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Formulation Study of a Poly(Amino Methacrylate) Film-Forming Solution for Transdermal Administration
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Formulation Study of a Poly(Amino Methacrylate) Film-Forming Solution for Transdermal Administration
by Chiara G. M. Gennari,Antonella CasiraghiORCID,Francesca Selmin *ORCID andFrancesco CilurzoORCID
Department of Pharmaceutical Sciences, Università degli Studi di Milano, via G: Colombo, 71, 20133 Milano, Italy
*
Author to whom correspondence should be addressed.
Pharmaceutics 2025, 17(1), 88; https://doi.org/10.3390/pharmaceutics17010088
Submission received: 20 December 2024 / Revised: 7 January 2025 / Accepted: 9 January 2025 / Published: 11 January 2025
(This article belongs to the Special Issue Emerging Trends in Skin Delivery Systems)
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Abstract
Background/Objectives: The objective of this paper is to design a novel film-forming system (FFS) based on Eudragit® E PO (EuE) polymeric solutions, differing in volatile solvents (i.e., isopropanol and ethanol) and plasticizers (i.e., tributylcitrate, glycerine, triacetin and PEG 400). Methods: The physicochemical and mechanical properties of the FFS and dried films were evaluated in terms of formation time, stickiness, Tg, tensile strength, break elongation and Young’s modulus. The in vitro skin permeation studies were conducted on formulations containing caffeine and testosterone. Results: The FFS, consisting of EuE and PEG400 in isopropyl alcohol and ethanol (80:20, v/v), exhibited rapid film formation within about 5 min and the dried film allowed a high skin permeability compared to other formulations due to the ability to increase the thermodynamic activity of both drugs. When triiodothyronine (T3) was loaded as a model of a very low soluble drug, tocopherol polyethylene glycol succinate (TPGS) was added as a co-solvent and it allowed for the improvement of T3 retention in the skin. Conclusions: Among the formulative variables, the nature and the amount of plasticizer represent the most critical variables to obtain an EuE-based film with satisfying physical and biopharmaceutical properties
Protecting Effect of Excipients in Freeze-Drying Liposomes Prepared by Ethanol-Injection
No full textThe production methods of liposomes is moving from the traditional techniques to the microfluidic and continuous crossflow injection approaches. These techniques allow to obtain quickly unilamellar vesicles avoiding the downsizing step, but require the use of a solvent, generally ethanol, that is usually removed. Lyophilization of these liposome dispersions would avoid this step, increasing concomitantly the shelf-life of the product. Nevertheless, the sublimation of ethanol, which does not freeze completely, may affect the quality of the freeze-dried product and, therefore, the reconstitution of the liposome dispersion. In the current Rapid Fire the feasibility of freeze-drying hydro-alcoholic liposomal dispersions is discussed, focusing the attention on residual ethanol content and possible protectant. In particular, the effect of threalose, poly(vinyl pyrrolidone) K12 and a combination thereof on the quality attributes of lyophilized products will be presented
Biodegradable nanoparticles for restenosis following PTA: a feasibility study
No full textINTRODUCTION
Percutaneous transluminal angioplasty (PTA) is known to effectively improve the prognosis of patients with vascular diseases1. However, poor reendothelialization, and excessive migration and proliferation of vascular smooth muscular cells in the tunica media, can result in obstructive neointimal hyperplasia, and are the major mechanisms involved in restenosis following PTA2. Many animal studies indicate that local delivery of intimal hyperplasia inhibiting drugs can enhance vascular reendothelialization and prevent restenosis2, although this remains controversial. This may be due to inadequate drug concentrations or to the short period that the effective drug concentrations is available locally. The local administration of drug by biodegradable nanoparticles could enhance the drug concentrations in vessel wall and, thereby, yield the desired therapeutic effects. Recently, anti-oxidants (AA) grafted on poly(lactide-co- glycolide) (g-AA-PLGA) were proposed as novel biodegradable materials stable to gamma irradiation, characterized by different surface properties and suitable for drug delivery3,4. In this work, we investigated the feasibility to prepare g-AA-PLGA nanoparticles as carriers for the local administration of drugs in the vessel wall during PTA. To achieve this goal, the rate and extent of cellular uptake of such nanoparticles in comparison with the naïve PLGA was studied using macrophages, smooth muscular and endothelial cells as representative of the cells present in the vessel wall.
EXPERIMENTAL SET-UP
g-AA-PLGA synthesis and characterization
Caffeic acid (CA) or resveratrol (RV) were grafted to PLGA (L/G ratio 50/50, Mw=26 KDa, Tg=47.1±0.5 °C) by a free radicals-induced strategy3,4. g-AA-PLGA were characterized by the DPPH assay, GPC analysis and DSC.
