Formulation and Evaluation of Bosentan Pulsatile Drug Delivery System by using Press Coated Technique

 

Shiva Srikrishna¹*, Kasula Sadhana¹, Ramya Sri S²

¹Department of Pharmaceutics, Samskruti College of Pharmacy,

Affiliated to JNTUH University, Hyderabad 501301, Telangana, India.

²Department of Pharmacy, University College of Technology,

Osmania University, Hyderabad - 500007, Telangana, India.

 

ABSTRACT:

In the present research work, we have designed a pulsatile formulation of Bosentan to treat High blood pressure as per the chronotherapeutic pattern of the disease. Core tablets were prepared by incorporating different concentration of disintegrants and were compressed in between different concentration of polymers. The core and compression coated tablets were subjected to pre-formulation, physicochemical and In-vitro drug release studies. FTIR studies revealed that there was not any chemical reaction between pure drug Bosentan and polymers. The pre and post-compressional parameters of tablets were also found to be within limits. Our optimized formulation F-6 releases Bosentan after a lag time of 2 hours and 98.01 % up to 12 hours.  Formulations were stable for at least 3 months under standard long-term and accelerated storage conditions.

 

 

 

INTRODUCTION:

Bosentan is chemically, 4-tetrabutyl-N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl) pyrimidin-4-yl] benzene-1-sulfonamide2. (Fig.1). It is a white crystalline powder .chemical formula C27H29N5O6S, and Molecular weight of551.6.¹ Bosentan is used to lower the pulmonary hypertension by blocking the action of endothelin-1 molecules responsible for narrowing the blood vessels and elevates high blood pressure².

 

Bosentan monohydrate was selected active therapeutic agent which is having 50% absolute bioavailability and 5 hours of terminal elimination half-life.

 

The innovator Trachleer is successful brand tablet formulation of Bosentan monohydrate US manufactured by PatheonInc and marketed by Acteleon pharmaceuticals US was found to be expensive and exhibits high cost benefit ratio.³

 

Anti-hypertensive agents hold a major share of drug market as hypertension is a major cause of health problems. The estimated market share of anti-hypertensive agents is $30 billion by 2016. As a consequence, the chances of adulteration increases due to increased market needs. Adulteration in any form is not acceptable for any drugs, especially for Anti-hypertensive agents.⁴ Hypertension is a condition in which the force of blood against the artery wall is too high usually systolic blood pressure greaterthan 140mm Hg or diastolic blood pressure greater than 90mm Hg or both over a sustained period. Hypertension is habitual heart disease; it is generally   increased with ageing.⁵ Hypertension can also accelerate atherogenesis and can induce changes favorable for aortic dissection and cerebrovascular hemorrhage.⁶

 

Pulsed or pulsatile drug release is defined as the rapid and transient release of a certain amount of drug molecules within a short time-period immediately after a predetermined off-release period.⁷ The principle rationale for the use of pulsatile release is for the drugs where a constant drug release, i.e., a zero-order release is not desired.⁸ Pulsatile drug delivery system has the advantage of avoiding drug tolerance or matching the chronotherapeutic needs.⁹ Advantages of Pulsatile drug delivery systems are Predictable, reproducible and short gastric residence time, Less inter- and intra-subject variability, Improve bioavailability, Reduced adverse effects and improved tolerability, Limited risk of local irritation.¹⁰ Limitations:  Multiple manufacturing steps in case of Multiparticulate drug delivery system,  Low drug loading capacity and incomplete release of drug,  In vivo variability in single unit pulsatile drug delivery system, Drug dose manipulation in case of child and elder patients is not possible, Immediate withdrawal of drug is not possible.¹¹

 

MATERIALS AND METHODS:

Bosentan Procured from Zydus Pharmaceuticals., Provided by Sura Labs, Dilsukhnagar, Hyderabad.  Croscarmellose sodium procured from Yarrow Chem. Products, Mumbai.  Carbopol 974P, HPMC K15 and Ethyl cellulose procured from S.D. Fine chemicals limited (Hyderabad). PVP K30 procured from FMC Biopolymers. Magnesium Stearate procured from Himedia Chem Lab, Mumbai. Microcrystalline cellulose procured from microcrystalline cellulose. Talc procured from ZIM Laboratories Ltd, Nagpur.

