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In this paper, injectable, thermosensitive smart hydrogel local drug delivery systems (LDDSs) releasing the model antitumour drug 5-fluorouracil (5-FU) were developed. The systems were based on biodegradable triblock copolymers synthesized via ring opening polymerization (ROP) of ε-caprolactone (CL) in the presence of poly(ethylene glycol) (PEG) and zirconium(IV) acetylacetonate (Zr(acac)4), as co-initiator and catalyst, respectively. The structure, molecular weight (Mn) and molecular weight distribution (Đ) of the synthesized materials was studied in detail using nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) techniques, the optimal synthesis conditions were determined. The structure corresponded well to the theoretical assumptions. The produced hydrogels demonstrated a sharp sol–gel transition at temperature close to physiological value, forming a stable gel with good mechanical properties at 37 °C. The kinetics and mechanism of in vitro 5-FU release were characterized by zero order, first order, Higuchi and Korsmeyer–Peppas mathematical models. The obtained results indicate good release control, the kinetics were generally defined as first order according to the predominant diffusion mechanism, and the total drug release time was approximately 12 h. The copolymers were considered to be biodegradable and non-toxic, the resulting hydrogels appear to be promising as short-term LDDSs, potentially useful in antitumor therapy.

Introduction: Arterial hypertension is a disease of civilization that requires long-term treatment. Recently, growing interest in natural and synthetic polymers as drug delivery vehicles in controlled release dosage forms for improving the efficacy of treatment has been observed. Areas covered: This review introduces biodegradable synthetic polyesters as macromolecular carriers of antihypertensive drugs. Although various, synthetic and natural polymer-drug conjugates and/or polymeric carriers of anticancer drugs are currently under preclinical and clinical studies, there is no such data for antihypertensive drugs. Therefore, it seems appropriate to use such materials for the treatment of hypertension. Expert opinion: There are currently only a few studies describing the use of synthetic polyesters in the arterial hypertension therapy. In order to the fact that there is a high demand for new, effective antihypertensive dosage forms, further studies for such drug carriers are certainly expected. Synthetic polyester carriers could improve the drug bioavailability and its pharmacokinetic properties by altering the pharmaceutical dosage form. This property is particularly useful for drugs with proven pharmacological action, but with limited application due to their inappropriate pharmacological properties. The development of new polymeric materials and technologies affords the opportunity to produce novel synthetic polyester DDSs.

Rectal drug delivery is an effective alternative to oral and parenteral treatments. This route allows for both local and systemic drug therapy. Traditional rectal dosage formulations have historically been used for localised treatments, including laxatives, hemorrhoid therapy and antipyretics. However, this form of drug dosage often feels alien and uncomfortable to a patient, encouraging refusal. The limitations of conventional solid suppositories can be overcome by creating a thermosensitive liquid suppository. Unfortunately, there are currently only a few studies describing their use in therapy. However, recent trends indicate an increase in the development of this modern therapeutic system. This review introduces a novel rectal drug delivery system with the goal of summarising recent developments in thermosensitive liquid suppositories for analgesic, anticancer, antiemetic, antihypertensive, psychiatric, antiallergic, anaesthetic, antimalarial drugs and insulin. The report also presents the impact of various types of components and their concentration on the properties of this rectal dosage form. Further research into such formulations is certainly needed in order to meet the high demand for modern, efficient rectal gelling systems. Continued research and development in this field would undoubtedly further reveal the hidden potential of rectal drug delivery systems.

Polymeric hydrogels play an increasingly important role in medicine, pharmacy and cosmetology. They appear to be one of the most promising groups of biomaterials due to their favorable physicochemical properties and biocompatibility. The objective of the presented study was to synthesize new poly(chitosan-ester-ether-urethane) hydrogels and to study the kinetic release of genistein (GEN) from these biomaterials. In view of the above, six non-toxic hydrogels were synthesized via the Ring-Opening Polymerization (ROP) and polyaddition processes. The poly(ester-ether) components of the hydrogels have been produced in the presence of the enzyme as a biocatalyst. In some cases, the in vitro release rate of GEN from the obtained hydrogels was characterized by near-zero-order kinetics, without “burst release” and with non-Fickian transport. It is important to note that developed hydrogels have been shown to possess the desired safety profile due to lack of cytotoxicity to skin cells (keratinocytes and fibroblasts). Taking into account the non-toxicity of hydrogels and the relatively highly controlled release profile of GEN, these results may provide fresh insight into polymeric hydrogels as an effective dermatological and/or cosmetological tool.

