Design, Formulation, Evaluation and Statistical Optimization of Coated Floating Pulsatile Tablets for Modified Chronopharmacotherapy of Rheumatoid Arthritis

doi:10.21203/rs.3.rs-3572886/v1

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Design, Formulation, Evaluation and Statistical Optimization of Coated Floating Pulsatile Tablets for Modified Chronopharmacotherapy of Rheumatoid Arthritis

https://doi.org/10.21203/rs.3.rs-3572886/v1

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Objective

The main aim of designing Coated Floating Pulsatile Tablets (CFPT) of Tramadol hcl for statistical optimization and to perform in vitro and in vivo buoyancy evaluation for modified chronopharmacotherapy of rheumatoid arthritis.

Methods

The formulation was designed with the immediate core covered with a compression coat followed by the upper buoyant layer. Best formulations of Immediate burst release core tablets were compression coated with polymer HPMC K15M, Ispaghula gum (IG), and Tamarindus gum (TG) to assign suitable lag time to formulation. HPMC K100M, Ispaghula gum, and their combination were compressed as the buoyant layers. Parameters such as BLT, TFT, %SI,% CDR were Statistical optimized by surface and contour plots AND invivo buoyancy was also done.

Results

Immediate release core tablets were optimized with formulation IF2 which contains sodium starch Glycolate 8% as immediate release agent, and then in compression coated buoyant formulation CFPT was optimized by DoE optimization showing BF4 and BF8 exhibiting good floating behavior and lag time, drug release for a period of 11 hrs. Abdominal X-ray imaging of rabbits after oral administration of the tablets, confirmed the floating behavior and lag time.

Conclusion

As the formulation showed delay in drug release both in in vitro and showed in vivo buoyancy, hence nighttime administration could be beneficial to reduce the rheumatoid arthritis complications in the early morning.

Pharmacokinetics

Rheumatoid arthritis

pulsatile coated floating tablets

Tramadol hcl

in vitro

in-vivo

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that arises more frequently in females than males and its prevalence rate is 0.5 to 1% of the population. RA mainly affects the synovial joints and is associated with progressive disability, premature death, and socio- economic burden. RA is a chronic disorder where there is no cure. Hence, the goal of RA treatment is to achieve the lowest possible levels of arthritis disease activity, minimize joint damage, and enhancing physical function and quality of life.^{(1, 2)}

Non steroidal anti-inflammatory agents (NSAIDS), corticosteroids, disease- modifying antirheumatic drugs (DMARDS), and other immunomodulators are treatment options. Analgesics are the agents which decrease the pain until DMARDS take effect. They act by reducing acute inflammation thereby decreasing pain and improving function. NSAIDS act by inhibiting prostaglandin synthesis and cause gastrointestinal risk. While in them coxibs reduce gastrointestinal effects but have a possible cardio vascular risk. Among these, opioid analgesics are the choice of drugs with fewer side effects. ^{(3, 4)}

Design of experiments is a statistical tool for obtaining interesting information in the design and optimization of dosage forms. Development of design approaches both meet the quality and cost criteria. Modified pulsatile systems have both immediate burst release followed by delayed release after a suitable lag time. This will provide greater patient compliance. In the present study of pulsatile coated floating tablets (PCFT) with factorial study design with three factors at two levels is suitable for chronopharmacotherapy of RA. ^{(5, 6)}

The drug Tramadol HCl was obtained from Hetero drugs pvt ltd, Hyderabad. Tamarindus kernel powder was collected from local market. To obtain Tamarindus Gum (TG) and Ispaghula gum (IG) were isolated by suitable procedures. Ingredients such as Sodium Starch Glycolate (SSG), kollidon CL, Cross Carmellose Sodium (CCS), Methocel K15M, Methocel K100, Sodium bicarbonate(SB) and citric acid were also obtained from yarrow chem. Products. Micro crystalline cellulose, talc, magnesium stearate, and lactose were of analytical grade.

