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Saudi Pharmaceutical Journal : SPJ logoLink to Saudi Pharmaceutical Journal : SPJ
. 2023 Feb 13;31(4):499–509. doi: 10.1016/j.jsps.2023.02.002

Development of depot PLGA-based in-situ implant of Linagliptin: Sustained release and glycemic control

Eman Gomaa a, Noura G Eissa a, Tarek M Ibrahim a,⁎, Hany M El-Bassossy b, Hanan M El-Nahas a, Margrit M Ayoub a
PMCID: PMC10102447  PMID: 37063437

Abstract

High percentage of diabetic people are diagnosed as type 2 who require daily dosing of an antidiabetic drug such as Linagliptin (Lina) to manage their blood glucose levels. This study aimed to develop injectable Lina-loaded biodegradable poly (lactic-co-glycolic acid) (PLGA) in-situ implants (ISIs) to deliver a desired burst effect of Lina followed by a sustained release over several days for controlling the blood glucose levels over prolonged time periods. The morphological, pharmacokinetic, and pharmacodynamic assessments of the Lina-loaded ISIs were performed. Scanning electron microscopy (SEM) study revealed the rapid exchange between the water miscible solvent (N-methyl-2-pyrrolidone; NMP) and water during the ISI preparation, hence enhancing the initial burst Lina release. While, triacetin of lower water affinity could lead to formation of more compact and dense ISI structure with slower drug release. By comparing various ISI formulations containing different solvents and different PLGA concentrations, the ISI containing 40 % PLGA and triacetin was selected for its sustained release of Lina (93.06 ± 1.50 %) after 21 days. The pharmacokinetic results showed prolonged half life (t1/2) and higher area under the curve (AUC) values of the selected Lina-loaded ISI when compared to those of oral Lina preparation. The single Lina-ISI injection produced a hypoglycemic control in the diabetic rats very similar to the daily oral administration of Lina after 7 and 14 days. In conclusion, PLGA-based ISIs confirmed their suitability for prolonging Lina release in patients receiving long-term antidiabetic therapy, thereby achieving more enhanced patient compliance and reduced dosing frequency.

Keywords: Linagliptin, In-situ implant, Poly (lactic-co-glycolic acid), Morphology, Pharmacokinetic study, Blood glucose levels

1. Introduction

Compared to the traditional dosage forms, the polymeric-based drug delivery systems are considered as attractive approaches to provide extended release of drugs over weeks, months or even years. Such delivery systems can achieve the desired therapeutic effect of the drug at lower concentrations with no fluctuation in its plasma level, thus eliminating the risk of the unwanted side effects (Rajgor et al., 2011). Over the last few years, much interest has been gained to develop new injectable delivery systems, such as nanoparticles (Qi et al., 2019), microparticles (Lagreca et al., 2020), vesicular systems (Verma et al., 2016), and micelles (Jhaveri and Torchilin, 2014), that become advantageous especially when they are related to chronic complications, such as heart disease, diabetes, tumors, etc. (Martins et al., 2018). Microparticles can be injected into the body through small needles causing low pain to the patients. In addition, their related multi-step manufacturing processes are more costly, their encapsulation efficiencies are often low, and the scale-up production is more difficult to achieve (Parent et al., 2013). Implants formed by melt extrusion process are implanted into the patients either surgically or by using large diameter needles and they must be surgically removed at the end of the therapy unless they are biodegradable (Dümichen et al., 2023). Therefore, substantial advancements in the fields of implants have been made to provide simple and painless drug administration and easy production procedures. One of these alternatives is the development of special smart systems, such as in-situ implants (ISIs) which have been introduced to the field of the sustained release parenteral formulations. These systems can overcome the limitations of conventional preformulated implants in terms of being less painful, their ability to deliver drugs prescribed at high doses, and utilization of smaller diameter needles to minimize the irritation of the body tissues. These merits can represent a good impact on improving the patient compliance with the course of the therapy (Kempe and Mäder, 2012).

Based on the solvent exchange, pH change, photo-responsive cross-linking, ionic cross-linking, temperature transition, chemical reactions, or other different mechanisms, the ISIs can be formed and help sustain the release of the entrapped drugs after injection (Ibrahim et al., 2021b). The type of the polymer used has a pivotal role on the release of the drugs from such formulations. Among various polymers, the biodegradable ones, such as carbopol 934, alginic acid, chitosan derivatives, hydroxypropyl methyl cellulose, polyvinyl alcohol, pectin, poly-lactic acid, and poly (lactic-co-glycolic acid) (PLGA) are preferred as their removal from the body does not require surgical procedures (Ahmed and Hussain, 2010, Serrano et al., 2023). PLGA, as a durable synthetic biodegradable polymer, has been approved by U.S. Food and Drug Administration (FDA) for parenteral use, diagnosis, and many clinical purposes to achieve a prolonged release of the entrapped drug (Yu et al., 2021, Pardeshi et al., 2023).

Linagliptin (Lina), as an antidiabetic drug, is classified as a dipeptidyl peptidase (DPP)-4 inhibitor and prescribed for the treatment of type II diabetes mellitus. The drug action in inhibiting this enzyme can retard the breakdown of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1. Therefore, these peptides can promote the release of insulin from the beta cells of the pancreas and reduce the secretion of glucagon from the pancreatic alpha cells. Both actions can decrease the hepatic glycogen breakdown and help stimulate the release of insulin in response to glucose (Yin et al., 2022, Andreadi et al., 2023). Lina is traditionally administrated as daily oral tablets and has low oral bioavailability of 29.5 % due to its hepatic metabolism (Shah et al., 2021). Based on such pharmacokinetics, there was a necessity to develop implantable formulations possessing a considerable initial drug release followed by sustained release profile to preserve the therapeutic drug plasma concentration, decrease the drug dosing frequency, and avoid the related adverse effects.