Nanoparticles preparation and characterization
Surfactant-free nanoparticles (NPs) were prepared by the solvent displacement method, adding dropwise 1 mL of 1% polymeric solution in organic solvent to 10 mL of MilliQ® water. Hydrodynamic diameter (Dh) and zeta potential () were determined by a Zetasizer Nano ZS (Malvern Instrument, UK). Fluorescent NPs with 10% w/w of a FITC- PLGA conjugate were also prepared.
Cellular uptake and exocytosis
Macrophages, smooth muscular and endothelial cells were exposed to the fluorescent nanosuspension (100 μg/mL) over a 24 h period. At predetermined times, media were removed and NP uptake was determined by measuring the intracellular fluorescence. The uptake efficiency was calculated normalizing the observed fluorescence intensity in each well (IOBS) for the mean fluorescence intensity of the negative control (INC) according to equation 1:
Uptake efficiency = (IOBS - INC)/INC eq.1
The exocytosis of nanoparticles was followed for up to 7 days. The absolute number of detected photons (i.e. the derived count rate, DCR), Dh and correlogram shape were considered to qualitatively establish NPs released by the cells. The cytotoxicity of the tested formulation was also evaluated by the MTT assay5.
Statistical analysis
One-way and two-way ANOVA followed by Tukey’s test (=0.05) were performed using OriginPro 2015 (USA). Outliers were discarded according to Dixon’s T-test.
RESULTS AND DISCUSSION
Polymer synthesis and characterization
g-AA-PLGA were synthesized by performing a two-step grafting procedure at room temperature. In the former step, the oxidation of ascorbic acid by H2O2 led to the formation of hydroxyl radicals able to activate the PLGA backbone; then, the reactive sites on the preformed PLGA macroradicals react with the AA molecules resulting in CA or RV insertion. This approach avoids the degradation of the AA due to high temperature and the generation of toxic by- products. Both types of PLGA based conjugates exhibited good free radical scavenging properties since the DPPH inhibition after 1 h resulted 90.0±0.4 and 27.0±0.8 % for g- CA-PLGA and g-RV-PLGA, respectively; while the naïve PLGA was ineffective. Moreover, the grafting procedure did not affect the main physico-chemical properties of PLGA, since no significantly variations in Mw and Tg occurred in both g-AA-PLGA.
Nanoparticles characterization
Independently of the polymer used, monodispersed NPs were obtained (Table 1). The addition of 10% FITC-PLGA conjugate did not significantly modify the main features of NPs. Moreover, the MTT assay demonstrated the absence of toxicity of g-AA-PLGA (100 μg/mL) compared to the naïve PLGA.
Cellular uptake and exocytosis evaluation
Macrophages took up NPs faster than the other cell lines probably due to their physiological phagocytic activity. Indeed, in these cells no statistical differences in NP uptake were detected considering the materials and the incubation time as factors (two-way ANOVA, p=0.05).
In the case of endothelial cells, the uptake of g-CA-PLGA NPs was significantly higher than that of g-RV-PLGA and PLGA (two-way ANOVA: g-CA-PLGA vs PLGA p=0.028 and g-CA-PLGA vs g-RV-PLGA p=0.032).
Moreover, g-RV-PLGA and PLGA NPs were similarly taken up (p>0.05). Lastly, regarding smooth muscular cells, the uptake of g-CA-PLGA NPs occurred faster compared to the other NPs (one-way ANOVA: g-CA-PLGA vs PLGA p=0.002; g-CA-PLGA vs g-RV-PLGA p=0.004 and g-RV- PLGA vs PLGA p=0.984). As an example, Figure 1 represents the uptake efficiency of the cells after 4 h of exposition to NPs.
Furthermore, we observed a time-dependent reduction of the amount of intracellular fluorescent g-CA-PLGA NPs, indicating that this type of NPs may be also released by cells. The DLS analysis suggested that the release of NPs occurred within 8 h and 48 h in macrophages and smooth muscular cells, respectively. At both time periods, the DLS correlation functions maintained the sigmoidal shape and the Dh of the NPs was around 200 nm. These data were in agreement with the images obtained by fluorescence microscopy.
CONCLUSION
All together, these results on cellular uptake and exocytosis demonstrate that g-CA-PLGA nanoparticles may be a suitable carrier to locally administer drugs used in the prevention of restenosis following PTA.