 

Formulation development of Tablets:¹⁰

Formulation of core tablets by direct compression: The inner core tablets were prepared by using direct compression method as shown in the Table 1. Powder mixtures of Bosentan, Croscarmellose sodium, Pvpk 30, Talc and Microcrystalline cellulose ingredients were dry blended for 20 min. followed by addition of Magnesium stearate. The mixtures were then further blended for 10 min., 200mg of resultant powder blend was manually compressed using , Lab press Limited, India with a 7 mm punch and die to obtain the core tablet.                     

 

Formulation of mixed blend for barrier layer:

The various formulation compositions containing Carbopol 974P, HPMC K15, Ethyl cellulose, Talc and Microcrystalline Cellulose. Different compositions were weighed dry blended at about 10 min and used as press coating material to prepare press-coated pulsatile tablets respectively by direct compression method.

 

Preparation of press-coated tablets:

The core tablets were press-coated with 100mg of mixed blend as given in Table. 150mg of barrier layer material was weighed and transferred into a 6mm die then the core tablet was placed manually at the center. The remaining of the barrier layer materiel was added into the die and compressed by using Lab press Limited, India.

 

Table 1: _{Formulation development of core tablets}

Ingredients	C1	C2	C3
Bosentan	62.5	62.5	62.5
Croscarmellose sodium	30	60	90
Pvpk 30	10	10	10
Magnesium stearate	3	3	3
Talc	2	2	2
Microcrystalline cellulose	Q.S	Q.S	Q.S
Total weight	200	200	200

_{Table 2:  Formulations for press coated tablets}

Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9
Carbopol 974P	20	40	60	-	-	-	-	-	-
HPMC K15	-	-	-	20	40	60	-	-	-
Ethyl cellulose	-	-	-	-	-	-	20	40	60
PVP K30	15	15	15	15	15	15	15	15	15
Magnesium Stearate	3	3	3	3	3	3	3	3	3
Microcrystalline cellulose	Q.S	Q.S	Q.S	Q.S	Q.S	Q.S	Q.S	Q.S	Q.S
Talc	2	2	2	2	2	2	2	2	2
Total weight	100	100	100	100	100	100	100	100	100

 

RESULTS AND DISCUSSION:

 

Fig 1: Standard Graph of Bosentan in 0.1N HCL

_{Standard graph of Bosentan in phosphate buffer (pH6.8)}

 

Fig 2:  Standard Graph of Bosentan _{in pH 6.8 phosphate buffer}

FT-IR (Fourier Transform Infrared Spectrophotometry)

 

 

The spectra for pure Bosentan and for the physical mixture of Bosentan and all the polymers were determined to check the intactness of the drug in the polymer mixture using FTIR Spectrophotometer.

 

The comparative FTIR studies of Drug and excipients combination had shown negligible variation in the values as compared with that of only pure form of Drug. Therefore it implies good compatibility of drug and excipients.

 

From the above table, the wave number of mixture of drug with excipients is within the range of wave number of pure drug. This implies that the excipients are compatible with the drug since their combination did not alter the functional groups of pure drug

 

Tablet powder blend was subjected to various pre-formulation parameters. The angle of repose values indicates that the powder blend has good flow properties. The bulk density of all the formulations was found to be in the range of 0.54±0.13 (gm/cm3) showing that the powder has good flow properties. The tapped density of all the formulations was found to be in the range of   0.617± 0.09 to 0.628± 0.08 showing the powder has good flow properties. The compressibility index of all the formulations was found to be ranging from 14.43±0.41 to 14.89±0.55 which were showed that the powder has good flow properties. All the formulations has shown the hausner ratio ranging from 1.1655± 0.05 to 1.1749± 0.03 indicating the powder has good flow properties.

 

All the parameters such as weight variation, friability, hardness, thickness and drug content were found to be within limits.

 

Weight variation and thickness:

All the formulations were evaluated for uniformity of weight using electronic weighing balance and the results are shown in table 3. The average tablet weight of all the formulations was found to be between 199.14 to 200.26. The maximum allowed percentage weight variation for tablets weighing <200 mg is 10 % and no formulations are not exceeding this limit. Thus all the formulations were found to comply with the standards given in I.P. And thickness of all the formulations was also complying with the standards that were found to be between 3.82 to 3.98.

 

Hardness and friability:

All the formulations were evaluated for their hardness, using monsanto hardness tester and the results are shown in table 3. The average hardness for all the formulations was found to be between (4.2– 4.6) Kg/cm² which was found to be acceptable.

