Formulation and Evaluation of Gastroretentive In Situ Gelling System of Ketoprofen
Article Category: Original Paper
Online veröffentlicht: 07. Okt. 2023
Seitenbereich: 10 - 19
Eingereicht: 24. Mai 2022
Akzeptiert: 28. Aug. 2023
DOI: https://doi.org/10.2478/afpuc-2023-0018
Schlüsselwörter
© 2023 AR. Shabaraya et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
The administration of drugs orally is widely favored for its convenience; however, it encounters challenges regarding the extent to which the body absorbs the drug due to various physiological limitations. These limitations encompass factors such as inconsistent movement through the gastrointestinal tract, incomplete release of the drug, and limited duration of drug presence.1,2 To address these concerns related to drug absorption, the employment of gastroretentive drug delivery systems (GRDDSs) has emerged as a highly promising strategy.3,4 The primary objective of GRDDS is to retain the drug formulation within the stomach for an extended period and facilitate a sustained release of its active components.3,5,6,8 In recent years, considerable research efforts have been dedicated to developing efficient GRDDSs for diverse therapeutic applications. Numerous studies have explored different methodologies to enhance the duration of gastric residence and maintain controlled drug concentration levels in the bloodstream. For example, floating matrix tablets of lansoprezol were devised to treat gastric ulcers, ensuring an extended residence time in the stomach and controlled release of the drug.9 Another investigation focused on formulating a gastroretentive metronidazole floating raft system to specifically target
Floating
The mechanism underlying raft-forming
Ketoprofen, a nonsteroidal anti-inflammatory drug (NSAID), possesses analgesic and antipyretic properties. It is highly absorbed from the gastrointestinal tract, with peak plasma concentration achieved within 0.5–2 h after oral administration. Ketoprofen inhibits cyclooxygenase-2 (COX-2) through the arachidonic acid pathway, leading to its anti-inflammatory effects. By reducing prostaglandin levels, ketoprofen alleviates fever, inflammation, and pain. It treats osteoarthritis, dysmenorrhea, rheumatoid arthritis, and moderate pain. However, oral administration of ketoprofen is associated with various adverse effects, including dizziness, edema, irritation, peptic ulcers, and gastrointestinal tract ulceration. In addition, due to its short half-life (1.5–2 h), frequent administration is required, which can result in treatment noncompliance. Consequently, several efforts have been made to sustain ketoprofen delivery. The concept of a floating drug delivery system can be employed to reduce the adverse effects of weakly acidic drugs by preventing direct contact with the mucosa. Given these properties, ketoprofen is a suitable candidate for controlled-release dosage formulations.18
The delivery of ketoprofen has been investigated using various systems, including floating microspheres and floating alginate beads.19,20 However, our research focuses explicitly on developing an
Our focus on developing ketoprofen
Ketoprofen was purchased from Yarrow Chem Products in Mumbai. Sodium alginate, gellan gum, calcium chloride, trisodium citrate, calcium carbonate, and hydroxypropyl methylcellulose (HPMC) K100M were also purchased from Yarrow Chem products. All the ingredients were of analytical quality.
The cation-driven gelation approach was used to synthesize a floating
Composition of ketoprofen floating in situ gel.
