Drugs with a short half-life and good gastrointestinal tract (GIT) absorption are rapidly removed from the bloodstream. These Drugs need to be taken often. Oral sustained release (SR) formulations have been prepared to address these issues. In this sense, there are numerous advantages to controlled drug delivery systems, such as enhanced therapy by boosting gastrointestinal transit time and efficacy, improved site-specific delivery to minimize undesirable side effects, and increased patient compliance by lowering dosing frequency [1]. Low-density systems with enough buoyancy to float over stomach contents and stay in the stomach for an extended amount of time are known as gastro-retentive floating microspheres. The drug is delivered gradually at the appropriate pace while the apparatus floats over the contents of the stomach, increasing gastric retention and minimizing variations in plasma drug concentration [2]. Solid, spherical, empty particles with a size range of 1 to 1000 µm are known as microspheres. A sustained release of a drug may be possible with solid biodegradable microspheres that contain a drug dissolved or disseminated throughout a particle matrix [3].

Low-density solids, such as sponges and floating microballoons, or systems that reduce in density when in contact with stomach contents due to the explosion of swelling agents or the production of carbon dioxide, are used to prepare floating drug delivery systems. The advantage of multiple unit particle dosage forms, such as microspheres and microballoons [4], include a customizable release that lowers inter-subject variability in absorption and homogeneity across the GIT to prevent the whims of stomach emptying.

The solvent evaporation approach has drawn a lot of interest among the different techniques prepared for the formulation of microballoons since it is simple to fabricate without sacrificing the action of drug. The FDA has approved mefenamic acid (MA; D4T, thymidine) for clinical use in the treatment of HIV infection, AIDS, and conditions associated with AIDS, either on its own or in conjunction with other antiviral drugs. MA is usually taken orally as an oral solution and pill [5]. The half-life of the virus-tatic drug is a relatively brief 1.30 h. However, lactic acidosis and neuropathy are side effects of MA. Because adverse effects of MA are dose-dependent, the severity of the toxicity is lessened when the overall dose is reduced.

Formulating and assessing MA microballoons for sustained release was the aim of the current study. As a result, several microballoon batches were made in accordance with the working plan. The resulting microballoons were assessed for in vitro drug release, particle size, entrapment effectiveness, and percentage yield. It was also investigated how the microballoons were affected by process factors.

Materials and Reagents

Mefenamic acid (MA) was a gift sample and was obtained from Yucca Enterprises, Mumbai, India, and hydroxylpropyl methylcellulose (HPMC E3), Eudragit RSPO, polyvinyl acetate 8 -10 cps (PVA- intermediate hydrolised), polyethylene glycol 400 was procured from Bo International Pvt. Ltd., New Delhi, India, and isopropyl alcohol were used and all the reagents and solvents were of analytical grade satisfying pharmacopoeial standards.

Preparation of Microballoons

The solvent evaporation method was used to prepare the microballoons. The drug-loaded HPMC E3 LDG and the produced granules were first sonicated after being distributed into the polymer solution (Eudragit RSPO, EC) in methanol and dichloromethane (1:1). Drop by drop, the resultant suspension was added to a 70°C aqueous solution of 1% w/v polyethylene glycol (Table 1). A mechanical stirrer was used to agitate the suspension for 2 h at 1500 rpm. The solid, distinct microballoons coated with the coating polymer were left in an aqueous solution of polyethylene glycol after the solvent evaporated during the stirring operation [6]. After being separated by filtration, the microballoons were allowed to dry for 24 h at room temperature in desiccators. The physical characteristics of microballoons, including weight homogeneity, were then assessed in further detail.

Table 1. Composition of low-density granular pellets for the preparation of microballons

Characterization of Microballoons

Particle Size Analysis

An optical microscope was used to measure the particle size distribution of microspheres. The calibration factor was determined using the stage micrometer. The number of ocular disc divisions that the particle occupied was multiplied by the calibration factor to determine the particle size. To determine each sphere size, fifty were selected at random [7].

