Development and Evaluation of Celecoxib Core in Cup Tablets for Pulsatile Drug Delivery

Vishalkumar D. Patel, Anand K. Yegnoor*

Department of Pharmaceutics V L College of Pharmacy, Raichur, India.

 

ABSTRACT:

Chronopharmaceutics,  the  drug  delivery  based  on  circadian  rhythm is  recently  gaining  much  attention worldwide.  Keeping an objective celecoxib pulsatile core-in-cup tablet was designed to deliver a rapid or transient and quantified drug after a predetermined lag period. Celecoxib core tablet was prepared by direct compression method and is used to prepare a set of core-in-cup tablets with swellable and rupturable polymers with different proportions with impermeable cup ethyl cellulose. Tablets were evaluated for precompression, postcompression and in vitro dissolution. The drug polymer interaction was studied by FTIR. The precompression data of core/core-in-cup tablet were within the acceptable limit and they can be compressed directly into tablets. The hardness, friability and uniformity in weight and disintegration time results were in accordance with the standard limit. The lag time is dependents on rupturing property of ehtyl cellulose and swelling property polymers. In all the formulations the best fit model was found to be peppas with exponential n value is > 1 indicates the drug release follows super case II transport mechanism. The initial burst release was observed after lag time and drug release was extended up to 12hr in all formulations. The in vitro drug release studies suggest that core-in-cup tablet prepared with ethyl cellulose and sodium alginate shows higher lag time than that of remaining formulations due to more swelling and delayed rupturing properties of sodium alginate and ethyl cellulose.

 

 

 

INTRODUCTION:

During the past several decades, conventional dosage forms have been widely used for treatment of various conditions. These dosage forms typically provide an immediate or rapid drug release, and supply a given concentration or quantity of the drug to the body^'s systemic circulatory system without any rate control. To maintain the effective plasma drug concentration, frequent administration is required. Due to poor drug efficacy, incidence of side effects, frequency of administration and patient compliance of these conventional and traditional dosage forms, leads replacement by second generation, modified drug release dosage forms.

 

Treatments of numerous diseases using traditional drug products are often inconvenient and impractical if disease symptoms occur during the night or early morning. Recent studies also reveal that the body^'s biological rhythm may affect normal physiological function, including gastrointestinal motility, gastric acid secretion, gastrointestinal blood flow, renal blood flow, hepatic blood flow, urinary pH, cardiac output, drug-protein binding, liver enzymatic activity and biological functions such as heart rate, blood pressure, body temperature, blood plasma concentration, intraocular pressure, stroke volume and platelet aggregation¹. Most organ functions vary with the time of the day, particularly when there are rhythmic and temporal patterns in the manifestation of a given disease state. The symptoms of many diseases, such as bronchial asthma, myocardial infarction, angina pectoris, hypertension, and rheumatic disease have followed the body^'s biological rhythm^2-4. Day night variation in asthmatic dyspnea and variations in the incidence of myocar­dial infarction occur throughout the early morning hours.

 

Chronopharmaceutics, the drug delivery based on circadian rhythm is recently gaining much attention worldwide^5,6. In chronopharmaceutics modified drug delivery systems suitable for diseases that have peak symptoms in the specific time and exhibit circadian rhythm^7,8. In case of arthritic pain and rheumatoid arthritis, patient experience more pain in the morning and patient with osteoarthritis have more pain in the evening hours⁹. However, because of circadian rhythms in physiological parameters and pathological conditions the conventional paradigm concerning drug concentrations “the flatter the better” may not be what the organism may need. Instead, to correlate with our biological needs, precisely timed drug delivery is required ‘pulsatile drug delivery’ is one such novel approach, which may maximize therapeutic efficacy, minimize dose frequency and reduce toxicity by avoiding side effects and drug tolerance. One way to classify pulsed drug delivery systems is based on the physicochemical and biological principles that trigger the release. These devices are classified into programmed and triggered drug delivery systems. In programmed delivery systems the release is completely governed by the inner mechanism of the device, i.e. the lag time prior to the drug release is controlled primarily by the delivery system^10-13. Keeping an objective, Celecoxib a sulfonamide nonsteroidal antiinflammatory drug (NSAID) and selective COX-2 inhibitor used in the treatment of osteoarthritis, rheumatoid arthritis and acute pain^14-16 selected as a model drug. The research work is aimed to prepare celecoxib core in cup pulsatile drug delivery tablets using swellable and rupturable hydrophilic polymers and evaluate their precompression and post compression parameters and in vitro drug release pattran.