The ISI systems are exemplary drug delivery systems subcutaneously or intramuscularly injected as liquids and can solidify once being in contact with the aqueous body fluids at the injection site (Van Hemelryck et al., 2021). Based on the solvent exchange mechanism, the biodegradable PLGA polymer can be dissolved in a biocompatible solvent, such as dimethyl sulfoxide (DMSO), ethyl acetate, triacetin, N-methyl-2-pyrrolidone (NMP), or 2-pyrrolidone. In such polymeric solution, the drug may be dissolved or suspended. Upon injection, the solvent diffuses out to the surrounding media, while the aqueous phase diffuses into the polymeric matrix. As a result, a gel-like mass depot can be generated which can sustain the release pattern of the drug (Khaing et al., 2022).

In general, the ideal solvents used for preparing the in-situ systems should have suitable properties in terms of their cytotoxicity, biocompatibility, and safety to be injected into the body. The rapid initial release of large amounts of solvents within a short time frame during the matrix solidification process is undesirable. This is because it may result in a local tissue irritation or systemic side effects. Therefore, the concentration and the safety of solvents should be taken in consideration while preparing the ISI systems (Ibrahim et al., 2021b). According to the International Conference on Harmonization (ICH) guidelines, the organic solvents are classified into class 1 (solvents to be avoided), class 2 (solvents to be limited), and class 3 (solvents with low or no toxic potential) (ICH, 2019). Class 3 solvents, such as ethyl acetate and DMSO are approved by ICH as less toxic solvents producing low hazard to the human. They have no adequate toxicological data, long-term toxicity, or carcinogenicity. Triacetin is generally recognized as safe by U.S. FDA and has been reported to be used as a parenteral nutrient (Bailey et al., 1991, Majstorović et al., 2023). In addition, the ICH guidelines recommend that NMP is placed in Class 2 and should be used within low concentrations in the pharmaceutical products. Ibrahim et al. (2020) reported that the aforementioned solvents have median lethal doses higher than 2 ml/Kg and considered to be safe for use in injectable implant systems.

The selection of organic solvents according to their miscibility in water is also fundamental where they can exhibit remarkable impacts on the phase inversion rate during the solution to gel conversion and the release profile of the drugs. Ahmed et al. (2014) studied the effect of using different water miscible and partially miscible solvents on the release of montelukast from the ISI systems. The miscible solvents, such as NMP and DMSO could facilitate the formation of homogeneous and fast phase inverting depots having merits of being low viscous and easily injectable. Besides, the finite solubility and the plasticizing action of the partially miscible solvents, such as triacetin and ethyl acetate could reduce the gelation rate of the ISIs and produce slower release profiles of the drugs than ISIs containing miscible solvents. On another side, using a mixture of water miscible and immiscible organic solvents is considered a superior strategy for achieving slow release profiles of the drugs from the ISI systems with achieving suitable viscosity and phase inversion. For instance, Liu and Venkatraman (2012) reported that the low burst release of metoclopramide monohydrochloride was observed by adding the hydrophobic triacetin as a cosolvent to the hydrophilic solvents used (NMP and DMSO). The suppression of the drug burst release was explained owing to the slow solvent exchange and the retarded phase inversion occurred. In another study, Liu et al. (2010) studied the influence of triacetin on achieving lower initial release and continuous release of thymosin alpha 1 up to one month in-vivo by virtue of the slower phase inversion of the polymer and the denser structures of the solidified ISI systems formed using such hydrophobic solvent. Therefore, studying the influence of using single or multiple organic solvents on the preparation, morphology of the ISI systems, and release profiles of the drugs from such systems should be taken into consideration.

The aim of the current study was to formulate Lina injectable therapy with a desirable low initial drug burst and satisfactory sustained release over several days using the biodegradable PLGA polymer at different concentrations with different organic solvents. The selected formulation showing prolonged in-vitro drug release over weeks was injected subcutaneously into the rats to assess the pharmacokinetic profile of the drug in-vivo. Reduced drug concentrations released from the ISI systems along with the long circulation effect of the drug in-vivo were sought for improving the effectiveness and the bioavailability of Lina. The superiority in controlling the blood glucose levels over a long period has made such formulation as an alternative for the commercial daily oral tablets of Lina. This can help avoid the peroral first pass effect of Lina, enhance its bioavailability, and in turn attain better patient compliance and adherence owing to the achieved lower drug dosing frequency.

2. Materials and methods

2.1. Materials

Lina was kindly supplied by Egyptian International Pharmaceutical Industries, 10th of Ramadan, Egypt. PLGA polymer (85:15) of a molecular weight of 60000–70000 Da and an intrinsic viscosity of 0.55–0.75 dl/gm was purchased from LACTEL International Absorbable Polymers, Birmingham, USA. Triacetin was supplied by Acros Organics, part of Thermo Fisher Scientific, New Jersey, USA. NMP and methanol were purchased from Fisher Scientific, New Jersey, USA. Ethyl acetate, dibasic potassium hydrogen phosphate, and monobasic sodium hydrogen phosphate were purchased from Spectrum Chemical Manufacturing Corporation, New Jersey, USA. All materials used were of analytical grade.

