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Medipelli A, Chinthala P. Formulation and In-Vitro Assessment of Torsemide -Loaded Microspheres for Controlled Drug Delivery. Biotech Res Asia 2024;21(4).
Manuscript received on : 11-07-2024
Manuscript accepted on : 18-10-2024
Published online on:  31-10-2024

Plagiarism Check: Yes

Reviewed by: Dr. Binit Vishnubhai Patel

Second Review by: Dr. Dinesh Kumar

Final Approval by: Dr. Chateen Izaddin Ali Pambuk

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Formulation and In-Vitro Assessment of Torsemide -Loaded Microspheres for Controlled Drug Delivery

Anitha Medipelli and Praveena Chinthala*

Department of Pharmaceutics, Chaitanya Deemed To Be University, Kishanpura, Hanamkonda, Telangana, india.

Corresponding Author E-mail:praveenamr18@gmail.com

ABSTRACT: The present work aimed at formulation development and evaluation of Torsemide (TOR) microspheres. The loop diuretic TOR is used to treat congestive heart failure and edema. Due to its short half-life of two to three hours, weak basicity, and high solubility, TOR is released rapidly and does not provide sustained drug release. To achieve controlled drug release at a predetermined rate, TOR was prepared into microspheres. A total of 12 formulations were prepared by combining Sodium alginate with varying proportions of the polymers Eudragit RL100 and Hydroxy propyl methyl cellulose K15 (HPMC K15) by the ionotropic gelation technique and evaluated for micromeritic properties, percentage yield, drug entrapment efficiencies and in- vitro dissolution studies. Stability tests were performed out on the optimized formulation. Particle size of formulations was within acceptable limits, with percentage yields ranging from 80.5±0.012 to 95.3±0.028 and entrapment efficiencies from 72.5±0.024 to 86.8±0.020. Formulation F6 exhibited the highest drug release of 100% in a controlled manner, thus it was considered the optimized formulation and no stability issues were found.

KEYWORDS: Eudragit RL100; HPMC; Ionotropic Gelation Technique; Torsemide; Sodium alginate

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Medipelli A, Chinthala P. Formulation and In-Vitro Assessment of Torsemide -Loaded Microspheres for Controlled Drug Delivery. Biotech Res Asia 2024;21(4).

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Introduction

A promising area of study and development is controlled drug delivery, which has the potential to significantly enhance the efficacy and safety of medication therapy. A method of administering drugs or therapeutic agents to a specific site of the body at predetermined rates and for predetermined amounts of time is known as controlled drug delivery. It entails the use of drug delivery systems or tools that control medication release, enabling the best possible therapeutic results while reducing adverse effects and enhancing patient compliance1.

Traditional medication administration techniques, including oral tablets or injections, can cause rapid drug release and changes in drug levels in the body. This may result in less effective treatment, ineffective drug use, and possible negative effects. These restrictions are intended to be overcome by controlled drug delivery systems, which offer a more accurate and regulated release of drugs. In controlled drug delivery systems, a variety of techniques and technologies are employed based on the particular application and goals2, 3.

Microspheres are small, spherical particles and size range usually between 1µm to 1000 µm4. They are useful for targeted drug delivery and sustained release applications as they can encapsulate and release active components. The biocompatible polymers can be used to formulate microspheres5.

Torsemide (TOR) is a loop diuretic. It is generally used to treat ailments such as congestive heart failure, liver disease, and kidney problems that are characterized by fluid retention. TOR works on the kidneys to help boost urine production and decrease extra fluid in the body. TOR acts by preventing sodium and chloride ions from being reabsorbed in the kidneys’ ascending loop of Henle. By preventing the re absorption of these ions, it promotes diuresis, which increases the outflow of water and electrolytes 6,7. The traditional formulations of TOR like tablets and capsules exhibits quick absorption, resulting in high plasma concentrations, more availability of drug and rapid elimination, that require more frequent administration. As a result, the controlled release formulation is essential. TOR-controlled release microspheres have a similar systemic exposure, and they are far more tolerable due to their large reduction in absorption rate and variations in plasma concentrations.

These considerations led to present study aiming to develop TOR-controlled-release microspheres by Ionotropic gelation method using Sodium alginate along with Hydroxy propyl methyl cellulose K15 and Eudragit RL100.

Materials and Methods

Materials

TOR was a gift sample from Yarrow Chemicals, Mumbai. Sodium alginate (CDH, New Delhi), Calcium Chloride (CaCl2) (Qualigens, Mumbai), Eudragit RL100 (S.D. Fine Chemicals, Mumbai.) Hydroxyl propyl methyl cellulose (HPMC K15), Hexane (Spectro chem Pvt. Ltd, Mumbai) was commercially obtained. All other reagents used in experiment were of analytical grade and purchased from their commercial sources.

