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Correction published on 7 December 2023, see Appl. Sci. 2023, 13(24), 13043.
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Article

Development of the Latanoprost Solid Delivery System Based on Poly(l-lactide-co-glycolide-co-trimethylene carbonate) with Shape Memory for Glaucoma Treatment

by
Aleksandra Borecka
1,*,
Jakub Rech
2,
Henryk Janeczek
1,
Justyna Wilińska
3,
Janusz Kasperczyk
1,
Magdalena Kobielarz
4,
Paweł Grieb
5 and
Artur Turek
3
1
Centre of Polymer and Carbon Materials, Polish Academy of Sciences, M. Curie-Skłodowskiej 34, 41-819 Zabrze, Poland
2
Department of Biotechnology and Genetic Engineering, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jedności 8, 41-200 Sosnowiec, Poland
3
Chair and Department of Biopharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jedności 8, 41-200 Sosnowiec, Poland
4
Department of Mechanics, Materials and Biomedical Engineering, Faculty of Mechanical Engineering, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
5
Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, A. Pawińskiego 5, 02-106 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Appl. Sci. 2023, 13(13), 7562; https://doi.org/10.3390/app13137562
Submission received: 10 May 2023 / Revised: 5 June 2023 / Accepted: 15 June 2023 / Published: 27 June 2023 / Corrected: 7 December 2023
(This article belongs to the Special Issue Advances in Biomaterials and Drug Technology)
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Abstract

:
Latanoprost (LTP) is a prostaglandin F2α analog used to lower intraocular pressure in glaucoma treatment administered daily as eye drops. In this study, a universal model based on poly(l-lactide-co-glycolide-co-trimethylene carbonate) with shape memory was proposed for the development of a solid biodegradable formulation with prolonged release administered intraconjunctivally, intravitreally, subconjunctivally, and subcutaneously. Solution casting and electron beam (EB) irradiation were applied to the matrix formulation. The properties of the native matrix and matrices degraded in a PBS buffer (pH 7.4) were monitored by NMR, DSC, GPC, and SEM. Water uptake (WU) and weight loss (WL) were also analyzed. LTP was released over 113 days in a tri-phasic and sigmoidal pattern without a burst effect and with a relatively long second release phase, in which changes were observed in the glass transition temperature, molecular weight (Mn), WU, and WL. EB irradiation decreased the initial Mn, increased WU, and accelerated LTP release with a shortened lag phase. This provides the opportunity to partially eliminate the use of drops at the start of treatment. SEM observations indicated that surface erosion is the prevalent degradation mechanism. The proposed model is an interesting solution during a preliminary study to develop final medicinal products that provide high adherence.