Angle of Repose

The fixed funnel method was used to calculate the angle of repose of  microballoons, which gauges their resistance to particle flow. The following formula was used to get the angle of repose based on the height and average radius:

where θ = Angle of repose, h = Height of the pile, r = Average radius of the circle.

Compressibility Index

A flowability of powder was assessed using a straightforward test that compared the powder's bulk and tapped densities as well as its rate of packing down [8]. The following formula was used to determine the Carr's index:

Drug Content

By dispersing 50.0 mg of the formulation in 10 mL of 95% ethanol and then stirring with a magnetic stirrer for up to 12 h to dissolve the polymer and extract the drug, the drug content of the produced microballoons was ascertained. After passing the solution through a 5 µm membrane filter, a double beam UV spectrophotometer was used to measure the drug concentration spectrophotometrically at 284 nm [8].

The percentage drug entrapment was calculated by using the formula:

Scanning electron microscopy (SEM)

SEM was used to analyze the surface morphology of MIC1 and MIC5 (JEOL, JSM5200, and Tokyo, Japan). The samples were fixed on a brass stub and coated with a gold-palladium layer using a gold sputter module in a high vacuum evaporator in an argon environment before being examined [10]. After that, the equipment was used to take the photos with an excitation voltage of 20 kV. Prior to and following the in vitro drug release investigation, the surface morphology of microspheres was examined.

In vitro Dissolution Studies

The produced microparticles were subjected to a dissolving test using 900 milliliters of 0.1 N HCl as the dissolution medium in the USP Apparatus Type II (Paddle) [USPNF, 2007]. Five milliliters of the samples were taken out at regular intervals of 1,2,4,6,8, and 12 h. To keep the sink conditions and volume constant throughout the experiment, the withdrawn volume was substituted for fresh medium up to the volume. The ELICO SL-210 Double Beam Spectrophotometer was used to quantify the amount of drug dissolved at 284 nm after the samples were appropriately diluted with the same dissolution liquid. The cumulative percentage of drug released was then computed [11].

In vitro Buoyancy Studies

Floating lag time and total floating time were used to characterize every prepared floating buoyancy research. A USP Type II Paddle Apparatus was used for the test, which involved rotating a paddle at 50 rpm and 37 ± 0.5°C while utilizing 900 cc of 0.1 N HCl [12]. Floating lag time and total floating time were defined as the amount of time needed for the microballoons to rise to the surface of the dissolving medium and the amount of time the floated continuously on the dissolution medium, respectively. Table 4 displays the findings.

Fourier Transform Infrared Spectroscopy (FTIR) Analysis

By using FTIR spectroscopy, drug-polymer interactions were investigated. FTIR was used to record the spectra of the drug-loaded microballoons and the pure drug (Model No. IR Presige-21, Shimadzu). KBr disks were used to prepare the samples (2 mg sample in 200 mg KBr). The resolution was 4 [1/cm], and the scanning range was 400–4000 cm⁻¹.

Differential Scanning Calorimetry (DSC) Analysis

To assess any potential drug-polymer interaction, the Shimadzu DSC 60 was used to perform DSC investigations of the pure drug and drug-loaded microballoons. Under a nitrogen flow rate of 25 ml/min, the analysis was carried out at a rate of 10.0°C/min from a temperature range of 30°C to 300°C [11].

It was investigated that the spectrophotometric technique for estimating MA in the dissolving liquid was linear and repeatable. With an R² value of 0.9971, the standard calibration curve produced a straight line, indicating that the drug complies with Beer's law in the concentration range of 2–10 μg/ml. Six independently weighed drug samples were analyzed to assess the reproducibility method. As a result, the technique was determined to be appropriate for estimating MA in a dissolution medium [12].

First, different concentrations of HPMC E3 were used to produce low-density granular pellets of MA. The floating lag time and in vitro drug release of the low-density granular pellets were assessed. Formulation F6, which included the drug HPMC E3 in a 1:5 ratio, demonstrated a floating lag time of 5 sec and an in vitro drug release of up to 2 h among the generated low-density granular pellets (Table 2). Using 1% w/v PEG 400 as the aqueous phase and Eudragit RSPO & EC 8 cps as coating polymers, this formulation was optimized for creating microballoons [13].