2.2. Effect of different organic solvents on saturation solubility of Lina

The measurement of the solubility of Lina in various organic solvents was carried out. An excess amount of Lina was transferred to glass tubes containing 10 ml of each organic solvent (NMP, ethyl acetate, and triacetin) followed by shaking in a thermobalanced shaking water bath (25 °C for 3 days). Samples were then centrifuged at 12000 rpm for 15 min and then filtered by 0.22 μm syringe filters in order to separate the supernatant containing the free drug. The dissolved drug was assayed spectrophotometrically at λmax 294 nm according to the data of spectrophotometric analysis of drug after appropriate dilutions with methanol using the corresponding medium as a blank. All measurements were expressed as mean values of three measurements ± standard deviation (SD) (Ayoub et al., 2020).

2.3. Preparation of Lina-ISI systems

The ISI formulations were prepared by dissolving the PLGA polymer (85:15) at different concentrations of 20 % and 40 % w/v in different solvents namely; NMP, ethyl acetate, and triacetin with a continuous stirring on a hot plate stirrer at 60 °C. Lina was added to the prepared clear polymeric solutions (10 mg/ml) and then left to cool at the ambient temperature. The prepared ISI formulations were stored in the refrigerator at 4 °C until further investigation (Ibrahim et al., 2021a).

2.4. In-vitro characterization of Lina-ISI formulations

2.4.1. Morphological study

To visualize the solution to gel transition step during the ISI preparation, the morphology of the Lina-loaded ISIs was determined. The solidification mechanism of the ISI systems would depend on the rate of the solvent–water exchange after being immediately injected to the external aqueous medium. Hence, the external shapes of the ISIs containing three different organic solvents (NMP, ethyl acetate, and triacetin) were optically compared according to the water miscibility of the solvents to estimate the solution to gel transition rate. The photographs of the external ISI structures after injection into Sörensen's phosphate buffer (pH 7.4) at 0 and 2 h were taken while maintaining the temperature at 37 °C.

2.4.2. Scanning electron microscopy (SEM)

The Lina-loaded ISI formulations containing the three different aforementioned organic solvents were further studied using the SEM study after 24 h of their injection into the aqueous buffer. The solidification process was examined by electron microscope to study the impact of using various solvents having different water miscibility on the solution to gel transition and the solidification of the ISIs after more time. Under a high vacuum, the solid samples were spread on aluminum stub and then coated with gold using a sputter coater. The photomicrographs were visualized at 500x magnification power at an accelerating voltage of 20 kV (Ibrahim et al., 2021a).

2.4.3. Determination of drug content

The drug contents of ISIs were measured by mixing 1 ml of each sample, equivalent to 10 mg of Lina, with a known volume of methanol by using a vortex. The samples were centrifuged (12000 rpm, 25 °C for 15 min) and then filtered by 0.22 μm syringe filters. The supernatants were analyzed using a spectrophotometer at 294 nm after appropriate dilutions with the corresponding media for determining the drug contents. The measurements were expressed as mean values of three measurements ± SD (Prabhu et al., 2005).

2.4.4. In-vitro drug release study

The Lina-loaded ISI formulations were prepared and the cumulative percent of the drug release from these preparations was monitored. In closed bottles, the ISI formulations, equivalent to 10 mg of Lina, were injected into 200 ml of Sörensen's phosphate buffer (pH 7.4). The bottles were shaken in a shaking water bath at 37 °C and 50 rpm. Aliquots of 3 ml were withdrawn from each receptor medium at 0, 2, 6, and 24 h. Then, the aliquots were continually taken at 2, 4, 8, 14, and 21 days. An equal volume of fresh buffer was returned to each receptor medium to keep its volume constant. The aliquots were filtered by 0.22 μm syringe filters and the Lina concentrations were analyzed spectrophotometrically at 294 nm using the corresponding medium as a blank. The values were measured as means of three measurements ± SD (Ibrahim et al., 2020).

2.4.5. Kinetic release studies

The in-vitro release data of Lina from the ISI formulations were assayed according to zero order, first order, and Higuchi models to elucidate the release kinetics of the drug by monitoring the highest correlation coefficient (R2) for each ISI formulation. The Korsmeyer-Peppas model was then employed for determining the release behavior mechanisms by comparing the resulting release exponent (n) values. The data were subjected to the following equations:

Zero order model: Qt = Ko.t.

First order model: Qt = 1 – e-Kt.

Higuchi model: Qt = KH.t1/2.

Korsmeyer-Peppas model: Qt/Q∞ = KKP.tn.

Where, Qt is the amount of Lina released at time (t), Q∞ is the amount of Lina released at time (∞), n is the release exponent, and Ko, K, KH, KKP are the release rate constants of the aforementioned models, respectively.

2.4.6. Differential scanning calorimetry (DSC) of selected ISI formulation

The DSC thermal profiles were recorded using Shimadzu-DSC 60 instrument. The DSC study was carried out for pure Lina, PLGA, triacetin, blank ISI formula, and selected 40 % PLGA-triacetin ISI formula. The samples were heated in hermetically sealed aluminum pans at the temperature range of 0–250 °C and a constant rate of 10 °C/min under a nitrogen purge (30 ml/min).

2.4.7. Stability studies of selected ISI formulation

The selected 40 % PLGA-triacetin ISI formula loaded with Lina was stored at three different temperatures (40, 25, and 4 °C) for 6 months. The formulation was evaluated for changes in the physical appearance and the drug content at the different temperatures (Ahmed et al., 2012).

2.5. In-vivo characterization of selected 40 % PLGA-triacetin ISI formulation

2.5.1. Ethics statement

The animal handling was performed according to the guidelines of the Institutional Animal Care and Use Committee of the Faculty of Pharmacy, Zagazig University, Egypt with a protocol number: ZU-IACUC/3/F/81/2020. Every effort was exerted to reduce the number of the animals and their suffering.