Preparation of TOR Microspheres

Ionotropic gelation method was employed to formulate microspheres containing TOR. Initially, a 1% Sodium alginate solution (1% solution of Sodium alginate was prepared in 100ml of distilled water) was prepared using a magnetic stirrer. After achieving a homogeneous mixture, HPMC K15 and Eudragit RL100 were added in combination to formulations F1-F6, HPMC alone to F7-F9, and Eudragit alone to F10-F12, as detailed in Table 1. The second step was preparation of a drug solution. For this drug was dissolved in 0.1N HCl with magnetic stirring and was slowly poured into the polymer solution on a magnetic stirrer. In the final step, a 5% CaCl2 solution was prepared and maintained at 600 RPM on a magnetic stirrer. The drug-polymer mixture was gradually added drop by drop to the 5% CaCl2 crosslinking solution using syringe with 20-gauge needle. The resulting microspheres were filtered, rinsed with hexane, and dried8,9.

Table 1: Composition of TOR microspheres formulations

Formulation code TOR

(mg)

Sodium alginate (mg) HPMC K15 (mg) Eudragit RL 100 (mg) Calcium chloride (%)
F1 20 1000 40 40 5
F2 20 1000 80 80 5
F3 20 1000 120 120 5
F4 20 1000 40 80 5
F5 20 1000 80 120 5
F6 20 1000 120 40 5
F7 20 1000 40 5
F8 20 1000 80 5
F9 20 1000 120 5
F10 20 1000 40 5
F11 20 1000 80 5
F12 20 1000 120 5

Evaluation of TOR microspheres

Micromeritic Characteristics

The micromeritic characteristics of the microspheres characterized by assessing their bulk density, tapped density, compressibility index, Hausner’s ratio and particle size.

Bulk Density

The bulk density of a microsphere is defined as the ratio of its entire mass to its bulk volume. A measuring cylinder was filled with one gram of weighted microspheres, and the bulk volume was noted.

Bulk density = Microspheres total weight / Bulk volume 

Tapped Density

Microsphere’s tapped density is determined by dividing its entire mass by its tapped volume. A measuring cylinder was filled with one gram of weighted microspheres and were tapped 100 times to obtain the tapped volume.

Tapped density = Microspheres total weight / Tapped volume

Hausner’s Ratio

Hausner’s ratio is the relationship between the bulk density and the tapped density of microspheres.

Hausner’s ratio = Tapped density/ Bulk density

Carr’s Index (% Compressibility)

The % compressibility of the bulk medication was calculated using the bulk density and the Tapped density.

Carr’s Index = Tapped density − Bulk density/ Tapped density X 100

Particle Size Determination

Microspheres were divided into various fractions of sizes, passing through a 10-minute screening process in a mechanical shaker using standard sieves with pore diameters that conformed to IP standards 10. Calculated the particle size by using formula:

Mean particle size = (Average particle size of fraction X weight fraction) / weight fraction

Particle Surface Morphology

Surface morphology of optimized formulation particles was assessed with Scanning Electron Microscope (SEM model LEO 430), which provides information about the microspheres’ surface and form. 

Practical Yield of Microspheres

Practical yield of the microspheres was calculated based on weight of the prepared microspheres obtained from each batch relative to the total initial weight of the drug and polymer11. The practical yield was determined using following formula;

% Yield = Weight of microsphere obtained / Total weight of drug and polymer X 100

Drug Entrapment Efficiency

Accurately weighed 25 mg samples of drug-loaded microspheres were combined with 25 ml of 0.1 N HCl and stirred using a magnetic stirrer for 24 hours. After this, 1 ml of the drug mixture was extracted, filtered, and appropriately diluted. The drug concentration was then measured using spectrophotometer at 290 nm. The drug entrapment efficacy (EE) of the microspheres determined using the formula provided 12.

Drug entrapment efficiency = (Actual drug content /Theoretical drug content) X100

In -vitro Drug Release Study

In- vitro studies of TOR microspheres determined using a USP basket type dissolution equipment (LAB INDIA DISSO 2000) with a paddle mesh size of #22. The study was conducted at 37°C for up to 12 hours. A 50 mg of prepared microspheres of each formulation was accurately weighed and mixed in 900 ml of 0.1 N HCl dissolution media for the first 2 hours, followed by a pH 6.8 phosphate buffer for the remaining time at 50 rpm. Samples were taken at regular intervals, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12hrs, immediately restored with the same amount of medium. Collected samples were properly diluted and spectrophotometrically analyzed at 290 nm 13.