Table 2. Floating lag times and total floating times of various microballoons of MA (mean ± S.D.; n=3)

The emulsion solvent evaporation method was used to prepare the floating microballoons. An agitated aqueous solution of polyethylene glycol was mixed with a suspension of Eudragit RSPO, ethyl cellulose, and LDG containing ethanol and dichloromethane. The polymer precipitated around the dichloromethane droplets as the ethanol quickly separated into the external aqueous phase. Internal cavities were prepared inside the microballoons as a result of the confined subsequent evaporation of dichloromethane [14]. A porous structure within the microballoons may result from the formulations integration of the drug-adsorbed HPMC E3. Drug-adsorbed HPMC E3 was prepared by ultrasonography in a fine subdivision state. The decrease of the necessary stirring times is one possible benefit of using big volumes of the external aqueous phase.

Dichloromethane dissolves in water at a rate of 1% w/v. When using a greater volume (400–500 mL), dichloromethane diffused into the aqueous phase and the particles solidified more quickly than when using 200 ml. Shorter stirring times could therefore result in the separation of particles. It was examined that smooth, high-yield microballoons were prepared by a saturated polymer solution [15]. The particles formed by the undissolved polymer were uneven and rod-shaped. The drug and polymer co-precipitated at 70°C, and the shell was prepared by the simultaneous evaporation of dichloromethane and the diffusion of ethanol into the aqueous solution.

Because the polymer solution solidified before forming droplets or because the temporary droplets were shattered before the solidification was finished, some of it aggregated in a structure resembling fibers. When Eudragit RSPO was dissolved in ethanol, it hardened into aggregates that resembled fibers as the ethanol swiftly diffused from the organic phase (polymer solution) into the aqueous phase [16]. Microspheres have been shown to coalesce when the solvent's diffusion velocity out of the emulsion droplet was too slow. On the other hand, embryonic microsphere droplets may aggregate if the diffusion of solvent rate is too high and it diffuses into the aqueous phase before stable emulsion droplets form.

Additionally, the morphology of the microballoons was influenced by the ratio of ethanol to dichloromethane; a spherical shape was best achieved when the ratio was 2:1. However, as the amount of EC and Eudragit RSPO grew, so did the average particle size and wall thickness (Table 3). The average particle size dropped while retaining its shape when the rotation speed of propeller raised from 300 to 1000 rpm [17]. Based on the drug concentration, size distribution, and particle size data, the ideal rotation speed for this experimental system was 1000 rpm. ‘

F6 microballoons had mean particle sizes of 110 µm, while formulations comprising 50–100 mg of HPMC E3 had mean particle sizes of 120 ± 12.114, 125 ± 24.6, 212 ± 26.311, 314 ± 30.12, 368 ± 33.98, 489 ± 40.78, 548 ± 61.62, 799 ± 70.72µm (Table 3). The range of the compressibility index was 12.23 ± 1.82 % to 16.23 ± 1.11%. All of the formulations had good flowability, as shown by the low CI value. The low angle of repose statistics, which varied from 22.56 ± 2.41% to 28.89 ± 1.29%, provided additional support for this. The superior flow characteristic suggests that the generated floating microballoons were not clumped together. Eudragit and EC microballoons based on HPMC E3 tended to be spherical in shape [18].

Table 3. Physical evaluation of MA microballons

Between 1 and 35 min was the floating lag time for the formulas F1–F5, which floated for up to 12 h. At least 15 seconds was the minimum floating time for the formulation F6, and it floated for up to 12 h.