 

MATERIAL AND METHODS:

Materials:

Celecoxib was a gift sample obtained from _{Shasun Laboratories, Himachal Pradesh,} PVP K90, HPMC K4M, ethyl cellulose, sodium alginate, sodium CMC, HPMC 6cps were procured from _{Sd fine-chem, limited, Mumbai and} Galen IQ720 procured from _{Beneo palatinit, Germany. All other ingredients used were of analytical grade and double distilled water was used throughout studies.}

 

Methods:

Press coated pulsatile core-in-cup tablets were designed for model drug celecoxib using impermeable cup, swellable and rupturable polymers at different rations for a optimized core formulation and studied precompression, postcompression and in vitro dissolution rate.

 

Preparation of core tablets:

The powder blend as per the table 1 were mixed in polybag and was compressed using 8mm punch in 10 station rotary tablet punching machine. During compression postcompression parameters were checked to get stable tablets core tablet. The formula of core tablet was given in (Table 1) and photograph of core tablet was given in (Fig 1).

 

Table 1: Formulae of core tablet.

 

 

Fig. 1: Digital photograph of VP-1 core tablets.

 

Preparation of core-in-cup tablets:

·         Prefilling the half amount of impermeable ethyl cellulose polymer material into the die.

·         Putting the core tablet B-I on the polymer bed of outer impermeable ethyl cellulose polymer and slightly pressed to fix.

·         Centring of the materials by adjusting the die cavity.

·         Filling the residual half amount with swelling and ruputrable material comprising of ethyl cellulose with sodium alginate, sodium CMC, HPMC6cps in different ratios.

·         Compression of the material by using 12mm punch.

·         Ejection of press coated tablet from the die.

 

The different formulae of core-in-cup tablets are given in (Table 2), manufacturing procedure in (Fig 2) and digital photograph of model core tablet, core-in-cup tablet and possible cup in (Fig 3).

 

Fig. 2: Manufactring of press coated core-in-cup tablets.

 

Figure 3: Digital photo graphs of core tablet, core-in-cup tablet and cup.

 

Table 2: Formulae of core-in-cup tablets.

Core tablet/polymers	F-1	F-2	F-3	F-4	F-5	F-6
B-1 core tablet (in mg)	210	210	210	210	210	210
Ethyl cellulose (in mg)	50	50	50	50	50	50
Sodium alginate (in mg)	25	25	-	50	-	-
Sodium CMC (in mg)	25	-	25	-	-	50
HPMC 6cps (in mg)	-	25	25	-	50	-
Ethyl cellulose (in mg)	150	150	150	150	150	150
Total weight (in mg)	460	460	460	460	460	460

 

FTIR spectroscopy studies:

Fourier transform infrared (FTIR) spectram were recorded on a Shimadzu FTIR-281-spectrophotometer. Samples were prepared in KBr disks prepared with a hydrostatic press at a force of 5.2T Cm^-2 for 3 min. The scanning range was 450-4000cm^-1 and the resolution was 1cm^-1.

 

Precompression evaluation:

All the ingredients as per the formulae of core tablet and core-in-cup tablet were weighed and grinded to fineness in a mortar and pestle. The powder was then shaken in a polybag for uniform mixing then transferred into a glass mortar. This blend is subjected for evaluation of rheological properties viz., bulk density, tapped density, compressibility index, flow properties (angle of repose). All studies were carried out in triplicate and mean values were reported.

