Title:  Conjugate of an active agent, a polyether and possibly a native protein regarded as acceptable by the body

United States Patent:  6,150,327

Assignee:  Deutsches Krebsforschungszentrum Stiftund des Offentlichen Rechts (DE)

Filed:  October 14, 1997

PCT NO:  PCT/DE96/00653

102(e) Date:  March 9, 1998

PCT PUB. Date:  October 17, 1996

Foreign Application Priority Data:  Apr 13, 1995[DE] (195 14 087)

This invention relates to the use of a conjugate comprising an active substance and a native protein which is not recognized as foreign protein for the production of a pharmaceutical preparation for treating and/or diagnosing inflammatory, infectious and/or skin diseases.

DETAILED DESCRIPTION OF THE INVENTION

It has long been a demand of concentrating pharmaceutical preparations in well-calculated fashion at the site of action. According to the invention this is attained by a conjugate comprising an active substance component, a polyether component and optionally a native protein component not regarded as exogenous, which is characterized in that the components are linked via an acid amide and/or acid ester bond.

The components of the conjugate according to the invention are given as educts below. In the conjugate according to the invention they are present in derivatized form.

The expression "active substance" comprises compounds of any kind which can be used for treating and/or diagnosing diseases such as tumoral diseases, infectious diseases, skin diseases and/or diseases of the immune system, and which are capable of forming acid amide and/or acid ester bonds.

Such compounds may be chemotherapeutic agents, e.g., antibiotics, virostatics, antiprotozoals and cytostatic agents. Examples of antibiotics are sulfonamides, tetracyclines, e.g., 7-chlorotetracycline, fusidic acid, gyrase inhibitors, e.g., quinolones, amphotericin, isoniazid, pyrazine-2-carboxylic acid and pyrazinamide. Examples of virostatics are amantadine and rimantadine. Examples of antiprotozoals are mefloquin and primaquin. Examples of cytostatic agents are anthracyclines, e.g., doxorubicin, topoisomerase inhibitors, mitomyclin A and C, bleomycinic acid, chlorambucil, melphalan and antifolates, e.g., methotrexate.

In addition, such a compound may be a photoactive compound, particularly a photoactive compound which is photoactive in aqueous media. Examples thereof are porphyrins, such as o-, m- and/or p-tetrahydroxyphenylporphin (THPP), o-, m- and/or p-tetracarboxyphenylporphin (TCPP), and o-, m- and/or p-tetrasulfophenylporphin, clorins, such as o-, m- and/or p-tetrahydroxyphenylchlorin, o-, m- and/or p-tetracarboxyphenylchlorin, and o-, m- and/or p-tetrasulfophenylchlorin, bacteriochlorins, such as o-, m- and/or p-tetrahydroxyphenylbacteriochlorin, o-, m- and/or p-tetracarboxyphenylbacteriochlorin, and o-, m- and/or p-tetrasulfophenylbacteriochlorin, and phthalocyanines such as phthalocyaninetetrasulfonic acid. The above photoactive compounds may include metal ions such as Al³⁺ or Zn²⁺, which may have a positive influence on the photoactivity.

The above compounds may be provided with a detectable labeling, e.g., radioactive iodine, a metal ion such as In³⁺ and/or Gd³⁺. As a result, conjugates according to the invention may also be used for diagnosing diseases.

One or more of the above compounds and analogues or derivatives thereof, respectively, may be present in a conjugate according to the invention. If several are present, they may be the same or differ from one another.

A conjugate according to the invention has a polyether or a derivative thereof, which are capable of forming acid amide and/or acid ester bonds. Examples of such polyethers are polyethylene glycols (PEG), particularly those in which the terminal hydroxyl groups are esterified or etherified by a C₁ -C₁₂ alkyl residue, preferably methyl. Representatives thereof are methoxypolyethylene glycol, diaminomethoxy-polyethylene glycol, methoxypolyethylene glycol-p-nitro-phenylcarbonate, methoxypolyethylene glycol succinimidyl succinate, methoxypolyethylene glycol tresylate, methoxy-polyoxyethylene amine (aminoPEG), methoxypolyoxyethylene-carboxylic acid and methoxypolyoxyethyleneimidazole-carbonyl. The polyether preferably has a molecular weight of 100 to 20,000 daltons, especially preferably about 5,000 daltons. In addition, the polyether may be provided with an above detectable labeling.

One or more of the above polyethers are present in a conjugate according to the invention. If several are present, they may be the same or differ from one another.

A conjugate according to the invention optionally contains a native protein which is not regarded as exogenous and is capable of forming acid amide and/or acid ester bonds. This protein preferably has a molecular weight of up to 90,000 daltons. Especially preferred is the protein albumin, particularly human serum albumin (HSA), and transferrin.

The components of a conjugate according to the invention are chosen such that the molecular weight of the conjugate has preferably more than about 10,000 daltons and especially preferably more than about 15,000 daltons.

The individual components of a conjugate according to the invention may be linked as desired with one another. The active substance is preferably bound to both the polyether and the protein, if present.

A process for the preparation of an above conjugate is also provided according to the invention. In such a process, conventional reactions occurring in chemistry are carried out, such as activation of an acid group and linkage of the activated acid group with an amino or hydroxyl group. 

Conjugates according to the invention distinguish themselves in that they concentrate in well-calculated fashion in certain cells of the body, particularly tumor cells and cells of inflammatory tissue and pathological skin. In addition, the conjugates according to the invention distinguish themselves in that they can be degraded rapidly if they do not reach the site of action. As a result, side effects can be minimized for the body.

Conjugates according to the invention are thus suitable in the best possible manner for treating diseases, e.g., tumoral diseases, infectious diseases, skin diseases, such as psoriasis, and/or diseases of the immune systems.

Claim 1 of 10 Claims

What is claimed:

1. A conjugate comprising an active substance component, a polyether component and a native protein component, wherein the components are linked via an acid amide and/or acid ester bond and wherein said native protein component is selected from the group consisting of albumin and transferrin.

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