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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access Full Text Article   Research Article

Design and Characterization of Aceclofenac-Loaded Microballoons using Eudragit with Hydroxypropyl Methylcellulose

Souvik Biswas ¹, Sindhuja Sengupta ², Padmanath Pegu ³, Nikita Dey ², Amartya Sen ⁴, Biplab Debnath ¹, Mrinmoy Nag ², Nurul Amin ², Arijit Das ¹, Soumya Datta ¹, Amlan Bishal ¹*

¹ Bharat Technology, Jadurberia, Uluberia, Howrah – 711316, India

² NEF College of Pharmaceutical Education & Research, Nagaon – 782001, India

³ School of Pharmaceutical Sciences, Girjananda Chowdhury University, Tezpur Campus, Tezpur, Bebezia Gaon, Assam–784501, India

⁴ ADAMAS University, Adamas Knowledge City, Barasat - Barrackpore Road, Jagannathpur, Kolkata, West Bengal – 700126, India

 

 

INTRODUCTION

Gastro retentive drug delivery systems developed to exhibit a prolonged gastric retention time (GRT), have sparked the interest of researchers due to their potential for controlled and targeted drug delivery ¹. Shorter half-life drugs that are simply absorbed from gastrointestinal tract (GIT) were found to be eliminated quickly from the Blood stream. Floating dosage forms will overcome these challenges since they release the medicine gently and aid to maintain a consistent drug concentration in the bloodstream for a longer length of time ². A few issues are being investigated in the development of controlled delivery frameworks for increased absorption and bioavailability. One such challenge is the difficulty to restrict the dosage form in the targeted region of the GI tract. It is widely assumed that the amount of medication absorbed in the gastrointestinal system is proportional to the time the drug is in connection with the small intestine mucosa ³. Site-specific orally administered drug delivery system needs to achieve prolonged residence time to get the desired effect. Prolonged stomach retention enhances the bioavailability, decreases drug waste, extends the period of drug release, and enhances the solubility of medications that are less soluble in environments with high pH. ⁴. Nonsteroidal anti-inflammatory medicines (NSAIDs), which have pain-relieving and anti-inflammatory qualities, have been widely utilized in the treatment of various illnesses since their development. NSAIDs act by blocking cyclo-oxygenase, a key enzyme in pain generation ⁵. Rheumatoid arthritis (RA) is an inflammatory joint condition that causes synovial expansion and cartilage degradation. NSAIDs are first-line medications. Aceclofenac is a novel NSAID with good analgesic, anti-inflammatory, and antipyretic properties for acute and chronic inflammation, as well as improved stomach tolerance. It was chosen as a model medication because of its short half-life (3-4 hours) and the fact that two-thirds (70-80 percent) of the dosage is eliminated by renal transport ⁶. Aceclofenac is a more recent derivative of diclofenac that is an excellent choice for modified release multiple dose formulation because of its shorter biological half-life (4 hours), lower risk of GIT complications, and higher dose frequency ⁷. Drug release rates from formulations in the stomach and upper section of the small intestine are being prolonged using floating drug delivery systems until the entire drug is released for the required amount of time. Rheumatoid arthritis (RA) is a long-term inflammatory condition of the joints that causes cartilage degradation and synovial development. The objective of the current work was to create an Aceclofenac hollow microballoons, to extend its retention in the upper gastrointestinal tract. This could lead to improved absorption and, ultimately, increased bioavailability ⁸.

MATERIALS AND METHODS 

Materials

The drug sample was purchased from Aarti Drugs Ltd. Maharashtra. Eudragit RS 100 was purchased from Evonik Industries, Mumbai. HPMC and Tween 20 were purchased from Colorcon Asia Pvt. Ltd., Goa, and Maya Chemtech India Private Limited, Delhi Dichloromethane and disodium hydrogen phosphate were purchased from Yarrow Chem Products, Maharashtra. Other chemicals like ethanol, concentrated HCL, Sodium Hydroxide, N Hexanes, Glyceryl monostearate, and Polyvinyl Chloride were used in this work with proper analytical grade.

