Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2002-03-29
2004-12-28
Acquah, Samuel A. (Department: 1711)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C528S288000, C528S289000, C528S302000, C528S339000, C525S420000, C525S437000, C525S440030, C525S540000, C424S444000, C424S457000, C435S001100
Reexamination Certificate
active
06835391
ABSTRACT:
The invention relates to new biologically degradable aliphatic copolymers of the polyesteramide or polyesterurethane type. The invention further relates to a method for preparing the copolymers and to products which can be manufactured from the new copolymers.
There is a very wide variety of polymers and copolymers. Depending on their application, they may have a great diversity of properties. Especially the mechanical properties are of importance for the use of (co) polymers in end products.
Because polymeric materials in general, and plastics in particular, are used on a very wide scale, they cause an enormous waste problem. Since the environment and pollution thereof are strong issues with the general public, there has been a trend to seek new polymeric materials which may degrade in a biological environment. It has been found difficult, however, to provide polymeric materials which have a good, i.e. fast, degradation profile, and at the same time possess very good mechanical properties.
Recently, a new class of copolymers of the polyesteramide or polyesterurethane type has been disclosed in WO-A-98/00454. These copolymers are based on symmetrical, crystalline diamide-diols, diamide-diacids or diurethane-diols, together with a secondary monomer. This secondary monomer is chosen from the group of alkanediacids alkanediacid-chlorides, alkanediols, poly(alkane ether)diols, hydroxy acids (lactones), diisocyanates and combinations thereof.
Although this new class forms a relatively successful attempt at providing a polymeric material having both good mechanical properties and degradation properties, there still remains room for improvement. Particularly, the degradation profile of the copolymers of WO-A-98/00454 is not optimal for a sufficient fast breakdown of the material under all circumstances. This makes the copolymers less suitable for use as carriers for release of active agents, such as drugs, or as biomaterials in e.g. tissue engineering.
It is therefore an object of the invention to provide a polymeric material which shows superior degradation characteristics, without this improvement in degradation properties leading to an undesired deterioration of the mechanical properties in comparison with prior art materials.
Surprisingly, it has been found that this goal can be reached by incorporating a polyalkylene glycol component into the copolymer of the polyesteramide or polyesterurethane type disclosed in WO-A-98/00454. Accordingly, the invention relates to a new class of copolymers comprising symmetrical constant blocks (CB) and variable blocks (VB) of the formula:
—(CB)—(VB)—
which copolymers comprise hydrophilic blocks. The definitions of the variables are given in claim
1
.
The present copolymer is thus built up from a chain of building blocks, which each in turn consist per copolymer of a block with a fixed chemical structure and therefore a constant block length (designated hereinafter “constant block”), a block with a variable chemical structure and block length (designated hereinafter “variable block”).
It has been found that the present copolymers have highly advantageous mechanical properties. Furthermore, they have very good degradation characteristics which can be controlled in a manner set forth below. More in particular, in an aqueous environment, articles of manufacture of the copolymers have been found to degrade throughout their structure, thus rendering such articles highly suitable for release of active agents.
The constant block is preferably an amide block or a urethane block. In this text, these terms may be used interchangeably. Depending on the desired properties of the copolymer, one or more types of constant block may be used within one copolymer. Variation can thus occur in the variable blocks. That is, one or more types of variable blocks can be used per copolymer. The required hydrophilic blocks, which are preferably variable blocks, offer another parameter to adjust the desired properties of the copolymer. Within one copolymer, different hydrophilic blocks may be present. These hydrophilic blocks may differ from each other chemically, in length or both. Although it is preferred that the hydrophilic blocks are variable blocks, it is also possible that the constant block is hydrophilic or comprises a hydrophilic block. In particular, it has been found feasible to incorporate polyethylene oxide (PEO) blocks in formula (2), as defined in claim
1
. In this case, Z
2
may comprise such a PEO block provided with suitable end groups.
The amide blocks are randomly distributed over the polymer length and the uniform block length is retained during the preparation of the copolymer. The uniformity of the urethane blocks can be disrupted by the occurrence of ester-urethane exchange reactions or by alcoholysis of the urethane block, which may result in longer urethane block lengths. The said reactions, however, were under the reaction conditions found to rapidly reach an (equilibrium) plateau value which corresponds to a maximum of 15% block of which the uniformity is lost.
The uniformity of the block length is important for a number of reasons. Uniformity of the block length induces a more rapid crystallization and give better defined lamellae thicknesses of the crystalline phase. The two effects are particularly advantageous for a faster processing and for good mechanical properties, such as a high and constant young's modulus over a wide temperature range and a good dimensional stability. These advantageous properties were attributed to a good phase separation and a rapid crystal nucleation and/or growth.
The block length itself is particularly important for the rate of biological degradation of the constant block. Biodegradability decreases with increased molecular weight and increases with increasing hydrophilicity. The amide and urethane blocks described herein are preferably short, contain only two amide or urethane bonds per unit, are usually water soluble, are completely biologically degradable and display no toxicity.
The copolymer may be prepared by starting from suitable monomers as will be set forth below.
The monomers for the constant block are symmetrical, crystalline, water-soluble and have a chemical structure in one of the following three categories:
in which R, R′, R″, R′″ and R″″ are the same or different and represent an H, hydrocarbyl or substituted hydrocarbyl or hydrocarbyl with protected O, N, and/or S functionality. This structure is further designated “diamide diol”.
The mol weight of these monomers is preferably a minimum of (n=1 m=2; R—R″″=H)=176 g/mol and a maximum of (n=15; m=12; R—R″″=H) 685 g/mol for linear monomers without side groups of other hetero-atoms in the chain. Methyl side groups can for instance be included (R′=CH
3
), as well as hetero-atoms in structure 1 such as for instance O.
This type of monomers can be manufactured by ring opening of lactones by a primary diamine, both in solution and in the melt, without external catalysts, as well as by condensation of a linear hydroxycarboxylic acid, or hydroxycarboxylic acid ester and a primary or secondary diamine. These possible lactones herein have the following general structure:
in which h is 2, 3, 4 or 5, i is 1 or 2, j is 1 or 2 and each R is an H or hydrocarbyl or substituted hydrocarbyl with protected O, N, and/or S functionality with a maximum of 30 carbon atoms. Preferred lactones are those in which R is hydrogen or methyl, and lactones which are particularly recommended are &egr;-caprolactone, &dgr;-valerolactone, glycolide and lactides.
in which R, R′, R″, R′″, R″″ and R′″″″ are the same or different and represent an H, hydrocarbyl or substituted hydrocarbyl with protected functionality. R″″ and R″′″ will usually be the same and are preferably not an H and n is preferably ≧4. This structure is further designated “diamide-diacid”.
The
Bezemer Jeroen Mattijs
Dijkstra Pieter Jelle
Feijen Jan
Acquah Samuel A.
Banner & Witcoff , Ltd.
Chienna B.V.
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