2.5.2. Animals

Adult albino rats with average weights of 250 gm were housed for one week at equal light–dark cycles at the ambient temperature before starting the studies to be adapted with the study conditions.

2.5.3. High performance liquid chromatography (HPLC) analysis

The HPLC instrument (Thermo Electron Corporation, Bellefonte, PA, USA) using Hypersil™ BDS C18 column (5 μm, 25 cm × 4.6 mm) was used for the drug analysis. Elution pumps ran modified isocratic mobile phase comprising of acetonitrile and methanol (85:15 % v/v). The autosampler utilized acetonitrile as a rinse solution. The injection volume was 20 μl and the flow rate was 0.8 ml/min. The HPLC assay was performed at 294 nm by using a photodiode array detector. The degassing of the mobile phase was achieved by sonication (Ferreira et al., 2019).

2.5.4. Quantification of Lina in plasma

A stock solution of Lina was prepared in methanol (100 μg/ml). The serial concentrations of the drug solutions (50, 100, 250, 500, 750, and 1000 ng/ml) were prepared and individually mixed with the plasma for 1 min using a vortex and 1 ml methanol was then added. The mixture was centrifuged at 12000 rpm (15 min at 25 °C). After separation of the supernatant, it was filtered using 0.22 μm syringe filter before injection into the HPLC system. The Lina concentrations were monitored at 294 nm. The validation parameters were obtained according to the requirements of the ICH guidelines including linearity range, limit of quantification, and limit of detection (ICH, 2005).

2.5.5. Pharmacokinetic study

In order to determine the blood concentrations of Lina, the animals were divided into two groups of six rats per each group. The group I animals received oral pure Lina suspended in triacetin and the group II animals were injected subcutaneously with the selected 40 % PLGA-triacetin ISI formulation (4 mg drug per Kg of rat weight) by using 18 gauge needles. Blood samples were collected in heparinized tubes at 2 and 6 h, then at 1, 2, 4, 8, 14, and 21 days. The collected blood samples were centrifuged for 10 min at 3000 rpm. The Lina concentration in each plasma sample was calculated after constructing the calibration curve of Lina in the plasma. The pharmacokinetic parameters of Lina from the in-vivo study were calculated using Phoenix 64® WinNonlin based on the non-compartmental analysis method (Benhabbour et al., 2019). These parameters included the maximum plasma concentration (Cmax), the time needed to reach the Cmax (Tmax), and the apparent elimination rate constant (Kel) as obtained from the terminal slope of the plasma concentration–time curves. The areas under the curve (AUC0-t and AUC0-∞) and the area under the first moment curve (AUMC0-∞) were calculated by the trapezoidal method. The elimination half life (t1/2) and the mean residence time (MRT) were also calculated. The pharmacokinetic parameters were assayed by using GraphPad Prism program version 5.04 through the Student’s t-test.

2.5.6. Postprandial blood glucose measurements

The rats were divided randomly into four groups (n = 6). The group I animals were considered as control rats (C) which received regular tap water and food pellets for six successive weeks. The group II animals were diabetes-induced rats (D) which received fructose (10 %) in the drinking water, NaCl (3 %), and high-fat diet (25 %) in the food pellets for three weeks followed by an intraperitoneal injection of 40 mg/Kg of streptozotocin (STZ). After the first week of the STZ injection, the animals with stable postprandial hyperglycemia (200–300 mg/dl) were considered as diabetic and received the vehicle for another two weeks (Park et al., 2023). The group III animals were confirmed as diabetic rats (as in group II) and they received daily oral Lina preparation (4 mg drug per Kg of rat weight) for another two weeks. The group IV animals were confirmed as diabetic rats (as in group II) and they were subcutaneously injected by the Lina-loaded 40 % PLGA-triacetin ISI formulation (4 mg drug per Kg of rat weight) once. After 7 and 14 days of treating the animals with either oral Lina or subcutaneous Lina-ISI preparations, the rats were fasted for 8 h. Two hours after the re-access to food, the blood glucose was measured by a glucose meter (ACCu-CHEK, Roche, Mannheim, Germany) from the tail droplet. The results were statistically analyzed using two way analysis of variance (ANOVA) and Tukey post hoc test.

3. Results and discussion

3.1. Effect of different organic solvents on saturation solubility of Lina

The solubility values of Lina in different organic solvents were measured as 40.43 ± 0.92, 1.40 ± 0.31, and 0.29 ± 0.05 mg/ml for NMP, ethyl acetate, and triacetin, respectively at 25 °C. Triacetin demonstrated the least saturation solubility value and this would favor the sustained release of Lina from the different ISI formulations.

3.2. In-vitro characterization of Lina-ISI formulations

3.2.1. Morphological observations

As shown in Fig. 1, the ISI formulations were optically observed and were found to have different external shapes after being injected into the buffer depending on the type of the used solvents. The hydrophilic solvent (NMP) led to a quick formation of a rigid compact depot with a soft and smooth surface within seconds (Fig. 1a). This might be owing to the rapid extraction of water miscible NMP solvent to the external medium showing a rapid solution to gel transition. This was followed by a rapid precipitation of the polymeric solution forming the matrix depot (Benhabbour et al., 2019, Kilicarslan et al., 2014). It was seen that no marked variation in the structure of the formed depot was observed within 2 h indicating the formation of a complete depot after the rapid solvent and non-solvent exchange (Fig. 1b) (Gad, 2016).