Drug Release Kinetics

The mechanism of drug release from the microspheres was examined by fitting the in- vitro dissolution data into zero order, first order, Higuchi’s release model, and Korsmeyer-Peppas model14.

Stability Studies

A stability analysis of the optimized formulation was carried out under various conditions in compliance with the standards of the ICH. For stability investigations, optimized microspheres were kept in stability equipment (REMI manufacture). For six months, accelerated stability investigations were conducted for the optimum formulations at room temperature 25 ± 2o C, refrigerated temperature 4 ± 2o C. During the stability study period, the microspheres were evaluated for their practical yield, EE, and cumulative percentage of drug released15.

Results and Discussion

Micromeritic Characteristics

The bulk density and tapped density values of formulations found to be between 0.8168±0.0060 to 0.8640± 0.0080 and 0.9456±0.006 to 0.9755±0.0060 g/cm3, respectively. This demonstrated the TOS microsphere compositions’ exceptional flow characteristics. The compressibility index and Hausner’s ratio ranged from 11.028±0.006 to 13.627±0.005 and from 1.123±0.0061 to 1.157±0.006, respectively, suggesting satisfactory formulation flow characteristics. The outcome values are shown in Table 2.

Table 2: Micromeritic characteristics of TOR microsphere formulations (F1-F12)

Formulation code Bulk density

(g/cc)

Tapped density

(g/cc)

Compressibility

index (%)

Hausner’s ratio

 

F1 0.8194±0.001 0.9487±0.009 13.627±0.005 1.157±0.005
F2 0.8168±0.006 0.9456±0.006 13.620±0.006 1.157±0.006
F3 0.8515±0.004 0.9661±0.002 11.862±0.003 1.134±0.003
F4 0.8519±0.008 0.9673±0.004 11.557±0.006 1.135±0.006
F5 0.8488±0.006 0.9598±0.008 11.564±0.007 1.130±0.007
F6 0.8499±0.004 0.9659±0.004 12.009±0.004 1.136±0.004
F7 0.8640± 0.008 0.9711±0.004 11.028±0.006 1.123±0.006
F8 0.8566±0.003 0.9655±0.007 11.279±0.005 1.127±0.005
F9 0.8583±0.002 0.9668±0.004 11.429±0.003 1.126±0.003
F10 0.8536±0.005 0.9662±0.007 11.653±0.006 1.131±0.006
F11 0.8642±0.002 0.9755±0.006 11.409±0.004 1.128±0.004
F12 0.8534±0.005 0.9712±0.007 12.129±0.005 1.138±0.005

Values are given as average mean ± S.D (n=3).

Particle Size Determination

The size of particles of all formulations F1- F12 ranged between 161.2 ± 0.96 to 187.3 ± 1.37μm and were within the acceptable limits (Table 3). The formulation F3 containing highest polymer concentration had the particle size 187.3 ± 1.37, and F7, F10 containing lowest polymer concentration exhibited lowest particle size. The polymer concentration has an impact on the microspheres’ particle size. When polymer ratio increased particle size increased. Increasing polymer concentration mostly leads to larger particle sizes, because higher concentrations result in more polymer available to encapsulate the drug, thereby increasing the size of the particles formed [13,14,17,18]. The particle size acceptable limit range in between 150 to 200μm (90 to 110%). The outcome values are included in Table 3.

Particle Surface Morphology

The shape of microspheres particles was spherical, smooth surface and nonporous. The microspheres were appeared in white to pale yellow in colour. The results are shown in Fig.1.

Figure 1: SEM images of microspheres of optimized formulation F6

Click here to view Figure

Percentage Yield of Microspheres

The percentage yield of all formulations ranged between 83.5% ± 0.012 to 89.2% ± 0.032. Formulation F3 had the highest polymer concentration, resulting in a more viscous solution as a consequence, it had a lower practical yield compared to other formulations. As the polymer ratio increased the practical yields of all formulations slightly decreased. Increased polymer concentration led to higher viscosity of the solution, which can hinder the formation or recovery of microspheres. The viscus polymer solution adhered to the walls of the beaker and magnetic bead during the process might led to the decreased practical yield of microspheres. 11,16,19,20. The results are included in Table 3.

