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BT44 is a novel, second generation glial cell line-derived neurotropic factor (GDNF) mimetic, with improved biological activity and a lead compound for the treatment of neurodegenerative disorders. Like many other small molecules, it suffers from intrinsic poor aqueous solubility, posing significant hurdles at various levels for its preclinical development and clinical translation. Herein, we report a poly(2-oxazoline)s (POx) based BT44 micellar nanoformulation with ultra-high drug loading capacity of 47 wt.%. The BT44 nanoformulation was comprehensively characterized by 1H-NMR spectroscopy, differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), dynamic light scattering (DLS) and cryo-transmission/scanning electron microscopy (cryo-TEM/SEM). The DSC, XRD and redispersion studies collectively confirmed that the BT44 formulation can be stored as a lyophilized powder and can be redispersed upon need. The DLS suggested that the redispersed formulation is suitable for parenteral administration (Dh ≈ 70 nm). The cryo-TEM measurements showed the presence of worm-like structures both in plain polymer and BT44 formulation. The BT44 formulation retained biological activity in immortalized cells and in cultured dopamine neurons. The micellar nanoformulation of BT44 exhibited improved absorption (after subcutaneous injection) and blood-brain barrier (BBB) penetration and no acute toxic effects in mice were observed. In conclusion, herein, we have developed an ultra-high BT44 loaded aqueous injectable nanoformulation, which can be used to pave way for its preclinical and clinical development for the management of neurodegenerative disorders.

Considering the largely chiral nature of biological systems, there is interest in chiral drug delivery systems. Here, we investigate for the first time polymer micelles based on poly(2-oxazoline) (POx) ABA-type triblock copolymers with chiral and racemic hydrophobic blocks for the formulation of chiral and achiral drugs. Specifically, poly(2-ethyl-4-ethyl-2oxazoline) (pEtEtOx) and poly(2-propyl-4-methyl-2-oxazoline) (pPrMeOx) were used as hydrophobic block B and poly(2-methyl-2-oxazoline) (pMeOx) as hydrophilic block A. Using these triblock copolymers, nanoformulations of curcumin (CUR), paclitaxel (PTX), and chiral (R and S) and racemic ibuprofen were prepared. For CUR and PTX, the maximum drug loading was significantly dependent on the structure of the hydrophobic repeat units, but not the chirality. In contrast, the maximum drug loading with chiral/racemic ibuprofen was affected neither by the polymer structure nor by chirality, but minor effects were observed with respect to the size and size distribution of the drug-loaded micelles.

The main objective of this study is to formulate a library of difficult to solubilize drugs with four slightly different poly(2-oxazoline)s (POx) and poly(2-oxazine)s (POzi) based amphiphilic triblock copolymers and to elucidate whether the drug-polymer compatibility, as estimated by solubility parameters (SPs) might be used as tool to guide formulation development. The theoretical and experimental SPs of different homo-/triblock copolymers and 21 different hydrophobic drugs were calculated by two group contribution methods (i.e. Hoftyzer Van-Krevelen and Yamamoto molecular break method) and determined experimentally by solubility testing in list of selective solvents (for polymers only). The obtained SPs were further utilized to calculate the distance between polymers and drugs (Ra) in 3 dimensional Hansen space. Out of 21 structurally diverse drugs, the loading capacity (LC) was found to be higher than 40, 30, 20 and 10 wt.% for 4, 4, 3 and 5 drugs, respectively. In the remaining of 5 drugs the maximum achievable LC was found below 10 wt.%. The experimental results obtained by formulation development were not in accordance with the results predicted by Ra calculation. In contrast to several reports found in the literature, the determination of SPs and concurrent compatibility estimation appeared not to be a suitable tool to predict polymer-drug compatibility in the present system. As the predictive power of SPs is based on simple mathematical calculations, limiting the precise prediction of overall polarity, hydrogen bonding ability of molecules and interplay between the hydrophilic and hydrophobic domains resulting in differing deviations than predicted interactions thus might compromise the predictive power of HSPs.