| F1 | 2 | 0.5 | - | - | 0.25 | 0.16 | 0.750 | 0.18 | 0.02 | 0.2 | 100 |
| F2 | 2 | 1 | - | - | 0.25 | 0.16 | 0.750 | 0.18 | 0.02 | 0.2 | 100 |
| F3 | 2 | 1.5 | - | - | 0.25 | 0.16 | 0.750 | 0.18 | 0.02 | 0.2 | 100 |
| F4 | 2 | - | 0.150 | - | 0.25 | 0.16 | 0.750 | 0.18 | 0.02 | 0.2 | 100 |
| F5 | 2 | - | 0.175 | - | 0.25 | 0.16 | 0.750 | 0.18 | 0.02 | 0.2 | 100 |
| F6 | 2 | - | 0.150 | 0.2 | 0.25 | 0.16 | 0.750 | 0.18 | 0.02 | 0.2 | 100 |
| F7 | 2 | - | 0.175 | 0.2 | 0.25 | 0.16 | 0.750 | 0.18 | 0.02 | 0.2 | 100 |
The physical appearance of the formulations was examined. At 25°C, the pH of ketoprofen
Hydrochloric acid solution (0.1 N, pH 1.2) was used as gelation solution to determine the
To assess the gelling time and duration, the following scores were given:
The viscosities of the different formulations were analyzed using Brookfield digital viscometer DV-II+Pro (Brookfield Engineering Laboratories, Middleboro, MA, USA). Twenty milliliters of the formulation was taken in a beaker. The T-bar spindle was dropped upright in the center of the beaker containing samples, taking care that the spindle did not touch the bottom of the jar. Viscosities were determined at 50 rpm. The temperature was maintained during the process. The average of three readings was considered for each measurement.24
A ultraviolet (UV)–visible spectrophotometer (Shimadzu Corporation, Kyoto, Japan) was used to determine the drug content in the
The formulation was added to a 40 ml solution of 0.1 N hydrochloric acid with a pH of 1.2. The formulation solution was transformed into a gel using a thermostatically controlled water bath. The resulting gel was then separated from the buffer solution using Whatman filter paper, followed by blotting to remove any excess buffer. The initial weight of the gel was determined, and 10 ml of distilled water was subsequently added to the gel. Every 30 min, the water was decanted and the weight of the gel was recorded. This process allowed for the calculation of the change in weight over time.27,28,29,30
The water displacement method was used to determine the density of the formulation. Ten milliliters of formulation solution was poured into 50 ml of 0.1 N hydrochloric acid. The gel was formed, and the formed gel was placed in a measuring cylinder to settle. The gel's volume and weight were measured. Using the volume and weight measurements, the gel density was estimated.28,32,33,34,40
The specific weight of 30 g of formed gel was used for the study. A 50-g weight was kept in the middle of the gel surface and allowed to pass through the gel. The time it took for the weight to sink 5 cm through the prepared gel was used to evaluate its strength. Three readings are averaged together.29,35,36
Drug release studies were carried out using USP type II apparatus with a paddle stirrer (Electrolab, India) at 50 rpm at 37°C ± 0.5°C using a dissolution medium of 900 ml of 0.1 N hydrochloric acid (pH 1.2).
The selected formulations were stored in amber-colored bottles and sealed tightly. As per the International Conference on Harmonisation (ICH) guidelines, stability studies were carried out at room temperature/relative humidity (RH) of 25°C ± 2°C/60% ± 5%, accelerated temperature/RH of 40°C ± 2°C/75% ± 5%, and refrigerated temperature for 90 days. The formulations were assessed for their physical appearance, drug content, pH,
The visual appearance of a formulation plays a significant role in patient compliance when it comes to oral drug administration. Therefore, it is an important parameter to consider. Our study examined the visual appearance of all the formulations and conducted pH measurements. The results are summarized in Table 2.
Physical appearance, pH, and gelling capacity of prepared in situ gel.
| F1 | Light yellow | 7.61 ± 0.03 | |
| F2 | Light yellow | 6.98 ± 0.01 | |
| F3 | Light yellow | 6.94 ± 0.04 | |
| F4 | Milky white | 6.95 ± 0.05 | |
| F5 | Milky white | 7.32 ± 0.02 | |
| F6 | Milky white | 6.89 ± 0.03 | |
| F7 | Milky white | 7.34 ± 0.01 |
The formulations labeled F1 to F3 exhibited a light yellow color, while those labeled F4 to F7 appeared milky white.
The pH range of all the preparations was from 6.89 to 7.61. This pH range is considered orally acceptable, indicating that the administration of the formulations will not cause any irritation to the oral cavity. Furthermore, at room temperature, the solutions showed a free-flowing consistency and no signs of gelation. This characteristic suggests that the formulations remain liquid until they come into contact with the gastric fluid in the stomach. Overall, the visual appearance of the formulations and the pH measurements indicated that the developed formulations were visually appealing and their pH values were well within the acceptable range for oral administration.
The measurement of gelation capacity is a crucial aspect when assessing
All the formulations demonstrated successful gelation, with three formulations (F1, F2, and F4) exhibiting immediate gelation. These formulations formed a gel that remained in its state for 12 h. On the other hand, formulations F3, F5, F6, and F7 also displayed immediate gelation, but maintained their gel form for more than 12 h.