Drug Entrapment Efficiency

The EE of TOR microspheres ranged from 73.8% to 86.9%. The EE of microspheres varied across different formulations. Optimized formulation among the formulations tested F1 to F12, F6 showed the highest EE when an optimized ratio of polymers HPMC K15 and Eudragit RL 100 was used. This suggests that the combination of these two polymers in specific proportions resulted in better drug entrapment. Formulations F1 to F5, which likely had higher combined polymer concentrations of HPMC and Eudragit, showed higher EE compared to F7 to F12. This suggests that the combination of both polymers generally led to better EE than formulations containing only one polymer type. Formulations containing only HPMC F7 to F9 showed higher EE compared to formulations containing only Eudragit F10 to F1212,16,17,19,21. This indicates that HPMC might be more effective in entrapping TOR compared to Eudragit RL 100.The outcome values are included in Table 3.

 Table 3: Characterization of TOR microspheres

Formulation code Practical yield (%) Entrapment efficiency (%) Drug content (%) Particle size (μm)
F1 88.9±0.032 82.5±0.024 88.28 ± 0.73 174.5 ± 1.21
F2 87.9±0.023 84.3±0.026 90.75 ± 0.89 176.1 ± 1.19
F3 83.5±0.012 86.8±0.020 96.35 ± 0.82 187.3 ± 1.37
F4 86.9±0.025 83.2±0.017 100.61 ± 1.04 175.5 ± 1.25
F5 86.2±0.025 85.6±0.013 10l.53 ± 0.95 182.8 ± 1.02
F6 89.2±0.032 86.9±0.021 101.49 ± 0. 87 162.9 ± 0.96
F7 88.5±0.043 76.9±0.031 85.37 ± 1.18 163.2 ± 0.96
F8 88.1±0.014 78.6±0.056 87.75 ± 0.93 171.2 ± 1.34
F9 87.2±0.034 79.5±0.032 89.81 ± 1.05 179.1 ± 1.06
F10 88.5±0.028 73.8±0.014 83.74 ± 1.14 161.2 ± 0.96
F11 87.9±0.026 75.3±0.028 89.04 ± 1.09 175.7 ± 1.27
F12 86.9±0.024 77.8±0.012 87.65 ± 1.21 178.4 ± 1.02

Values are given as average mean ± S.D (n=3). 

In- vitro Studies

In-vitro studies behaviour was examined over a 12-hour period under conditions simulating physiological environments, gastric fluid (0.1N HCl, pH 1.2) for initial 2 hrs and synthetic intestinal fluid (pH 6.8) for later by in-vitro dissolution method. After 11 hrs, F1 released 99.6% of the medication, whereas F2 released 98.1%. Formulation F3 showed 88.9% drug release rate throughout 12-hour period indicating extended drug release profile. In a 12-hour period, formulations F4, F5, and F6 demonstrated 100%, 99.1%, and 100% drug release, respectively. F4 and F6 demonstrated themselves to be suitable for controlled drug release. The formulations F7 to F9 prepared using HPMC K15 were unsuccessful in achieving the desired 12-hour drug release period even with increasing concentration of HPMC K15. Subsequently, formulations F10 to F12, which used Eudragit RL 100 instead, also did not achieve the 12-hour drug release target. This suggests that neither the increase in concentration of HPMC K15 nor the use of Eudragit RL 100 was effective in extending the drug release period to 12 hours as intended [16,18,20,21,22]. The results are shown in Fig.2.

Figure 2: In- vitro studies of TOR microspheres F1- F12 

Click here to view Figure

Drug Release Kinetics

The R2 values of zero order kinetics for all formulations found to be in between the range of 0.953 to 0.989. The R2values of first order kinetics for all the formulations were found to be in between the range of 0.700 to 0.909. The R2values of Higuchi model for all formulations were found to be in between the ranges of 0.842 to 0.933. The R2values of Korsmeyer peppas model for all the formulations were found to be in between the range of 0.760 to 0.866.

The regression coefficient for the zero-order plot was 0.982, which was close to unity (1.0). In kinetic studies, a regression coefficient close to 1 indicates good linearity and suggests that the data points fit the zero-order kinetics model well. The plot according to the first-order equation shows less linearity compared to the zero-order plot. Therefore, based on the higher regression coefficient (0.982) for the zero-order plot and the better fit of the data to the zero-order kinetics compared to the first-order kinetics, it was reasonable to conclude primary mechanism of drug release was zero-order kinetics. The R² values for Higuchi model ranged in between 0.842 to 0.933, suggesting a diffusion-controlled release mechanism. The R² values for the Korsmeyer-Peppas model ranged from 0.760 to 0.866, indicating a decent fit, but potentially suggesting additional mechanisms or complexities in the release process, and it was non- Fickian diffusion [14]. The kinetic values are included in Table 4 and the kinetic graphs of optimized formulation F6 are shown in Fig. 3, 4, 5, 6.