Identification of drug and spectral studies by FTIR:

The drug was identified by performing UV-spectroscopy and its absorption maxima are 271nm. Drug excipient interaction studies were performed by FTIR. Spectral studies were established by conducting one- month compatibility of the drug and optimized formulation excipients at 40⁰C and 75% relative humidity. The obtained spectra were shown in Fig. 1

Isolation of Tamarindus gum:

TG was extracted from the tamarind kernel powder available in the market. The 20 g of defatted tamarind seed kernel powder was added to 200 ml of cold distilled water to prepare slurry. The slurry was then poured into 800ml of boiling distilled water containing citric acid (0.2%). The solution was boiled for 20 min with stirring in a water bath. The resulting thin clear solution was kept overnight (24 h) so that most of the proteins and fibers settled out, following which the solution was centrifuged at 5000 rpm for 20 min. Supernatant liquid was separated and poured into the excess of absolute alcohol with continuous stirring (1:1). The precipitate was washed with 200 ml of absolute ethanol, diethyl ether, and petroleum ether and/or acetone and dried at 50–60°C for 10 h. Dried polymer was powdered, sieved, and stored in desiccators ^{(7, 8)}

Isolation of Ispaghula gum:

Ispaghula Seeds were collected and soaked in distilled water for 48 h, boiled for 10–30 min until the mucilage was formed. This extracted mucilage was passed through a muslin cloth, so the obtained filtrate, acetone was added to precipitate the mucilage. Separate this precipitated mucilage, and dried in an oven 40⁰C, passed through #80 sieves, and stored in desiccators.

Formulation Development:

Modified release formulation consists of the immediate release formulation followed by the compression coat formulation. At first, the immediate release layer and rapid release core tablets were formulated by using super disintegrants such as SSG, kollidon CL, CCS by direct compression method. These formulations were represented in Table 1. These tablets were compression coated with both natural and synthetic polymers (MethocelK15M, KG and TG). These polymers according to table no 2 as CF1 to CF6 were mixed, 2/3 rd portion of the mixture was introduced in the die cavity, then the core tablet was placed and added the remaining 1/3rd portion, then compressed using 8mm punch. In the next step the buoyant compositions in Table no 5 using Ispaghula gum and Methocel K100M as major polymers for delayed floating were blended and compressed over the prepared compression coated tablet by using 9mm punch to obtain the coated floating tablets as BL1 to BL8 and finally the immediate release layer was compressed ^{(9, 10)}

Table 1

2³ Factorial Design for buoyant layer
Independent Variables	Actual values\|(mg)		Coded values		Dependent Variables
Independent Variables	Low (-)	High (+)	Low (-)	High (+)	Y1 = Buoancacy Lag Time(BLT)
HPMCK 100 (X1)	80	100	-1	+ 1	Y2 = Total floating time (TFT)
IG (X2)	25	50	-1	+ 1	Y3= % Swelling index (%SI)
SB (X3)	50	75	-1	+ 1	Y4 = % Drug Release (%DR)

Table 2

Composition of prepared tablets
Composition of Immediate Release tablet		IF1	IF2	IF3	IF4	IF5		IF6
S.NO	Formulation Ingredients	IF1	IF2	IF3	IF4	IF5		IF6
1	Tramadol hcl	100	100	100	100	100		100
2	SSG	4	8	-	-	-		-
3	Kollidon CL	-	-	4	8	-		-
4	CCS	-	-	-	-	4		8
5	MCC	42	38	42	38	42		38
6	Talc	2	2	2	2	2		2
7	Magnesium stearate	2	2	2	2	2		2
Total weight		150	150	150	150	150		150
Composition of compression coat		CF1	CF2	CF3	CF4	CF5		CF6
1	Methocel K15	200	-	-	150	150		120
2	KG	-	200	-	-	-		40
3	TG	-	-	200	50	50		40
4	MCC	10	10	10	10	10		10
Total weight		210	210	210	210	210		210
Composition of buoyant layer		BL1	BL2	BL3	BL4	BL5	BL6		BL7	BL8
1	Methocel K100	80	100	80	100	80	100		80	100
2	IG	25	25	50	50	25	25		50	50
3	SB	50	50	50	50	75	75		75	75
4	Citric acid	20	20	20	20	20	20		20	20
5	Lactose	15	-	15	-	15	-		15	-
6	Talc	5	5	5	5	5	5		5	5
7	Magnesium stearate	5	5	5	5	5	5		5	5
Total weight		560	560	560	560	560	560		560	560