BT44 is a novel, second generation glial cell line-derived neurotropic factor (GDNF) mimetic, with improved biological activity and a lead compound for the treatment of neurodegenerative disorders. Like many other small molecules, it suffers from intrinsic poor aqueous solubility, posing significant hurdles at various levels for its preclinical development and clinical translation. Herein, we report a novel poly(2-oxazoline)s (POx) based BT44 micellar nanoformulation with ultra-high drug loading capacity of 47 wt.%. The BT44 nanoformulations were comprehensively characterized by 1H-NMR spectroscopy, differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), dynamic light scattering (DLS) and cryo-transmission/scanning electron microscopy (cryo-TEM/SEM). The DSC, XRD and redispersion studies collectively confirmed that the BT44 formulation can be stored as a lyophilized powder and can be redispersed when needed. The DLS further suggested that the redispersed formulation is suitable for parenteral administration (Dh ≈ 70nm). The cryo-TEM analysis revealed the presences of worm like structures. The BT44 formulation retains biological activity in immortalized cells and in cultured dopamine neurons. The micellar formulation of BT44 exhibited improved absorption and blood-brain barrier (BBB) penetration and produced no acute toxic effects in mice. In conclusion, herein, we have developed an ultra-high BT44 loaded aqueous injectable nanoformulation, which can be used to pave way for its preclinical and clinical development for the management of neurodegenerative disorders.

Adrenocortical carcinoma (ACC) is a malignant tumor originating from the adrenal gland cortex with a heterogeneous but overall dismal prognosis in advanced stages. For more than 50 years, mitotane has remained a cornerstone for the treatment of ACC as adjuvant and palliative therapy. It has a very poor aqueous solubility of 0.1 mg/l and high partition coefficient in octanol/water (log P) value of 6. The commercially available dosage form is 500 mg tablets (Lysodren®). Even at doses up to 6 g/day (12 tablets in divided doses) for several months, > 50% patients do not achieve therapeutic plasma concentration > 14 mg/l due to poor water solubility, large volume of distribution and inter/intra-individual variability in bioavailability. This article aims to give a concise update of the clinical challenges associated with the administration of high-dose mitotane oral therapy which encompass the issues of poor bioavailability, difficult-to-predict pharmacokinetics and associated adverse events. Moreover, we present recent efforts to improve mitotane formulations. Their success has been limited, and we therefore propose an injectable mitotane formulation instead of oral administration, which could bypass many of the main issues associated with high-dose oral mitotane therapy. A parenteral administration of mitotane could not only help to alleviate the adverse effects but also circumvent the variable oral absorption, give better control over therapeutic plasma mitotane concentration and potentially shorten the time to achieve therapeutic drug plasma concentrations considerably., Plain Language summary Mitotane as tablet form is currently the standard treatment for adrenocortical carcinoma. It has been used for 5 decades but suffers from highly variable responses in patients, subsequent adverse effects and overall lower response rate. This can be fundamentally linked to the exceedingly poor water solubility of mitotane itself. In terms of enhancing water solubility, a few research groups have attempted to develop better formulations of mitotane to overcome the issues associated with tablet dosage form. However, the success rate was limited, and these formulations did not make it into the clinics. In this article, we have comprehensively reviewed the properties of these formulations and discuss the reasons for their limited utility. Furthermore, we discuss a recently developed mitotane nanoformulation that led us to propose a novel approach to mitotane therapy, where intravenous delivery supplements the standard oral administration. With this article, we combine the current state of knowledge as a single piece of information about the various problems associated with the use of mitotane tablets, and herein we postulate the development of a new injectable mitotane formulation, which can potentially circumvent the major problems associated to mitotane's poor water solubility.

Despite decades of research, our understanding of the molecular interactions between drugs and polymers in drug-loaded polymer micelles does not extend much beyond concepts such as "like-dissolves-like" or hydrophilic/hydrophobic. However, polymer-drug compatibility strongly affects formulation properties and therefore the translation of a formulation into the clinics. Specific interactions such as hydrogen-bonding, π-π stacking, or coordination interactions can be utilized to increase drug loading. This is commonly based on trial and error and eventually leads to an optimized drug carrier. Unfortunately, due to the unique characteristics of each drug, the deduction of advanced general concepts remains challenging. Furthermore, the introduction of complex moieties or specifically modified polymers hampers systematic investigations regarding polymer-drug compatibility as well as clinical translation. In this study, we reduced the complexity to isolate the crucial factors determining drug loading. Therefore, the compatibility of 18 different amphiphilic polymers for five different hydrophobic drugs was determined empirically. Subsequently, the obtained specificities were compared to theoretical compatibilities derived from either the Flory-Huggins interaction parameters or the Hansen solubility parameters. In general, the Flory-Huggins interaction parameters were less suited to correctly estimate the experimental drug solubilization compared to the Hansen solubility parameters. The latter were able to correctly predict some trend regarding good and poor solubilizers, yet the overall predictive strength of Hansen solubility parameters is clearly unsatisfactory.

