Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-11-04
1998-05-19
Kishore, Gollamudi S.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514546, 514547, 514553, 424422, 435174, 435177, 435181, 530810, 530812, 530815, A61K 3800, A61K 3122, A61K 31185
Patent
active
057536112
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/NL/93/00061, filed Mar. 15, 1993.
The invention relates to a pharmaceutical composition having site-specific and in particular tissue-specific delivery, in addition to a method for producing same.
Pharmaceutical compositions having site-specific delivery are sometimes made by starting from an inactive variant ("prodrug") of a therapeutically or diagnostically active substance which is converted into the active form only after reaching a determined place in the body such as a specific organ or tissue. Another possibility is the combining of the active substance with a pharmaceutical carrier in particle form, such as liposomes for instance, or a soluble macromolecular carrier, such as polypeptides for instance, which have a preference for a specific place in the human or animal body and there release the active substance.
In the case that a polypeptide or other soluble macromolecular material is used as carrier for the active substance, it is preferred to couple this carrier with the active substance by covalent bonds. On arrival at the desired location in the body these covalent bonds then have to be broken, this such that the active substance is released. Problems can however occur here. Despite the fact that many macromolecular carriers are biologically degradable, they sometimes do not release the active substance in the correct form or at the desired rate, In order to obviate this problem molecules of a compound serving as spacer can be linked between the active substance and the carrier, but the selection of a suitable spacer results in turn in new problems. With a view to an efficient and/or controlled decoupling of the active substance and the carrier, particular attention must be given to the nature of the active substance, the type of covalent bond of the active substance to the spacer and also to the length and branching degree of the spacer. The spacer itself and its breakdown products must further be non-toxic.
It has now been found during further research that .alpha.-hydroxy acids and poly-.alpha.-hydroxy acids are eminently suitable for use as spacer between an active substance and a soluble macromolecular carrier provided the active substance has a terminal carboxyl group. The .alpha.-hydroxy acids can namely be bonded by esterification (between the .alpha.-hydroxy group of the .alpha.-hydroxy acid and the carboxyl group of the active substance) to the active substance and be moreover coupled by any covalent bond (between the carboxyl group of the .alpha.-hydroxy acid and a reactive group of the macromolecular carrier) to the soluble macromolecular carrier. Both types of bonds are normally resistant to the conditions in the bloodstream of a human or animal body but, after arrival at a tissue at which the macromolecular carrier is specifically targeted, the ester bond between active substance and spacer could easily be broken by enzymes (esterases), so that the active substance is released in the original (active) form. Since the .alpha.-hydroxy acids and poly-.alpha.-hydroxy acids are not toxic and allow of relatively easy coupling and decoupling, they represent an attractive option for the selection of a spacer in pharmaceutical compositions of the stated type. It has moreover been found that the rate of delivery of the active substance into the desired tissues can be controlled by variation of the type of .alpha.-hydroxy acid and also by variation of the length and/or the branching degree of the poly-.alpha.-hydroxy acid that is used as spacer in the pharmaceutical composition.
The invention therefore provides a pharmaceutical composition having site-specific delivery and comprising:
at least one therapeutically and/or diagnostically active compound, said compound having a terminal carboxyl group,
a soluble macromolecular pharmaceutical carrier, and
an .alpha.-hydroxy acid or poly-.alpha.-hydroxy acid functioning as a spacer between active compound and carrier and being coupled through an ester bond to the active compound and through any covalent bond to th
REFERENCES:
Larsen, "Macromolecular prodrugs, XII. Kinetics of release of naproxen from various polysaccharide ester prodrugs in neutral and alkaline solution", International Journal of Pharmaceutics, vol. 51, No. 3, May 1, 1989, pp. 233-240.
Franssen et al., "Low Molecular Weight Proteins as Carriers for Renal Drug Targeting. Preparation of Drug-Protein Conjugates and Drug-spacer Derivatives and Their Catabolism in Renal Cortex Homogenates and Lysosomal Lysates", Journal of Medicinal Chemistry, vol. 35, Apr. 1992, pp. 1246-1259.
Duncan, Selective Endocytosis of Macromolecular Drug Carriers. p. 587, Marcel Dekker, 1987.
Meijer Antiviral Res. 18, 1992 215-258.
De Zeeuw Dick
Franssen Erik J. F.
Meijer Dirk K. F.
Moolenaar Frits
Kishore Gollamudi S.
Rijksuniversiteit Groningen
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