Development and Evaluation of Sustained Release Matrix Tablet of Repaglinide and Miglitol Using Processed Aloe Vera Mucilage as Release Modifier

Diabetes mellitus is a chronic endocrine disorder characterized by hyperglycemia due to insulin deficiency or resistance. Repaglinide, a short-acting insulin secretagogue, stimulates pancreatic β-cells, while Miglitol, an alpha-glucosidase inhibitor, delays carbohydrate digestion and glucose absorption in the intestine. Despite their effectiveness, both drugs exhibit short elimination half-lives, necessitating multiple daily dosing, which reduces patient compliance. Natural polymers have gained attention due to their biodegradability, safety, and availability. Aloe vera mucilage contains polysaccharides that swell in aqueous environments, forming a gel-like matrix capable of controlling drug diffusion. This property makes it a promising release modifier in SR formulations.

MATERIAL AND METHODS

METHODOLOGY

Drug Study

• Tests such as Drug excipient compatibility were undertaken
• IR spectral studies were conducted on the pure drug and its physical mixes using an FTIR spectrophotometer in the wave number range of 4000 cm-1 to 400 cm-1. A comparison of the pure drug spectra and the physical mixes spectra were done.
• Studies for drug stability
• Studies for drug compatibility
• Studies for evaluation of drug
• Drug Content (Assay)
• Kinetic study of dissolution data

Aloe Vera mucilage extraction

• Fresh aloe Vera plant leaves were gathered and cleaned with water for elimination of dirt and debris.
• Cut leaves were placed in water for 5-6 hours prior to cooking for 30 minutes and standing time 1 hour for proper mucilage release.
• Three volumes of acetone were added to the filtrate to precipitate the mucilage after the material was pressed off the cloth to eliminate marc from the solution.
• Mucilage was separated and dried at a temperature of 50 degrees Celsius in an oven.
• No. 80 sieve was used to sieve dried powder and kept in a dessicator for later use.
• Flow characteristics were assessed;
• Bulk density was assessed;
• Compressibility index was assessed

Matrix tablets preparation:

Various tablet formulations will be made with various drugs: 1:1, 1:2, 1:3, 1:4, 1:5 are the polymer ratios. Before compression, the powder blend was examined.

1. Powder blend evaluation
2. Tablets' evaluation Thickness
3. Weight variation test
4. Friability and hardness
5. The drug's composition
6. Characteristics of swelling
7. Experiments on release in vitro.
8. Profile of kinetic release
1. Stability studies at a faster pace

Experimental Studies on Aloe Vera Extraction of mucilage:

A range of procedures were used to extract aloe Vera mucilage. To begin, plant leaves were collected and thoroughly cleaned in clean water to eliminate dirt and debris. For the release of mucilage in water, cutting of leaves and placement in water for 5-6 hours was done. It was then boiled for 30 minutes and left to stand for 1 hour. This causes precipitation of the mucilage, three liters of acetone. No. 80 sieve was used to sieve the powder after drying, before being stored in a desiccator. Before tablet compression, the mucilage was tested for flow characteristics.

Fig 24: Procedure of extraction

Fig. 25: Bulk density apparatus

Fig. 26: Funnel method for determination of angle of repose

Figure 27: FT-IR spectrum of Repaglinide and Miglitol (pure form)

Figure 28: FT IR Spectrum of PAG and Repaglinide and Miglitol

Time	Cumulative Drug Release %
	MKT	PAG 1	PAG 2	PAG 3	PAG 4	PAG 5
0	0	0	0	0	0	0
0.5	8.42	12.15	10.78	10.22	6.98	6.54
1	50.53	25.67	22.28	21.65	20.67	20.12
2	66.74	50.89	30.83	24.17	22.62	22.56
3	74.56	68.32	42.92	32.43	28.23	25.65
4	80.51	78.71	60.89	38.54	32.98	30.28
5	88.15	89.84	72.65	52.21	42.78	36.69
6	90.15	94.73	84.38	64.66	53.91	46.65
7			90.97	74.43	64.17	56.31
8			96.92	84.98	72.49	64.73
9				89.53	76.72	70.93
10				92.89	85.89	78.91
11					95.29	89.72
12						98.89

Fig. 31: In-vitro dissolution of PAG 1

Fig. 32: In-vitro dissolution of PAG 2

Fig. 33: In-vitro dissolution of PAG 3

Fig. 34: In-vitro dissolution of PAG 4

Fig. 35: In-vitro dissolution of PAG 5

Fig. 36: In-vitro dissolution of MKT (Marketed)

Figure 37: Dissolution characteristics of PAG1 to PAG5 Formulations

Fig. 38: Zero order release kinetics of optimized formulation PAG 5

Fig. 39: First order release kinetics of optimized formulation PAG5

Fig. 40: Higuchi model release kinetics of optimized formulation PAG5

Fig. 41: Korsmeyer and Peppas release kinetics of optimized formulation PAG5

Fig 42: Swelling index of PAG1, PAG2, PAG3, PAG4, PAG5 matrix tablets

The f- ratio value is 5.51729. The p-value is 0.000484. The result is significant at p<.05.