Fig. 1.

Fig. 1

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Optical photographs of ISIs after injection into buffer (a) PLGA-NMP ISI at 0 h (b) PLGA-NMP ISI after 2 h (c) PLGA-ethyl acetate ISI at 0 h (d) PLGA-ethyl acetate ISI after 2 h (e) PLGA-triacetin ISI at 0 h (f) PLGA-triacetin ISI after 2 h.

While, the hydrophobic solvent (ethyl acetate) demonstrated a slow phase inversion rate within hours with formation of ISI with an irregular appearance and large cavities (Fig. 1: b-c). Besides, the hydrophobic triacetin showed no solution to gel transition after the immediate ISI injection into the aqueous medium (Fig. 1e). This might be ascribed to the lower water miscibility of triacetin and the slower diffusion of the solvent into the aqueous phase. Within 2 h, the polymeric solution started to precipitate followed by a formation of a dense structure of the ISI (Fig. 1f). Ahmed et al., 2014, Ibrahim et al., 2021b reported that slow phase inverting systems could be formed by using hydrophobic solvents in the ISI preparation resulting in reduced liquid–liquid phase separation rate and slower solution to gel transition.

3.2.2. SEM study

Further investigation of the Lina-loaded ISI formulations by SEM after mixing with Sörensen's phosphate buffer (pH 7.4) for 24 h was performed as shown in Fig. 2. The utilized solvent in the ISI preparation could exert an influence on the ISI morphology. NMP as a water miscible solvent could lead to the formation of ISI system having an irregular porous internal structure (Fig. 2a). This could be ascribed to the rapid exchange between the water miscible NMP and the external aqueous media. Hence, the formed structure could enhance the initial burst release of Lina after solidification of ISI systems (Ahmed et al., 2014, Zhang et al., 2019). Regarding the ISI system containing ethyl acetate, the structure was full of large holes (Fig. 2b). This might be owing to the presence of such ISI system in a semifluid state forming an incomplete solidified depot which in turn might result in a high burst release of the drug afterwards. On the other hand, the solvent of a low water affinity such as triacetin might slow down the process of the solvent exchange leading to the formation of ISI system of a less porous structure. As shown in Fig. 2c, the triacetin-ISI formulation had less numerous pores with diameters smaller than ISIs containing other solvents. Liu et al. (2010) reported that slower phase inversion of the polymer could lead to a formation of more compact and denser structure of the ISI system after solidification, hence resulting in a slower release of drug.

Fig. 2.

Fig. 2

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SEM images of (a) PLGA-NMP ISI (b) PLGA-ethyl acetate ISI (c) PLGA-triacetin ISI after injection into the buffer after 24 h.

3.2.3. Determination of drug content

The drug content values were determined for all ISI formulations loaded with Lina and were found to be more than 98 % (Table S1 supplementary material) confirming the efficient preparation method followed and the precise dose of Lina loaded in each formulation.

3.2.4. In-vitro release study

First, the release steps of the drug from the ISI systems is divided into some successive stages which are initial burst drug release during the ISI solidification followed by diffusion and erosion processes (Amini-Fazl, 2022). Once the PLGA-ISI system is contacted with the aqueous body fluids after injection, the system undergoes a phase inversion step and the precipitation of the polymer solution into a solid or semisolid depot occurs (Gad, 2016). The phase inversion step relies on the exchange rate between the organic solvent present in the ISI preparation and the external aqueous body fluids (Ibrahim et al., 2021b). The solvent outflow and the non-solvent influx are the key factors of the phase inversion of the ISI. Different scenarios can exist depending on the composition of the ISI system and the water miscibility of the solvent used in the preparation, hence positively or negatively affecting the drug release stages.

In our study, the results of cumulative release of Lina from the ISI formulations are shown in Fig. 3. The ISI formulations, equivalent to 10 mg of Lina, showed a biphasic release profile with variable sustained drug release patterns over days depending on the different PLGA concentrations and the different organic solvents used. The results revealed that increasing the PLGA concentration from 20 to 40 % could result in a remarkable decrease in the Lina release in spite of the type of the solvent utilized in the preparation. This could be explained as increasing the PLGA concentration could reduce the water affinity to the solution and facilitate the formation of more dense and less porous solidified preparation. As a result, the rate of the solvent–water exchange could be decelerated and more sustained drug release pattern could be monitored (Bode et al., 2018, Wang and Burgess, 2021). Moreover, lower concentrations of organic solvents, as a result of utilizing higher PLGA concentrations, could certainly exhibit more viscous ISI formulations showing more delayed liquid–liquid mixing and retarded drug diffusion. These findings could be consistent with those reported by Parent et al., 2013, Hosny and Rizg, 2018.

Fig. 3.

Fig. 3

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In-vitro Lina release from ISI formulations containing different organic solvents using different concentrations of PLGA.

With regard to the type of solvent used in the ISI preparation, the nature and the properties of the utilized solvent could markedly impact the initial burst release and the drug diffusion after the solidification of the ISI systems in the external medium (Lin et al., 2012). As shown in Fig. 3, the initial burst release of Lina from 20 or 40 % PLGA-triacetin ISI formulations at 2 and 6 h was remarkably lower than those containing NMP or ethyl acetate using the same PLGA concentrations. The higher burst release shown by the NMP solvent as a hydrophilic organic solvent could be attributed to the rapid diffusion of NMP towards the external aqueous buffer forming a fast phase inverting system with higher burst release of Lina. Parent et al. (2013) reported that the fast inverting systems based on hydrophilic solvents could facilitate the formation of the interconnected networks that could increase the possibility of the loaded drug access to the matrix surface and raise its burst release. On another side, PLGA-ethyl acetate ISI formulations showed an increase in the initial Lina burst release at 2 and 6 h than those containing NMP at the first day. This might be ascribed to the slower phase inversion rate induced by ethyl acetate which in turn resulted in slower solution to gel transition in comparison to the faster phase inverting systems formed by the NMP utilization. Therefore, higher burst release of the drug from the ISI formulations containing ethyl acetate in the first day could be attributed to the rapid transition of both solvent and drug together out of the system before the ISI solidification (Ahmed et al., 2012).