Factorial Design of Buoyant Formulation:

2³ factorial design was selected by using minitab 21.4.1 software demo version, where 3 factors each at 2 levels were considered. In formulations, independent variables selected are amounts of HPMC K 100(X1), IG (X2), and SB (X3), whereas Buoyant Lag Time (FLT), Total floating time (TFT), %Swelling Index (%SI) and % Drug Release AT 10th hr (%DR) were selected as dependent variables. The main effects (X1, X2, and X3) represent the average result of changing 1 factor at a time from its low to high value. The interaction terms (X1X2, X2X3, and X1X3) show how the response changes.⁽¹¹⁾

Preformulation studies : The drug and polymers were selected and identified

Characterization of TG and IG

The separated TG and IG powder was evaluated for solubility, swelling index, density, flow, and derived properties. Phytochemical tests such as Molisch’s test, Ninhydrin test, Ferric chloride test, Wagner’s test, Keller-Killani test, Fehling’s test, Shinoda test, ruthenium red test were performed for both gums. ⁽¹²⁾

Table 3

Post compressional characteristics of the prepared formulations
Formulation code	Weight variation	Hardness (kg/cm2)	Friabilty (%)	Thickness (mm)	Content uniformity
IF1	101 ± 0.54	6.42	0.72	2.5 ± 0.04	99.88 ± 0.22
IF2	97 ± 0.22	6.32	0.68	2.6 ± 0.02	99.26 ± 0.28
IF3	98 ± 0.64	5.28	0.69	2.6 ± 0.04	101.2 ± 0.42
IF4	97 ± 0.26	5.76	0.66	2.7 ± 0.02	97.88 ± 0.24
IF5	97 ± 0.82	5.67	0.68	2.6 ± 0.05	99.21 ± 0.26
IF6	99 ± 0.84	6.42	0.65	2.6 ± 0.03	98.29 ± 0.22
BL1	101 ± 0.74	4.62	0.66	5.88 ± 0.05	98.64 ± 0.43
BL2	97 ± 0.56	4.46	0.78	6.0 ± 0.04	101.31 ± 0.29
BL3	98 ± 0.26	4.62	0.74	6.13 ± 0.02	99.94 ± 0.46
BL4	97 ± 0.22	5.16	0.67	6.28 ± 0.05	99.83 ± 0.68
BL5	99 ± 0.36	4.48	0.64	6.22 ± 0.02	101.4 ± 0.72
BL6	97 ± 0.84	4.64	0.68	5.82 ± 0.03	101.2 ± 0.43
BL7	98 ± 0.28	4.61	0.69	6.28 ± 0.06	101.27 ± 0.45
BL8	99 ± 0.22	4.68	0.68	6.22 ± 0.03	99.86 ± 0.54
All Values ± Std Dev

Physical Characterization of tablets

The formulated core tablet powder blends were evaluated for pre compression and post compression properties and were represented in Table 3. The compressed coated and coated floating tablets were evaluated for various parameters such as weight variation, hardness, friability, thickness, disintegration time and drug content were represented in Table 9. ⁽¹³⁾

In-vitro buyonacy time

In vitro buoyancy studies were performed for all formulations. 100 ml beakers each containing simulated gastric fluid, pH1.2 were taken as the medium and buyonacy results were obtained as per USP. Buyonacy lag time (BLT) and total floating time (TFT).