REFERENCES
1. Singh, M.; Rihal, C.S.; Berger, P.B.; Bel, M.R.; Grill, D.E.; Garratt, K.N.; Barsenes, G.W. and Holmes, D.R. Improving outcome over time of percutaneous coronary interventions in unstable angina. J. Am. Coll. Cardiol. 36, 674-678 (2000).
2. Jukema, J.W.; Verschuren, J.J.; Ahmed, T.A. and Quax P.H. Restenosis after PCI. Part 1: pathophysiology and risk factors. Nat. Rev. Cardiol. 9, 53–62 (2001).
3. Cilurzo, F.; Puoci, F.; Selmin, F.; Iemma, F. and Minghetti, P. Pyrogallic acid-PLGA conjugate as new biodegradable material suitable for final sterilization by irradiation. Polym. Adv. Technol. 22, 2201–2205 (2011).
4. Selmin, F.; Puoci, F.; Parisi, O.I.; Franzé, S.; Musazzi, U.M. and Cilurzo, F. Caffeic acid-PLGA conjugate to design protein drug delivery systems stable to irradiation. J. Funct. Biomater. 6, 1-13 (2015).
5. Denizot,F.andLang,R.Rapidcolorimetricassayforcell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J. Immunol. Methods 89(2), 271-277 (1986)
How to Meet Legitimate Expectations of Patients when Authorized Medicinal Products are not Available
No full textPoly(sodium methacrylate, methyl methacrylate) to design highly loaded orodispersible films
No full textINTRODUCTION
In the design of a new technological platform for orodispersible films (ODF), the following aspects have to be considered. First, ODF should exhibit suitable mechanical properties to overcome the tensile stress generated during the manufacturing procedures. Secondly, ODF should disintegrate in few minutes as well as other orodispersible dosage forms. Thirdly, the stickiness of ODF should be also avoided to favour the patients’ handling. As a matter of fact, polymers used to design ODF are highly hygroscopic materials that can become sticky upon exposure to the ambient humidity [1].
This work aims to evaluate the use of poly(sodium methacrylate, methyl methacrylate) (NaPMM) [2] to design ODF prepared by casting technique, using PEG400 as plasticizer. The impact of the polymer/plasticizer ratio and the residual water content on film properties was investigated using placebo ODF. Moreover, the drug loading capacity of the ODF was assessed using ketoprofen (KP) and paracetamol (PAR), as model drugs.
MATERIALS
NaPMM was prepared salifying a 15% w/w Eudragit®S100 (Evonik Industries, G) aqueous suspension with sodium hydroxide [2]. KP (MIAT S.p.A., I); PAR (Farmalabor, I); PEG400 and Tween®80 (Carlo Erba Reagenti, I); Span®80 (Croda, E).
METHODS
ODF preparation
The casting solutions were obtained adding PEG400 to the NaPMM solution in different polymer/plasticizer ratio (90/10 - 40/60 % w/w). In drug-loaded ODF, active ingredients were added to the slurry to reach a final concentration of 25%, 50% w/w for KP and 50%, 70% w/w for PAR. The dispersion was cast at the rate 1 m/min over a silicone release liner to obtain film thickness of about 100 μm (Mathis LTE-S(M), CH). The drying conditions were set to vary the different residual water content in ODF.
Films were cut and packed in individual airtight seal packs using a triple layer film and stored at 25±1 °C until use.
ODF characterization
The residual water content of ODF was expressed as loss of drying (LOD), which was determined gravimetrically using a thermobalance and (Gilbertini, I) keeping samples at 105 °C until constant weight.
ODF stickiness was evaluated by thumb tack test and probe tack test.
Mechanical properties
Flexibility: the test was carried out by bending a ODF over an 8-mm mandrel. Films were considered flexible if no cracks over the bending area were visible at a 5x magnification.
Tensile properties: the test was conducted according to ASTM D882-02 test using an Instron 5965 texture analyser, equipped with a 50 N load cell (Instron, UK). Initial grip separation and crosshead speed were 40 mm and 12.5 mm/min, respectively. The tensile strength (σmax), percent elongation at break () and Young’s modulus (Y) were determined for each sample.
Disintegration test
The disintegration test was carried out in water on 2x3 cm sample using a Ph. Eur. apparatus.
ATR-FTIR spectroscopy
The ATR-FTIR spectra of raw Eudragit®S100 and drug loaded ODF were collected over the wavenumber region 4000–650 cm−1 (32 runs) using a SpectrumTMOne spectrophotometer (PerkinElmer, USA).