In contrast, the initial burst release of Lina from 20 or 40 % PLGA-triacetin ISI formulations at the first day was markedly lower than those containing other organic solvents. This might be owing to the lower drug solubilization capacity of triacetin than that of NMP and ethyl acetate which could allow lesser amounts of free Lina to be diffused out to the external medium during the solidification of the ISI (Ibrahim et al., 2020, Van Hemelryck et al., 2021). In addition, Parent et al. (2013) pointed out that slow phase inverting systems based on hydrophobic solvents such as triacetin could produce an ISI structure of low porosity inducing minimized drug diffusivity and subsequently decreased burst release of the drug. Hence, not only the solvent hydrophobicity and its capacity to solubilize the drug but also the kinetics of the phase inversion could significantly influence on the initial burst release and also on the following diffusion and the erosion release stages (Gad, 2016, Thakur et al., 2014). These explanations might be in consistence with our results shown in the morphological observations section.

Furthermore, following the burst release stage, there was another drug release stage called the diffusion phase which could continue for several weeks (Eldeeb et al., 2022). The drug release throughout this period could be affected by several aspects, such as its solubility in the used solvent, its diffusivity through the matrix, and the porosity of the diffusion pathway. It was reported that a small amount of drug released during such period could result in a nearly constant release manner between the initial burst stage and the erosion stage afterwards (Parent et al., 2013). According to Fig. 3 results, the drug solubilization capacity of the organic solvent could influence the cumulative Lina release over days. It was noticeable that ISIs containing triacetin of lower solubilization capacity of Lina displayed more sustained cumulative release of the drug than those containing solvents of higher solubilization (ethyl acetate and NMP). The Lina solubility in triacetin could favor the entrapment of the dispersed drug particles inside the ISI systems resulting in more sustained release (Ibrahim et al., 2020).

Based on our results, the 40 % PLGA-triacetin ISI formulation displayed an approximate constant release manner with a cumulative release of 93.06 ± 1.50 % after 21 days (Fig. 3). Such formulation was selected for further characterizations owing to the less burst release profile shown by using triacetin and higher PLGA concentration. Where, the less susceptibility to burst release could be beneficial as this could minimize the potential local or systemic toxicity as stated by Sheshala et al., 2019, Kamali et al., 2019. In addition, the satisfactory release pattern of the drug diffused from such ISI formulation showed a sustained release of Lina up to 3 weeks. Ahmed et al. (2012) reported that the concentration of the polymer and the type of the solvent could exhibit evident impacts on the in-vitro drug release from the ISI systems. Where, the utilization of triacetin having low aqueous affinity and low drug solubilization capacity was reported to made haloperidol to be suspended in the polymeric matrix which in turn could induce a prolonged release of the drug at high PLGA concentration (40 %).

3.2.5. Kinetic release studies

As shown in Table 1, the in-vitro release data were analyzed to determine the model which fitted the pattern of the drug release. The highest R2 could suggest the order of the Lina release. Our results revealed that the first order model was the best fit model for the tested formulations owing to the higher R2 values of the first order model than those of the zero order and Higuchi models. This could indicate that the release of the drug is dependent on the dose (Franklin-Ude et al., 2007). However, the 40 % PLGA-triacetin ISI formulation exhibited a release profile best fitted to the Higuchi model equation (R2 = 0.9874) which indicated the diffusion mechanism of the Lina release (Ibrahim et al., 2022). Regarding the n values for each formulation, the Korsemeyer-Peppas model could be followed to investigate the subsequent release mechanisms; diffusion-controlled release (Fickian mechanism) when n ≤ 0.43, anomalous release (non-Fickian mechanism) when n = 0.43–0.85, or relaxation-controlled release (case II transport mechanism) when n ≥ 0.85 (Patel et al., 2022, Konovalova et al., 2023). As displayed by Table 1, the tested ISI formulations manifested anomalous or non-Fickian release mechanisms suggesting the combination of both diffusion and erosion. However, the 20 % and 40 % PLGA-ethyl acetate ISI formulations demonstrated n values<0.43 referring to their diffusion-controlled release mechanism.

Table 1.

Kinetic release data of Lina-ISI formulations.

Formula Zero order model
 First order model
 Higuchi release model
 Korsmeyer-Peppas model
R2 R2 R2 R2 n
20 % PLGA-NMP ISI 0.8534 0.9950 0.9840 0.9877 0.5534
40 % PLGA-NMP ISI 0.8119 0.9956 0.9813 0.9814 0.5078
20 % PLGA-ethyl acetate ISI −0.1504 0.9813 0.6380 0.9279 0.2205
40 % PLGA-ethyl acetate ISI −0.9119 0.9062 0.2546 0.9213 0.1654
20 % PLGA-triacetin ISI 0.6070 0.9903 0.9141 0.9199 0.4459
40 % PLGA-triacetin ISI 0.7297 0.9731 0.9874 0.9879 0.4827
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R2, correlation coefficient; n, release exponent; PLGA, poly (lactic-co-glycolic acid); NMP, N-methyl-2-pyrrolidone; ISI, in-situ implants.