Based on the results of the gelation study, it can be inferred that formulations F3, F5, F6, and F7 demonstrated favorable gelation properties compared to the other formulations.
The ability of formulations F3, F5, F6, and F7 to form an immediate gel and sustain its gel state for an extended period suggests that these formulations have a higher gelation capacity. This characteristic is advantageous for
Therefore, formulations F3, F5, F6, and F7 can be considered the best among the tested formulations to achieve immediate and prolonged gelation. These formulations have the potential to provide sustained drug release and enhanced therapeutic outcomes due to their ability to prolong the retention of the drug within the gastrointestinal tract.
The viscosity of formulations is a crucial factor to consider when designing oral drug delivery systems. The viscosity should be optimized to ensure ease of administration for the patient. The viscosities of all the formulations were measured, and the results are presented in Table 3. The measured viscosities ranged from 133.8 ± 0.07 to 225.9 ± 0.03 cps.
Viscosity of prepared in situ gel of ketoprofen.
| F1 | 209.0 ± 0.2 |
| F2 | 225.9 ± 0.03 |
| F3 | 239.7 ± 0.32 |
| F4 | 133.8 ± 0.07 |
| F5 | 138.9 ± 0.51 |
| F6 | 153.7 ± 0.03 |
| F7 | 155.3 ± 0.06 |
The order of viscosity obtained indicated an increase in viscosity as the concentration of the gelling polymer increases. This can be attributed to the increased cross-linking of the polymer, resulting in a higher viscosity. Specifically, the increase in sodium alginate and gellan gum composition led to a significant rise in viscosity.
These findings highlight the importance of polymer concentration in determining the viscosity of the formulations. By adjusting the polymer concentration, it is possible to control the viscosity and ensure that it falls within the optimum range for easy administration by the patient.
Overall, the viscosity measurements of the formulations indicated that the viscosity was within an acceptable range for oral administration. The increase in viscosity with higher polymer concentrations suggests that the formulations can achieve the desired consistency for effective drug delivery.
The
In vitro buoyancy study of prepared in situ gel of ketoprofen.
| F1 | 45 | >24 |
| F2 | 30 | >24 |
| F3 | 24 | >24 |
| F4 | 69 | >24 |
| F5 | 64 | >24 |
| F6 | 37 | >24 |
| F7 | 22 | >24 |
Based on the
Figure 1.
In vitro buoyancy study of formulation F7.
The ability of these formulations to rapidly form a gel and sustain their buoyancy for an extended period is advantageous for GRDDS. It allows for prolonged drug release, ensuring sustained therapeutic effects. Immediate gel formation suggests that F3 and F7 quickly transform into a gel upon contact with the gastric fluid, contributing to their extended floating duration.
Based on these findings, F3 and F7 can be considered the best formulations among the tested ones, with regard to their immediate gel formation and extended floating duration. These formulations can potentially provide sustained drug release and improved therapeutic outcomes.
Percentage drug content results are reported in Table 5. The percentage of drug content in all the formulations was in the range of 83.45% ± 0.03% to 95.53% ± 0.01%, indicating uniform distribution of the drug as per the monograph. Among the formulations, F3, F5, and F7 exhibited the highest percentage of drug content. Specifically, formulation F3 had a drug content of 92.42%, formulation F5 had a drug content of 93.65%, and formulation F7 had the highest drug content at 95.53%.
Drug content, gel strength, density of prepared in situ gel of ketoprofen.
| F1 | 83.45 ± 0.03 | 30.1 ± 0.22 | 0.575 ± 0.0102 |
| F2 | 90.50 ± 0.53 | 36.14 ± 0.03 | 0.615 ± 0.0021 |
| F3 | 0.632 ± 0.0062 | ||
| F4 | 86.71 ± 0.31 | 21.21 ± 0.04 | 0.522 ± 0.0028 |
| F5 | 93.65 ± 0.31 | 27.54 ± 0.02 | 0.550 ± 0.0025 |
| F6 | 90.09 ± 0.72 | 73.65 ± 0.31 | 0.613 ± 0.0166 |
| F7 | 0.616 ± 0.0025 |
The water content within a drug delivery system plays a significant role in drug release, affecting water penetration into the polymer matrix and subsequent drug release via diffusion or dissolution. The percentage of water uptake by the gels was determined within a timeframe of 2 h. The percentage of water uptake by all the formed gels was found to be in the range of 11.98%–20.02%.
