INTRODUCTION:

Lymphangioleiomyomatosis (LAM) damage the Alveoli and unable the blood to get fully oxygenated and collapsed lung¹. Presently no cure/ drugs that improve lung function. Oxygen therapy and lung transplantation are the solutions for this issue. But organ transplantation arises rejection by the body and need immunosuppressant^2,3.

Sirolimus (SRS) is an immunosuppressant, prescribed to patients after organ transplantation to repel anti-rejection reaction by the body. SRS is an orphan drug and is also used to tackle the rare orphan disease LAM. SRS is of BCS class II drug with the issues of solubility⁴.

Extended drug delivery systems with controlled SRS discharge can be realized by various techniques among them matrix system is simple, inexpensive and effective⁵. The use of costly polymers can be discharged by economical and easily available herbal leave mucilage from Hibiscus rosa sinensis leaves mucilage (HRLM)⁶.

MATERIALS AND METHODS:

Material:

The materials required in this work are illustrated in table 1.

Table 1. List of materials

Materials	Suppliers/Manufacturer
Sirolimus	Gift sample by Zydus Biogen, Ahmedabad
HPMC	Fischer Chemic Ltd, Hyderabad
Lactose	Fischer Chemic Ltd, Hyderabad
Silicon dioxide (colloidal)	Fischer Chemic Ltd, Hyderabad
Talc	Fischer Chemic Ltd, Hyderabad
Water	Distillation unit of our Lab

Methods:

Identification of Sirolimus:

Identification of SRS was scrutinized for a physical look, melting point and solubility⁷.

Sirolimus calibration curve:

The procedure for plotting SRS calibration curve as illustrated in figure 1.

Figure 1. Procedure for obtaining Sirolimus calibration curve

Extraction of mucilage:

The extraction and purification were done as styled by Ahad et al., 2010. The fresh Hibiscus rosa sinensis leaves were washed, soaked and boiled in water. Later filtered isolated with Acetone, dried, # 80 sieved⁸.

Drug excipient compatibility studies:

Differential scanning calorimetry (DSC):

The DSC analyses of SRS and blend were done with Perkin Elmer, FTIR spectrophotometer to check any drug-excipient interaction. Each sample was placed in an aluminium pan separately with heating rates of 10°C/min from 50-300°C under nitrogen 50 ml/min.

FTIR study:

FTIR spectra and distinctive peaks of SRS and SRS with excipient blend were made by Bruker IR spectrophotometer.

Formulation of tablets by wet granulation technique:

Table 2. Composition of the tablets

Ingredients (mg)	Formulation
Ingredients (mg)	F-1	F-2	F-3	F-4	F-5	F-6
Sirolimus	1	1	1	1	1	1
Hibiscus rosa sinensis leaves mucilage	10	20	30	40	50	60
Lactose	15	15	15	15	15	15
Micro Crystalline Cellulose	64	54	44	34	24	14
Silicon dioxide (colloidal)	5	5	5	5	5	5
Talc	5	5	5	5	5	5
The weight of the tablets	100	100	100	100	100	100

Steps involved in the preparation of prolonged-release tablets (PRT) shown in figure 2.

Figure 2. Steps involved in matrix tablet preparation

Pre formulation studies:

The dried granules were checked for the flow patterns for checking their easy movement from hopper to tablet dyes for compression^9,10.

Post formulation studies:

The tablets were characterized for the following parameters^11,12.

Thickness of tablets:

A sliding caliper was used to know the thickness of 5 tablets from each batch.

Uniformity of weight:

20 tablets from each batch were weighed solely and the mean weight was also resolute. Later the unorthodoxy of individual weights was calculated.

Tablet hardness:

5 tablets were arbitrarily taken from each batch and hardness was dogged by using Pfizer tester.

The loss on friability:

A pre-weighed 10 tablets from each batch were allowed for 100 falls (4 min) from 6 inches and weighed after de-dusting.

Determination of drug content in tablets:

SRS content in the PRT was dogged by the procedure explained^13,14 in figure 3.

Figure 3. Procedure for determining the drug content in the tablets

In vitro dissolution studies

The dissolution conditions adopted for drug dissolution¹⁵ were concise in table 3.