3.2.6. DSC study of selected 40 % PLGA-triacetin ISI formulation

The DSC study was performed to observe any shift or disappearance of the thermal peaks of the studied samples. This could help distinguish the nature of Lina and the changes in its crystallinity after loading in the ISI formulation. The thermal behaviors of pure Lina, PLGA, triacetin, blank ISI, and selected 40 % PLGA-triacetin ISI formula are shown in Fig. 4. The pure Lina showed a characteristic melting endothermic peak at 206.31 °C which could indicate its crystallinity at this characteristic melting point. PLGA displayed a glass-transition temperature at 47.15 °C. Triacetin showed a broad endothermic peak at 175.75 °C. In comparison to the thermal behavior of the blank ISI formulation, the the selected 40 % PLGA-triacetin ISI formulation showed the presence of the drug peak at 205.97 °C with lower intensity. This might indicate the encapsulation of a part of the drug in the ISI formulation in a crystalline form (Shang et al., 2018). Desai et al. (2008) reported that the presence of the crystalline peak of 2-methoxyestradiol in the thermal profile of the drug-loaded implant formulation with a reduced intensity might be ascribed to the lower drug loading although the drug was still present in a crystalline state. Besides, these findings could be in consistence with the low solubility of Lina in triacetin solvent that in turn could lead to retarding the Lina release from the selected 40 % PLGA-triacetin ISI preparation.

Fig. 4.

Fig. 4

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DSC thermograms of (a) pure Lina (b) PLGA (c) triacetin (d) blank ISI (e) selected 40% PLGA-triacetin ISI formulation.

3.2.7. Stability studies of selected 40 % PLGA-triacetin ISI formulation

The selected 40 % PLGA-triacetin ISI formulation was observed during the storage conditions at three different temperatures (40, 25, and 4 °C) for 6 months. Results of Table 2 showed an insignificant change in the drug content values (p < 0.05). Visually, the selected formulation demonstrated no change in the formulation color and no sedimentation of the drug after storage was observed. These results could indicate the high physical stability of the tested formulation.

Table 2.

Drug content measurement in 40 % PLGA in triacetin-ISI formulation after storage at different temperatures for 6 months (n = 3).

Time Drug content (%)
40 °C 25 °C 4 °C
0 month 96.15 ± 1.45 98.22 ± 2.12 100.00 ± 1.21
3 months 95.78 ± 2.01 97.89 ± 1.58 99.65 ± 1.77
6 months 94.05 ± 1.26 96.62 ± 2.08 98.17 ± 2.30
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3.3. In-vivo characterization of selected 40 % PLGA-triacetin ISI formulation

3.3.1. Quantification of Lina in plasma

The calibration curve of Lina in the plasma is shown in Fig. 5. The curve possessed a good linearity within the concentration range (50–1000 ng/ml) and R2 value of 0.9982. The limit of detection was 15.2929 ng/ml and the limit of quantification was 46.3411 ng/ml.

Fig. 5.

Fig. 5

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Standard curve of Lina in rat plasma.

3.3.2. Effect of oral preparation and subcutaneous 40 % PLGA-triacetin ISI preparation loaded with Lina on pharmacokinetic parameters

The plasma concentration–time profile of Lina was determined after the oral administration of pure Lina preparation and the subcutaneous injection of the selected 40 % PLGA-triacetin ISI formulation as shown in Fig. 6 and the pharmacokinetic parameters were calculated as presented in Table 3. The mean Cmax of the oral Lina preparation was 820.74 ± 4.51 ng/ml and gradually decreased within 6 h. When the 40 % PLGA-triacetin ISI formulation was subcutaneously administered, the mean Cmax was 495.54 ± 5.11 ng/ml after 4 h, which was about 1.65-fold lower than that of the pure Lina preparation. The t1/2 was significantly increased from 7.64 ± 0.058 h for the pure drug preparation to 1371.05 ± 2.14 h for the 40 % PLGA-triacetin ISI formulation. Also, the AUC0-∞ was 20966.88 ± 20.56 ng/ml.h in case of the oral preparation, while that of the ISI formulations was 660022.88 ± 19.42 ng/ml.h. These results could manifest the long-sustained release of Lina from the subcutaneous ISI preparations that could provide a valuable alternative for the potential clinic application. Said and Elmenoufy (2017) pointed out that sustained release systems producing decreased plasma concentrations of the drug could reflect improving the effectiveness and the bioavailability of the drug with minimization of related side effects. As shown in Table 3, the MRT, as an indicative of the long circulating property of the drug in the blood, was measured where the selected 40 % PLGA-triacetin ISI formulation displayed a significant longer MRT than that of the oral preparation. This could signify the long circulating activity of Lina while being loaded in the ISI preparation and the slow degradation characteristics, thus leading to higher drug bioavailability (Ozer et al., 2023).

Fig. 6.

Fig. 6

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Plasma concentration–time profiles of oral Lina preparation and 40 % PLGA-triacetin ISI formulation after subcutaneous injection in rats (n = 6).

Table 3.

Pharmacokinetic parameters after administration of oral Lina preparation and subcutaneous injection of selected Lina-ISI formulation (mean ± SD, n = 6).