 

Bulk density (BD):

Bulk density was determined by using bulk density apparatus, during measurement accurately weighed quantity of the powder were taken in a measuring cylinder and recording the volume and weight of the total powder. Bulk density is expressed in gm/ml and is given by,

 

Where,

BD = Bulk density (gm/ml), M = Weight of granules (gm), Vo = bulk volume of granules (ml)

 

Tapped density (TD):

Tapped density was determined by using tapped density apparatus during measurement accurately weighed quantity of the powder were taken in a measuring cylinder and recording the volume of powder after 100 tapping and weight of the total powder.

 

Where,

 TD= Tapped density (gm/ml), M = Weight of powder (gm), V = Tapped volume of powder (ml)

 

Compressibility index:

Compressibility index was determined by placing the powder in a measuring cylinder and the volume (V₀) was noted before tapping, after 100 tappings again volume (V) was recorded.

Compressibility index = (1- ) X 100

Where, V₀ = Volume of powder, V = Volume of powder after 100 tappings.

 

Carr’s index:

The Carr’s compressibility index of the powder blend was determined by using the formula,

 

Where, TD = Tapped density, BD = Bulk density

 

Hausner’s ratio:

The Hausner’s ratio is a number that is correlated to the flow ability of a powder or granular blend.

Hausner’s Ratio = TD / BD

Where,   TD = Tapped density, BD = Bulk density

 

Angle of repose (θ):

It is defined as the maximum angle possible between the surface of pile of the powder and the horizontal plane. Fixed funnel method was used. A funnel was fixed with its tip at a given height (h), above a flat horizontal surface on which a graph paper was placed. Powder was carefully poured through a funnel till the apex of the conical pile just touches the tip of funnel. The angle of repose (θ) was then calculated.

θ = tan^-1(h/r)

Where,

θ = Angle of repose, h = Height of pile, r = Radius of the base of the pile

 

Post compression:

The fabricated core and core-in-cup tablets were subjected for post compression evaluation viz., diameter, thickness, weight variation, hardness, friability, disintegration time and in vitro dissolution under standard procedures and conditions.

 

Thickness and diameter:

The thickness and diameter of the tablets were measured using Vernier calipers and the measurements were in mm. Average of three readings were taken and the results were tabulated.

 

Hardness test:

Hardness of the tablets was evaluated by using Pfizer hardness tester. Scale was adjusted to zero, load was gradually increased until the tablet fractured. The value of the load at that point gives a measure of hardness of the tablet. Hardness was expressed in Kg/cm².

 

Weight variation:

Randomly selected twenty tablets were weighed individually and together in a single pan balance. The average weight was noted and standard deviation and percent coefficient of variance was calculated and computed.

 

Friability test:

Tablet friability was tested using Roche friabilator. Preweighed tablets were allowed for 100 revolutions (4 min), taken out and dedusted. The percentage weight loss was calculated by reweighing the tablets. The percentage friability was calculated by using following formula,

 

Where, F-friability; W_in-Initial weight of the tablets; W_final-Weight of the tablet after test

 

Disintegration time:

Disintegration test was performed for the tablets in 900 ml 2% w/v sodium lauryl sulphate solution by using USP disintegration apparatus. Time was noted with a digital chronometer. Average of three readings was taken and the results were tabulated.

 

Drug content uniformity:

From each batch three randomly selected tablets were weighed accurately and powdered in a clean and dry glass mortar with pestle. Powder equivalent to 20mg of drug was transferred into 50 ml volumetric flask containing 30ml of methanol shaken for 30 min the remaining volume was made up to 50 ml with methanol. This was kept undisturbed for 1hr and the solution was filtered, make up desired dilutions with 2% w/v sodium lauryl sulphate solution and analysed for drug content at 254.5 nm using UV spectrophotometer. The drug content was calculated from the calibration curve.

