INTRODUCTION:

The fast-dissolving drug delivery system is an advancement that combats over the use of the tablets, syrups, capsules. Sublingual administration of the drug means placement of the drug under the tongue and the drug reaches directly into the bloodstream through the ventral surface of the tongue and floor of the mouth¹.

Systemic drug delivery through the sublingual route had emerged from desire to provide immediate onset of pharmacological effect. Dysphagia (difficulty in swallowing) is a common problem of all age groups, especially elderly, children, and patients who are mentally retarted, uncooperative, nauseated or on reduced liquid- intake/diets have difficulties in swallowing these dosage forms². The portion of drug absorbed through the sublingual blood vessels bypasses the hepatic first‐pass metabolic processes giving acceptable bioavailability³.

Cilnidipine is calcium channel antagonist, which is used in the treatment of Hypertension. Cilnidipine belongs to class II drug in BCS classification the major problems with its low solubility in biological fluids, which results into poor bioavailability after oral administration and late onset of action⁴. In order to enhance the solubility of cilnidipine and subsequently dissolution and absorption. Antisolvent crystallization method was used to prepare nanocrystals by using both solvent and antisolvent system⁵. The optimized formulation of Cilnidipine nanocrystals were selected and used in the preparation of cilnidipine films by solvent casting method, which offers superiority over other.

Advantages of cilnidipine fast dissolving film include ^6,7

· Patient of increases Hypertension not capable to swallow large quantities of water.

· In case of high blood pressure quick onset of action required because uncontrolled high blood pressure create Strokes, Heart attack, Kidney Problem.

· Hypertension markedly reduces functional ability and extremely restlessness in such cases rapid onset of action required.

· No Marketed cilnidipine film available in India.

· Specially intended to geriatric patients who have problem of swallowing.

MATERIALS AND METHODS:

Materials:

Cilnidipine, HPMC E5, HPMC E15, HPMC E50 from Yarrow Chemicals Pvt Ltd and PEG 400, Citric acid, Mannitol were collected from Standard deviation (SD) Fine Chemicals, Mumabi, India. All other chemicals used were of analytical Grade.

Methods:

Preparation of Crystals:

Antisolvent method: Crystals of Cilnidipine were prepared by antisolvent crystallization technique using different solvent systems and antisolvent. Ethanol and acetone was selected as solvents and water was used as antisolvent. A solution of Cilnidipine (100mg) in 5ml of acetone or ethanol was prepared in a beaker. And water as antisolvent is taken in another beaker. The mixture of clear Cilnidipine solution is added drop wise to beaker containing antisolvent until precipitations occur. The mixture is allowed to stand for 10 min and finally filtered the solution using whatmann filter paper. The collected crystals were dried at room temperature 37.5°C for 24 hours.⁸

Crystallization under ultrasonication in antisolvent: Crystals of Cilnidipine were prepared by antisolvent sonocrystallization technique by applying a ultrasonication. It involved a solvent and antisolvent system. Ethanol and acetone were selected as solvent, water as antisolvent. A solution of Cilnidipine (100mg) in 5ml of acetone or ethanol was prepared. The clear Cilnidipine solution was added drop wise to the beaker containing antisolvent (15ml water). Simultaneously ultrasound energy was applied by ultrasonication (probe) at with 9 duty cycle and 50% power for a duration of 5 min. Simultaneously ultrasound energy was applied by bathsonication for a duration of 5min. After the sonication filter the solution and collected crystals are dried at room temperature for 24hours.¹⁰

Table 5: Formulation of Cilnidipine crystals from A1 to PE3

Formulation code	Cilnidipine (mg)	Acetone (ml)	Ethanol (ml)	Distilled Water (ml)
A1	100	5	-	10
E1	100	-	5	10
BA2	100	5	-	10
BE2	100	-	5	10
PA3	100	5	-	10
PE3	100	-	5	10

Characterization and Evaluation of pure drug and prepared crystal:

Fourier Transform Infrared Spectroscopy: The FTIR spectra of pure drug and the prepared crystals were recorded on a BRUKER IR spectrophotometer and scanned in the spectral region between 600-4000 cm^-1at the room temperature to ascertain compatibility.⁹

Differential Scanning Calorimetry: The DSC thermograms of pure drug and prepared crystals were recorded on a DSC-60 calorimeter (Shimadzu, Japan). The samples of drug and the prepared crystals was taken in aluminium pan, sealed with aluminium cap and kept under nitrogen purging (atmosphere) with a flow rate of 50ml/min. The samples were scanned from 0-300°C with the heating rate of 10°C rise/min using differential scanning calorimeter.¹⁰