In-vitro swelling studies

The swelling index of tablets was determined by placing the tablets in the basket of dissolution apparatus using dissolution medium pH 1.2 buffer at 37 ± 0.5º C and tested after 0.5, one, two, three, four, five, six, seven, and up to twelve hours. Each dissolution basket containing the tablet was taken out and blotted with tissue paper to remove the excess water and weighed on the analytical balance. The experiment was done in triplicate for each time point, the swelling index was calculated. ^{(14, 15)}

$$\text{S}\text{w}\text{e}\text{l}\text{l}\text{i}\text{n}\text{g} \text{i}\text{n}\text{d}\text{e}\text{x}=\frac{(\text{W}\text{e}\text{t} \text{w}\text{e}\text{i}\text{g}\text{h}\text{t} \text{o}\text{f} \text{t}\text{a}\text{b}\text{l}\text{e}\text{t} - \text{D}\text{r}\text{y} \text{w}\text{e}\text{i}\text{g}\text{h}\text{t} \text{o}\text{f} \text{t}\text{a}\text{b}\text{l}\text{e}\text{t})}{\text{D}\text{r}\text{y} \text{w}\text{e}\text{i}\text{g}\text{h}\text{t} \text{o}\text{f} \text{t}\text{a}\text{b}\text{l}\text{e}\text{t} ]}\text{*}100$$

In-vitro dissolution study:

The release rate of Tramadol Hydrochoride formulated tablets was determined using United States Pharmacopoeia (USP) Dissolution Testing Apparatus 2 (paddle method). The dissolution test was performed using 900 ml of 0.1N HCl for 12 hrs. A sample (5 ml) of the solution was withdrawn every time from the dissolution apparatus and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45µ membrane filter and diluted to a suitable concentration with 0.1N HCl for 12 hrs. samples were analysed using UV-visible spectroscopy.⁽¹⁶⁾

Drug release kinetics and stability studies:

Coated Floating Pulsatile Tablets of Tramadol Hcl tablets were subjected to various kinetic studies like zero order (Cumulative percentage drug released vs. Time), first order (Log cumulative percentage of drug unreleased vs. Time), Higuchi equation (Cumulative percentage of drug unreleased vs. Square root of time) and Korsemeyer’s (Log cumulative percentage released vs. Log time). Accelerated stability study was carried out for the optimized batch (F8) at 40 ± 2∘C/75 ± 5% RH over 3-month period according to ICH guidelines in the stability chamber (Thermolab India). At the end of the 3 months, the tablets were examined for physical characteristics, drug content, in vitro drug release (lag time), and buoyant lag time. ⁽¹⁷⁾

In- Vivo Buoyancy Studies:

The in vivo X-ray study was conducted on overnight fasted rabbits (2-2.5kg) by oral administration of CFPT formulation to observe the buoyancy ability and gastric retention of formulation. Prior permission was sought from the Institutional Animal Ethics Committee (IAEC) for conducting the study, for this part of the tablet content (30mg) were replaced with with barium sulphate (BaSO₄) and the procedure has been done under the guidance of a radiologist. Using barium sulphate X-ray visibility was enhanced. At different time intervals (0, 1, 2, 4, 5, and 6 h after administration of tablets), the rabbits were anaesthetized using ketamine HCl at a dose of 20 mg/kg and exposed to abdominal X-ray imaging at 40 mA, 45 KV, and 5 mAs.⁽¹⁸⁾ The distance between the source of X- ray and rabbit was kept constant (80 cm) for all images.

Properties of gum

Solubility studies of the gums concluded that both TG and IG were soluble in hot water. The isolated gums were physico chemically evaluated. Particle size of TG is 0.15mm while that of Ispaghula gum is 0.12mm on average. The pH values are 6.2, and 2.1, respectively. Both the gums show good flow properties. Carbohydrates, proteins, alkaloids, and glycosides are present in TG while carbohydrate and reducing sugars are present in IG. Both are having good mucilage production ability and showed good swelling property. The swelling property of these gums and mucilage forming ability are responsible for considering them as one of the excipients or polymers with special properties.