Table 3. In vitro dissolution conditions

Parameter	Description
Apparatus	USP-II
Rotation (rpm)	100
Medium	0.1 M HCl for first 2 h then in pH 6.8 phosphate buffer solution for 10 h
Volume	900 ml
Temperature	37±0.5°C
Sampling at	1, 4, 6, 8, 10 and 12 h
Wavelength	278 nm

RESULTS AND DISCUSSION:

Results API characterization:

SRS appearance, melting point, and solubility were listed in figure 4.

Figure 4. Sirolimus identification parameters

Compatibility studies:

Neither loss of precise peaks nor productions of new peaks were seen in the DSC of SRS thermogram when equated to pure SRS which signposts no incompatibility of SRS with polymers used (table 4). The characteristic peaks present in the pure drug were also found even in the drug excipient combination indicating the compatibility of the drug with the excipients used (figure 5).

Pre formulation studies:

The flow parameters of the granules were illustrated in table 5.

Table 5. Flow parameters of the granules

	Flow properties
Formulation	Angle of repose (^o)	Bulk Density	Tapped Density	Carr’s Index	Hausner’s Ratio
F-1	26.35±0.01	0.521±0.02	0.545±0.02	4.403±0.09	1.046±0.01
F-2	28.54±0.15	0.522±0.03	0.569±0.03	8.260±0.15	1.090±0.02
F-3	25.38±0.25	0.489±0.05	0.521±0.06	6.142±0.04	1.065±0.03
F-4	27.49±0.14	0.456±0.09	0.501±0.04	8.982±0.12	1.098±0.05
F-5	28.01±0.19	0.465±0.04	0.510±0.02	8.823±0.02	1.096±0.01
F-6	28.96±0.17	0.415±0.06	0.451±0.08	7.982±0.19	1.086±0.06

Readings in mean ±SD; The number of trials (n=3)

Table 6. Physical Characteristics of the matrix table

	Physical parameter
Formulation	Uniformity of weight (mg)	Hardness (cm²)	Thickness (mm)	Friability (%)	Assay (%)
F-1	102.4±1.68	6.8±0.04	5.06±0.04	0.55±0.02	98.8±0.96
F-2	101.4±1.07	5.2±0.06	5.01±0.05	0.66±0.01	97.8±4.19
F-3	100.1±1.84	4.8±0.07	5.09±0.09	0.39±0.05	97.7±1.21
F-4	102.7±2.55	7.3±0.08	5.03±0.02	0.48±0.02	99.6±2.30
F-5	101.3±0.15	6.0±0.09	5.02±0.01	0.23±0.02	98.4±2.48
F-6	100.8±0.12	5.8±0.05	5.01±0.03	0.38±0.01	97.8±3.29

Values in mean ±SD; The number of trials (n=3)

SRS calibration curve (figure 6) shows a slope of 0.0745x-0.0099 with a regression (R²) value of 0.9996 (Figure 2.)¹⁶. The in vitro drug release chart of the formulated matrix tablets were illustrated in figure 7.

Figure 6. Calibration curve of Sirolimus

Figure 7. Drug release profile of prepared tablets

CONCLUSION:

The authors in this study experiential that Sirolimus matrix tablet covers the emission rate for the prolonged duration (>12 h) with increased bioavailability and devoid of repetitive dosing and dose. This was also noted that Hibiscus rosa sinensis leaves mucilage can be a good polymer in combination with HPMC for controlling the drug discharge with reduced adverse effects and cost and with improved patient happiness and effectiveness.

ACKNOWLEDGMENTS:

The authors would like to thank RERDS- CPR. Ananthapuramu, India for providing the facilities for performing the work.

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Received on 16.06.2021 Modified on 01.07.2021

Res. J. Pharma. Dosage Forms and Tech.2021; 13(4):276-280.

DOI: 10.52711/0975-4377.2021.00045

DSC sample	Endothermic events (°C)			ΔH Fusion	Inference
DSC sample	T onset	T peak	T End	Enthalpy (J)	Inference
Sirolimus	178.4	185.5	195.6	-389.37	An endothermic peak
Sirolimus+ Polymers	171.3	181.8	193.7	-358.84	A shift in peak to left due to positive blending of Sirolimus with polymers