Dissolution tests were conducted using the USP Paddle Method (Apparatus II) first on the LDG and subsequently on all microparticle formulations. The drug release of LDG was prolonged for up to 3 h. Formulation F6 was further chosen from among the developed formulations to prepare the microballoons. In formulations F6f–F6g, which contained EC and Eudragit RSPO as rate-controlling polymers, respectively, the duration of the drug release from the microballoon formulations was prolonged to 12 h (Fig. 1). Drug release has not been prolonged for up to 12 h by formulations F6a–F6f, which were made using EC and Eudragit RSPO at the same doses as rate-controlling polymers [11].

Figure 1. Drug release profile of (a) MA granular pellets and (b) MA floating microballoons

It was examined that every floating microballoon formulation was linear, with a zero-order release rate and R² values between 0.9773 ±0.03 and 0.9971 ±0.07. All of the microparticle formulations have nonlinear zero order charts. All of the microparticle drug release rates of all the formulations were therefore linear with zero-order release rate constants (K1) and concentration-dependent. With the exception of F6a–F6g, all of the floating microparticle formulations had Higuchi constants between 12 and 15 mg, which suggests that the drug release from the dosage form was regulated. Plots of drug release vs time were found to be linear, with R² values ranging from 0.9881 ±0.07 to 0.9977 ±0.09. The diffusion process was responsible for the drug's release from the microballoons [8,9].

Table 4. Drug release profile of MA sustained release floating microballoons

The surface properties of the microspheres following dissolution were then examined using the SEM images shown in Fig. 2. A smooth, less porous surface was observed on the microsballons loaded with Pure MA-EC/HPMC, along with a few drug crystals. Polymer properties, concentration, and preparation method all affect surface properties of microsballons [12]. When the dispersion is rotated at a high stirring rate, the high rate of solvent evaporation may also contribute to surface porosity. The microsballons were gathered and dried at the conclusion of the in vitro release investigation.

Figure 2. SEM image of (a) MA granular pellets and (b) MA floating microballoons

To investigate any drug-excipient interactions, FTIR spectrum analyses were conducted on a few chosen MA formulations. The BRUKER FTIR Spectrophotometer was used to do FTIR spectral analyses. Initially, the FTIR spectra of the pure MA drug were obtained in order to verify the presence of basic functional groups. Fig. 3 display the spectra of various compositions and MA pure drug, respectively (Fig. 3). All of the peaks were seen at certain wave numbers as those of their corresponding pure drugs, and the spectral analyses of the MA formulation showed no further changes in the principal peaks. The distinctive OH stretching, in the case of the microballoons, the pure drug C-H, C=O, and NH stretching of a secondary amine remained unaltered [9]. These investigations therefore showed that the drug, polymers, and excipients included in the microballoons did not interact significantly.

Figure 3. FTIR spectrum of (a) pure MA, (b) F6, and (c) F6g floating microballoons

The interaction between the drug and the excipients utilized was investigated using DSC experiments on MA and the optimized formulation; the findings are displayed in Fig. 4. The melting point of MA, which is 172.70°C, was shown by a prominent endothermic peak in the DSC thermogram. Sharp endothermic peaks for MA were visible in the DSC thermograms of the optimized formulations F6f and F6g at temperatures of 230.14 °C and 221.46 °C, respectively, with no sudden changes in the peaks. This suggests that the formulations did not contain any drug-excipient interactions [10].

Figure 4. FTIR spectrum of (a) pure MA, (b) F6, and (c) F6g floating microballoons

Solvent evaporation was used to prepare mefenamic acid- sustained release floating microballoons. To reduce the processing variables, all of the microballoons were made in the same way. For the drugs and polymers, the solvent evaporation approach worked well. It was examined that the microballoon formulations made with the polymers EC and Eudragit RSPO were appropriate for prolonging drug release for up to 12 h. The drug release increased and the floating lag time reduced as the amount of polymer in the microparticle formulation increased. Drug release followed a non-Fickian diffusion mechanism, and all of the mefenamic acid formulations that were prepared showed first-order release kinetics. The mefenamic acid-controlled release floating microballoon compositions F6f and F6g shown promising carrier. Further study required to explore the in vivo safety profile.

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