 

 

Fig. 4: Comparative FTIR spectrum.

In vitro release study:

In vitro dissolution studies of both core tablet and core-in-cup tablets were performed by USP XXII type II paddle apparatus under standard conditions. 900 ml of 2% w/v sodium lauryl sulphate solution used as dissolution medium maintained at 37 ± 0.5 °C with a speed of 60rpm. The drug release at different time intervals was measured at 254.5nm using a double beam UV spectrophotometer.

 

Mechanism of drug release:

In order to gain insight into the drug release mechanism from the core-in-cup tablet formulations were examined and model fitting according,

 

Zero order

Q ₁ = Q ₀ + K₀t

Where, Q₁ is the amount of drug dissolved in time t, Q₀ the initial amount of drug in the solution, and K ₀ is the zero order release constant.

 

First order

ln Q _t = ln Q ₀ K₁t

Where, K₁ is the first order release constant, Q₀ the initial amount of drug in the solution, and Q₁ is the amount of drug dissolved in time t.

Higuchi's square root of time mathematical models

Q = [t D C _s (2C − C _s )]^½

Where, Q is the amount of drug release in time t, C the initial drug concentration, C_s the drug solubility in the matrix, and D is the diffusion constant of the drug molecule in that liquid.

 

Hixson and Crowell powder dissolution method

3 √Q₀ -3 √Qt =K _HC^.t

Where, Q₀ is the initial amount of drug, Qt is cumulative amount of drug release at time `t’, K _HC is Hixson crowel release constant, t is time in hours

 

Korsemeyer and Peppas model, and the release exponent `n’ was calculated.

Q _t /Q_∞ = a t ⁿ

Where, a is the constant incorporating structural and geometric characteristics of the drug dosage form, n the release exponent (indicative of the drug release mechanism), and Q _t /Q_∞ is the fractional release of the drug.

 

RESULTS AND DISCUSSION:

FTIR studies:

The compatibility between pure drug and polymers were studied by FTIR. The comparative FTIR spectra were given in (Fig 4) and data in (Table 3). The FTIR spectra of pure celecoxib shows characteristic bands -NH stretching primary amine at 3332.69cm^-1, S=O symmetric stretching at 1345.50 cm^-1, and -CF₃ bending at 1276.30 cm^-1 and 1225.98 cm^-1. The characteristic celecoxib bands viz., -NH stretching primary amine was observed in the range of 3333.66 cm^-1 to 3337. 71 cm^-1 ; S=O symmetric stretching 1346.33cm^-1 to 1348.05cm^-1; and -CF₃ bending 1276.10cm^-1 to 1279.53cm^-1 and 1226.06cm^-1 to 1229.10cm^-1 in core and core-in-cup tablets. All the characteristic celecoxib bands were observed in core tablets as well as core-in-cup formulations with slight shifting towards higher/lower wave length due to mild to no interaction suggest lack of significant interaction between celecoxib and selected polymers used in the formulation of core tablets and core-in cup tablets.

 

Table 3: Comparative FTIR data of pure celecoxib and core-in-cup tablets.

 

Table 4: Precompression evaluation data of core tablet and core-in-cup tablet blend.

 

Precompression studies:

The precompression evaluation data results obtained for core tablet and core-in-cup tablet blend were within the acceptable range and having good flow property, enough compressibility strength with good packing ability. The results suggest the powder blend can be easily subjected for direct compression. The data were given in table 4.