Methods

Preparation of standard curve

The primary stock solution of Aceclofenac was made by dissolving 100 mg of Aceclofenac in a tiny quantity of methanol and adjusting the volume to 100 ml with 0.1 N HCl. A range of concentration from 1-10 μg/ml was prepared by diluting the primary stock solution (1000 μg/ml). Using a UV-Visible double beam spectrophotometer, the absorbance of these solutions was measured at 275 nm against 0.1 N HCI as a blank. Then, using the X-axis for concentration and Y-axis for absorbance, a calibration curve was generated.

Preparation of standard curve of Aceclofenac in phosphate buffer of pH 6.8

Aceclofenac standard curve was produced using a pH 6.8 phosphate buffer and 100 mg of Aceclofenac. The primary stock solution was then diluted to prepare 1-10 μg/ml of solution. At 275 nm, absorbance was determined against phosphate buffer as blank. Then, using a concentration in g/ml on the X-axis and Y-axis as absorbance, a calibration curve was plotted.

Preparation of microballoons following quality by design approach

Defining the Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQAs) 

As the first step towards Quality by Design (QbD)-based product development for floating microballoons of Aceclofenac, the definition of the patient-centric QTPP included a review of the drug product's quality attributes in order to produce a delayed release profile for medication delivery. A number of Quality Attributes (QAs) were identified in order to meet the QTPP, including EE (indicative of drug loading in the hollow microspheres), particle size (imperative for discerning the drug release and absorption potential through GI tract), percentage of drug release in 12 hrs. (i.e., Q12h) and time required for 60% drug release (i.e., T60%) (marker of drug release from microballoons). Various elements of QTPP for development of floating microballoons of Aceclofenac have been summarized in Table 1, while Table 2 enlists the respective justification(s) of selecting each CQA.

 

 

Table 1: Quality target product profile (QTPP) for GR hollow microballoons of Aceclofenac

 

Table 2: Critical quality attributes (CQAs) for GR hollow microballoons of ITH and their justifications

 

Table 3: Formulation composition of GR hollow microballoons prepared as per central composite design

 

 

Table 4: Translation of coded factors into physical units

 

 

Optimization of GR microballoons using experimental design

Systematic optimization of GR microballoons was accomplished employing Central Composite Design (Table 3 and Table 4) using the highly influential CMA/CPPs selected using the factor screening and risk assessment studies. The design matrix as per CCD containing a total of nine different formulations prepared employing different concentration of Eudragit RS100 and HPMC as the CMA/CPPs at three different levels, i.e., low (-1), intermediate (0) and high (+1) levels. All the prepared formulations were evaluated for various CQAs viz. EE, particle size, Q12h and T60%, respectively.

Evaluation of microballoons

Particle size analysis

In assessing the release properties and floating properties, particle size analysis is crucial. Microballoons diameters were determined using a series of conventional sieves with sizes ranging from 14, 16, 18, 22, 30, and pan. From top to bottom, the sieves were stacked in increasing order. The microballoons were run through several sieves, and the number of microballoons maintained on every sieve was weighed to determine the percent weight of microballoons retained by each sieve. The mean particle size can be obtained by applying the formula ^9,10.

Mean particle size = Total weight of the formulation / % Total weight of microballoons.

Floating property of microballoons

100 mg of microballoons were dissolved in 300 mL of 0.1 N HCI with 0.02 % Tween 20 followed by stirring at 100 rpm. After 1, 2, 4, and 6 hours, the buoyant microballoon layer was pipetted and filtered out. The microballoons were collected and dried overnight in a desiccator ¹⁰.

Microballoons were determined using the subsequent formula:                                      

% Microballoons = (Weight of microballoons / Initial weight of microballoons) × 100

Drug entrapment

Microballoons were passed through a drug entrapment test to check the amount of drug present in the prepared formulation. Microballoons samples (50 mg each) of different batches were taken and powdered to dissolve in a small amount of ethanol. The volume was composed to 100 ml using 0.1 N HCl. The solution was then filtered followed by double dilution to prepare a concentration of 1µg/ml and at 275 nm, The absorbance was measured in relation to a blank of 0.1 N HCI. The percentage of drug entrapment was calculated by the following equation ¹¹.