Table 3: Post compression parameters of Core tablet:

Formulation code	Average Weight (mg)	Hardness (kg/cm2)	Friability (%loss)	Thickness (mm)	Drug content (%)	In vitro disintegration time (min)
C1	199.95	4.6	0.36	3.98	99.31	35
C2	200.26	4.2	0.25	3.82	98.14	26
C3	199.14	4.3	0.23	3.90	100.09	20

 

 

Friability was determined to estimate the ability of the tablets to withstand the abrasion during packing, handling and transporting. All the formulations were evaluated for their percentage friability using roche friabilator and the results were shown in table 3. The average percentage friability for all the formulations was between 0.23-0.36 which was found to be within the limit.

 

Drug content:

All the formulations were evaluated for drug content according to the procedure described in methodology section and the results were shown in table 3. The drug content values for all the formulations were found to be in the range of 98.14 to 100.09. According to IP standards the tablets must contain not less than 95% and not more than 105% of the stated amount of the drug. Thus, all the formulations comply with the standards given in IP.

 

In vitro disintegrating time:

All the formulations were evaluated for in vitro disintegration time according to the procedure described in methodology section and the results were shown in table 3. The in vitro disintegration time values for all the formulations were found to be in the range of 20 to 35.

 

Tablet powder blend was subjected to various pre-formulation parameters. The angle of repose values indicates that the powder blend has good flow properties. The bulk density of all the formulations was found to be in the range of 0.326±0.98 – 0.511±0.03 (gm/cm³) showing that the powder has good flow properties. The tapped density of all the formulations was found to be in the range of 0.477±0.23 - 0.614±0.11 showing the powder has good flow properties. The compressibility index of all the formulations was found to be ranging from 17.04±0.06 to 22.27±0.05 which show that the powder has good flow properties. All the formulations has shown the hausner ratio ranging between 1.193±0.99 to 1.313±0.16 indicating the powder has good flow properties.

 

 

Table 4: Post compression parameters of Coated tablet:

Formulation code	Average Weight (mg)	Hardness (kg/cm2)	Thickness	Friability (%loss)	Drug  content (%)
F1	99.39	5.3	3.69	0.36	98.30
F2	98.72	5.6	3.58	0.58	99.12
F3	100.01	5.9	3.31	0.42	98.25
F4	98.25	5.0	3.92	0.30	97.10
F5	97.66	5.6	3.76	0.18	96.32
F6	96.85	5.3	3.86	0.27	98.53
F7	98.50	5.1	3.51	0.62	99.14
F8	98.21	5.8	3.93	0.51	98.99
F9	99.15	5.4	3.75	0.73	98.35

 

Post compression parameters for tablets:

All the parameters such as weight variation, friability, hardness, thickness and drug content were found to be within limits.

 

Weight variation and thickness:

All the formulations were evaluated for uniformity of weight using electronic weighing balance and the results are shown in table 4. The average tablet weight of all the formulations was found to be between 96.85 to 100.01. The maximum allowed percentage weight variation for tablets weighing >100 mg is 5% and no formulations are not exceeding this limit. Thus all the formulations were found to comply with the standards given in I.P. And thickness of all the formulations was also complying with the standards that were found to be between 3.31 to 3.93.

 

Hardness and friability:

All the formulations were evaluated for their hardness, using monsanto hardness tester and the results are shown in table 4. The average hardness for all the formulations was found to be from 5.0 to 5.9Kg/cm² which were found to be acceptable.

 

Friability was determined to estimate the ability of the tablets to withstand the abrasion during packing, handling and transporting. All the formulations were evaluated for their percentage friability using roche friabilator and the results were shown in table 4. The average percentage friability for all the formulations was between 0.18 – 0.73 which was found to be within the limit.

 

Drug content:

All the formulations were evaluated for drug content according to the procedure described in methodology section and the results were shown in table 4. The drug content values for all the formulations were found to be in the range of (96.32 to 99.14). According to IP standards the tablets must contain not less than 95% and not more than 105% of the stated amount of  the drug. Thus, all the formulations comply with the standards given in IP.

 

In Vitro Drug release studies of Bosentan core tablet:

In vitro dissolution studies of Bosentan core tablets were performed using USP XXIII Type II rotating paddle dissolution apparatus  by using phosphate buffer (pH 6.8) as a dissolution medium. From formulation C1-C3 Bosentan core tablets, C3 showed faster drug release than the other formulations. Faster drug release can be correlated with the high disintegration time.  So, C3 formulation was selected as best formulation for further press coating and enteric coating formulations. In vitro drug release profiles of all Bosentan core tablets were shown in Table 6.