 

The thickness of the core-in-cup tablet were found to be in the range of 3.72 ± 0.017 to 3.79 ± 0.010 mm for F-1 to F-6; 3.74 ± 0.017 to 3.80 ± 0.010 mm for F-7 to F-12 formulations where as the diameter of the core-in-cup tablets were found to be in the range of 12.05 ± 0.004 to 12.09 ± 0.004 mm for F-1 to F-6; 12.05 ± 0.004 to 12.09 ± 0.003mm for F-7to F-12 formulations indicated proper relation with coating material and was maintained properly. The average percent weight deviation in core-in-cup tablet was found to be in the range of 0.108 ± 0.001 to 0.260 ± 0.007 for F-1 to F-6; 0.065 ± 0.001 to 0.391 ± 0.007 for F-7 to F-12 formulations indicated the results were within the IP limit and it passes the weight variation test. The hardness of press coated core-in-cup tablet was found to be in the range of 7.42 ± 0.152 to 7.82± 0.115 kg/cm² for F-1 to F-6; 7.3 ± 0.115 to 7.5 ± 0.100 kg/cm² for F-1 to F-12 formulations. The results indicate the formulated tablets have good strength. The percentage weight loss of core-in-cup tablet in friability studies was found to be in the range of 0.54 ± 0.115 to 0.95 ± 0.115 for F-1 to F-9; 0.43 ± 0.002 to 0.65 ± 0.002 for F-7 to F-12 formulations. The results were less than 2% indicating good strength of tablet. The drug content in press coated core-in-cup tablet was found to be in the range of 98.39 ± 0.422 to 99.06 ± 0.31 for F-1 to F-6; 98.36 ± 0.40 to 99.46 ± 0.210 for F-7 to F-12 formulations. The drug content was found to be uniform among all formulation with low SD and CV values table 5.

 

Table 5: Post compression data for core and core-in-cup tablets

 

Disintegration studies:

The disintegration time was found to be 41min B-1 core tablet. The disintegration of core-in-cup was carried out for 24hr in order to check the influence of hydrophilic, swellable and rupturable polymers used in the core-in-cup and the results suggest that the disintegration was time dependent and polymers. The disintegration is depends on the binding power of the PVP/HPMC K4M and Galen IQ 720 added in the core tablet and swelling and bursting nature of the swellable and rupturable polymer and impermeable behavior of ethylcellolose used in outer shell of the cup tablet. The PVP/HPMC K4M in the inner core and swellable and rupturable polymer, ethyl cellulose in outer shell delayed the disintegration rate to great extent and the sequential changes during disintegration of core-in-cup tablets were shown in the figure 5. The disintegration time for the core-in-cup tablets directly related to the lag period of the study.

 

Figure 5: Digital photographs of sequential changes during disintegration of core-in-cup tablets.

 

 

Dissolution studies

Core tablets:

In vitro drug release studies were carried out in 900 ml of 2% w/v sodium lauryl sulphate solution using USP XXII dissolution apparatus type II. The core tablet consists of pure drug celecoxib and different concentrations of HPMC K4M, PVP K90 and Galen IQ720. B-1 core tablet prepared with 1:2 ratios of PVP K90: HPMC K4M shows 89.74 percent drug release at the end of 120 min. This core tablet was tried in the formulation of pulsatile core-in-cup tablets. The dissolution profile was given in figure 5

 

Core-in-cup tablets:

The developed press coated core-in-cup pulsatile tablets consist of three components, the central core tablet made up pure drug celecoxib and different concentrations of HPMC K4M, PVP K90 and Galen IQ720, the impermeable layer ethyl cellulose and the pulsatile layer consist of mixture of swellable and rupturable polymer viz., sodium alginate, HPMC 6cps, sodium CMC and ethyl cellulose. The dissolution profiles were given in figure 5.

