Review articleBiocompatible poly(methylidene malonate)-made materials for pharmaceutical and biomedical applications
Introduction
In 2000, the biomaterial engineering served a huge global market evaluated approximately at US$ 39 billion. Expectedly, at an average annual growth rate of 12%, estimations forecasted a worldwide turnover of US$ 55 billion for 2003. Presently, orthopaedic, cardiovascular, drug delivery, dental, surgical and wound care sectors represent the largest sources of applications and revenues for biomaterial-based products while, according to available data, drug delivery, urology and ophthalmic fields showed the highest annual growth rate, at over 16%. Many significant companies, like Baxter Healthcare, Bausch & Lomb, Convatec, Smith & Nephew, Alkermes, ALZA, Biocompatibles, Boston Scientific, Cordis (J&J), Genzyme Biosurgery, IsoTis, etc. are involved in this very competitive market segment [1].
Besides ceramics and metals, synthetic polymers and polymer-based biomaterials were first extensively considered for biomedical applications in the fifties, sixties and seventies and are still the topic of many investigations throughout the world [2], [3], [4], [5], [6]. Especially, Merrill’s group spent considerable efforts understanding what could cause biocompatibility of a material when it was in contact with blood or other physiological fluids [7], [8]. For the past 40 years both hydrophobic (e.g. poly(methyl methacrylate), polysiloxanes, polyethylene, polyurethanes, etc.) [9] and hydrophilic (e.g. poly(ethylene oxide)) [10] polymers were studied and tested in various biomedical or pharmaceutical applications. Synthetic polymeric materials have been used in a wide range of formulations such as gels, hydrogels, films, coatings or particle suspensions and became key elements of tissue engineering, constituants of implantable devices, drug reservoirs or drug vehicles. The design, preparation and characterization of such materials now represent a still growing part of worldwide biomaterials R&D efforts and investments [11]. Either bioresorbable or fully stable over time, these polymeric systems incorporate various types of homopolymers or copolymers made of poly(esters), poly(anhydrides), poly(acrylates) or many others. In the context of chemical engineering science and biopharmaceutical engineering, these polymeric materials have played a crucial role in the development of controlled drug delivery and targeting systems and were the topic of many reviews in this field [12], [13], [14], [15].
As a matter of fact, during the mid-late seventies, synthetic polymers and especially acrylic polymers started to be carefully considered for the advanced formulation of drugs [16]. Poly(methylmethacrylate) [17], poly(acrylamide) [18], poly(N-(2-hydroxypropyl)methacrylamide) [19], poly(styrene) [20] and poly(alkylcyanoacrylate) [21] were first retained for such an application and drug-loaded particulate systems (i.e. nanospheres or microspheres) were produced and carefully studied.
In the mid-1980s, Laboratoires UPSA, a French analgesia world leader company of high repute for its unique know-how in production of effervescent drug formulations, wished to perpetuate and reinforce its leadership in pharmaceutical technology and decided to invest in the development of proprietary pharmaceutical technologies based on the use of poly(methylidene malonate)-made materials [22], [23]. Initially involved in the preparation of novel nanoparticulate systems that can be drug loaded [24], poly(methylidene malonate) and, more specifically, poly(methylidene malonate 2.1.2) (PMM 2.1.2), were extensively studied by Laboratoires UPSA and then by VIRSOL, after Bristol-Myers and Squibb took over Laboratoires UPSA in 1994. In the past years, VIRSOL has explored different pharmaceutical and biomedical applications where methylidene malonate 2.1.2- (MM 2.1.2) and PMM 2.1.2-based materials could be of interest.
This paper aims at reviewing the main R&D advancements having been accomplished for the past 15 years on MM 2.1.2, PMM 2.1.2 and all of their derivatives.
Section snippets
General structure
The general formula of methylidene malonate species is depicted on Fig. 1a. The structural backbone is a malonic acid, for which the two carboxyl functions are esterified by various residues R1 and R2, identical or different, that can represent linear or branched alkyl, alicyclic, alkenyl or alkynyl groups optionally being substituted by one or more functional groups such as ether, epoxide, halogeno, cyano, ester, aldehyde, ketone, aryl, etc. Carbon 2 of malonate is substituted by a methylene
Preparation and characterization
In the late 1980s and early 1990s, the Department of Medicinal Chemistry of Catholic University of Louvain (Belgium) and Laboratoires UPSA (France) first developed and characterized poly(methylidene malonate) nanoparticles [24], [38], [39], [40], [41], [42]. The group of Prof. Dumont at Catholic University of Louvain got focused on poly(dialkyl methylidene malonate) and, more specifically, on poly(diethyl methylidene malonate) (PDEMM)-made nanoparticles. In 1991, De Keyser et al. [38] published
Peptide and polypeptide formulation and delivery
Whereas PMM 2.1.2 and OMM 2.1.2 were mostly considered for the preparation of colloidal and microparticulate systems involved in drug delivery approaches, these polymeric and oligomeric materials were also at the basis of new implantable drug reservoirs which could advantageously release their payload locally over a long period of time. These implants could be designed to hold various physical and mechanical characteristics such as softness/hardness, elasticity, flexibility, resistance or
MM 2.1.2-based materials as potent wound suture devices
One particular and attractive application of MM 2.1.2-based materials was their use as a wound suture device as described and patented in 2003 by Bru-Magniez et al. [96].
Prior to this innovation, only alkylcyanoacrylate-made products (e.g. Dermabond® from Ethicon) had been described and developed and several of them had been marketed for the suture of benign skin wounds [97]. These products, which have represented an alternative to stitches, staples or adhesive strips, have held several
MM 2.1.2-based copolymers
As shown in the present review, proprietary methylidene malonate and poly(methylidene malonate)-based materials provide numerous development opportunities in the field of drug delivery systems and medical devices where they could represent valuable alternatives to existing products. Thus, these molecular and macromolecular species, alone or in combination with other biocompatible polymers, appear as a technological platform which could be cleverly expanded in order to offer new and potent drug
Conclusion
As new proprietary and biocompatible materials, MM 2.1.2-based oligomers, polymers and copolymers were extensively studied by Laboratoires UPSA and Virsol, together with a large panel of internationally acknowledged scientists. From this research consortium, fundamental and key data, original macromolecular species, and novel drug delivery systems, which further allowed the identification of various valuable biomedical applications, were obtained. The present review tried and summed up the
Acknowledgements
The authors gratefully thank and are deeply acknowledgeable to American, Bulgarian, Canadian, French and Swiss scientists who have participated in researches on methylidene malonate-based materials and on their various biomedical applications.
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