1. Introduction

The ocular hypotensive effect of topical prostaglandins by increasing the uveoscleral outflow has been used as an accurate concept in the treatment of glaucoma [1]. This discovery influenced the introduction of prostaglandin analogs into therapy in the form of eye drops, of which latanoprost (LTP) was the first of the currently available topical analogs [2]. LTP is an esterified prodrug of prostaglandin F2α, making it more lipophilic than the parent compound and better absorbed through the cornea, where the ester undergoes hydrolysis into LTP acid [3,4]. Phase III clinical trials and later clinical practice revealed that topical LTP with once-daily eye drops was safe and effective in both short- and long-term glaucoma therapy [5,6]. It should be underlined that conjunctival hyperemia and darkening of the color of the iris were noted, but these were the only significant side effects [7]. Similarly, good results for safety and tolerability were also confirmed in later studies [8,9,10]. It was also revealed that prostaglandins induce the growth of hair, which manifests itself as a gradual change in the appearance of the eyelashes [7]. This is largely due to the effect of administrating the drug substance in topical eye drops. Generally, in the case of eye drops, issues such as poor adherence and low bioavailability have been often described [11,12,13,14,15,16,17,18]. Pointed disadvantages may be excluded using biodegradable drug delivery systems (DDSs), ensuring a prolonged and stable release pattern that reduces the frequency of administration and the contact of the drug substance with eyelashes. In recent years, alternative formulations of LTP have been developed. One solution is to use contact lenses as a platform to introduce drug carriers loaded with LTP, such as silicone contact lenses modified with polyethylene glycol (PEG) solid lipid nanoparticles [19], poly(2-hydroxyethyl methacrylate) lenses with methoxy PEG (mPEG)-poly(lactide) micelles [20], commercial contact lenses [21], and lenses based on polymerized methafilcon and poly(l-lactide-co-glycolide) (l-PLGA) [22]. These LTP delivery systems allow prolongation of the release period of the drug substance tested in vitro; in the first three cases, the release period was in the range of 4–8 days, and in the last case, it was 28 days [19,20,21,22]. A similar solution is glutaraldehyde crosslinked polyvinyl alcohol nanofibers, which release LTP over 23 days [23]. In addition to relatively short time releases, the major disadvantages of contact lenses such as DDSs include an exposure of the eye to the lens, especially in the elderly, dryness of the eye, pain, irritation of the eye, or the occurrence of infections with prolonged or incorrect lens wear [24,25]. Other solutions include formulations based on a medium with modified density, e.g., a biodegradable chitosan/gelatin-based hydrogel that releases LTP over 7 days in vitro designed for intravitreal injection [26]; a hyaluronic acid sodium salt/hexamethylene diisocyanate-functionalized 1,2-ethylene glycol bis(dilactic acid) hydrogel that releases the drug substance over more than 60 days in vitro designed for subconjunctival administration [27]; a niosomal gel that releases LTP in vitro in less than 50 h [28], eye drops in a hyaluronic acid-chitosan nanoparticle (in vivo test) [29] or biodegradable/soluble DDSs for subconjunctival administration, i.e., poly(d,l-lactide) (d,l-PLA)/mPEG nanoparticles that releases LTP over nearly 14 days in vitro [30]; and phytantriol cubosomes that release LTP in vitro over 1 day [31]. For topical injections, the gel form is slightly similar to a solution, while nanoparticles often do not provide an opportunity to introduce the appropriate dose of the medicinal substance, and the large surface area often results in a burst effect. It should be pointed out that continuous subcutaneous infusion of 0.005% LTP solution over 7 days using mini pumps inserted in the backs of adult male normotensive Wistar rats effectively lowered intraocular pressure [32]. The solid biodegradable formulations seem to be the most appropriate. Therefore, a biodegradable subcutaneous implant releasing LTP peripherally should also be considered.
Poly(lactide-co-glycolide) (PLGA) copolymers have been proposed relatively often as carriers in ocular DDSs for a wide variety of drug substances. The properties of PLGA (50:50–75:25) copolymers allow the formulation of biodegradable DDSs administered via different routes (i.e., intraconjunctivally, intravitreally, or subconjunctivally) for drug substances with various physicochemical properties (e.g., mitomycin C, brimonidine tartrate, cyclosporine A, tacrolimus, and triamcinolone acetonide). Such formulations ensure a prolonged release period measured in weeks rather than minutes or hours [33,34,35,36,37], which can significantly increase adherence. This represents a significant step forward for registered medicinal products. However, their administration may be associated with high invasiveness.
Considering the above, in this study, a shape memory poly(l-lactide-co-glycolide-co-trimethylene carbonate) P(l-LA:GA:TMC) was used to design terpolymer matrices with LTP as a universal model administered intraconjunctivally, intravitreally, subconjunctivally, or subcutaneously. As a drug carrier, P(l-LA:GA:TMC) is a significant alternative to existing proposals based on PLGA copolymers because of its mixed degradation mechanism (i.e., bulk erosion and surface erosion) and possibly better control of drug release [38,39,40,41]. It should be pointed out that for PLGA copolymers, the release patterns result from bulk erosion only [42,43,44]. Previously, it was revealed that formulations based on P(l-LA:GA:TMC) terpolymers ensured prolonged release without significant release deterioration of 17-β-estradiol [40], risperidone [45], and aripiprazole [46] as a result of the stable mixed mechanism of degradation. Moreover, the P(l-LA:GA:TMC) terpolymers possess the important mechanical properties required for ocular formulations. First, it is characterized by low stiffness and a ductile mode of deformation under mechanical stresses [46], which are important features for intravitreal, subconjunctival, or subcutaneous administrations. Second, the ability to return to its original permanent shape from a temporarily fixed shape upon exposure to a thermal stimulus has been proven previously [47]. Changing the shape and size of drug formulations appears to be particularly important for reducing the invasiveness of administering DDSs, especially by implantation.
This study aimed to develop an LTP solid biodegradable delivery system based on P(l-LA:GA:TMC) with shape memory to reduce its invasiveness. The study was performed in three stages: (i) formulation of terpolymer matrices with LTP as a universal model for preliminary study; (ii) determination of the influence of the degradation rate on the release pattern of LTP; and (iii) application of electron beam (EB) irradiation as a modulating factor for the degradation rate and release pattern.

2. Materials and Methods

2.1. Terpolymer Synthesis

P(l-LA:GA:TMC), with a ratio of 64.7:17.3:18.0 (59.4 kDa), was synthesized in bulk by the ring opening polymerization of l-lactide (l-LA), glycolide (GA), and trimethylene carbonate (TMC) (Huizhou Foryou Medical Devices Co., Ltd., Huicheng District, Huizhou, Guangdong Province, China) purified by recrystallization from anhydrous ethyl acetate (Sigma-Aldrich, Poznań, Poland). The synthesis was performed at 120 °C for 72 h in the presence of zirconium (IV) acetylacetonate (Zr(Acac)4) (Sigma-Aldrich, Poznań, Poland) (initiator/monomer molar ratio of 1:1200). The synthesis of the terpolymer was carried out using a pressure reactor 4848 Floor Stand Reactor (Parr Instrument Company, Moline, IL, USA) with computer control of the polymerization parameters. The obtained terpolymer was dissolved in chloroform (Avantor Performance Materials, Gliwice, Poland) and precipitated by dropwise addition to cold methanol (Avantor Performance Materials, Gliwice, Poland) with continuous stirring for purification. Finally, the terpolymer was dried under vacuum conditions at room temperature [45].

