-2-aminohexanedioic acid, D,L-2-aminoheptanedioic acid, 2-aminooctanedioic acid, two glycine molecules bonded to one another (Gly.Gly), glycine and alanine bonded to one another (Gly.Ala) or tris(2-aminoethyl)amine.

3. Transport system conjugate according to claim 1 or 2, characterized in that Y is the radical of lysine, aspartic acid, glutamic acid, omithine, L-2,3-diamino-propionic acid, L-α

,γ

-butyrylamino acid, citrulline, homocitrulline, L-2-aminoadipic acid, L-2-aminoheptanedioic acid or L-2-aminooctanedioic acid, preferably of lysine.

4. Transport system conjugate according to one of claims 1-3, characterized in that the radical of formula (I) has the formula —

Y—

NH—

CH₂CH₂—

NH—

C(O)—

R.

5. Transport system conjugate according to one of claims 1-4, characterized in that the radical R—

C(O)—

is the carbonyl radical of butyric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, Δ

⁹-dodecylenic acid, oleic acid, linoleic acid, arachidonic acid or ricinoleic acid, preferably the radical of caprylic acid, lauric acid, myristic acid, palmitic acid or stearic acid.

6. Transport system conjugate according to one of claims 1-5, characterized in that the radical of formula (II) is bonded directly to an NH group of Y or is bonded to a carbonyl group of Y via a linker, preferably via the group —

(NH—

C_nH_2n—

NH)—

.

7. Transport system conjugate according to claim 6, characterized in that the radical of formula (II) as a D,L-6,8-dithiooctanamide radical is attached directly to the amino-terminal end of the amino-terminal side chain and/or to the NH radical in the α

-position of Y.

8. Transport system conjugate according to one of claims 1-5, characterized in that, in the radical of formula (III), m=4 and p=1, and in that this radical is attached directly to the amino-terminal end and/or to the NH radical in the α

-position of Y.

9. Transport system conjugate according to one of claims 1-8, characterized in that the pharmaceutically and/or cosmetically active compound is bonded directly to an NH group or to a carbonyl group of Y, optionally via a suitable linker, and is preferably attached to the amino-terminal end and/or to the NH radical in the α

-position of Y.

10. Transport system conjugate according to one of claims 1-9, characterized in that it has formula (IV) or formula (V):

11. Transport system conjugate according to one of claims 1-10, characterized in that the pharmaceutically and/or cosmetically active compound is a peptide or non-peptide active ingredient.

12. Transport system conjugate according to claim 11, characterized in that the pharmaceutically and/or cosmetically active compound is a peptide, preferably an α

-amino acid, or a polypeptide preferably having 2-20 amino acid units, preferably Glu-Glu-Glu-Asp, Glu-Glu-Glu-Asp-Lys, Glu-Glu-Glu-Asp-Ser-Thr-Ala-Leu-Val-Cys, Ala-Glu-Glu-Asp, Glu-Glu-Glu-Glu, Ala-Glu-Glu-Glu, Glu-Glu-Glu-Asp-Ala-Thr-Ala-Leu-Val-Cys, Glu-Glu-Glu-Asp-Leu-Thr-Ala-Leu-Val-Cys or Leu-Gly-Asp.

13. Transport system conjugate according to claim 12, characterized in that the polypeptide is an oligopeptide with an average molecular weight of up to 20 kDa, preferably with the sequences Glu-Glu-Glu-Asp, Glu-Glu-Glu-Asp-Lys, Leu-Gly-Asp and Glu-Asp-Tyr-His-Ser-Leu-Tyr-Asn-Ser-His-Leu, and analogous sequences, as well as corresponding salts, preferably TFA salts, acetates or propionates or salts formed with H₃PO₄ or HBr.

14. Transport system conjugate according to claim 12 or 13, characterized in that the polypeptide is provided with protective groups attached to reactive groups present.

15. Transport system conjugate according to one of claims 1-14, characterized in that the pharmaceutically and/or cosmetically active compound is a vitamin, hormone or antibiotic, preferably vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin C, vitamin D, vitamin E or vitamin K, Adiuretin, oxytocin, a melanocyte stimulating hormone, calcitonin, a glucocorticoid, an androgen or an oestrogen.

16. Transport system conjugate according to one of claims 1-15, characterized in that it is conjugated with oligonucleotide analogues.

17. Process for the preparation of a transport system conjugate according to one of claims 1-16, characterized in that a pharmaceutically and/or cosmetically active compound known per se, preferably an amino acid with any kind of amino-terminal side chain and a carbonyl-terminal end, is coupled in a manner known per se, via an amide structure, with a suitable starting compound corresponding to the radical —

Y—

, directly or via a linker, at its amino-terminal end and/or carboxy-terminal end, one or more protective groups optionally being introduced beforehand or afterwards, and the resulting intermediate is then reacted in a manner known per se with the appropriate starting compounds, corresponding to the radical —

C(O)R and the formulae (II) and/or (III), to give the transport system conjugate.

18. Process for the preparation of a transport system conjugate according to one of claims 1-16, characterized in that the procedure is first to prepare the compound of formula (Ia):

H—

Y—

(NH—

C_nH_2n—

NH)_r—

C(O)—

R 

 

(Ia)

which is not yet coupled with the radicals of formulae (II) and/or (III) and the pharmaceutically and/or cosmetically active compound, and then to react the compound of formula (Ia) in a manner known per se with the appropriate starting compounds of the radicals of formulae (II) and/or (III) and the pharmaceutically and/or cosmetically active compound.

19. Use of the transport system conjugates according to one of claims 1 to 16 for topical and transdermal applications in dermatology and cosmetics or for drugs with a systemic action.

20. Use of the transport system conjugates according to one of claims 1 to 16 for controlling skin aging, inflammation, cellulitis, psoriasis, antimelanoma, arthritis, acne, neurodermatitis, eczema, paradontitis or burns, as free radical scavengers or agents for tanning or bleaching the skin, for promoting or inhibiting hair growth, as immunostimulants, for transporting regenerating substances or antibiotics, or for use in the field of wound healing.

21. Use of a transport system according to one of claims 1 to 16 for the preparation of remedies for topical and transdermal applications in dermatology and cosmetics or for drugs with a systemic action.

22. Remedy containing a transport system according to one of claims 1 to 16 for topical and transdermal applications in dermatology and cosmetics or for drugs with a systemic action, preferably for controlling skin aging, inflammation, cellulitis, psoriasis, antimelanoma, arthritis, acne, neurodermatitis, eczema, paradontitis or burns, as free radical scavengers or agents for tanning or bleaching the skin, for promoting or inhibiting hair growth, as immunostimulants, for transporting regenerating substances or antibiotics, or for use in the field of wound healing.