% Drug entrapment = (Calculated drug concentration / Theoretical drug concentration) × 100

Determination of true density

The liquid displacement technique was introduced to determine the true density of microballoons using a pycnometer and n-hexane as the solvent. First, the weight of the pycnometer was recorded (a), followed by the addition of 25 ml of n-hexane and the recording of the weight (b). The pycnometer was emptied, the weight amount of the microballoons was added and weight (c) was recorded. Now n-hexane was added to fill the vacant areas within the microballoons until the volume, i.e., 25 ml, was occupied by the microballoons and n-hexane. Final weight (d) was taken and true density was calculated using the formula ¹².

The density of liquid (ρ) =  

True density = 

Determination of tapped density

It is the proportion of a particular mass of microballoons to the volume of the microballoons after tapping. The tapping method was used to estimate the density of microballoons. An exact weight of microballoons was placed into a 10 ml measuring cylinder. After viewing the initial volume of floating micro spheres, tapping on a hard surface was maintained until no further volume change was seen and the tapped density was calculated using the formula ^11,13.

Tapped density = (Mass of microballoons / Volume of microballoons after tapping)

Percentage compressibility index 

The percentage compressibility index was calculated using the same tapping approach.

% Compressibility index  

The volumes of the sample after and before standard tapping are V and V₀, respectively ¹².

Percentage yield

By weighing the microballoons after drying, the percentage yield of various formulations was calculated using the formula ¹⁴.

% Yield = (Total weight of microballoons / Total weight of drug and polymer) × 100

Angle of repose

The angle of repose of the floating microspheres is commonly used to determine the flow characteristics of microballoons. It is the highest angle between the free-floating surface of a heap of floating micro balloons and the horizontal plane that can be achieved. The fixed funnel method was used to estimate the angle of repose of microballoons. The microballoons were free to tumble down a funnel until the conical pile's peak just brushed the funnel's tip.

The angle of repose   was determined according to the following formula ^14,15.

 

[Where, h = height of pile, r = radius of the pile formed by the microballoons]

FT-IR analysis

For the examination of drug-polymer interaction and drug stability throughout the microencapsulation process, a Fourier transform infrared analysis was performed. Pure Aceclofenac, Eudragit RS 100, HPMC, and microballoons were analysed using the Fourier transform infrared spectrum ¹⁵.

Stability Study

The ideal formulation (F₄) was selected for stability studies. The produced formulation (F₄) was kept for 45 days at ambient temperature (27±2°C), oven temperature (42±2°C), and refrigerator temperature (5-8°C) in borosilicate screw-capped glass containers. At two-week intervals, the samples were tested for drug content ¹⁶.

RESULTS AND DISCUSSION

The standard curve of Aceclofenac in 0.1 N HCL follows a linear equation where y = 0.0235x and R² value is = 0.9972 and the same drug in Phosphate buffer at pH 6.8 follows a linear equation where, y = 0.053x and R² value is = 0.9999 The standard curve in both the medium was showed in Figure 1(a) and 1 (b). The absorbance at different concentration is given in Table 5.

 

 

Table 5: Concentration vs Absorbance table

 

 

1(a)                                                                             1(b)

Figure 1(a): Standard curve of 0.1 N hydrochloric acid and 1(b): standard curve of the model drug in Phosphate buffer at pH 6.8

 

 

Particle size analysis

Particle size determination was performed by the sieving method. In general, if the magnitude of the micro balloons is less than 500 microns, the drug release rate will be high and the floating ability will be reduced, but if the size is between 500 and 1000 micron, the floating ability will be greater and the drug release rate will be sustained. The mean particle size of micro balloons was in the range of 603 – 858 µm 

Floating property of microballoons

To simulate stomach fluid, microballoons were distributed in 0.1 NH₄Cl containing tween 20 (0.02% w/v). The floating ability of various formulations was identified to change depending on the Eudragit and HPMC ratios. In 6 hours, F₁-F₄ formulations had the best floating ability (90.47-72.17%). The floating ability of the F₅-F₉ formulation was lower (60.12-25.61%) than that of the F₅-F₇ formulation. By increasing the HPMC ratios, the floating ability of the microspheres was decreased. Percentage buoyancy for different formulations is discussed in Table 6.

The % Buoyancy decreased for a different formulation was represented in Figure 3.