2.2. Matrices Formulation

Matrices (n = 50) with LTP based on P(l-LA:GA:TMC), containing 5% w/w of LTP (Everlight Chemical, Taipei, Taiwan) (P(l-LA:GA:TMC) matrix-LTP), 10.00 mm ± 0.02 mm in diameter and 0.25 mm ± 0.03 mm thick were formulated by solution casting at 25 °C. Then, 2.0 g of P(l-LA:GA:TMC) was dissolved in 2 mL 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) (Sigma-Aldrich, Poznań, Poland) and 0.1 g of LTP was dissolved in 1 mL of the same solvent. The solutions were mixed in a Teflon mold, deprived of air under a vacuum line, and left for the solvent to evaporate in a laminar box (7 days).
Next, 25 native matrices were irradiated in an EB accelerator (EB-P(l-LA:GA:TMC) matrix-LTP) (10 MeV, 360 mA, 25 kGy) (The Institute of Nuclear Chemistry and Technology, Warsaw, Poland; Certificate no. 625/217/E).

2.3. Matrix Degradation

The matrices were incubated in a PBS buffer (pH 7.4) (Sigma-Aldrich, Poznań, Poland) under constant conditions at a temperature of 37 °C with shaking at 240 rpm.

2.4. Terpolymer Composition Study

Proton nuclear magnetic resonance (1H NMR) spectroscopy was used to study the composition of raw P(l-LA:GA:TMC), P(l-LA:GA:TMC) matrix-LTP, and EB-P(l-LA:GA:TMC) matrix-LTP. The 1H NMR spectra were recorded in DMSO-d6 (Sigma-Aldrich, Poznań, Poland) with a Bruker Avance II Ultrashield Plus spectrometer (Karlsruhe, Germany) operating at 600 MHz using a 5 mm sample tube, 32 scans, an 11 μs pulse width, and a 2.65 s acquisition time. Signals observed in the 1H NMR spectra were assigned to the appropriate sequences in the polymer chain according to a previously described procedure [48]. The molar percentages of the monomer units of lactide (FLL), glycolide (FGG), and carbonate (FTMC) were calculated.

2.5. LTP Loading Efficiency Study

The 1H NMR spectroscopy study (see Section 2.4) was used to determine the efficiency of LTP loading into the polymer using native P(l-LA:GA:TMC) matrix-LTP. Six concentrations of LTP in DMSO-d6 (Sigma-Aldrich, Poznań, Poland) (1 μg/mL, 10 μg/mL, 50 μg/mL, 100 μg/mL, 500 μg/mL, and 1 mg/mL) were prepared to make a standard curve. The signals were assigned to the hydrogen-containing molecular groups present in the LTP structure. The efficiency of the LTP loading into the matrix was calculated using Equation (1):
Loading efficiency (%) = (amount of LTP in matrix)/(amount of LTP introduced into matrix) × 100

2.6. Thermal Study

The thermal parameters of raw P(l-LA:GA:TMC), P(l-LA:GA:TMC) matrix-LTP, and EB-P(l-LA:GA:TMC) matrix-LTP were analyzed by the differential scanning calorimetry (DSC) method with a DSC Q2000 apparatus (TA Instruments, New Castle, DE, USA). The instrument was calibrated with high-purity indium and operated under a nitrogen atmosphere at a flow rate of 50 mL/min. In the first run, the matrices were heated at a rate of 20 °C/min to 200 °C, and the melting temperature (Tm) was determined. Next, the melted samples were rapidly cooled to −20 °C. In the second run, the matrices were heated at a rate of 20 °C/min to within a range of −20–200 °C, and the glass transition temperature (Tg) was determined as the midpoint of the heat capacity change in the amorphous sample.

2.7. Molecular Weight and Molecular Weight Distribution Studies

The molecular weight (Mn) and molecular weight distribution (D) of raw P(l-LA:GA:TMC), P(l-LA:GA:TMC) matrix-LTP, and EB-P(l-LA:GA:TMC) matrix-LTP were determined by gel permeation chromatography using a Viscotek Rlmax chromatograph (Malvern Panalytical Ltd., Malvern, Worcestershire, UK) equipped with two Viscotek 3580 columns and a Shodex SE 61 detector. The process was carried out with chloroform (Avantor Performance Materials, Gliwice, Poland) at a flow rate of 1 mL/min. The Mn value was calibrated using polystyrene standards.

2.8. Water Uptake and Weight Loss Studies

Changes in the water uptake (WU) and weight loss (WL) of P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP were calculated using Equation (2) and Equation (3), respectively:
WU (%) = (wet matrix mass-dry matrix mass)/(dry matrix mass) × 100
WL (%) = (initial matrix mass-dry matrix mass)/(dry matrix mass) × 100

2.9. Morphology Study

The morphological changes in the P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP were observed utilizing a scanning electron microscope (SEM) (Quanta 250 FEG/FEI, Thermo Fisher Scientific, Waltham, MA, USA). The SEM was operated with an acceleration voltage of 5 kV under low vacuum conditions (80 Pa) from secondary electrons collected by a large field detector. The matrices were mounted on microscope stubs with the use of double-sided adhesive carbon tape.
The software ImageJ® version 1.49e (National Institutes of Health, Bethesda, MD, USA) was used for further characterization of the outer morphology. The most representative areas of the sample surface were selected for the determination of heterogeneity, circularity, and solidity. The measurements were performed after the calibration and conversion to binary images. The following assumptions were made: (i) a circularity value of 1.0 indicates a perfect circle; (ii) a solidity value as the area of a particle divided by its convex hull area indicates the monolithic area, where a value of 1.0 means total solidity; and (iii) heterogeneity signifies the percentage of the elevation area compared to the total area.