Scanning Electron Microscopy: The surface morphology is most commonly measured by Scanning Electron microscopy. The samples of drug and the prepared crystals were sputter coated using an electrically conducting metal such as gold onto a drug and crystals (Sputter coating equipment details). Then the shape and surface topography of drug and crystals were observed through a scanning electron microscope (ZEISS EVO LS15).¹¹

Powder X Ray Diffraction:

The powder X-ray diffraction patterns were recorded using an X-ray Diffractometer (Smart Lab SE, Rigaku Corporation, Tokyo, Japan), with Cu as anode material and crystal graphite monochromator operated at a voltage of 30mA, 40 kV. The samples were analysed in the 2θ angle range of 5 to 60 at a scanning speed 10.00º/min and step width reproducibility of 0.01ºC for pure drug and prepared crystals. The position and intensities of diffraction peaks were considered for the identification and comparison of crystallinity of the drug and prepared crystals.¹²

Solubility Studies: Excess amount of drug and crystals obtained after crystallization was added to 10ml volumetric flask containing distilled water, 0.1 N HCL (pH 1.2) and phosphate buffer solution (pH 6.8). The volumetric flasks were agitated on a rotary shaker for 48 h at 100 rpm maintained at room temperature. At the end of 48 h, the mixture was filtered, filtrate was suitably diluted and analyzed at 240nm by using UV-visible spectrophotometer (UV-1800, Shimadzu, Japan).¹³

In-Vitro Drug Release Studies:

The In-vitro drug dissolution study of Cilnidipine and Cilnidipine crystals was performed by using the USP Type II dissolution apparatus (Eight station dissolution test apparatus, TDT-08L, Electrolab, India) with a paddle speed of 50rpm. Dissolution medium consisted of 900 ml of distilled water maintained at 37±0.5ºC. Samples of each preparation equivalent to 100mg of drug were added into the dissolution medium. At a predetermined time intervals (5 to 60min), an aliquot was withdrawn and replenished with fresh dissolution medium to keep the volume constant during the experiment. The withdrawn samples were filtered through whatmann filter paper. The amount of drug dissolved in each aliquot was measured on a UV-Visible spectrophotometer (UV-1800, Shimadzu, Japan) at 240 nm using suitable blank. All the trials were conducted in triplicate and the average (±S.D) reading was noted.⁸

Drug Content: Prepared crystals equivalent to 10mg of Cilnidipine crystals was weighed accurately and transfer into a 10ml volumetric flask and dissolved, make up to the volume with phosphate buffer solution (pH 6.8). The solution was filtered through whatmann filter paper, diluted suitable and drug content was analysed at λ_max240nm against blank by UV-Visible Spectrophotometer (UV-1800, Shimadzu, Japan). The actual drug content was calculated using the following equation as follows.¹⁴

Actual amount of Drug

% Drug = ---------------------------------------------- X 100

Content Theorectical amount of Drug

Formulation of fast dissolving sublingual films: Fast dissolving sublingual films were prepared by solvent casting method. Firstly, HPMC E5 or HPMC E15 was dissolved in 10ml distilled water and stirred until the solution becomes clear. The solution was allowed to stand for 1hr so that the air bubbles were cleared completely.⁹⁵ Another solution was prepared by dissolving drug, plasticizer and mannitol in required quantity of distilled water. Both the prepared solutions were mixed together and were stirred for 1.5hrs. After stirring, solution was poured into a 9cm petri plate and was dried in hot air oven at 45^oC for overnight. A film of 2×2cm² dimensions was cut down from the petri plate. Prepared films were evaluated for weight uniformity, thickness, tensile strength, drug content and dissolution study.¹⁵

Table 8: Formulation of fast dissolving sublingual films

Ingredients(mg)	F1	F2	F3	F4	F5	F6
Drug (Cilnidipine)	10	10	10	10	10	10
HPMC-E5	500	600	--	--	--	--
HPMC-E15	--	--	500	600	--	--
HPMC-E50	--	--	--	--	500	600
PEG 400(ml)	0.5	0.5	0.5	0.5	0.5	0.5
Mannitol	10	10	10	10	10	10
Citric acid	50	50	50	50	50	50
Water	Q.S	Q. S	Q. S	Q. S	Q.S	Q. S

Evaluation of Formulated Fast Dissolving Sublingual Film:

i) Physical appearance: All the films were visually inspected for color, clarity, flexibility and smoothness.¹⁶

ii) Weight Uniformity:

