Biodegradable, injectable oligomer-polymer composition

Details Biodegradable, injectable oligomer-polymer composition Biodegradable, injectable oligomer-polymer composition

2002-01-16

2004-11-09

Sanders, Kriellion A. (Department: 1714)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Processes of preparing a desired or intentional composition...

C523S113000, C523S124000, C524S314000, C524S315000, C524S317000

Reexamination Certificate

active

06815469

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
In the present invention relates to a biodegradable, injectable oligomer-polymer composition consisting of a combination of at least two biologically degradable inactive materials and at least one biologically active ingredient.
2. Description of the Related Art
Implants for applying biologically active materials can be produced by compacting under aseptic conditions. These implants have the disadvantage that they are incapable of adapting to the spatial conditions of the site of the application and cause a sensation of pressure or pain there after the application.
A known solution to the problem of producing injectable implants furthermore consists of the use of microcapsules. The most common methods for producing microcapsules or microspheres are the so-called solvent evaporation technique, the spray-drying technique or the double emulsion technique. These methods require organic solvents or solvent mixtures such as dichloromethane, trichloromethane or a mixture of dichloromethane and methanol, which are toxic or at least physiologically hazardous for the living organism. The residual solvent content is therefore a common disadvantage of these methods. Moreover, the spray-drying method is associated with a relatively high expenditure for equipment.
Furthermore, the possibility exists of producing an implant in situ, when a solution or suspension of the biologically active material is applied parenterally. The in situ formation of an implant can be induced in various ways.
In the U.S. Pat. No. 4,938,763, the biologically active substance is dissolved or dispersed in a solution of the biodegradable polymer, such as a polylactide, and this solution or dispersion is injected. After the injection, a solid implant, consisting of the precipitated or coagulated biodegradable polymer and the biologically active substance, is formed on contact with the body fluid. The solvent migrates out of the implant and is distributed in the organism. It is a disadvantage of this method, that the solvents used, such as N-methyl-2-pyrrolidone, are physiologically active and therefore can be applied parenterally only to a slight extent, if at all.
Furthermore, in the patents cited, as well as in other patents (U.S. Pat. Nos. 5,278,201 and 5,278,202), liquid acrylate-terminated prepolymers, which can be synthesized, for example, by reacting poly(D,L-lactide-co-&egr;-caprolactone) with reactive acrylic acid derivatives, are proposed as in situ implant materials. The liquid prepolymer is injected in admixture with the biologically active substance and a suitable initiator, such as (dibenzoyl peroxide), which initiates the curing of the prepolymer and, with that, the formation of the implant in the body. The considerably higher synthesis and purification expenses for preparing the biologically degradable polymers and the parenteral administration of a physiologically hazardous, free radical-forming substance as initiator are disadvantages of this method. In addition, there has been no prior experience with the biocompatibility of said acrylate-terminated prepolymers or with the biodegradable of the implant formed form these substances.
In the U.S. Pat. No. 5,702,717, the block copolymers of polyethylene glycol and polylactide or polycaprolactone are described, which, in aqueous solution at room temperature, are in the form of an injectable liquid and, at body temperature, form a gel, which contains the biologically active material. It is a disadvantage of this variation that the temperature for the transition from sol to gel depends on a plurality of different parameters, such as the composition and the degree of polymerization of the individual blocks in the block copolymer, the molecular weight of the block copolymer as well as the polymer concentration in the aqueous solution.