2.10. LTP Release

The LTP released from P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP during degradation was analyzed by high-performance liquid chromatography (HPLC) using an Elite LaChrom HPLC system (VWR Hitachi, Merck, Warsaw, Poland) with a UV–VIS detector (Diode Array Detector L-2355, VWR Hitachi, Merck, Warsaw, Poland) set at 254 nm with a column 5 µm in diameter (LiChrospher RP-18 250-4, Sigma-Aldrich, Poznań, Poland). The mobile phase was acetonitrile (Sigma-Aldrich, Poznań, Poland) and an aqueous solution of ammonium acetate (10%) (Sigma-Aldrich, Poznań, Poland) in the ratio of 60:40, with a flow rate 0.8 mL/min.

3. Results and Discussion

In this study, the P(l-LA:GA:TMC) terpolymer with a monomer composition of 64.7:17.3:18.0, a Tg of 36.1 °C, and an Mn of 59.4 kDa (Table 1) was synthesized in the presence of Zr(Acac)4 as a low-toxicity initiator [45,49,50]. Previous studies revealed that P(l-LA:GA:TMC) terpolymers with analogous features ensured the possibility of formulating wafers by solution casting and rods by hot melt extrusion [40,45,46]. The Tg was close to the human body temperature, which may ensure the release of the drug substance without a long lag phase. Moreover, the DSC analysis did not reveal endotherms during the first heating run for the raw terpolymer (Table 1), which may suggest an amorphous state and higher bioavailability compared to the semi-crystalline material [44]. In this study, the synthesis conditions ensured that the Mn was suitable for further processing. This is an important feature because of the risk of it decreasing during formulation [45,51,52].
The matrices were designed as a universal and appropriate model for the preliminary study of ophthalmic topical solid formulations such as an insert, shield, minidisc, plug, or implant (e.g., rod or bead) that releases drugs peripherally.
Solution casting was applied as the method of choice due to the following factors: (i) the low processing temperature; (ii) the possibility of combining the liquid drug substance with the solid drug carrier; (iii) high loading efficiency; and (iv) the relatively low Mn decrease in the polymer after formulation. It should be noted that LTP possesses low thermal stability, which was one of the clues for the exclusion of formulation methods using thermal processing. Morgan and coworkers revealed that LTP remained stable both at 4 °C and 25 °C [53]. In this study, solution casting also allowed liquid LTP and P(l-LA:GA:TMC) to be combined at 25 °C with 95% efficiency loading of the drug substance determined by 1H NMR spectroscopy, which was satisfactory and more predictable compared to other formulation methods, for which differences were observed. For example, Kim and coworkers in a study on iontophoretic ocular delivery of LTP from PLGA (50:50) nanoparticles achieved an encapsulation efficiency ranging from 21% to 31% using oil-in-water emulsification [54], whereas Oliveira and coworkers, for poly-ε-caprolactone nanocapsules with LTP designed for alopecia treatment, achieved a much higher efficiency of encapsulation with nanoprecipitation equal to ~94% [55].
Generally, the formulation processes influence the changes in parameters, such as Tg and Mn, especially for thermal-dependent formulation methods [45,51,52]. In this study, the second heating run for the native P(l-LA:GA:TMC) matrix-LTP revealed an increase in the Tg from 36.1 °C to 39.9 °C compared to that of the raw P(l-LA:GA:TMC) (Table 1 and Table 2), which can be interpreted as anti-plasticization. This phenomenon, as a result of the introduction of a drug substance into a polymer matrix, was also observed previously, i.e., for l-PLGA with risperidone and poly(d,l-lactide-co-glycolide) or d,l-PLA with leuprorelin [44,56]. However, PLGA plasticization is mentioned much more often in the literature. For PLGA copolymers, plasticization by PEG, ethyl pyruvate, ethyl salicylate, methyl salicylate, triacetin, and triethyl citrate has been described [57,58]. During the hydrolytic degradation of PLGA, water also acts as a plasticizer [59]. It should be noted that the phenomena of plasticization and anti-plasticization may result from the concentration of plasticizers or drug substances. This issue has been described for mixtures of indomethacin and polymers such as Eudragit E PO, polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone K30, and poloxamer P188 [60]. In our study, the content of drug substance was low.
Plasticizers increase polymer chain mobility, whereas anti-plasticizers cause the opposite effect. According to the chemical taxonomy, LTP belongs to the carboxylic ester derivatives of a fatty acid. It occurs in the liquid state and is viscous [61]. These features may decrease the polymer chain mobility and increase the Tg. This effect did not result from the drug–polymer interaction because analysis of the first and second heating runs of P(l-LA:GA:TMC) matrix-LTP did not reveal additional endotherms and exotherms compared to the raw terpolymer (Table 1 and Table 2). This is also reflected in the literature [62,63]. Therefore, the observed Tg increase results rather from the rheological properties of LTP. It should be added that anti-plasticization may prolong polymer degradation and release patterns of drug substances. This is significantly important in the case of polymer–drug carriers with a relatively low Tg.
A noticeable decrease in the Mn was observed after solution casting in HFIP for P(l-LA:GA:TMC) matrix-LTP from 59.4 kDa to 42.2 kDa compared to the raw terpolymer (Table 1 and Table 2). It should be noted that a comparable decrease, i.e., from 58.8 kDa to 41.1 kDa, was noted for a P(l-LA:GA:TMC) wafer with risperidone formulated by solution casting using methylene chloride [45].