 

 

Table 6: Percentage buoyancy for different formulations

 

 

Figure 3: % Buoyancy decreased for a different formulation

 

 

Drug entrapment

The drug entrapment effectiveness of varied formulations ranged from 43.14 to 74.12% w/w. Drug entrapment effectiveness in microballoons reduces somewhat when HPMC concentration increases and the Eudragit ratio lowers. This is owing to the permeability properties of HPMC, which may enable the diffusion of some of the encapsulated drugs to the surrounding media during the production of microballoons.

 

Percentage yield

The percentage yield for each formulation was determined by weighing the microballoons after they had dried, and it varied from 55.10% to 84.67%.

True density

Using n-hexane as the solvent, the liquid displacement method was used to measure the true density of micro balloons. The value was determined to fall between 0.482 to 0.916 gm/cm3 which is lower than gastric fluid (1.004 gm/cm³), indicating a good flow property.

Tapped density

The tapped density values for different formulations were found to be in the range between 0.201 to 0.405 gm/cc lower than the gastric fluid density of 1.004 gm/cm³, indicating a good buoyancy property in the stomach.

Percentage compressibility index

The percentage compressibility index, which was determined using the tapping method, ranged from 8.34 ± 0.641% to 17.45 ± 1.01%, suggesting a good flow property. Value for all formulations is discussed in Table 7.

Angle of repose

Angle of repose was calculated using the fixed funnel method and ranged from 24.09º to 38.12º, suggesting a good flow property (˂40º).

 

 

Table 7: Micromeritics of Aceclofenac loaded microballoons

*Average of three Preparation

 

 

FT-IR spectrum analysis

Aceclofenac, Eudragit RS 100, HPMC, physical mixing of drug-polymer and F₄ formulation FT-IR spectra were observed. FTIR spectra revealed the presence of Aceclofenac in formulation F₄. The distinctive peaks for pure Aceclofenac seem to be at 662.31, 1715.13. 1769.49, and 1343.21 for C – H Bending, C = O Stretching, C = O Stretching, and C – N Stretching shown in Table 8, due to polynuclear aromatic ring, secondary aromatic, carboxylic group, esters to the group. All these peaks were observed in the formulation and physical mixing, showing that there was no chemical interaction between Aceclofenac and the polymer. It also demonstrated the drug's stability during the microencapsulation procedure. It is depicted in Table 10. The FTIR Spectrum of HPMC, Eudragit RS 100, Aceclofenac, and F₄ Formulation were represented in Figure 4, 5, 6, 7 respectively.

 

 

 

Table 8: FT-IR spectrum range of Aceclofenac

 

Figure 4: FTIR spectrum of HPMC

 

Figure 5: FTIR spectrum of Eudragit RS 100

 

Figure 6: FTIR Spectrum of Aceclofenac pure

Figure 7: FTIR spectrum of Drug and polymer mixture

In vitro drug release study

Table 9: %Cumulative Drug Release of all the formulations (F1-F9)

Here, Average of six tablets is taken and at SD (Standard deviation) is calculated 

 

From the above results given in Table 9. it has been observed that formulation F₄ and F₇ gives the better results than other formulations when physical characteristics and drug release is considered as per Figure 8. F₄ gives better appearance of microballoons and Formulation F₇ shows best sustainability as the concentration of both Eudragit and HPMC is higher in this formulation. But % buoyancy of F₇ formulation not showed good results so F₄ is considered best among both the formulations. Further stability study results of F₄ formulation proved it to be a robust formulation.

 

 

 

Figure 8: % Cumulative Drug Release of all formulations (F₁-F₉)

 

Drug release kinetics

The drug release kinetics of all the formulation was checked which comprises of Zero Order (Figure 9a), First Order (Figure 9b), Higuchi Plot (Figure 9c), and Korsmeyer Peppas Plot (Figure 9d) from where the diffusional exponent was calculated.

 

 

 

(a) Zero order Plot                                                                       (b) First Order Plot

 

(c) Higuchi Plot                                                              (d) Korsmeyer- Peppas Plot

Figure 9: Drug release Kinetics of all formulations include (a) Zero order Plot, (b) First order Plot, (c) Higuchi Plot, and (d) Korsmeyer Peppas Plot

 

 

Since the diffusional exponent (n) is coming below 0.45 (Table 10)., hence it can be concluded that the drug release mechanism followed Fickian diffusion and the drug release kinetics mechanism followed Korsmeyer-Peppas model with initial first order release rate followed by zero order-controlled release.