A novel and promising hydrogel drug delivery system (DDS) capable of releasing 5‑fluorouracil (5-FU) in a prolonged and controlled manner was obtained using &epsilon, ‑caprolactone‑poly(ethylene glycol) (CL-PEG) or rac‑lactide-poly(ethylene glycol) (rac‑LA-PEG) copolymers. Copolymers were synthesized via the ring-opening polymerization (ROP) process of cyclic monomers, &epsilon, ‑caprolactone (CL) or rac-lactide (rac-LA), in the presence of zirconium(IV) octoate (Zr(Oct)4) and poly(ethylene glycol) 200 (PEG 200) as catalyst and initiator, respectively. Obtained triblock copolymers were characterized by nuclear magnetic resonance (NMR) and gel permeation chromatography (GPC) techniques, the structure and tacticity of the macromolecules were determined. The relationship between the copolymer structure and the reaction conditions was evaluated. The optimal conditions were specified as 140 &deg, C and 24 h. In the next step, CL-PEG and rac-LA-PEG copolymers were chemically crosslinked using hexamethylene diisocyanate (HDI). Selected hydrogels were subjected to in vitro antitumor drug release studies, and the release data were analyzed using zero-order, first-order, and Korsmeyer-Peppas mathematical models. Controlled and prolonged (up to 432 h) 5-FU release profiles were observed for all examined hydrogels with first-order or zero-order kinetics. The drug release mechanism was generally denoted as non-Fickian transport.

Polymer-drug conjugates are currently being more widely investigated for the treatment of hypertension. In view of the above, in the first stage of our work, we used nontoxic &beta, cyclodextrin (&beta, CD) as effective, simple, inexpensive, and safe for the human body initiator for the synthesis of biocompatible and biodegradable functionalized polymers suitable for the medical and pharmaceutical applications. The obtained polymeric products were synthesized through a ring-opening polymerization (ROP) of &epsilon, caprolactone (CL), d,l-, and l,l- lactide (LA and LLA). The chemical structures of synthesized materials were elucidated based on 1H NMR and solid-state carbon-13 cross-polarization/magic angle spinning nuclear magnetic resonance (13C CP/MAS NMR) analysis, while the incorporation of &beta, CD molecule into the polymer chain was confirmed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Furthermore, molecular modeling has been applied to investigate the intrachain rigidities and chain architectures for several representative structures. The obtained and thoroughly characterized branched matrices were then used to generate the first &beta, cyclodextrin/biodegradable polymer/&beta, blocker conjugate through the successful conjugation of pindolol. The conjugates were fabricated by carbodiimide-mediated coupling reaction. The branched biodegradable materials released the drug in vitro in a sustained manner and without &ldquo, burst release&rdquo, and thus have the ability to treat different heart diseases.

In this study, “predominantly isotactic”, disyndiotactic, and atactic polylactides (PLAs) and poly(e-caprolactone)s (PCLs) were loaded with anticancer agents, epirubicin (EPI) and cyclophosphamide (CYCLOPHO), to investigate their properties as highly controlled delivery devices. It was found that the kinetic release of drugs from the obtained polyester matrices tested in vitro at 37 °C and pH 7.4 was strongly dependent on average molecular weight (Mn) of the polymers as well as the PLAs' microstructure. EPI and CYCLOPHO were released from various obtained matrices according to the diffusion, diffusion-degradation, and degradation mechanisms in a rather regular and continuous manner. Importantly, in some cases, the kinetics of the EPI and CYCLOPHO release was nearly zero-order, suggesting predominantly polymer degradation. It is shown that the drug release profiles can be tailored by a controlled design of the microstructure and Mn of polyesters, allowing use of the synthesized matrices for the development of highly controlled biodegradable anticancer drug delivery systems.

Recently, growing interest in polymers (natural and synthetic) as drug carriers in controlled release formulations and drug targeting systems that may improve the efficacy of treatment and reduce the side effects of a drug therapy, has been observed. Special attention has been paid to improving the effectiveness of antibiotics, which constitute a very important, often life-saving group of drugs. In this paper, we review polymers as macromolecular carriers of fluoroquinolones, a group of antibiotics with a broad spectrum of activity. We consider both physical intermixtures and chemical conjugates, although we discuss in greater depth the latter type of coupling, in which covalent bonds between drug molecules and polymers occur.