In this study, the 1H NMR measurements showed that solution casting did not significantly influence the composition of the terpolymer of P(l-LA:GA:TMC) matrix-LTP, which reflects previous studies [45,64]. For the FLL and FGG, the changes were observed from 64.7 mol% to 62.7 mol% and from 17.3 mol% to 19.4 mol%, respectively, which may result from the use of solvent and the dissolution process. No significant changes in the FTMC were noted (Figure 1, Table 1 and Table 2).
The degradation of the P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP revealed smooth changes in the unit distribution, which contributed to a steady and stable character of the degradation process. Initially, P(l-LA:GA:TMC) matrix-LTP contained a predominant FLL (62.7 mol%), as well as lower FGG and FTMC (19.4 mol% and 17.9 mol%, respectively). A noticeable gradual increase in the FLL and a decrease in the FGG and FTMC were observed during the 113 days of degradation to the final values equal to 69.9 mol%, 14.0 mol%, and 16.1 mol%, respectively. From the 43rd day, a slight fluctuation in the values of all monomer contents was noted (Figure 1, Table 2).
This observation reflects the previous degradation study on P(l-LA:GA:TMC) terpolymers, i.e., for rods with 17-β-estradiol or aripiprazole, a similar character of composition changes was obtained [40,46,65]. Loo and coworkers indicated the influence of EB irradiation on the hydrolytic degradation of PLGA films without an analysis of the changes in polymer composition during degradation [66]. For EB-P(l-LA:GA:TMC) matrix-LTP, the EB irradiation did not result in significant changes in the unit distribution of the native matrix. However, during degradation, more dynamic changes for FLL, FGG, and FTMC to the final values of 76.0 mol%, 12.2 mol%, and 11.8 mol%, respectively, were observed (Table 2). Analogous results were obtained for the degradation of non-irradiated and EB-irradiated P(l-LA:GA:TMC) rods with aripiprazole [46].
The DSC analysis revealed that initially amorphous matrices (Table 1) changed the character and/or the matrix structure underwent a process of ordering during degradation. During the first heating run for P(l-LA:GA:TMC) matrix-LTP, between the 43rd and 113th days of degradation, endothermic peaks with maxima ranging from 81.5 °C to 94.1 °C were observed (Figure 2, Table 2).
These observations are consistent with degradation studies on the degradation of l-PLGA copolymer and P(l-LA:GA:TMC) terpolymers [40,44,46]. In this study, the second heating run for P(l-LA:GA:TMC) matrix-LTP showed a decreasing trend for the Tg in the range from 45.7 °C to 29.6 °C with fluctuations in values (Figure 2, Table 2). EB irradiation influenced the chain scission of P(l-LA:GA:TMC) [46]. The values of the Tm, ΔH, Tg, and Mn during the 1st and 85th day of degradation were the result of this phenomenon (Figure 2, Table 2). The “homogenization” or “unification” of the terpolymer chain can be mentioned here.
Clear and visible differences in the degradation characteristics of P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP are shown in the intensity changes in parameters such as the Mn, WU, and WL (Figure 3, Table 2). In the case of aliphatic polyesters and polyester carbonates, the degradation has a hydrolytic character and results from the hydrolysis of ester bonds [42]. Therefore, degradation changes are closely related to the susceptibility of WU. Previously, it was shown that for P(l-LA:GA:TMC) rods with aripiprazole, pore formation may intensify WU [46]. But, this is not a necessary phenomenon because evident porous surfaces were not observed for P(l-LA:GA:TMC) rods with 17-β-estradiol [40].
Generally, a decrease in Mn increases the presence of more hydrophilic end groups. In this study, for P(l-LA:GA:TMC) matrix-LTP, the decrease in Mn from 42.2 kDa to 5 kDa between 0 and the 57th day of hydrolytic degradation influenced the intensive increase in WU from 12.4% to 97.1% between the 57th and the 113th days (Figure 3, Table 2). Moreover, Loo and coworkers observed that EB irradiation influenced the additional decrease in Mn [66], which accelerated the increase in WU. Therefore, for the EB-P(l-LA:GA:TMC) matrix-LTP, the changes in WU and Mn were more dynamic (Figure 3, Table 2). An intensive increase in WU equal to 35.0% was noted on the 43rd day. It should be pointed out that the values of Mn at almost every stage of degradation were lower compared to P(l-LA:GA:TMC) matrix-LTP. Moreover, EB irradiation caused smoother changes in Mn (Figure 3, Table 2).
Previously, it was pointed out that an increase in WL is direct proof of the degradation process, whereas parameters such as Tm, Tg, and Mn provided information about structural, morphological, and thermal changes [46]. It should be noted that the change in WL for the EB-P(l-LA:GA:TMC) matrix-LTP was gradual, and it was difficult to indicate a clear effect of EB irradiation (Figure 3, Table 2), which was noted previously for P(l-LA:GA:TMC) rods with aripiprazole [46]. This may be a result of the physicochemical features of the drug substances.
In this study, the ImageJ® software was used to develop the outer morphology by determining parameters such as heterogeneity, circularity, and solidity for native and degraded matrices. The measurements were performed on the surfaces of the matrices (Figure 4 and Figure 5, Table 3).
The degradation period influenced the heterogeneity of P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP from 16.5% to 81.7% and from 16.8% to 78.7%, respectively (Table 3). This value has grown over time and had a similar course for both matrices. During degradation, the occurrence of different morphological elements was observed: from a solid surface at the beginning to a sponge-like structure through oval elements and single pores (Figure 4 and Figure 5).