SUMMARY OF THE INVENTION
It is an object of the present invention to make available an oligomer-polymer composition as injectable implant, which overcomes the disadvantages of the state of the art.
Pursuant to the invention, this objective is accomplished owing to the fact that an oligomer-polymer composition, consisting of a combination of at least two biologically degradable inert materials and at least one biologically active ingredient is made available.
Pursuant to the invention, the biologically degradable inert materials preferably are polymerization products of identical or different hydroxycarboxylic acids.
Lactic acid or glycolic acid are particularly preferred as hydroxycarboxylic acids.
It is furthermore preferred pursuant to the invention that in each case at least one of the biologically degradable inert materials is a liquid low molecular weight oligomer and the other a solid, higher molecular weight polymer.
Furthermore, it is preferred, pursuant to the invention, that the liquid, low molecular weight oligomer is a compound of the general Formula I, II or III
wherein
R is the same or different for the variables m, n, o, p, q and r and represents —CH
2
—, —CH(CH
3
)—, —(CH
2
)
5
—, —CH
2
—CH
2
—O—CH
2
—, —CH
2
—CH
2
—O—CH
2
—CH
2
—O—CH
2
— or their homologues with up to 5 further C atoms in each case;
R
1
represents —CH
2
—COOY, —CH(CH
3
)—COOY, —CH
2
—CH
2
—COOY, —CH
2
—CH
2
—CH
2
—COOY, —CH
2
—CH
2
—CH
2
—CH
2
—COOY, —CH
2
—CH
2
—CH
2
—CH
2
—CH
2
—COOY, —CH
2
—CH(CH
3
)—Y, —(cyclo-C
6
H
11
) or —CH
2
—CH
6
H
5
—;
R
2
represents —CH
2
—CH(CH
3
)—, —CH
2
—CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—CH
2
—, —CH
2
—CH
2
—CH
2
—CH
2
—CH
2
—, —(CH
2
)
2
—O—(CH
2
)
2
—O—(CH
2
)
2
—, —(CH
2
)
2
—O—(CH
2
)
2
—O—(CH
2
)
2
—O—(CH
2
)
2
—, —(CH
2
)
2
—O—(CH
2
)
2
—O—(CH
2
)
2
—O—(CH
2
)
2
—O—(CH
2
)
2
—, —CH
2
—CH(—Y)—CH
2
—, cyclohexane-1,2-diyl cyclohexane-1,3-diyl or cyclohexane-1,4-diyl;
R
3
represents (—CH
2
)
2
CH—, (—CH
2
)
3
C—CH
3
or (—CH
2
)
3
C—CH
2
—CH
3
,
Y is —H, —CH
3
, —C
2
H
5
, —C
3
H
7
or —C
4
H
9
, and
m, n, o, p, q and r denote, independently of one another, an integer from 2 to 18.
m, n, o, p, q and r independently of one another being a whole number from 2 to 18.
It is especially preferred if R is —CH(CH
3
)—, R
1
is —CH(CH
3
)—COOY, Y is —C
2
H
5
and m, n, o, p, q or r is a whole number from 2 to 4.
Therefore, for the synthesis of the implants, preferably poly(hydroxyesters), such as poly-(L-lactides), poly-(D,L-lactides), polyglycolides, poly-(caprolactones), poly(dioxanones), poly-(hydroxybutyric acids), poly-(hydroxyvaleric acids, poly-(glycosalicylates) and copolymers of these compounds are used. In particular, poly-(hydroxy esters), which are synthesized by a ring-opening polymerization of lactones in the presence of a biocompatible starter molecule, are preferred. Suitable lactones for carrying out the ring-opening polymerization preferably are, for example, L-lactide, D,L-lactide, glycolide, p-dioxanone and e-caprolactone. Suitable biocompatible starter molecules are preferably aliphatic or cycloaliphatic compounds, which contain one or more free hydroxyl groups. Particularly suitable starter molecules are, for example, alkyl esters of L-lactic acid, cholesterol, 1,2-dihydroxypropane, triethylene glycol, glycerol or pentaerythritol.
It is furthermore preferred that the ratio of solid higher molecular weight polymers to the liquid lower molecular weight oligomers is 1:100 to 1:1 and especially 1:10 to 1:2.
The inventive, pharmaceutical composition is furthermore characterized in that the biologically active ingredient is selected from the group comprising the hormones, immune modulators, immune suppressive agents, antibiotics, cytostatic agents, diuretics, gastrointestinal drugs, cardiovascular drugs, and neuropharmacological drugs.
Pursuant to the invention, the biologically active ingredient preferably is present in dissolved or suspended form in the combination of inert materials.
Pursuant to the invention, the pharmaceutical composition is in the form of an injectable agent which, after the injection, can form a coagulate under the influence of the body fluid.
Furthermore, an object of the present invention is an injectable implant, which

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