Evaluation of tablets

Pre compression parameters were studied for all tablet powder blends and are represented in Table 8. All excipients show good flow properties. Post compression properties are included for the core and coated floating tablets were represented in Table 9. Weight variations for all mentioned formulations were within the range of 97 to 101%, hardness values varies from 4.65 to 6.4 kg/cm², friability values ranged from 0.65 to 0.75 and all values were within specified limits. Content uniformity of the tablets ranged from 98.29 to 101.4%. Core tablets showing good disintegration time varying from1.5 to 3.1 min.

In-vitro buyonacy time:

In-vitro buyonacy time is denoted by both buoyancy lag time (BLT) and total floating time (TFT). These results were based on the composition of polymer, IG and sodium bicarbonate in the above formulations. Based on the obtained values, BL4 and BL8 showed better results and it is noted that IG has shown synergistic effect when combined with sodium bicarbonate. In the total formulations, BLT values ranged from 128 to 156 sec. while that of TFT ranges from 7 to 10 hrs. This floating behavior of the formulated tablets was photographically shown in Fig. 2

In-vitro swelling studies

From the results, swelling study was represented as % SI and it was concluded that as the polymer gradually absorbs water, the swelling increases with respect to time, this is because of the hydrophilic nature of the polymer as well as the gums. Among all, BF8 showed a maximum swelling index of 97.33% and which may be due to the presence of Methocel K100 and Ispaghula gum at their maximum concentrations. All remaining formulations also showed characteristic SI% as per their compositions.⁽¹⁹⁾

In-vitro dissolution study

The drug release from immediate release layer were represented graphically shown in Fig. 3 which shows that the formulation which consists of SSG at its high concentration releases the drug within 45 min. for the pulsatile floating formulations also in-vitro dissolution of BL8 was reported in Table 4 and Fig. 3. BL4 and BL8 both shows the drug release of 97.68% and 99.82%up to 10 hr and 11h respectively with lag period of 4 h. HPMC K100 with IG and SB helps in buoyant behavior of formulations.

Table 4

Optimization data analysis and ANOVA table
Formulation code	Buyonacy Lag Time (sec) [BLT]	Total floating time (h) [TFT]	% Swelling index[SI %]		% Drug release at the end of 10h [%DR]
BL1	156	8	91.66		98.88
BL2	148	8	92.24		95.58
BL3	146	9	93.88		98.26
BL4	132	10	94.66		97.68
BL5	136	7	92.88		92.16
BL6	130	7	91.64		98.160
BL7	132	9	95.28		94.66
BL8	128	10	97.36		92.88
ANOVA table
RESPONSE	Sum of squares	df	Mean of squares	F value	P value	P < 0.05
BLT
Regression	566.68	3	188.89	4.82	0.02	Significant
Residual	22.65	3	8.24	4.82	0.02	Significant
TFT
Regression	9.00	3	3.00	12.00	0.02	Significant
Residual	0.5200	4	0.1240	12.00	0.02	Significant
SI%
Regression	24.65	3	8.22	9.65	0.03	Significant
Residual	2.46	4	0. .680	9.65	0.03	Significant
Drug release at 10 th hr (%DR)
Regression	71.74	3	13.45	12.92	0.024	significant
Residual	7.36	5	1.27	12.92	0.024	significant

Optimization of data

Total nine formulations were analysed using Minitab 21.4.1 software trial version (minitab, Inc., USA, trail version). It was seen that the quadratic models were bestfitted to study the responses, that was, buoyanacy lag time (BLT), total floating time (TFT), % Swelling Index (SI) and % drug release at 10 th hr (DR_10h). The polynomial equations generated for the responses were given as