RESULTS
Placebo ODF, containing PEG400 in the 10-30 % w/w range and 10-15 % w/w of LOD, were homogeneously transparent in appearance, easy-to-handle and able to disintegrate within 30 s. Non-sticky films were obtained only for PEG400 content lower than 40% w/w (Table 1). At higher concentrations, the ODF stickiness increased with the residual water content. In particular, the probe tack test evidenced that, at the highest LOD value in ODF plasticized by 40% w/w of PEG400, the maximum detachment stress should not exceed 12±2 kPa to assure a film ease to handle.
Figure 1 exemplifies the possible tensile patterns of placebo ODF. At low strain values, a linear region, associated to the reversible deformation, was evident. Increasing the strain, the behaviour shifted from elastic to plastic, the curve lost linearity and the deformation became irreversible, until the maximum force was reached. Then, three profiles were identified increasing the PEG400 concentrations and/or LOD values (Figure 1). First, the maximum force value was followed by a significant decrease of the stress, indicating local reduction of the cross section, namely “necking”, that propagated along the length of the sample until rupture (code N). Secondly, the film showed a tear behaviour characterized by a slow and smooth decrease of cross section upon increasing the tensile stress (code T). Finally, the elongation at break at values higher than 200% indicated formulations characterized by a ductility unsuitable for packaging (code D). From a quantitative point of view, increasing the PEG400 concentration, both σmax and Y values dropped down and the ductility prevailed (Table 1). This trend, along with the progressive increase of the values, is in line with a plasticization-dominated mechanism.
NaPMM plasticized by 20% w/w PEG400 allowed up to 70% w/w of PAR loading (20.5 mg/cm2), without significant alteration of tensile and disintegration properties. In case of KP (pKa=4.45), the drug substance was efficiently loaded up to 50% w/w (8.3 mg/cm2); however, the ODF swelled without disintegrating within 30 min along with the shift of pH medium from 7.6 to 4.4.
ATR-FTIR spectroscopy evidenced that this feature was attributed to a partial protonation of NaPMM (Figure 2) since the intensity of anti-symmetrical (1560 cm-1) and symmetrical vibrations (1300-1400 cm–1) of the carboxylate groups underwent a significant depression in presence of KP with respect to the placebo film. Nevertheless, the addition of 5% w/w surfactants (i.e., Tween® 80 and Span® 80) to the composition allowed 25% w/w KP-loaded ODF to disintegrate within 30 s without compromising the film mechanical properties.
CONCLUSION
All the presented data underlined the versatility of NaPMM to design ODF with satisfactory tensile properties and high drug content (50-70 % w/w).
REFERENCES
1. Cilurzo, F.; Musazzi, U.M.; Franzè S.; Selmin, F.; Minghetti, P. Orodispersible dosage forms: biopharmaceutical improvements and regulatory requirements. Drug Discov. Today., in press (2017).
2. Cilurzo, F.; Minghetti, P.; Selmin, F.; Casiraghi, A.; Montanari, L. Polymethacrylate salts as new low-swellable mucoadhesive materials, J. Control. Rel., 88, 43-53 (2003)
Regenerated keratin proteins as potential biomaterial for drug delivery
No full texthis work aims to preliminarily evaluate the reliability of regenerated keratins (RKs) in the design of microparticulate drug delivery systems by studying their processability and cytotoxicity. RKs were extracted by sulfitolysis from wool waste. A 4.5% w/w RK solution was spray-dried, and microparticles were sterilized by steam vapor under pressure. Scanning electron microscope, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and Fourier transform infrared spectroscopy were used to characterize RKs and microparticles thereof. The in vitro cytotoxicity was determined by assessing the release of lactate dehydrogenase in the human monocytic cell line Tamm–Horsfall glycoprotein-1. RK-based microparticles with a narrow and unimodal particle size distribution (~6 μm) were obtained. They had a raisin-like structure with a smooth surface. Both microparticle morphology and RK molecular weight were well-preserved after sterilization. The curve fitting of the amide I bands showed that RK in the microparticles was prevalently present in the disordered/α-helix secondary structures which made the protein soluble in water. To promote crystallization in the β-sheet secondary structure and, therefore, water insolubility, RK-based microparticles were immersed in an aqueous solution of acetic acid at pH 3.5 overnight. RK did not induce any appreciable cellular cytotoxicity at any of the concentrations (from 1 up to 1000 μg sterile microparticles in 1 ml cell culture medium) or time-points (24–72 h) tested. These preliminary data suggest the feasibility of producing RK biocompatible microparticles using waste wool as starting material
Olanzapine orodispersible films: how preparation methods can impact on the biopharmaceutic performances
No full textINTRODUCTION
The design of drug products to be administered to pediatric patients should consider the presentation of the treatment to the end-user (i.e., patient, caregiver, healthcare provider) which includes the dosage form, formulation, dose, dosing frequency and packaging. Patient-centric drug products would also avoid the practice of manipulating tablets or capsules which may compromise the dose accuracy, patient safety and treatment efficacy. In this context, orodispersible films (ODF) have been reported to improve administration, compliance and medication adherence in patients having difficulties with swallowing [1]. The main ODF production processes can be referred to solvent-based or heating-based technologies. Alternatively, in the attempt to produce small batches or to compound personalized therapies, printing technologies have been proposed [2]. However, these processes can cause unintended drug phase transformations, which directly affect its dissolution rate and, therefore, biopharmaceutical performances. This work aimed to assess the relevance of the preparation process, namely solvent casting and hot-melt ram printing, on the biopharmaceutical performances of olanzapine orodispersible films (ODF) made of maltodextrins. Beside the clinical rationale, olanzapine (OLZ) was selected since it is subjected to polymorphism which impacts on its bioavailability [2]. OLZ was selected as model drug since it is also used off-label for treating pediatric diseases [3].