As one kind of "smart" material, thermogelling polymers find applications in biofabrication, drug delivery and regenerative medicine. In this work, we report a thermosensitive poly(2-oxazoline)/poly(2-oxazine) based diblock copolymer comprising thermosensitive/moderately hydrophobic poly(2-N-propyl-2-oxazine) (pPrOzi) and thermosensitive/moderately hydrophilic poly(2-ethyl-2-oxazoline) (pEtOx). Hydrogels were only formed when block length exceeded certain length (approximate to 100 repeat units). The tube inversion and rheological tests showed that the material has then a reversible sol-gel transition above 25 wt.% concentration. Rheological tests further revealed a gel strength around 3 kPa, high shear thinning property and rapid shear recovery after stress, which are highly desirable properties for extrusion based three-dimensional (3D) (bio) printing. Attributed to the rheology profile, well resolved printability and high stackability (with added laponite) was also possible. (Cryo) scanning electron microscopy exhibited a highly porous, interconnected, 3D network. The sol-state at lower temperatures (in ice bath) facilitated the homogeneous distribution of (fluorescently labelled) human adipose derived stem cells (hADSCs) in the hydrogel matrix. Post-printing live/dead assays revealed that the hADSCs encapsulated within the hydrogel remained viable (approximate to 97%). This thermoreversible and (bio) printable hydrogel demonstrated promising properties for use in tissue engineering applications.

Alginates are the most commonly used bioink in biofabrication, but their rheological profiles make it very challenging to perform real 3D printing. In this study, an advanced hybrid hydrogel ink was developed, a mixture of thermogelling diblock copolymer, alginate and clay i.e. Laponite XLG. The reversible thermogelling and shear thinning properties of the diblock copolymer in the ink system improves handling and 3D printability significantly. Various three-dimensional constructs, including suspended filaments, were printed successfully with high shape fidelity and excellent stackability. Subsequent ionic crosslinking of alginate fixates the printed scaffolds, while the diblock copolymer is washed out of the structure, acting as a fugitive material/porogen on the (macro)molecular level. Finally, cell-laden printing and culture over 21 d demonstrated good cytocompatibility and feasibility of the novel hybrid hydrogels for 3D bioprinting. We believe that the developed approach could be interesting for a wide range of bioprinting applications including tissue engineering and drug screening, potentially enabling also other biological bioinks such as collagen, hyaluronic acid, decellularized extracellular matrices or cellulose based bioinks.

Hydrogels that can be processed with additive manufacturing techniques and concomitantly possess favorable mechanical properties are interesting for many advanced applications. However, the development of novel ink materials with high intrinsic 3D printing performance has been proven to be a major challenge. Herein, a novel 3D printable organic-inorganic hybrid hydrogel is developed from three components, and characterized in detail in terms of rheological property, swelling behavior and composition. The nanocomposite hydrogel combines a thermoresponsive hydrogel with clay LAPONITE (R) XLG and in situ polymerized poly(N,N-dimethylacrylamide). Before in situ polymerization, the thermogelling and shear thinning properties of the thermoresponsive hydrogel provides a system well-suited for extrusion-based 3D printing. After chemical curing of the 3D-printed constructs by free radical polymerization, the resulting interpenetrating polymer network hydrogel shows excellent mechanical strength with a high stretchability to a tensile strain at break exceeding 550%. Integrating with the advanced 3D-printing technique, the introduced material could be interesting for a wide range of applications including tissue engineering, drug delivery, soft robotics and additive manufacturing in general.