No evident porous surfaces were observed for the native and degraded P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP. However, the value of circularity observed during degradation ranged from 0.039 to 0.684 and from 0.036 to 0.719, respectively. It should be noted that a value of 1.0 for circularity means perfect circles, which indicates the presence of pores. In this study, the relatively high value of this parameter for degraded samples without evident porosity resulted from the degradation process. For the native P(l-LA:GA:TMC) matrix-LTP and the native EB-P(l-LA:GA:TMC) matrix-LTP, the values of circularity were 0.039 and 0.036, respectively. During degradation, on the 113th day, sponge-like structures were observed, which influenced the circularity increase to 0.652 and 0.719 for P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP, respectively (Figure 4 and Figure 5, Table 3).
The presence or absence of pores may be one of the features indicating the differences between bulk erosion and surface erosion. This was shown by Bohr and coworkers, who compared the morphological features during the degradation of poly(ethylene carbonate) and PLGA films loaded with rifampicin [67]. In this study, the P(l-LA:GA:TMC) should represent a mixed mechanism at the level of morphological features, i.e., l-LA and GA are responsible for bulk erosion, and TMC for surface erosion. Previously, P(l-LA:GA:TMC) rods with 17-β-estradiol revealed more features characteristic of surface erosion [40]. This thesis is also supported by Laracuente and coworkers, who pointed out, after interpreting our results, that surface erosion dominated over bulk erosion [68], whereas for the P(l-LA:GA:TMC) rods with aripiprazole, the presence of pores indicated the dominant role of bulk erosion [46]. It should also be pointed out that the physicochemical properties of drug substances may change their morphological features, thus influencing the main degradation characteristics. In this study, single pores were observed for the EB-P(l-LA:GA:TMC) matrix-LTP on the 15th, 29th, and 85th days of degradation (Figure 5), with circularity values of 0.499, 0.416, and 0.562, respectively (Table 3). Previously, it was shown that for EB-irradiated rods based on P(l-LA:GA:TMC), earlier pore formation resulted in an increase in WU, or vice versa [46]. In turn, Loo and coworkers revealed that the microcavities facilitated the degradation of EB-irradiated PLGA films [66], which may also contribute to pore formation. The presence of oval elements on the 1st and 57th days of degradation for the P(l-LA:GA:TMC) matrix-LTP (Figure 4) and on the 71st day of degradation for the EB-P(l-LA:GA:TMC) matrix-LTP (Figure 5) may also be considered for circularity. However, clear changes in the values of this parameter related to this morphological feature were not noted (Table 3). In a study by Oliveira and coworkers on poly-ε-caprolactone nanocapsules with LTP designed for alopecia treatment, morphological analysis performed using SEM revealed predominantly spherical structures on the surface. But the study was only carried out for the native formulation [55].
The solution casting and EB irradiation processes did not result in unfavorable features, such as disintegration, cracks, microcavities, and slits, which confirmed the ImageJ® measurements of solidity. For the native P(l-LA:GA:TMC) matrix-LTP and the native EB-P(l-LA:GA:TMC) matrix-LTP, the values of solidity were 0.81 and 0.83, respectively, where a value of 1.0 means total solidity. The 113 days of degradation influenced the decrease in this parameter to 0.19 and 0.21, respectively, which reflected the increase in morphological diversity. The lack of significant differences in solidity between both matrices during degradation pointed out the lack of unfavorable changes caused by EB irradiation (Table 3).
In this study, a controlled and prolonged release of LTP from P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP over 113 days was achieved (Figure 6), which may enable less frequent administration of the final medicinal product and may improve LTP bioavailability compared to eye drops. Both profiles were characterized by (i) a tri-phasic and sigmoidal pattern; (ii) a lack of burst effect; and (iii) a relatively long second release phase. The release of LTP from P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP indicated heterogeneous degradation [69,70].
For P(l-LA:GA:TMC) matrix-LTP, the release process of LTP took place in three phases, over 15 days, 63 days, and 35 days, with 2.2%, 90.4%, and 7.4% of LTP released, respectively (Figure 6). In the first phase, the lack of a burst effect was noted, which may reflect the high efficiency of LTP loading (95.0%) in P(l-LA:GA:TMC) and/or its rheological features. A relatively long second phase may have resulted from the lack of surface pores (Figure 4). Moreover, the surface erosion caused by the presence of TMC may have been responsible for the prolonged second phase. The second phase was also related to changes in the degradation parameters, such as Tg, Mn, WU, and WL (Table 2). For repeated administration, the last phase is not of significant therapeutic importance due to the low amount of LTP released.
For EB-P(l-LA:GA:TMC) matrix-LTP, the drug substance was also released in three phases. However, differences in the duration of the individual phases and release rate were revealed. The release phases lasted sequentially for 8 days, 70 days, and 35 days, with 1.9%, 95.3%, and 2.8%, respectively, of the released drug substance (Figure 6). It should be pointed out that the EB-P(l-LA:GA:TMC) matrix-LTP had a lower initial Mn, higher WU ability, and faster LTP release (Figure 6 and Table 2), which provides the opportunity to partially eliminate the use of drops during the first phase of the release process. The lack of significant changes in other phases of the LTP release profile is an advantage in DDS design with prolonged release.