Parameter Oral Lina preparation Selected Lina-ISI formulation
Cmax (ng/ml) 820.74 ± 4.51 495.54 ± 5.11 *
Tmax (h) 6 ± 0.00 6 ± 0.00
Kel (h−1) 0.091 ± 0.002 0.0005 ± 0.0001 *
t1/2 (h) 7.64 ± 0.058 1371.05 ± 2.14 *
AUC0-t (ng/ml.h) 20746.17 ± 35.31 153914.87 ± 25.86 *
AUC0-∞ (ng/ml.h) 20966.88 ± 20.56 660022.88 ± 19.42 *
AUMC0-∞ (ng/ml.h2) 303242.79 ± 31.92 1291544494.00 ± 50.42 *
MRT (h) 14.46 ± 0.54 1956.82 ± 21.98 *
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ISI, in-situ implants; Cmax, maximum plasma concentration; Tmax, time needed to reach the Cmax; Kel, apparent elimination rate constant; t1/2, half life; AUC0-t, area under the curve; AUC0-∞, area under the curve from time zero to infinity; AUMC0-∞, area under the first moment curve; MRT, mean residence time.

* significant at p < 0.05 level.

3.3.3. Effect of oral preparation and subcutaneous 40 % PLGA-triacetin ISI preparation loaded with Lina on postprandial hyperglycemia

The measurement of the postprandial blood glucose levels of the rats was conducted for the assessment of the antidiabetic activity of the Lina-loaded ISI. The diabetic animals showed a marked impaired glycemic control as indicated by the significant stable elevations of the postprandial blood glucose levels at the 7th and 14th days following the diabetes induction compared with the corresponding time points of the control animals (all at p < 0.05, Fig. 7). The daily administration of the oral Lina preparation (4 mg drug per Kg of rat weight) clearly improved the glycemic control of the diabetic animals as indicated by the significant decrease in the postprandial blood glucose levels at the 7th and 14th days following the diabetes induction (both at p < 0.05) compared with the corresponding time points of the diabetic animals. The single subcutaneous injection of the selected Lina-loaded 40 % PLGA-triacetin ISI formulation (4 mg drug per Kg of rat weight) produced a very similar improvement in the glycemic control of the diabetic animals that produced by the daily administration of the oral Lina preparation as indicated by the significant decrease in the blood glucose levels at the 7th and 14th days following the diabetes induction compared with the corresponding time points of the diabetic animals (all at p < 0.05, Fig. 7). Finally, our findings could magnified the desirable potential of the subcutaneous ISI systems to sustain the Lina release for extended time periods in-vivo, hence accounting for their prospective use for clinical purposes.

Fig. 7.

Fig. 7

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Effect of oral and ISI preparations loaded with Lina on postprandial hyperglycemia in diabetic rats. Values are expressed as mean ± SEM. C: control animals, D: diabetic animals. Oral Lina: diabetic animals received daily administration of oral Lina (4 mg drug/kg), Long Lina: diabetic animals received single subcutaneous injection of Lina-ISI formulation (4 mg drug/kg).* indicates p < 0.05 compared to control group. # indicates p < 0.05 compared to D by two-way ANOVA and Tukey post hoc test.

4. Conclusions

In the present study, Lina was successfully incorporated in an injectable ISI system providing a long-term sustained release over 21 days. The SEM study showed that a fast phase inversion of ISI containing water miscible NMP was observed upon injection into aqueous environments, while a much slower phase inversion was represented by the ISI containing hydrophobic triacetin. Lina represented a biphasic release profile when being loaded in ISI. Triacetin solvent exhibited the slowest in-vitro release of Lina among the other studied solvents using 40 % PLGA. In addition, the influence of the increment of PLGA concentration on the decrement of Lina release was explained. The pharmacokinetic study of Lina confirmed the lower Cmax and the higher AUC values following the subcutaneous administration of the ISI in the rats when compared to those of the oral preparation indicating the enhanced effectiveness and bioavailability of Lina-loaded ISI. Furthermore, the ISI formulation represented its pharmacodynamic capability to control the blood glucose levels of the animals over extended time periods. In conclusion, subcutaneous Lina-loaded PLGA-based ISI systems could confirm their feasibility to provide a long-term diabetic therapy with more enhanced patient compliance.

Funding

This paper is based upon work supported by Science, Technology & Innovation Funding Authority (STDF) under grant number 43554.

CRediT authorship contribution statement

Eman Gomaa: Methodology, Writing – review & editing, Validation, Writing – original draft, Visualization. Noura G. Eissa: Conceptualization, Methodology, Visualization. Tarek M. Ibrahim: Data curation, Writing – original draft, Software, Writing – review & editing, Formal analysis, Methodology. Hany M. El-Bassossy: Resources, Supervision, Project administration, Funding acquisition. Hanan M. El-Nahas: Investigation, Project administration, Resources, Writing – review & editing, Supervision. Margrit M. Ayoub: Conceptualization, Methodology, Writing – original draft, Validation.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

This paper is based upon work supported by Science, Technology & Innovation Funding Authority (STDF) under grant number 43554.

Footnotes

Peer review under responsibility of King Saud University.

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jsps.2023.02.002.

Contributor Information

Eman Gomaa, Email: eman_pharmaceutics@yahoo.com.

Noura G. Eissa, Email: nouraeissa@zu.edu.eg.

Tarek M. Ibrahim, Email: tarekmetwally333@gmail.com.

Hany M. El-Bassossy, Email: helbassossy@pharmacy.zu.edu.eg.

Hanan M. El-Nahas, Email: hananelnahas@gmail.com.

Margrit M. Ayoub, Email: margritayoub1@gmail.com.

Appendix A. Supplementary material

The following are the Supplementary data to this article:

Supplementary data 1
mmc1.docx (16.5KB, docx)

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