Fast dissolving films from each batch were randomly selected and 1cm² films was cut at five different places in the caste film and weighed individually on electronic balance. Mean weight of film (n=3) of each formulation was recorded.¹⁵

iii) Thickness: The thickness of the Cilnidipine crystals loaded fast dissolving films was measured with the help of digital screw gauge. The thickness of each film was determined at six different places and average was calculated.¹⁵

iv) Surface pH: The film to be tested was placed in a petridish and was moistened with 10 ml of distilled water and kept for 30s. The pH was noted after bringing the electrode of the pH meter in contact with the surface of the formulation and allowing equilibration for 1min. The average of three determinations for each formulation was done.¹⁵

v) Folding Endurance: The flexibility of films can be measured quantitatively in terms of folding endurance. Folding endurance of the film was determined by repeatedly folding a small strip of the film (approximately 2x2 cm) at the same place till it broke. The number of times film could be folded at the same place, without breaking gives the value of folding endurance.¹⁵

Drug content uniformity of films: The films were tested for drug content uniformity by UV Spectrophotometric method. Films of 2×2 cm size were cut from three different places from the casted films. Each film was placed in 100 mL volumetric flask and dissolved in simulated saliva pH 6.8 and 2 mL is taken and diluted with water up to 10 ml. The absorbance of the solution was measured at λ_max 240 nm using UV/ visible spectrophotometer (Shimadzu). The percentage drug content was determined.¹⁷

Tensile Strength: The Tensile strength of the implants was determined by the Universal strength testing machine. It consists of two load cell grips, the lower one is fixed and the upper one is movable. The test fims of specific size (2*2 cm²) were fixed between these cell grips and force was gradually applied till the implants breaks.¹⁸Tensile strength was calculated by using formula:

Force at break (N)

Tensile strength = ------------------------------------------

Initial cross-sectional area of films (mm²)

In-vitro drug release:

The release rate of cilnidipine fast dissolving oral films was determined by using USP dissolution testing apparatus II at 50 RPM. The film with 2×2cm was placed in the 500ml of phosphate buffer pH 6.8 as dissolution medium, and temperature was maintained at 37°C. From this dissolution medium, 5 mL of the sample solution was withdrawn at different time intervals. The samples were filtered through Whitman filter paper and absorbance was determined 240nm using double beam UV- Visible spectrophotometer.¹⁹

Stability studies: Stability studies on the optimized formulation were carried out to determine the effect of temperature and humidity on the stability of the drug. The film (optimized batch) was stored in the stability chamber at 5±3⁰C for 90 days. The samples were withdrawn after 90 days and subjected for weight of film and In-vitro drug release studies.²⁰

RESULTS AND DISCUSSION:

Drug polymer compatibility study:

The drug polymer compatibility was studied by FT-IR Spectroscopy (BRUKER ALPHA E). FT-IR spectrum for Cilnidipine and Optimized formulation (PE3) are shown in Figure: 11 and 12.

Fig 11: FTIR of Pure Cilnidipine

Fig 12: FTIR of Optimized formulation (PE3)

Differential Scanning Calorimetry:

The DSC thermograms of Cilnidipine and prepared crystals were shown in the Figure 13 and 14. The DSC thermogram of Cilnidipine showed an endothermic peak at 108.94 °C and the prepared crystals in ethanol by ultrasonication (Probe) showed endothermic peak at 114.96°C. There was no appreciable change in the melting point endotherm of prepared crystals compared to that of pure drug.

Fig 13: DSC of Pure Cilnidipine

Fig 13: DSC of Optimized Formulation (PE3)

Scanning Electron Microscopy:

Surface morphology of pure drug and prepared crystals were examined by Scanning electron microscopic studies. SEM micrographs of pure drug are shown in the Figure 15. The morphology of pure drug is improved after ultrasonic crystallization and the crystals are smaller than pure drug. The morphology of formulation (PE3) shows much smaller crystals that are shown in Figure 16 compare to the morphology of pure drug.

Fig 15: SEM Image of pure drug Cilnidipine

Fig 16: SEM Images of Optimized Formulation (PE3)

Figure 21: Comparison of In-vitro dissolution profile of Pure Drug and prepared crystals by Anti-solvent crystallization method.

Compatibility study of Cilnidipine crystals with polymers:

The Crystals with polymer compatibility was studied by FT-IR Spectroscopy is shown in Figure 23. The IR spectra of physical mixture similar peaks present in polymers and crystals also, there is no much deviation in the peak position. Hence it shows that polymer was compatible with the crystals.