Table 4: In- vitro release kinetics of all formulations (F1- F12).

Formulation code Zero order R2 First order R2 Higuchi model R2 Korsmeyer peppas model R2
F1 0.987 0.852 0.842 0.760
F2 0.988 0.700 0.930 0.859
F3 0.992 0.852 0.893 0.831
F4 0.987 0.885 0.933 0.842
F5 0.991 0.639 0.906 0.832
F6 0.973 0.867 0.903 0.858
F7 0.989 0.825 0.930 0.859
F8 0.990 0.864 0.916 0.835
F9 0.991 0.864 0.904 0.833
F10 0.993 0.852 0.903 0.861
F11 0.996 0.885 0.933 0.844
F12 0.990 0.909 0.933 0.866
Figure 3: Drug release kinetics of optimized formulation F6 Zero order.

Click here to view figure

Figure 4: Drug release kinetics of optimized formulation F6 First order.

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Figure 5: Drug release kinetics of optimized formulation F6 Higuchi model

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Figure 6: Drug release kinetics of optimized formulation F6 – Peppas model

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Stability Studies

Optimized formulation F6 was chosen for stability analysis because of its high entrapment efficiency, cumulative percentage of drug releases and R2 value of zero order kinetics. In accordance with ICH norms, stability investigations were carried out for 6 months. Based on the findings, it was indicated that the optimized formulation was stable and has mostly preserved its original qualities [15].  Color of microspheres was not changed after stability studies. However particle size, EE and drug content were slightly warried because of temperature effect. The stability study outcome values are shown in Table 5 and release shown in Fig. 7. 

Table 5: Stability studies of optimized formulation F6

Storage condition Time intervals (Months) Particle size (µm) Entrapment efficiency (%) Drug content (%)
 

Room temperature

(25 ± 2oC)

Initial 162.9 ± 0.96 86.9 ±0.021 101.49 ± 0.87
1 162.9 ± 0.95 86.9 ± 0.021 101.39 ± 1.02
2 162.1 ± 0.19 86.8 ± 0.022 101.35 ± 1.32
3 161.5 ± 0.19 86.8± 0.52 101.34± 1.15
6 161.2 ± 1.01 86.7 ± 0.32 101.27 ± 1.12
 

Refrigerated temperature

(4 ± 2oC)

Initial 162.9 ± 0.96 86.9 ± 0.021 101.49 ± 0.87
1 162.9 ± 1.35 86.9 ± 0.022 101.43 ± 1.03
2 162.9 ± 1.14 86.9 ± 0.026 101.39 ± 1.12
3 163.1± 1.15 86.9± 0.034 101.37± 1.13
6 163.2 ± 1.27 86.9 ± 0.036 101.35 ± 1.25

All the values were expressed in average mean ± SD (n=3).

Figure 7: % Cumulative drug release of optimized formulation before and after stability studies.

Click here to view Figure

Conclusion

TOR microspheres were formulated by inotropic gelation method using sodium alginate in combination with Eudragit RL100 and HPMC K15 in different concentrations. The prepared microspheres were assessed for particle size, practical yield, drug entrapment efficiency, and in- vitro studies. Formulation F6 was selected as the optimal formulation, as it exhibited acceptable results with respect to various evaluation parameters. The in- vitro release data of formulation F6 showed 100% regulated release up to 12 hours following zero order kinetics. Additionally, no considerable change in drug content was observed in optimized formulation during a six-month period of stability testing. Therefore, it can be assumed that the TOR microspheres are promising pharmaceutical dosage forms as they provide controlled-release drug delivery system.

Acknowledgments

Authors would like to thank the secretary and correspondent of Chaitanya Deemed to be University, Hanamkonda, Telangana, for providing the research facilities and their support and encouragement.

Funding Sources

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of Interest

The authors do not have any conflict of interest.

Data Availability Statement

This statement does not apply to this article.

Ethics Statement

This research did not involve human participants, animal subjects, or any material that requires ethical approval.

Informed Consent Statement

This study did not involve human participants, and therefore, informed consent was not required.

Authors’ Contribution

Ch. Praveena, M. Anitha  : Conceptualization,

Anitha,: Writing – original draft preparation,

Ch. Praveena. : writing review and editing,

All authors have read and agreed to the published version of the manuscript.

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