POLYNOMIAL EQUATION

FLT = 143.25 + -1 * X₁ + -7.11494 * X₂ + 1.5 * X₃ + 14.75 * X₁X₃

SI % =93.6963 + 0.70625 * X1 + 0.41625 * X2 + 0.32125 * X3 + 1.55125 * X1X3 + 0.06125 * X2X3

TFT = 8.375 + -0.125 * X₁ + 0.875 * X₂ + 0.625 * X₃ + -0.125 * X₁X₂ + 0.125 * X₂X₃

DR_10h = 95.3138 + -2.76875 * X₁ + -1.09375 * X₂ + -0.17375 * X₃ + -0.45125 * X₁X₂ + -0.64125 * X₁X₃ + 0.50375 * X₂X₃ + 0.15125 * X₁X₂X₃

Where X1, X2, and X3 were coded values and were represented in Table 1. The positive value of a factor in the above equations point out the enhancement of that response and vice versa. In Table no 4, all values of the correlation coefficient (R²), standard deviation, % coefficient of variation, and the other results are shown in Tables 4. A value of R² and the results of ANOVA for the dependent variables confirmed that the model was significant for the observed response variables.⁽²⁰⁾ P value less than 0.05 is indicative that the responses were significant. Response surface methodology and contour plots have been used as the experimental design to determine the effect of independent variables on all possible dependent variables. Experimental design based on the preliminary experiments and our previous studies, three factors HPMC K100, IG, SB were identified as key factors responsible for all responses. The IG to SB ratio is significant for the buoyancy behavior of CFPT formulations. When increasing the concentration of polymer, it forms a stiff layer over the drug which helps in prolonged drug release and helps in buoyancy behavior and all values were shown in Fig. 4.

Drug release kinetics

The release kinetics profile of Tramadol hydrochloride CFPT tablets was found to obey zero- order kinetics (R² of 0.988) and Higuchi kinetics (R² of 0.997).

In- Vivo Buoyancy Studies

To study the buoyancy behavior X-ray imaging of rabbits were selected and showed good results. From the 4th hr, tablets shows good swelling and buoyancy and continued up to 11th hr. After 4th hr changed in the position of the tablet was observed, this showed that the tablet did not adhere to gastric mucosa in Fig. 5D.

Table 5

Stability data of the optimized formulation
Response	Initial	After 3 months
BLT	128	132
TFT	10th hr	10th hr
%SI	97.36	95.32
%DR	99.82	98.86

Stability studies

Accelerated stability study indicated that the optimized formulation F8 was physically as well as chemically stable after 3 months.

Rheumatoid arthritis chronotherapy based coated pulsatile floating tablet of Tramadol HCl was successfully developed. Optimized CFPT batch BL8 showed a lag time of 4 h and 128 sec floating lag time along with maximum drug release (98.82 ± 2%). In vivo X-ray study indicated that CPFT may increase gastric residence time due to the combination of IG with SB as an effervescent agent. The optimized BL-8 may be used for administration at bed time which will release Tramadol HCl in the early morning when the chances of arthritic pain are more. Tramadol HCl CPFT can achieve prolonged gastric residence time and pulsatile release of the drug in a time-controlled manner following erosion of the coating. However, there is further need of investigation for clinical acceptance of this novel drug delivery system.

Acknowledgement :

The authors would like to acknowledge Hetero drugs, Hyderabad for providing a gift sample of Tramadol HCl and Acharya Nagarjuna University, Guntur, for carrying out spectral analysis studies. The authors would also like to acknowledge Jawaharlal Nehru Technological University, Kakinada and Vikas College of Pharmacy, AP, India, for providing a facility for experimentation.

Competing interests: The authors declare no competing interests on this article

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Design, Formulation, Evaluation and Statistical Optimization of Coated Floating Pulsatile Tablets for Modified Chronopharmacotherapy of Rheumatoid Arthritis

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Abstract

Objective

Methods

Results

Conclusion

Figures

Introduction

Materials and methods

Identification of drug and spectral studies by FTIR:

Isolation of Tamarindus gum:

Isolation of Ispaghula gum:

Formulation Development:

Factorial Design of Buoyant Formulation:

Drug release kinetics and stability studies:

Results and discussion

Evaluation of tablets

POLYNOMIAL EQUATION

Conclusion

Declarations

References

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