Fig 22: FT IR spectra of Cilnidipine crystals

Fig 23: FT IR spectra of physical mixture of crystals polymers

Scanning electron microscopy:

The SEM of placebo and drug loaded films reveal that the surface of films was smooth and free from air bubbles. The results are shown in Figure 24 and 25.

Fig 24: SEM images of placebo Films

Fig 25: SEM images Drug loaded Films

Evaluation of Fast Dissolving Sublingual Films:

All the films prepared with different polymer concentrations were found to be flexible, smooth, translucent, non-sticky and homogeneous. The drug and polymer distribution were uniform. The mean value of weight for HPMC E5 based films were between 6.14±0.13mg to 6.45±0.08mg and for HPMC E15 films were found between 5.27±0.13 to 5.98±0.12mg and for HPMC E50 films were found between 6.28 ±0.10mg to 5.33±0.11mg. The weight of film was increased with increase in polymer concentration. The thickness of the Films formulations F1 – F6, developed with HPMC E5, E15 and E50 were found ranging from 0.104±0.0274mm to 0.147±0.0282mm. From the obtained thickness data, it was observed that the thickness of the film was increased by increasing in the concentration of the film former. Hence, the thickness of the film was directly proportional to its film former concentration. The pH of films were measured in triplicate for each sample and found in the range from 6.2–6.8 within average of around pH 6.80 which, indicated that pH range was well within the targeted pH. The results are shown in Table 14.

The folding endurance was more than 250 times which reflects the flexibility of the films. Tensile strength was determined by Digital tensile strength apparatus. Tensile strength ranging from: 1.05 N/mm2 to 1.48 N/mm2.Drug content uniformity test was carried out, in order to make sure about the uniform dispersion of drug in the films. The drug content was analyzed using UV- Vis Spectrophotometer at 240 nm. The results indicated that the drug was uniformly dispersed the procedure of preparing polymeric solution gives the reproducible results ranging from 88.81% to 94.72%. The results are shown in Table 15.

In-vitro Dissolution studies for Fast Dissolving Sublingual Films:

Phosphate buffer pH 6.8 was used which were similar to the pH of saliva. Since the films should be immobile in the sublingual cavity. From the in-vitro drug release, it was observed that the drug release was found to be faster from films containing higher concentration of HPMC E5 and HPMC E15 than HPMC E50 based films. The results of in-vitro drug release are shown in Table 16 and Figure 26 the Cumulative percentage of formulation ranges from 88.65% to 95.55%. The release of the drug from HPMC E5 films was found to be higher compared to all other films. Among all six formulations F2 with 95.55% shows maximum drug release compare to other formulation.

Table 14: Weight Uniformity, Thickness, Surface pH (n=3)

Formulation code	Weight Uniformity (mg) ±RSD (%)	Thickness(mm) ±RSD (%)	Surface pH ±RSD (%)
F1	6.14 ± 0.13	0.124±0.0294	6.7±0.74
F2	6.25 ± 0.08	0.147±0.0282	6.8±0.97
F3	6.07 ± 0.13	0.104±0.0274	6.5±0.42
F4	6.18 ± 0.12	0.127±0.0311	6.8±0.12
F5	6.11 ± 0.10	0.119±0.0279	6.6±0.97
F6	6.13± 0.11	0.136±0.0245	6.5±0.74

Table 15: Folding Endurance, Tensile Strength, Drug Content Uniformity(n=3)

Formulation code	Folding Endurance ±RSD (%)	Tensile strength (N/mm² ) ±RSD(%)	Drug Content Uniformity (%) ±RSD (%)
F1	121±1.5	1.05	88.817±0.47
F2	136±0.81	1.24	93.757±0.23
F3	130±0.81	1.35	92.913±0.19
F4	124±0.35	1.14	93.757±0.83
F5	139± 0.95	1.32	90.970±0.16
F6	143± 0.5	1.48	92.724±0.26

Table 16: In-vitro dissolution studies of Fast Dissolving Sublingual Films of from F1 to F6 in Phosphate buffer 6.8

Time (min)	% Drug Release
Time (min)	F1	F2	F3	F4	F5	F6
0	0	0	0	0	0	0
2	27.11±0.65	29.18±0.76	23.60±0.95	25.58±0.73	21.89±0.71	22.70±0.65
4	42.62±0.32	45.52±0.92	39.43±0.61	41.25±0.22	37.43±0.34	38.43±0.79
6	65.20±0.78	67.13±0.48	59.37±0.73	63.47±0.71	54.74±0.31	56.11±0.43
8	79.77±0.56	81.89±0.21	76.08±0.95	77.75±0.42	71.96±0.99	73.34±0.66
10	94.05±0.25	95.55±0.45	91.97±0.78	93.47±0.84	87.65±0.78	88.67±0.52

Figure 26: Comparison of In-vitro dissolution profile of Cilnidipine Crystals and prepared Fast Dissolving Sublingual Films.