Polymeric micelles are typically characterized as core-shell structures. The hydrophobic core is considered as a depot for hydrophobic molecules, and the corona-forming block acts as a stabilizing and solubilizing interface between the core and aqueous milieu. Tremendous efforts have been made to tune the hydrophobic block to increase the drug loading and stability of micelles, whereas the role of hydrophilic blocks is rarely investigated in this context, with poly(ethylene glycol) (PEG) being the gold standard of hydrophilic polymers. To better understand the role of the hydrophilic corona, a small library of structurally similar A-B-A-type amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s is investigated by varying the hydrophilic block A utilizing poly(2-methyl-2-oxazoline) (pMeOx; A) or poly(2-ethyl-2-oxazoline) (pEtOx; A*). In terms of hydrophilicity, both polymers closely resemble PEG. The more hydrophobic block B bears either a poly(2-oxazoline) and poly(2-oxazine) backbone with C3 (propyl) and C4 (butyl) side chains. Surprisingly, major differences in loading capacities from A-B-A > A*-B-A > A*-B-A* is observed for the formulation with two poorly water-soluble compounds, curcumin and paclitaxel, highlighting the importance of the hydrophilic corona of polymer micelles used for drug formulation. The formulations are also characterized by various nuclear magnetic resonance spectroscopy methods, dynamic light scattering, cryogenic transmission electron microscopy, and (micro) differential scanning calorimetry. Our findings suggest that the interaction between the hydrophilic block and the guest molecule should be considered an important, but previously largely ignored, factor for the rational design of polymeric micelles. Non

Introduction: The current work was aimed to design and synthesize novel crosslinked pH-sensitive gelatin/pectin (Ge/Pec) hydrogels using different polymeric ratios and to explore the effect of polymers and degree of crosslinking on dynamic, equilibrium swelling and in vitro release behavior of the model drug (Mannitol). Methods: The Ge/Pec based hydrogels were prepared using glutaraldehyde as the crosslinker. Various structural parameters that affect their release behavior were determined, including swelling study, porosity, sol-gel analysis, average molecular weight between crosslinks (Mc), volume fraction of polymer (V2,s), solvent interaction parameter (χ) and diffusion coefficient. The synthesized hydrogels were subjected to various characterization tools like Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and DSC differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Results: The hydrogels show highest water uptake and release at lower pH values. The FTIR spectra showed an interaction between Ge and Pec, and the drug-loaded samples also showed the drug-related peaks, indicating proper loading of the drug. DSC and TGA studies confirmed the thermal stability of hydrogel samples, while SEM showed the porous nature of hydrogels. The drug release followed non-Fickian diffusion or anomalous mechanism. Conclusion: Aforementioned characterizations reveal the successful formation of copolymer hydrogels. The pH-sensitive swelling ability and drug release behavior suggest that the rate of polymer chain relaxation and drug diffusion from these hydrogels are comparable which also predicts their possible use for site-specific drug delivery.

Polymer micelles offer the possibility to create a nanoscopic environment that is distinct from the bulk phase. They find applications in catalysis, drug delivery, cleaning, etc. Often, one simply distinguishes between hydrophilic and hydrophobic, but fine-tuning of the microenvironment is possible by adjusting the structure of the polymer amphiphile. Here, we investigated a small library of structurally similar amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s with respect to their solubilization capacity for two extremely water insoluble drugs, curcumin and paclitaxel. We found very significant and orthogonal specificities even if only one methylene group is exchanged between the polymer backbone and side chain. More strikingly, we observed profound synergistic and antagonistic solubilization patterns for the coformulation of the two drugs. Our findings shed new light on host-guest interaction in polymer micelles and such pronounced host-guest specificities in polymer micelles may not only be interesting in drug delivery but also for applications such as micellar catalysis.