4. Conclusions

In this study, a universal solid biodegradable model for a preliminary study on DDSs administered intraconjunctivally, intravitreally, subconjunctivally, or subcutaneously for prolonged and stable LTP release for glaucoma treatment was designed. The release of LTP from the P(l-LA:GA:TMC) matrices was achieved over 113 days without a burst effect and with a long second release phase. EB irradiation influenced a lower initial Mn, higher WU, and faster LTP release with a shortened lag phase, which will reduce the period of use of drops. In addition to the known sterilization effect of EB irradiation, it also modifies the release profile in the first phase. The proposed model is an interesting step on the way to developing the final medical products, such as an insert, shield, minidisc, plug, or implant, with high therapeutic adherence.

Author Contributions

Conceptualization, J.K., P.G. and A.T.; methodology, A.B., J.K., H.J. and A.T.; validation, A.B., H.J., J.K., M.K. and A.T.; formal analysis, A.B., H.J, M.K., J.W. and A.T.; investigation, A.B., J.R., H.J. and A.T.; resources, A.B. and A.T.; data curation, A.B., J.R., H.J. and A.T.; writing—original draft preparation, A.B. and A.T.; writing—review and editing, J.R., H.J. and A.T.; visualization, J.R. and A.T.; supervision, A.T.; project administration, A.T.; funding acquisition, A.T. All authors have read and agreed to the published version of the manuscript.

Funding

This work has been supported by the Medical University of Silesia in Katowice (grant numbers PCN-1-066/N/1/F and PCN-1-010/K/2/F).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available upon request from the corresponding authors.

Conflicts of Interest

The authors declare no conflict of interest.