METHODS
An amount of 10 mg OLZ was loaded into 23 cm ODF prepared by solvent-casting and hot-melt ram-extrusion printing using maltodextrin DE 6 and glycerol as film forming material and plasticizer, respectively. X-ray diffraction and thermal analysis (i.e., DSC and TGA) were carried out to study the drug solid state. ODF were characterized in terms of thickness, stickiness, loss on drying. Moreover, disintegration time and the in vitro dissolution profiles were also evaluated in buffers mimicking pH values of different GI districts.
RESULTS
The adopted experimental conditions permitted to obtain ODF without visual defects, easy to handle with a thickness around 140 μm and 278 μm for cast and printing, respectively. Residual water content in ODF was in the 6-8% w/w range. All ODF disintegrated within 80 s, complying the Pharmacopeia specifications. Dissolution testing in 3 mL of artificial saliva at pH = 6.8 evidenced that cast and printed ODF released after 5 min about 2% and 100%, respectively. At higher volume, a yellow precipitate was formed after disintegration of the cast ODF. At pH = 1.2, the t85% for cast ODF was reached after about 20 min and only the 90% OLZ was dissolved increasing the pH value to 6.8. These differences were explained by DSC, TGA and X-ray diffraction data which demonstrated that the casting method, including the preparation of an aqueous slurry, favors the conversion from Form I to a hydrated one, which could be responsible of this anomalous behavior. Extruded ODF resulted physically stable after 30 months
CONCLUSIONS
The understanding of possible relations between formulation and process variables (e.g., solvents, moisture, and temperature) with solid-state characteristics needs to be addressed also to make the compounding of personalized therapy for pediatric patients a reality. Regarding the loading of OLZ in ODF, the main criticism is the possible conversion from the anhydrous towards hydrated forms with concomitant decrease in solubility. Based on these data hot-melt ram extrusion printing seems to be promising since it limits the exposure of OLZ to stress-factors (i.e., water and temperature) which can trigger solid-state modifications.
REFERENCES
1. Cilurzo F., et al. (2018) Orodispersible dosage forms: biopharmaceutical improvements and regulatory requirements. Drug Discov. Today, 23, 251-259.
2. Selmin F., et al. (2021) Relevance of production method on the physical stability and in vitro biopharmaceutical performances of olanzapine orodispersible film. Int. J. Pharm., doi: 10.1016/j.ijpharm.2021.120697.
3. Giurin M.S., et al. (2022) Safety of off-label pharmacological treatment in pediatric neuropsychiatric disorders: a global perspective from an observational study at an Italian third level children’s hospital. Front. Pharmacol., doi: 10.3389/fphar.2022.837692
Orodispersible films: current trend and future potentials in individualized therapy
No full textOrodispersible films (ODF) are single or multilayer sheets consisting an edible water-soluble polymer which rapidly liberates the loaded drug to provide a fine suspension or solution when placed in the buccal cavity without the need of water intake or mastication. Due to their peculiarities, ODF offer several advantages including ease of administration and improved compliance in the treatment of both local or systemic pathologies; moreover, ODF are suitable dosage forms for patients with restricted intake of water or uncooperative patients. On the other hands, the restricted formulation space allows only loading of potent active pharmaceutical ingredients or nutraceuticals; hence, not all molecules are suitable candidate for ODF formulation. ODF result also promising dosage forms for individualize therapy for subpopulation of patients with special needs, especially pediatric and geriatric. This review aims to provide an appraisal of key aspects of ODF formulation technologies, characterization, biopharmaceutical performance, and some regulatory issues, their position on the global pharmaceutical market and what the future holds for them in the individualized therapy
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