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the family of statins have been suggested as therapeutic options in various tumors. Atorvastatin is a statin with the potential to cross the blood-brain barrier; however, the concentrations necessary for a cytotoxic effect against cancer cells exceed the concentrations achievable via oral administration, which made the development of a novel atorvastatin formulation necessary. We characterized the drug loading and basic physicochemical characteristics of micellar atorvastatin formulations and tested their cytotoxicity against a panel of different glioblastoma cell lines. In addition, activity against tumor spheroids formed from mouse glioma and mouse cancer stem cells, respectively, was evaluated. Our results show good activity of atorvastatin against all tested cell lines. Interestingly, in the three-dimensional (3D) models, growth inhibition was more pronounced for the micellar formulation compared to free atorvastatin. Finally, atorvastatin penetration across a blood-brain barrier model obtained from human induced-pluripotent stem cells was evaluated. Our results suggest that the presented micelles may enable much higher serum concentrations than possible by oral administration; however, if transport across the blood-brain barrier is sufficient to reach the therapeutic atorvastatin concentration for the treatment of glioblastoma via intravenous administration remains unclear.

Polymeric micelles are typically characterized as core-shell structures. The hydrophobic inner core is considered as depot for hydrophobic molecules such as drugs or catalysts and the corona forming block acts as protective, stabilizing and solubilizing interface between the hydrophobic core and the external aqueous milieu. Tremendous efforts have been made to tune the hydrophobic block to increase the drug loading and stability of the micelles, while the role of hydrophilic blocks regarding drug loading and stability of micelles is rarely studied in detail. To do so, we investigated a small library of structurally similar A-B-A type amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s by varying the hydrophilic block A utilizing poly(2-methyl-2-oxazoline) (A) or poly(2-ethyl-2-oxazoline) (A*), both excellently water-soluble polymers that are able to provide beneficial stealth properties. Surprisingly, major differences in loading capacities from A-B-A > A*-B-A > A*-B-A* highlight the impact of the hydrophilic corona of the polymer micelles on drug loading and stability. 1H-NMR spectroscopy revealed that the hydrophilic pEtOx exhibits a stronger interaction with the cargo compared with its more hydrophilic counterpart pMeOx, reducing colloidal stability of the drug loaded micelles at lower drug loading. To gain more insights, formulations were also characterized by diffusion ordered and nuclear Overhauser effect NMR spectroscopy, dynamic light scattering and (micro) differential scanning calorimetry. Our findings suggest that the interaction between the hydrophilic block and the guest molecule should be considered an important but previously largely ignored factor for the rational design of polymeric micelles.

Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14–20 mg L\(^{-1}\)) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT‐loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X‐ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI‐H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.

Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14-20 mg/L) even after many months of treatment which is caused by low water solubility and unfavorable pharmacokinetic properties such as poor bioavailability and high volume of distribution of MT. The clinical need and previously reported extraordinary high drug loading of poly(2-methyl-2-oxazoline)-block-poly(2-butyl-2-oxazoline)-block-poly(2-methyl-2-oxazoline) (A-pBuOx-A) based micelles for paclitaxel (PTX), led us to develop MT loaded micelles which may enable an injectable formulation. We successfully solubilized up to 6 g/L of MT in an aqueous formulation. The MT loaded nanoformulations were characterized by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD), confirmed the amorphous nature of drug in the formulations. The polymer itself did not show cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI-H295 both in monolayers and tumor cell spheroids, we demonstrated micellar MT to exhibit comparable efficacy to its ethanol solution. We postulate that this formulation would be suitable for i.v. application and more rapid attainment of therapeutic plasma concentrations. In conclusion, we consider our micellar formulation a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity towards ACC in vitro.

Despite decades of research, our understanding of the molecular interactions between drugs and polymers in drug loaded polymer micelles does not extend much beyond concepts such as “like-dissolves-like“ or hydrophilic/hydrophobic. However, polymer-drug compatibility strongly affects formulation properties and therefore the translation of a formulation into the clinics. Specific interactions such as hydrogen-bonding, π-π stacking or coordination interactions can be utilized to increase drug-loading. This is commonly based on trial-and-error and eventually leads to an optimized drug carrier. Unfortunately, due to the unique characteristics of each drug, the deduction of advanced general concepts remains challenging. Furthermore, the introduction of complex moieties or specifically modified polymers hampers systematic investigations regarding polymer drug-compatibility as well as clinical translation. In this study, we reduced the complexity in order to isolate crucial factors determining drug-loading. Therefore, the compatibility of 18 different amphiphilic polymers for 5 different hydrophobic drugs was determined empirically. Subsequently, the obtained specificities were compared to theoretical compatibilities derived from either the Flory-Huggins interaction parameter or Hansen solubility parameters. In general, Flory-Huggins interaction parameters were less suited to correctly estimate the experimental drug solubilization compared to the Hansen solubility parameters. The latter were able to correctly predict some trend regarding good and poor solubilizers, yet the overall predicitive strength of Hansen Solubility parameters is clearly unsatisfactory.