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Applsci 13 07562 g001
Figure 1. 1H NMR spectra (600 MHz, DMSO-d6) of P(l-LA:GA:TMC) matrix-LTP (a) and EB-P(l-LA:GA:TMC) matrix-LTP (b) during degradation. 1H NMR spectra: methine proton region of the lactidyl units (1), methylene proton region of the glycolidyl (2), and carbonate units (3).
Figure 1. 1H NMR spectra (600 MHz, DMSO-d6) of P(l-LA:GA:TMC) matrix-LTP (a) and EB-P(l-LA:GA:TMC) matrix-LTP (b) during degradation. 1H NMR spectra: methine proton region of the lactidyl units (1), methylene proton region of the glycolidyl (2), and carbonate units (3).
Applsci 13 07562 g001
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Figure 2. DSC curves of the first (a,c) and the second heating runs (b,d) of P(l-LA:GA:TMC) matrix-LTP (a,b) and EB-P(l-LA:GA:TMC) matrix-LTP (c,d).
Figure 2. DSC curves of the first (a,c) and the second heating runs (b,d) of P(l-LA:GA:TMC) matrix-LTP (a,b) and EB-P(l-LA:GA:TMC) matrix-LTP (c,d).
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Figure 3. Changes (%) in molecular weight (Mn), water uptake (WU), and weight loss (WL) during the degradation of P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP.
Figure 3. Changes (%) in molecular weight (Mn), water uptake (WU), and weight loss (WL) during the degradation of P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP.
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Figure 4. SEM images showing changes in the surface morphology of P(l-LA:GA:TMC) matrix-LTP during degradation.
Figure 4. SEM images showing changes in the surface morphology of P(l-LA:GA:TMC) matrix-LTP during degradation.
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Figure 5. SEM images showing changes in the surface morphology of EB-P(l-LA:GA:TMC) matrix-LTP during degradation.
Figure 5. SEM images showing changes in the surface morphology of EB-P(l-LA:GA:TMC) matrix-LTP during degradation.
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Figure 6. LTP cumulative release profiles achieved for P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP.
Figure 6. LTP cumulative release profiles achieved for P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP.
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Table 1. Parameters characterizing raw P(l-LA:GA:TMC).
Table 1. Parameters characterizing raw P(l-LA:GA:TMC).
Raw P(l-LA:GA:TMC)
FLL
(mol%)		FGG
(mol%)		FTMC
(mol%)		Tm
(°C)		Tg
(°C)		Mn
(kDa)		D
64.717.318.0ND36.159.42.241
FLL, FGG, FTMC—molar percentage of lactidyl, glycolidyl, and carbonate units in the terpolymer, respectively, Tm—melting temperature, Tg—glass transition temperature, Mn—molecular weight, D—molecular weight distribution, and ND—non-detected.
Table 2. Parameters characterizing the P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP during degradation.
Table 2. Parameters characterizing the P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP during degradation.
P(l-LA:GA:TMC) Matrix-LTP
Time (Days)FLL (mol%)FGG (mol%)FTMC (mol%)Tm (°C)ΔH (J/g)Tg (°C)Mn (kDa)DWU (%)WL (%)
062.719.417.9NDND39.942.22.06100
163.118.918.0NDND45.742.02.0261.27.6
1563.118.618.3NDND43.534.32.3653.015.0
2963.118.618.3NDND42.322.02.2223.216.4
4362.318.419.381.58.139.412.22.3135.617.2
5764.516.818.783.817.032.45.03.03112.418.7
7166.415.618.088.426.633.32.11.62246.849.0
8565.616.118.394.131.529.61.91.53778.269.7
9967.815.316.985.529.633.11.91.54488.684.1
11369.914.016.191.339.130.11.81.66297.198.2
EB-P(l-LA:GA:TMC) Matrix-LTP
Time (Days)FLL (mol%)FGG (mol%)FTMC (mol%)Tm (°C)ΔH (J/g)Tg (°C)Mn (kDa)DWU (%)WL (%)
062.519.717.8NDND43.329.52.25500
163.118.918.0NDND37.929.02.3082.33.8
1563.518.118.4NDND36.020.62.3843.211.7
2963.518.118.4NDND35.810.32.4605.512.5
4362.717.919.479.74.834.14.22.50235.015.5
5763.318.418.380.212.127.82.31.80449.232.1
7164.918.017.181.117.728.92.21.82265.753.1
8565.416.318.383.822.930.52.01.58078.271.2
9970.911.417.792.144.233.91.91.53488.385.7
11376.012.211.892.344.335.21.61.52095.498.7
FLL, FGG, FTMC—molar percentage of lactidyl, glycolidyl, and carbonate units in the terpolymer, respectively, Tm—melting temperature, ΔH—melting enthalpy, Tg—glass transition temperature, Mn—molecular weight, D—molecular weight distribution, WU—water uptake, WL—weight loss, and ND—non-detected.
Table 3. Heterogeneity, circularity, and solidity of the surface of P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP during degradation, calculated using ImageJ®.
Table 3. Heterogeneity, circularity, and solidity of the surface of P(l-LA:GA:TMC) matrix-LTP and EB-P(l-LA:GA:TMC) matrix-LTP during degradation, calculated using ImageJ®.
P(l-LA:GA:TMC) Matrix-LTP
Time (Days)Area (µm2)Heterogeneity (%)CircularitySolidity
04,796.116.50.0390.81
14,454.817.40.1370.82
154,739.129.70.3520.75
294,364.128.90.3490.78
434,677.241.30.6840.51
574,673.853.30.4910.45
714,678.258.40.4140.50
854,220.969.00.1620.31
994,772.566.10.1420.35
1134,564.281.70.6520.19
EB-P(l-LA:GA:TMC) Matrix-LTP
Time (Days)Area (µm2)Heterogeneity (%)CircularitySolidity
04,583.716.80.0360.83
14,671.816.70.0370.83
154,096.138.80.4990.74
294,568.238.60.4160.75
434,091.438.50.2100.75
574,527.138.70.2020.73
714,884.063.60.1520.49
854,628.560.70.5620.43
994,844.768.50.1470.29
1134,533.178.70.7190.21
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Borecka, A.; Rech, J.; Janeczek, H.; Wilińska, J.; Kasperczyk, J.; Kobielarz, M.; Grieb, P.; Turek, A. Development of the Latanoprost Solid Delivery System Based on Poly(l-lactide-co-glycolide-co-trimethylene carbonate) with Shape Memory for Glaucoma Treatment. Appl. Sci. 2023, 13, 7562. https://doi.org/10.3390/app13137562

AMA Style

Borecka A, Rech J, Janeczek H, Wilińska J, Kasperczyk J, Kobielarz M, Grieb P, Turek A. Development of the Latanoprost Solid Delivery System Based on Poly(l-lactide-co-glycolide-co-trimethylene carbonate) with Shape Memory for Glaucoma Treatment. Applied Sciences. 2023; 13(13):7562. https://doi.org/10.3390/app13137562

Chicago/Turabian Style

Borecka, Aleksandra, Jakub Rech, Henryk Janeczek, Justyna Wilińska, Janusz Kasperczyk, Magdalena Kobielarz, Paweł Grieb, and Artur Turek. 2023. "Development of the Latanoprost Solid Delivery System Based on Poly(l-lactide-co-glycolide-co-trimethylene carbonate) with Shape Memory for Glaucoma Treatment" Applied Sciences 13, no. 13: 7562. https://doi.org/10.3390/app13137562

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