Short-term stability studies: The short-term stability study was carried out as per ICH Guidelines on the most satisfactory Formulation F2 temperature at 40±2^oC and 75±5% RH for a period of 90 days. At fixed time, the formulation was evaluated after for their physicochemical parameters and in-vitro drug release. There was no significant difference in the physicochemical parameters and in-vitro drug release with the initial results. The results are shown in Table 17, this indicates that the prepared Fast dissolving sublingual films were found to be stable.

Table 17: Physicochemical evaluation of Optimized formulation F2 after stability studies (40 ± 2^oC)

Sl. No.	Parameters	Before stability testing	After stability testing
1.	Weight Uniformity	6.45 ± 0.08	6.42±0.57
2.	Thickness	0.147±0.0282	0.143±0.66
3.	Surface pH	6.5±0.42	6.6±0.54
4.	Folding Endurance	126±0.81	125±0.11
6.	Drug Content Uniformity	93.757±0.83	91.987±0.19
7.	In-vitro Dissolution study	95.55±0.45	95.07±0.27

CONCLUSION:

Preformulation studies for Cilnidipine encompassed solubility, melting point, λmax determination, and calibration curve plotting. Notably, Cilnidipine exhibited varying solubility across different solvents, with highest solubility in acetone, ethanol, and dichloromethane. Utilizing antisolvent crystallization techniques, successful preparation of Cilnidipine crystals was achieved, validated by FTIR and DSC analyses indicating polymer-drug compatibility. Ultrasonication with ethanol yielded smaller crystals with reduced X-ray diffraction peak intensity. PE3 crystals, particularly synthesized via ethanol ultrasonication, displayed markedly enhanced solubility and dissolution rates compared to pure drug and other crystal forms. PE3 was thus selected as the optimized formulation. Incorporating PE3 into Fast Dissolving Sublingual Films via solvent casting method. polymer-crystals compatibility was confirmed by FTIR spectra. SEM analysis showed mechanically stable films with suitable surface pH for sublingual administration. Evaluation parameters including thickness, folding endurance, and tensile strength indicated mechanical stability, with uniformity in weight and drug content across formulations. In vitro drug release studies demonstrated sustained release for over 10 minutes, favouring formulation F2 as the optimal choice. Short-term stability studies validated the stability of F2 formulation per ICH guidelines. Probe sonication notably improved Cilnidipine's dissolution and bioavailability, with PE3 successfully integrated into fast-dissolving sublingual films. Future research should explore in vivo and ex vivo studies to assess efficacy. In conclusion, formulating fast-dissolving sublingual films for Cilnidipine offers a convenient, water-free administration method, promising rapid onset of action and potentially enhancing patient compliance and therapeutic outcomes.

REFERENCES:

1. Bhura N, Sanghvi K, Patel U, Parmar B. A review on fast dissolving film. The International Journal of Pharmaceutical Research and Bio-Science. 2012; 1(3): 279-285.

2. Narang N, Sharma J. Sublingual mucosa as a route for systemic drug delivery. Int J Pharm Pharm Sci. 2011; 3(2): 18-22.

3. Saha PU, Verma SU, Das PS. Sublingual drug delivery: an indication of potential alternative route. International Journal of Current Pharmaceutical Research.

4. Sharma A K. Development and evaluation cilnidipine fast dissolving tablet by using is apghula husk as natural super disintegrant. Tablet. 2019; 11(1); 01-11.

5. Thorat V P, Mahaparale P R and Gonjari I D. Fast Dissolving Drug Delivery System of Cilnidipine using Gelucire 50/13. Research J. Pharm. and Tech. 2019; 12(5):2185-2188.

6. Park MW, Yeo SD. Antisolvent crystallization of carbamazepine from organic solutions. Chemical Engineering Research and Design. 2012 Dec 1;90(12):2202-8.

7. Kaza R, Yalaravathi PR, Ravoru N. Design and Characterization of Fast Dissolving Films of Valsartan. Turk J Pharm Sci. 2014; 11(2):175-84.