DISCUSSION

Determination whether direct compression or alternative granulation procedure is affected by the mixture flowability, assortation of excipient. Aloe barbadensis is a succulent from which mucilage of aloevera is taken which pertains a yellow color. Matrix tablet preparation was done from it. 30° was the angle of repose of the mucilage which showed satisfactory flow. Flow ability of the powder blend's was inspected. A satisfactory flow was obtained The tablets were directly compressed. From the dry powdered mucilage following parameters were inspected which were as follows; angle of repose, LBD, TBD, Carr's index, and Hausner's ratio. Carr's index (percent) value seen was 9.779 ± 1.35 to 12.28 ± 1.29. Angle of repose seen was 25.67±01.84 to 27.35±1.79. Also 0.250±0.005 to 0.289±0.003 reading was seen in LBD and 0.285±0.012 to 0.317±0.012 TBD respectively. Hausner's factor was 1.096±0.22 to 1.142±0.14. Flowability was checked for the powder blend's. The results showed excellent flowability. This was further supported by lower Carr’s index values. A range till 15% depicts very good flowability. The output product was reviewed for pharmacopoeial standards. Ideal prarameters for difference in weight was obtained by the product. A steady breadth of tablet was measured. Shock proofing was obtained by The condition to be hard was>5 kg/cm2 and chances of crumpling less than 1%. An ideal amount of Repaglinide and Miglitol seen in the manufactured tablets. Checking of thickness, drug content, friability (crumping capacity), and hardness for all tablets were done, and all the parameters were found admissible. Results demonstrated. The measured variation of 197±2.24 to 203±2.01 (weight variation) was seen. Difference (% variation) on an average was unobjectionable (adequate), attributing approval of official weight test by all tablets. Difference in hardness was assessed 5.7±0.2 to 6.6 ± 0.1 kg/cm2 for 10 tablets. Crumpling capacity in percentage (friability) for 10 tablets were assessed as 0.077±0.31 to 0.087±0.13%. All of the tablet formulations had a percentage friability of less than 1%. The drug content of several batches of tablets (n = 20) was found to be consistent, ranging from 98.10±0.3 to 99.67±0.4. All of the tablet formulations' swelling indexes were calculated over time. Because the weight obtained by the tablet rose proportionally as the rate of hydration increased up to a specific limit, the swelling index increased as time passed. Later on, as the tablet's outermost gelled coating dissolves into the dissolving media, it steadily shrinks. Swelling index and polymer concentration had a direct connection, with swelling index increasing as polymer concentration rose. Figure 42 shows the swelling index of the produced tablets. The swelling index was shown to grow with time, but then decrease. In the PAG5 formulation, the proportion of edema was higher. When cumulative percentage of drug release for PAG1, PAG2, PAG3, PAG4, PAG5 were 94.73%, 96.92%, 92.89%, 95.29% and 98.89% respectively at the end of 12 h. Formulation of PAG1 failed to sustain release beyond 6 h. Among all the preparations PAG5 showed 98.89% at the end of 12 h. It was observed that cumulative percentage of drug release decreased with increase in processed aloevera concentration.

Drug release kinetics

The data were fitted to various mathematical models to evaluate the kinetics and mechanism of drug release. The coefficient (regression coefficient) obtained for zero order kinetics were seen higher (R2=0.987 to 0.994), in comparison to first order kinetics (R2=0.772 to 0.864) indicating that for all formulation drug release followed zero order kinetics. In this analysis the in vitro release profile of drug from all these formulations could be best expressed by Higuchi’s equation which relates to the drug dissolution of water-soluble drug. This is because this plot showed highest linearity (R2=0.984 to 0.991). In order to relate and confirm the diffusion mechanism the data were fitted to Korsemeyer-Peppas equation. It was observed that all these formulations showed good linearity (R2=0.936 to 0.964) with slope (n) value ranging from 0.55 to 0.647. For the preparation of PAG1 to PAG5, the mechanism of release showed behaviour of anomalous (non-Fickian) diffusion. The ratio of drug and processed aloevera matrix increases it leads to the increase in n value. Coupling of diffusion, erosion mechanism (anomalous non-Fickian diffusion) is indicated by this n value. Therefore, it can be stated that diffusion coupled with erosion might be mechanism for drug release from aloevera matrix sustained release matrix tablets of Repaglinide and Miglitol. To conclude that in order to maintain effective plasma concentration, an ideal drug release with preset kinetics must be maintained for SR tablets. This can be consummated by such tablet fabrication which would release drug in calculable and repeatable way. Frequency of drug release can be calculated by researching the biopharmaceutical and pharmacokinetic characteristics.56 After 2 hours, drug release from the produced tablets was determined to be >20 percent, with zero-order release kinetics. When tablets made with A. Vera gel mucilage were compared to marketed tablets made with A. Vera gel mucilage, the rate of drug release from the marketed preparation was higher, confirming its release retardant qualities. The diffusion process and the de-integration procedure affects drug release. The PAG1 formulation had the greatest medication release rate. Within two hours, 12.15 - 50.89% of the medication had been released. Surface erosion of the matrix tablet prior to the creation of the gel layer surrounding the tablet core has been suggested as a possible reason. When compared to commercially available tablets, PAG5: the tablet with the greatest content of Aloe Vera mucilage displayed sluggish Repaglinide and Miglitol release. The PAG5 formulation released 64.73 percent of the medication in 8 hours, compared to 80 percent in 4 hours for commercially available Repaglinide and Miglitol tablets. A notable thing to be mentioned is that this formulation had more amount of aloe vera mucilage, which inhibited or delayed drug release. Calculation of drug release for 6 hrs depicted PAG1 having 94.73%. Where as when seen for 8 hrs. in PAG2 was 96.92%. PAG 3 being third had 84.98%. PAG 4 had 72.49%. When PAG1, PAG2, PAG3, PAG4 and PAG5 formulations were compared, PAG5 had more A. vera mucilage, which worked as a release retardant. According to the stability experiments, the formulation PAG5 did not alter significantly in terms of physical appearance, hardness, or drug content. As a result, the formulation remained stable under various storage circumstances. The findings clearly show that PAG may be used to modulate medication release by employing it in different ratios. We can eventually infer from the aforementioned experiments that aloevera mucilage can delay drug release. However further in IVIVC (invitro-in vivo correltion) can be established using in vivo animal models to claim the potential use of aloevera extract mucilage as release modifier.

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