The present study evaluated a new concept of combined scaffolds as a promising bone replacement material for patients with a bone tumour or bone metastasis. The scaffolds were composed of hydroxyapatite doped with selenium ions and a biodegradable polymer (linear or branched), and contained an active substance—bisphosphonate. For this purpose, a series of biodegradable polyesters were synthesized through a ring-opening polymerization of e-caprolactone or d,l-lactide in the presence of 2-hydroxyethyl methacrylate (HEMA) or hyperbranched 2,2-bis(hydroxymethyl)propionic acid polyester-16-hydroxyl (bis-MPA) initiators, substances often used in the synthesis of medical materials. The polymers were obtained with a high yield and a number-average molecular weight up to 45,300 (g/mol). The combined scaffolds were then manufactured by a direct compression of pre-synthesized hydroxyapatite doped with selenite or selenate ions, obtained polymer and pamidronate as a model drug. It was found that the kinetic release of the drug from the scaffolds tested in vitro under physiological conditions is strongly dependent on the physicochemical properties and average molecular weight of the polymers. Furthermore, there was good correlation with the hydrolytic biodegradation results of the scaffolds fabricated without drug. The preliminary findings suggest that the fabricated combined scaffolds could be effectively used for the sustained delivery of bioactive molecules at bone defect sites.

Novel and promising macromolecular conjugates of the α1-adrenergic blocker prazosin were directly synthesized by covalent incorporation of the drug to matrices composed of biodegradable polymers and α-amino acids for the development of a polymeric implantable drug delivery carrier. The cyto- and genotoxicity of the synthesized matrices were evaluated using a bacterial luminescence test, protozoan assay, and Salmonella typhimurium TA1535. A new urethane bond was formed between the hydroxyl end-groups of the synthesized polymer matrices and an amine group of prazosin, using 1,1'-carbonyldiimidazole (CDI) as a coupling agent. The structure of the polymeric conjugates was characterized by various spectroscopy techniques. A study of hydrogen nuclear magnetic resonance ((1)H-NMR) and differential scanning calorimetry (DSC) thermodiagrams indicated that the presence of prazosin pendant groups in the macromolecule structures increased the polymer's rigidity alongside increasing glass transition temperature. It has been found that the kinetic release of prazosin from the obtained macromolecular conjugates, tested in vitro under different conditions, is strongly dependent on the physicochemical properties of polymeric matrices. Furthermore, the presence of a urethane bond in the macromolecular conjugates allowed for obtaining a relatively controlled release profile of the drug. The obtained results confirm that the pharmacokinetics of prazosin might be improved through the synthesis of polymeric conjugates containing biomedical polymers and α-amino acids in the macromolecule.

The need for development of comprehensive therapeutic systems, (e.g., polymer-apatite composites) as a bone substitute material has previously been highlighted in many scientific reports. The aim of this study was to develop a new multifunctional composite based on hydroxyapatite porous granules doped with selenite ions (SeO32−) and a biodegradable branched copolymer-bisphosphonate conjugate as a promising bone substitute material for patients with bone tumours or bone metastasis. A series of biodegradable and branched copolymer matrices, adequate for delivery of bisphosphonate in the bone-deficient area were synthesized and physico-chemically and biologically (cyto- and genotoxicity assays) characterized. Branched copolymers were obtained using a hyperbranched bis-MPA polyester-16-hydroxyl initiator and Sn(Oct)2, a (co)catalyst of the ring-opening polymerization (ROP) of l,l-lactide (LLA) and ε-caprolactone (CL). A new amide bond was formed between the hydroxyl end groups of the synthesized copolymer carriers and an amine group of pamidronate (PAM)—the drug inhibiting bone resorption and osteoclast activity in bone. The dependence of the physico-chemical properties of the copolymer matrices on the kinetic release of PAM from the synthesized branched copolymer conjugate-coated hydroxyapatite granules doped with selenite ions was observed. Moreover, the correlation of these results with the hydrolytic degradation data of the synthesized matrices was evidenced. Therefore, the developed composite porous hydroxyapatite doped with SeO32− ions/biodegradable copolymer-PAM conjugate appears most attractive as a bone substitute material for cancer patients.

To evaluate the effects of ionic liquids (ILs) on the microstructural features of aliphatic polyesters for biomedical applications, a series of copolymers were synthesized by lipase ring opening polymerization of rac-lactide (rac-LA) and ε-caprolactone (CL). The chemical structures of resulting polymers were characterized by 1H- and 13C-NMR and the average molecular weight (Mn) and dispersity index were characterized by gel permeation chromatography. The structure of the copolymers confirms the presence of linear polymer chains with end-functional hydroxyl groups allowing covalent coupling of the therapeutic agents. Chain microstructure of copolymers indicates the presence of both random and block copolymers depending on the synthesis conditions. Moreover, it was found that CL is the most active co-monomer during copolymerization which enhances the polymerizability of rac-LA and allows to obtain higher Mn of the copolymers. The results demonstrate that ILs could be promising solvents in synthesis of aliphatic esters for biomedical applications.