8. Chethan Patel DN, Shrenath A. A solubility enhancement of aceclofenac by new crystallization technique. Asian Journal of Pharmaceutical and Clinical Research. 2022;15(2):113-118.

9. Maghsoodi M, Shahi F. Combined Use of Polymers and Porous Materials to Enhance Cinnarizine Dissolution. Pharmaceutical Sciences. 2019;25(4):331-337.

10. Ammar HO, Ghorab M, Kamel R, Salama AH. A trial for the design and optimization of pH-sensitive microparticles for intestinal delivery of cinnarizine. Drug Delivery and Translational Research. 2016;6(3):195-209.

11. Singh H, Kumar M, Gupta S, Sekharan TR, Tamilvanan S. Influence of hydrophilic polymers addition into cinnarizine-β-cyclodextrin complexes on drug solubility, drug liberation behaviour and drug permeability. Polymer Bulletin. 2018; 75(7): 2987-3009.

12. Shahba AA, Ahmed AR, Alanazi FK, Mohsin K, Abdel-Rahman SI. Multi-layer self-nanoemulsifying pellets: An innovative drug delivery system for the poorly water-soluble drug cinnarizine. AAPS Pharm SciTech. 2018; 19(5): 2087-2102.

13. Janrao KK, Gadhave MV, Banerjee SK, Gaikwad DD. Preparation and Characterization of Spherical Crystals of Simvastatin to enhance the Solubility and Micrometric Properties. Asian Journal of Pharmaceutical Research and Development. 2014; 2(2): 96-104.

14. Mohapatra S, Sahoo SK, Kar RK. Application of central composite design for optimization of effervescent floating Tablets Using Hydrophilic Polymers. Asian Journal of Pharmaceutical and Clinical Research. 2015; 8(1): 293-298.

15. Modh.N H, Mahe.M, Pan H. Formulation and evaluation of sublingual film of prazocin HCl. Journal of Emerging Technologies and Innovative Research 2021;8(5):596-607.

16. Kaur P, Kumar V. Formulation development and evaluation of fast dissolving bioadhesive sublingual film of sumatriptan. World Journal of Pharmaceutical Research. 2017; 6(14): 385-410.

17. Aher SS, Sangale VD, Saudagr RB. Formulation and evaluation of sublingual film of Hydralazine Hydrochloride. Research Journal of Pharmacy and Technology. 2016; 9(10): 1681-90.

18. Harshitha KN, Shruthi BN, ST B. Design and Characterization of Fast Dissolving Films of Cilnidipine Solid Dispersions. 2018; 8(14): 207-218.

19. Velrajan G, Sambasivarao P, Kannan S. Design and evaluation of moxifloxacin periodontal films. World Journal of Pharmaceutical Research. 2014; 3(3): 4208- 4216.

20. Wadetwar RN, Ali F, Kanojiya PR. Formulation and Evaluation of Fast Dissolving Sublingual Film of Paroxetine Hydrochloride for Treatment of Depression. Asian Journal of Pharmaceutical Clinical Research. 2019; 12(10): 126-32.

Received on 19.10.2024 Revised on 13.12.2024

Accepted on 06.01.2025 Published on 27.02.2025

Available online from March 05, 2025

Asian J. Pharm. Tech. 2025; 15(1):25-33.

DOI: 10.52711/2231-5713.2025.00005

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

Time (min)	% Drug Release
Time (min)	Pure Drug	A1	E2	BA2	BE2	PA3	PE3
0	0	0	0	0	0	0	0
5	0.74±0.18	5.23±0.43	5.88±0.32	7.34±0.35	9.65±0.16	7.54±0.45	9.41±0.17
10	0.94±0.22	7.82±0.56	9.97±0.24	11.67±0.51	15.16±0.41	17.65±0.15	16.53±0.91
20	1.18±0.14	12.67±0.78	16.75±0.77	19.34±0.72	27.73±0.54	26.74±0.73	30.27±0.85
30	2.20±0.08	19.80±0.16	25.47±0.29	27.45±0.84	40.17±0.52	37.85±0.81	42.20±0.71
40	3.16±0.10	26.56±0.65	31.43±0.36	39.34±0.47	52.88±0.28	50.45±0.74	55.24±0.48
50	4.80±0.18	35.19±0.58	46.87±0.47	51.86±0.65	63.78±0.14	63.65±0.24	65.72±0.32
60	6.96±0.20	47.83±0.92	52.54±0.86	68.75±0.71	74.41±0.76	75.45±0.37	82.56±0.18