 

Table 5: Drug release of Bosentan core tablets

Time (min)	C1	C2	C3
0	0	0	0
5	25.19	32.21	43.36
10	40.57	45.26	56.81
15	47.36	58.62	69.06
20	53.19	67.73	77.43
30	65.98	78.89	82.99
45	72.52	85.11	92.35
60	83.42	92.34	99.73

 

In vitro drug release study of Bosentan pulsatile tablets:

Based on the above characters formulation C3 was selected as best formulation and that C3 formulation were used for the further study i.e., delayed release using press coated method.  The time dependent pulsatile tablets were prepared by using different concentrations of Croscarmellose sodium. The formulations C1, C2, and C3 showed maximum drug release at immediately.

 

Table 6: Cumulative % drug release of Coated Bosentan tablets

Time (hr)	F1	F2	F3	F4	F5	F6	F7	F8	F9
0	0	0	0	0	0	0	0	0	0
0.5	0.51	0.30	0.21	1.39	0.52	0.14	0.82	0.50	0.23
1	4.49	1.81	0.92	2.52	1.14	1.01	1.86	1.16	1.10
2	5.14	4.96	2.81	4.81	3.76	2.43	2.92	2.29	2.02
3	40.36	37.93	32.72	43.26	35.83	28.79	27.17	20.71	18.21
4	45.91	40.65	38.40	56.81	47.91	34.67	36.53	28.63	23.69
5	51.52	46.49	44.11	69.99	53.25	41.33	41.75	39.82	32.23
6	68.40	55.66	50.82	78.53	67.56	52.10	46.19	41.95	37.42
7	73.98	65.91	63.97	83.19	75.90	60.79	55.83	50.38	45.87
8	87.12	72.54	66.34	91.46	81.11	75.21	59.71	56.12	53.21
9	96.76	73.28	71.77	98.82	85.47	80.34	66.11	60.95	59.62
10		85.41	84.82		90.59	86.13	75.86	67.12	65.37
11		92.09	90.91		93.76	95.59	84.25	72.10	70.15
12			96.89		96.93	98.06	93.93	89.57	87.21

 

The formulations F4 to F6 containing different concentrations of HPMC K15, at low concentration of coating material it was not delayed up to desired time the core tablet immediately release at 2 hr. whenever the coating material concentration was increased to 60 mg the maximum % drug release of core tablet from coated tablet at 12 hrs. So F6 formulation was retarded the drug release up to 12hrs. Hence F6 formulation was good formulation, So F6 was considered as optimized formulation.

 

The formulations F7 to F9 were containing Ethyl cellulose. At low concentration such as 40, 60mg of Ethyl cellulose was unable to delay the drug release up to desired time hence that formulations were not considered. Then the coating polymer concentration was increased to 60mg F9 was showed maximum % drug release 87.21 % at 12 hours.

 

Release kinetics:

              

Fig 3: Zero order plot of optimized formulation

 

This formulation was following Zero order release mechanism with regression value of 0.969.

CONCLUSION:

·      A chronomodulated drug delivery system for Bosentan for the treatment of pulmonary artery hypertension was successfully developed. The system was found to be satisfactory in terms of release of the drug after a lag time of 2 hrs.

·      The formulation (F6) HPMC K15 (60mg)) gave satisfactory release lag time of 2 hrs and it was found to be successful in achieving pulsatile drug delivery.

·      The technology (press-coating) used for the preparation of press-coated pulsatile tablets (PCPT) is a relatively simple manufacturing process which can be easily adopted in industrial units on a commercial scale.

·      From formulation C1-C3 Bosentan core tablets, C3 showed faster drug release than the other formulations. Faster drug release can be correlated with the high disintegration time.  So, C3 formulation was selected as best formulation for further press coating and enteric coating formulations. Among All Formulations F6 was showed maximum % drug release 98.01 % at 12 hours.  Hence F6 Formulation was considered as optimized Formulation.

 

ACKNOWLEDGEMENT:

Thе Authors arе thankful to Principal, Department of Pharmacy, Samskruti College of Pharmacy, for extending the support to carry out the research work. Finally, the authors express their gratitude to the Sura Labs, Dilsukhnagar, Hyderabad, for providing research equipment and facilities.

 

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Received on 08.10.2022       Modified on 10.11.2022

Accepted on 29.11.2022   ©AandV Publications All Right Reserved