Absorbable copolylactides and their use

Details Absorbable copolylactides and their use Absorbable copolylactides and their use

2000-08-18

2002-10-29

Truong, Duc (Department: 1711)

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

Synthetic resins

From carboxylic acid or derivative thereof

C528S485000, C528S495000, C528S501000, C528S503000

Reexamination Certificate

active

06472502

ABSTRACT:

The invention relates to novel copolylactides which have been polymerized from units of racemic lactide and the comonomers &egr;-caprolactone, &dgr;-valerolactone, 1,4-dioxan-2-one or 1,3-dioxan-2-one in a lactide/comonomer molar ratio of about 90-80/10-20 in the presence of tin(II) di(ethylhexanoate) as initiator and of a cocatalyst at about 160° C., and have a glass transition temperature between about 30 and 43° C., a molecular weight M
n
of about 15,000 to 50,000 and a polydispersity P
n
(M
2
/M
n
) of about 1.2 to 2. The novel copolylactides are particularly suitable in an outstanding manner for the management of all types of wounds.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,045,418 describes a copolymer consisting of D,L-lactide and &egr;-caprolactone in the presence of tin(II) caprylate as initiator. The copolymer is transparent, rigid and brittle and is used as a disposable product and molding in the automobile industry, in the home and in the packaging industry. The molecular weights are between 100,000 and 300,000. These copolymers are unsuitable in dissolved form for medical applications, for example as surgical incise drapes or a sliquid gloves because, after spraying onto the skin, they cure as a film, with evaporation of the solvent, and therefore become brittle and crazed.
FR-2126270 discloses film-forming polymers of lactic acid and glycolic acid in solvents such as, for example, ethyl acetate, which additionally comprise pharmacological active ingredients and can be employed, for example, as spray dressings.
A disadvantage of these polylactones is the fact that they are suitable only as active ingredient carriers on intact skin because the polymer/drug mixture is always applied as solution to the skin. However, chloroform, difluorodichloromethane or ethyl acetate which are used as solvents would seriously harm an open wound.
EP-B1-270,987 describes a process for preparing catalyst-free absorbable homopolymers or copolymers based on hydroxy acids. Lactide and glycolide are mainly employed for copolymer formation. However, glycolide is unsuitable for obtaining copolymers for the desired topical application because glycolide copolymers are degraded too quickly.
EP-0 509,203 relates to the use of copolymers of racemic lactide and &egr;-caprolactone, &dgr;-valerolactone, &ggr;-decalactone or &bgr;-hydroxybutyric acid, prepared by reacting the monomers in a molar ratio of lactide to reactant of about 95-70:5-30 with the addition of tin(II) di(ethylhexanoate) initiator at temperatures of about 150° C. over a period of 16 to 48 hours, for the topical treatment of human or animal skin. The said earlier property right of the applicant then states further that the copolymers most suitable for topical applications have a molar ratio of initiator to reactant of about 1:100 to 1:500. To remove remaining monomers, short-chain oligomers or, if appropriate, also excess plasticizers, the reaction composition is usually precipitated with 600-800 times the amount of alcohol. It is true that the copolymers obtained as disclosed in EP 0509203 show properties which are more suitable for topical wound treatment than the polymer products of U.S. Pat. No. 4,045,418. However, they still do not have optimal characteristics in respect of flexibility, adhesiveness, avoidance of tackiness etc. In addition, complying with the preparation conditions disclosed frequently results in products with non-reproducible and occasionally unusable properties.
SUMMARY OF THE INVENTION
The teaching of the present invention is based on the object of further improving in a plurality of ways absorbable, physiologically acceptable copolylactides of the type described. An important fact in this connection is that application to uninjured skin requires copolylactides with high adherence, flexibility and stretchability. The permeability to water vapor is of less importance here than for application to wounds, and the degradation may also take place somewhat faster but ought not to take less than 24 hours for a film thickness of about 3-5 &mgr;m even in an aqueous medium. Impermeability to hydrophilic and lipophilic allergens is a requirement. Accordingly, amorphous copolylactides, although with low viscosity (=short-chain polymers), are to be preferred for these applications too. The permeability to water vapor is a crucial criterion for use on injured skin and cannot be achieved solely by the copolymers because they are hydrophobic and of low permeability (<60 ml/h/m
2
). The need in this case is either for a relatively high monomer content in the reaction product or else for the addition of hygroscopic/hydrophilic substances (for example glycerol), resulting in a vapor permeability initially at high levels (>150 ml/h/m
2
), which decreases over the course of days (in accordance with the wound discharge).
Impermeability to microbes with a film thickness of 25-50 &mgr;m for a period of at least 14 days is a requirement. This can be achieved only by relatively long molecule chains (=higher viscosity).
It is furthermore important that the copolymers intended for the predefined purpose of use do not have a tacky consistency. This object is now achieved by the copolylactides according to the invention.
The invention thus relates to a flexible, transparent copolylactide which is composed of polymerized units of racemic lactide and the comonomers &egr;-caprolactone, &dgr;-valerolactone, 1,4-dioxan-2-one or 1,3-dioxan-2-one and has a glass transition temperature (T
g
) between 30 and 43° C., a number average molecular weight M
n
of from 15,000 to 50,000 and a molecular weight distribution (polydispersity P
n
) of from 1.2 to 2. A consequence of this is that the weight average molecular weight M
w
of the copolylactide has a value of distinctly less than 100,000.
The properties of these copolylactides according to the invention differ distinctly from those in U.S. Pat. No. 4,045,418 and EP 0509 203, as is evident from the table below and is explained hereinafter. Thus, as has been shown in comparative examples, the glass transition temperature, for example, of the copolymers of EP 0509 203 is distinctly below 30° C., whereas it is over 45° C. for the products of U.S. Pat. No. 4,045,418.
Particularly advantageous copolylactides which are preferred for the purpose of the invention have a glass transition temperature of from 30 to 40° C., in particular 33 to 37° C., and a number average molecular weight M
n
of from 25,000 to 40,000, with a polydispersity of from 1.4 to 1.7. These particularly preferred properties are possessed in particular by copolylactides comprising &egr;-caprolactone as comonomeric unit. However, surprisingly, &dgr;-valerolactone, 1,4-dioxan-2-one or 1,3-dioxan-2-one are also suitable according to the invention, as are mixtures of the individual comonomers, whereby it is possible where appropriate to achieve fine adjustment of the required properties.
As for virtually every polymeric compound, the properties of the copolylactides according to the invention depend on the conditions and parameters in the process for their preparation.
The invention thus also relates to a process for preparing a corresponding copolylactide, in which a racemic lactide is reacted with a comonomer selected from &egr;-caprolactone, &dgr;-valerolactone, 1,4-dioxan-2-one or 1,3-dioxan-2-one or mixtures thereof. The molar ratio of lactide to comonomer in this process is 90-80:10-20. Particularly preferred lactide/comonomer ratios are 84:16, 85:15 or 86:14.
It is preferred for the polymerization of the monomeric units to give the copolymers with the required properties to use tin(II) di(ethylhexanoate) as initiator and a cocatalyst for accurate control of the polymerization process.
In order to obtain particularly good results, it is preferable for the initiator to be purified immediately before the polymerization reaction. Since the purchased initiator (tin(II) di(ethylhexanoate)) may contain up to 20% impurities in the form of water and free octanoic acid, these are preferably removed. The liquid init

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