Formulations F3 and F7 demonstrated better water uptake than the other formulations (19.03% and 20.02%, respectively) at the 2-h mark. The higher water uptake observed in F3 and F7 can be attributed to the maximum swelling ability of the polymer in these formulations. As the polymer concentration increased, there was an increase in the water uptake by the gel.
The higher water uptake in F3 and F7 indicates that these formulations have a greater capacity to absorb water, which can contribute to improved drug release characteristics. The increased water uptake allows enhanced penetration into the polymer matrix, potentially facilitating a faster and more efficient drug release process.
Overall, the water uptake results suggest that formulations F3 and F7 exhibit favorable water absorption and swelling ability characteristics. These formulations can potentially enhance drug release due to their higher water uptake capacity. The correlation between polymer concentration and water uptake further supports the role of polymer swelling in facilitating water absorption within the gels.
Low density is a crucial characteristic for gastroretentive floating
In our study, the density of all the formulations was measured, and the results are reported in Table 5. The densities ranged from 0.575 to 0.616 g/cm3 for the
The results showed that the densities of the formulations were lower than those of the gastric contents, confirming their ability to float in the stomach. This characteristic facilitates the desired prolonged gastric retention of the formulations, allowing for sustained drug release and improved therapeutic efficacy.
The low density of the formulations compared to the gastric contents is advantageous, as it ensures that the formulations remain buoyant and do not sink or pass through the gastrointestinal tract too quickly.
Overall, the density measurements confirm that the formulations possess the desired low density, making them suitable for floating in gastric fluids.
Gel strength is an important parameter that reflects the ability of a gelled mass to withstand peristaltic movement
In our study, the gel strength of the formulations was measured, and the results are presented in Table 5. The gel strength values ranged from 21.21 to 78.65 s.
Formulations F3 and F7 exhibited good gel strength, with values of 45.21 and 78.65 s, respectively. This higher gel strength can be attributed to the higher concentration of sodium alginate and gellan gum combined with HPMC K100M in these formulations. The presence of sodium alginate and gellan gum, along with HPMC K100M, likely contributed to the improved gel strength observed in F3 and F7. These polymers have a higher capacity for cross-linking and gel formation, resulting in a stronger gel structure. The higher concentration of these polymers further enhanced the gel strength.
The good gel strength of F3 and F7 indicates their ability to withstand peristaltic movement in the gastrointestinal tract, ensuring the integrity of the gel during transit. This property is crucial for GRDDS, as it allows the formulation to remain intact and provide sustained drug release.
A drug release study was conducted for 11 h using a 0.1 N dissolution medium with a pH of 1.2. The drug release pattern is graphically represented in Fig. 2. The study results revealed that the formulations with higher polymer concentrations, specifically sodium alginate at 1.5% and a combination of gellan gum and HPMC K100M at 0.175% and 0.2%, respectively, exhibited a higher degree of sustained drug release.
Figure 2.
In vitro release profile of ketoprofen in situ gel formulations.
Among the tested formulations, F3 and F7 demonstrated the highest drug release. This indicates that these formulations successfully achieved sustained drug release over the 11-h study period. The higher polymer concentrations in F3 and F7 likely contributed to their ability to control and prolong drug release.
The sustained drug release observed in F3 and F7 can be attributed to the polymers’ properties, including sodium alginate, gellan gum, and HPMC K100M. These polymers are known for their ability to form a gel matrix and control drug release by diffusion or dissolution mechanisms.
Overall, the drug release study results suggest that formulations F3 and F7 can achieve sustained release of the drug over an extended period. The higher polymer concentrations in these formulations likely contributed to their superior performance in terms of sustained drug release. These findings support the potential of F3 and F7 as suitable formulations for achieving prolonged therapeutic effects through controlled drug release.
The formulations did not exhibit any noteworthy changes in appearance and percentage buoyancy during the stability study. The drug content of the formulations F3 and F7 was around 91.39% and 93.99%, respectively, after 2 months. There was no substantial difference observed in the drug release after the study. This indicates that
We focused on developing a floating