Eudragit E 100 and polycaprolactone (PCL) floating microspheres for enhanced gastric retention and drug release were successfully prepared by oil in water solvent evaporation method. Metronidazole benzoate, an anti-protozoal drug, was used as a model drug. Polyvinyl alcohol was used as an emulsifier. The prepared microspheres were observed for % recovery, % degree of hydration, % water uptake, % drug loading, % buoyancy and % drug release. The physico-chemical properties of the microspheres were studied by calculating encapsulation efficiency of microspheres and drug release kinetics. Drug release characteristics of microspheres were studied in simulated gastric fluid and simulated intestinal fluid i.e., at pH 1.2 and 7.4 respectively. Fourier transform infrared spectroscopy was used to reveal the chemical interaction between drug and polymers. Scanning electron microscopy was conducted to study the morphology of the synthesized microspheres.

Poly(2-oxazoline)s have been investigated for decades as biomaterials. Pioneering early work suggested that hydrophilic poly(2-oxazoline)s are comparable to poly(ethylene glycol) regarding their potential as biomaterials, but the ready commercial availability of the latter has led to its meteoric rise to become the gold standard of hydrophilic synthetic biomaterials. In contrast, poly(2-oxazoline)s almost fell into oblivion. However, in the last decade, this family of polymers has gained much more interest in general and as biomaterials in particular. The rich chemistry and comparably straightforward synthesis of poly(2-oxazoline)s gives many opportunities for tailoring the properties of the resulting biomaterials, allowing the chemist to explore new conjugation chemistry, and to fine-tune the molar mass, hydrophilic-lipophilic balance as well as architecture. Thus, the wide range of demands for various applications of biomaterials can be suitably addressed. This review aims to give a comprehensive and critical update of the development of poly(2-oxazoline) based biomaterials, focusing on the last 5 years, which have seen an explosive increase of interest. We believe that the research regarding this diverse family of polymers will remain strong and will keep growing, in particular after the promising first-in-human studies of a poly(2-oxazoline) drug conjugate. This review aims at researchers and students new to this polymer family and seasoned poly(2-oxazoline) experts alike and attempts to showcase how the chemical diversity of poly(2-oxazoline)s allows a relatively facile and broad access to biomaterials of all kinds.

Objectives The present work aimed to design and synthesize pH-sensitive cross-linked Ge/SA hydrogels using different ratios of each polymer, and to investigate the effect of each polymer on dynamic, equilibrium swelling, and in vitro release pattern of cetirizine hydrochloride, which was selected as a model drug. Materials and methods These gelatin and sodium alginate hydrogels were prepared at room temperature through free radical polymerization using glutaraldehyde as a crosslinker. These polymeric composites were used as model systems to envisage various important characterizations. The in vitro release pattern of drug was investigated in three different mediums (phosphate buffer solution of pH 1.2, 5.5, 7.5 whose ionic strength was kept constant). Various structure property relationships that affect its release behavior were determined such as swelling analysis, porosity, sol-gel analysis, average molecular weight between crosslinks (Mc), solvent interaction parameter (χ), volume fraction of polymer (V2,s) and diffusion coefficient. The structural, crystallinity, and thermal stability were confirmed using FTIR, XRD, and DSC analysis. Results These hydrogels showed maximum swelling at pH 1.2. Zero-order, first-order, Higuchi, and Peppas models were applied to demonstrate the release pattern of drug. The release of drug occurred through non-Fickian diffusion or anomalous mechanism. Porosity was found increased with an increase in concentration of both polymers, and porosity decreased when the concentration of the crosslinker was increased. Gel fraction increased with an increase in concentration of SA, Ge, and glutaraldehyde. Conclusion The prepared pH sensitive hydrogels can be used as a potential carrier for the sustained delivery of cetirizine hydrochloride.