 

 

Table 10: Drug release diffusional exponent from Korsmeyer Peppas Plot

 

 

 

                                                                  

 

Stability study

A different range of temperatures was used to perform the stability study for F₄ formulation for 45 days. Drug content was checked at regular intervals and no remarkable change was found. The details are given in Table 11. 

 

 

Table 11: Stability study data for F₄ formulation

Sl. No	Days	% Drug remaining 2-8°C	% Drug remaining 25 ± 2°C	% Drug remaining 40 ± 2°C
1.	0	100 ± 00	100 ± 00	100 ± 00
2.	14	99.6 ± 0.015	99.9 ± 0.003	99.4 ± 0.041
3.	28	99.5 ± 0.013	99.8 ± 0.027	99.2 ± 0.036
4.	45	99.4 ± 0.15	99.6 ± 0.012	99.1 ± 0.02

 

 

CONCLUSION

Gastro retentive dosage forms are a promising approach for prolonged and predictable drug delivery in the upper gastrointestinal tract to control the gastric residence time. Because of their low density, microballoons have good floating qualities and the benefits of multiple-unit systems, making them one of the most effective buoyant medication delivery devices. Moreover, the drug is released slowly at the desired rate when it floats over gastric contents resulting in reduced fluctuations in plasma drug concentration. It is supposed to be an efficient means of enhancing bioavailability. Biocompatible and cost-effective polymers like HPMC in combination with Eudragit RS100 were used to formulate an efficient floating microparticulate system. Hence, it can be concluded that the prepared floating microballoons of Aceclofenac proved to be a potential and promising candidate for multiple-unit delivery devices adaptable for safe and effective sustained drug delivery. The importance of gastro-retentive dosage forms, especially floating microballoons for drugs Aceclofenac, is relevant nowadays due to increasing demand for targeted, controlled, and precise drug delivery systems. These classes of dosage forms prolong and stabilize the drug release profiles, which are especially advantageous for the agent that can be only absorbed in the high gastrointestinal tract or that have a narrow absorption window, by prolonging the retention times of the drugs inside the stomach. Such technologies have successfully been able to make an impact in the current healthcare scenario in which optimizing therapeutic efficacy and patient compliance are a top priority. They float on top of the stomach solution to release the drug over a prolonged period and therefore it lessens the need for frequent doses and stabilize plasma drug concentrations. Drugs like Aceclofenac are usually prescribed for chronic conditions like arthritis and inflammatory disorders, where consistency in effects is very important. Using these biocompatible and inexpensive polymers, like HPMC and Eudragit RS100, would support the current tendency towards more affordable and patient-friendly health care. This will not only ensure better patient adherence but also broader access. It would, therefore, be a part of future drug delivery to better tailor therapies to needs while keeping them effective and adaptive and patient-cantered, based on the trends related to personalized medicine and emphasis on sustained and localized delivery.

Authors Contribution

Souvik Biswas: Conceptualization, original draft preparation, figure preparation

Sindhuja Sengupta: Original draft preparation, Editing 

Padmanath Pegu: Review and editing

Nikita Dey: Secondary editing and Scientific evaluation

Amartya Sen: Primary editing, design

Biplab Debnath: Supervision and Project administration

Mrinmoy Nag: Conceptualization and study design   

Nurul Amin: Collection and sorting of data

Arijit Das: Software applications for study design

Soumya Datta: Investigation, Data curation 

Amlan Bishal: Supervising the work, conception, and Project administration

Acknowledgment: The authors are thankful to Mr. Amlan Bishal, Department of Pharmaceutical Technology, Bharat Technology, Uluberia, Howrah, India while conducting this work.

Conflict of Interest: The authors declare that they have no conflict of interest

Availability of raw data and material: Raw data and information on material should be obtained from the corresponding author upon request.

Source of Support: Nil

Funding: The authors declared that this study has received no financial support.

Informed Consent Statement: Not applicable.

Ethics approval: Not applicable.

 

 

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