International audience; The study provides detailed information on the differences in the structural, thermal and degradation properties of poly(ε-caprolactone) synthesized in two different ionic liquids, 1-butyl-3-methylimidazolium hexafluorophosphate [bmim][PF6] and 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [bmim][NTf2], regarding its further usage in the pharmaceutical field. The polymer structure confirms the presence of both linear polymer chains with end-functional hydroxyl groups allowing covalent coupling of the therapeutic agents, and cyclic macromolecules, both affecting the degree of crystallinity of polymer. The highest macrocyclic content (64%) after 7 days of polymerization at 80 8C was observed for [bmim][NTf2]. For [bmim][PF6], the macrocyclic content value was not dependent on the reaction time and remained at a similar level (10–14% at 80 8C). The results of degradation test revealed that hydrolytic degradation of ester bonds is more pronounced for PCLs synthesized in [bmim][NTf2], due to their lower degree of crystallinity compared with PCLs obtained in [bmim][PF6]. A high purity, low polydispersity index of the obtained polymers and high yield of the process (ca., 90%) indicate that ionic liquids seem to be promising solvents for the synthesis of biomedical polymers.

Antimicrobial peptides (AMPs) are prospective therapeutic options for treating multiple-strain infections. However, clinical and commercial development of AMPs has some limitations due to their limited stability, low bioavailability, and potential hemotoxicity. The purpose of this study was to develop new polymeric carriers as highly controlled release devices for amphibian peptides citropin 1.1 (CIT) and temporin A (TEMP). The release rate of the active pharmaceutical ingredients (APIs) was strongly dependent on the API characteristics and the matrix microstructure. In the current work, we investigated the effect of the polymer microstructure on in vitro release kinetics of AMPs. Non-contact laser profilometry, scanning electron microscopy (SEM), and differential scanning calorimetry (DSC) were used to determine the structural changes during matrix degradation. Moreover, geno- and cytotoxicity of the synthesized new carriers were evaluated. The in vitro release study of AMPs from the obtained non-toxic matrices shows that peptides were released with near-zero-order kinetics. The peptide “burst release” effect was not observed. New devices have reached the therapeutic concentration of AMPs within 24 h and maintained it for 28 days. Hence, our results suggest that these polymeric devices could be potentially used as therapeutic options for the treatment of local infections.

Camptothecin-polylactide conjugates (CMPT-PLA) were synthesized by covalent incorporation of CMPT into PLA of different microstructure, i.e., atactic PLA and atactic-block-isotactically enriched PLA (Pm = 0.79) via urethane bonds. The kinetic release of CPMT from CMPT-PLA conjugates, tested in vitro under different conditions, is possible in both cases and notably, strongly dependent on PLA microstructure. It shows that release properties of drug-PLA conjugates can be tailored by controlled design of the PLA microstructure, and allow in the case of CMPT-PLA conjugates for the development of highly controlled biodegradable CMPT systems—important delivery systems for anti-cancer agents.

In this study, new composite bisphosphonate delivery systems were obtained from polyurethanes (PUs) and nanocrystalline hydroxyapatite (HA). The biodegradable PUs were first synthesized from poly(ε-caprolactone) diols (PCL diols), poly(ethylene adipate) diol, 1,6-hexamethylene diisocyanate, 1,4-butanediol and HA. Moreover, the PCL diols were synthesized by the ring-opening polymerization catalysed by the lipase from Candida antarctica. Next, composite drug delivery systems for clodronate were prepared. The mechanical properties of the obtained biomaterials were determined. The cytotoxicity of the synthesized polymers was tested. The preliminary results show that the obtained composites are perspective biomaterials and they can be potentially applied in the technology of implantation drug delivery systems.

The development and characterization of novel macromolecular conjugates of ampicillin using branched biodegradable polymers has been described in this study. The conjugates have been prepared coupling the β-lactam antibiotic with branched polymer matrices based on the natural oligopeptide core. The cyto- and genotoxicity of the synthesized polymers were evaluated with a bacterial luminescence test, two protozoan assays and Salmonella typhimurium TA1535. The presence of a newly formed covalent bond between the drug and the polymer matrices was confirmed by 1H-NMR and FTIR studies. A drug content (15.6 and 10.2 mole %) in the macromolecular conjugates has been determined. The obtained macromolecular products have been subjected to further in vitro release studies. The total percentage of ampicillin released after 21 days of incubation was nearly 60% and 14% and this resulted from the different physicochemical properties of the polymeric matrices. This is the first report on the application of branched biodegradable polymeric matrices for the covalent conjugation of ampicillin. The obtained results showed that the synthesized macromolecular drug-conjugates might slowly release the active drug molecule and improve the pharmacokinetics of ampicillin.