 

The F-1 was designed with an active B-1 core tablet using hydrophobic cup with impermeable ethyl cellulose and pulsatile layer with 1:0.5:0.5 ratios of ethyl cellulose: sodium alginate: sodium CMC. The lag time is maintained for 4.5h with 7.38% drug release after lag time the initial burst release was found to be 60.83% at the end of 5hr, 93.52% release at the end of 12^thhr. The F-2 was designed with an active B-1 core tablet using hydrophobic cup with impermeable ethyl cellulose and pulsatile layer with 1:0.5:0.5 ratios of ethyl cellulose: sodium alginate: HPMC 6cps. The lag time is maintained for 4h with 9.71% drug release after lag time the initial burst release was found to be 60.64% at the end of 4.5hr, 90.17% release at the end of 12^thhr. The F-3 was designed with an active B-1 core tablet using hydrophobic cup with impermeable ethyl cellulose and pulsatile layer with 1:0.5:0.5 ratios of ethyl cellulose: sodium CMC: HPMC 6cps. The lag time is maintained for 3.5h with 8.50% drug release after lag time the initial burst release was found to be 51.71% at the end of 4hr, 94.99% release at the end of 12^thhr. The F-4 was designed with an active B-1 core tablet using hydrophobic cup with impermeable ethyl cellulose and pulsatile layer with 1:1 ratios of ethyl cellulose: sodium alginate. The lag time is maintained for 5h with 9.14% drug release after lag time the initial burst release was found to be 62.20% at the end of 6hr, 95.40% release at the end of 12^thhr. The F-5 was designed with an active B-1 core tablet using hydrophobic cup with impermeable ethyl cellulose and pulsatile layer with 1:1 ratios of ethyl cellulose: HPMC 6cps. The lag time is maintained for 4h with 7.68% drug release after lag time the initial burst release was found to be 49.76% at the end of 4.5hr, 96.33% release at the end of 12^thhr. The F-6 was designed with an active B-1 core tablet using hydrophobic cup with impermeable ethyl cellulose and pulsatile layer with 1:1 ratios of ethyl cellulose: sodium CMC. The lag time is maintained for 3.5h with 8.04% drug release after lag time the initial burst release was found to be 43.81% at the end of 4hr, 95.19% release at the end of 12^thhr.

 

The model fitting regression values ‘r’ was found to be in the range of 0.9094 to 0.9594 for zero order, 0.8917 to 0.9530 for first order, 0.7604 to 0.8580 for matrix, 0.9385 to 0.9734 for peppas and 0.9056 to 0.9610 for hixan crowel for F-1 to F-6 core-in-cup tablets. The model fitting regression values ‘r’ was found to be in the range of 0.8965 to 0.9251 for zero order, 0.8972 to 0.9573 for first order, 0.7574 to 0.8434 for matrix, 0.9408 to 0.9628 for peppas and 0.9019 to 0.9542 for hixan crowel for F-6 to F-12 core-in-cup tablets. The best fit model was found to be Korsemeyer Peppas in all the formulations with exponential ‘n’ value was found to be in the range of 1.5249 to 1.9834 for F-1 to F-6 core-in-cup tablets and 1.5001 to 2.0456 for F-6 to F-12 core-in-cup tablets. From the kinetic model fitting studies it concludes that in all the core-in-cup formulations the best fit model was found to be first order kinetics with regression values ‘r’> 0.9000 and Korsemeyer peppas exponential value ‘n’ was found to be greater than 1 indicating the drug release follows super case II transport mechanism.

 

Mechanism of drug release in core-in-cup tablets:

When the dissolution medium come in contact with core-in-cup tablet, the pulsatile layer consisting of swelling and rupturing polymers starts absorbing dissolution medium as a consequence the polymer swells and expanded and bursting of the layer. As the time goes on the swelling process acts as disintegrating force which facilitates the destabilization of the pulsatile layer itself and additionally rupturing property of the polymer prone to disintegration of the tablet. Finally depending on the nature of the swelling and rupturing polymers the top layer is completely removed i.e., lag time, as a result the dissolution of drug increases sharply due to increased access of dissolution medium into the core of the tablet as shown in the figure 6.

 

Lag time:

Lag time is the time before the drug release started or the time in which less than 10 percent of the drug released. Incorporation of core tablet into press coated core-in-cup tablet produce a lag time prior to drug release.

 

The pulsatile layer intended to regulate the function of the system and modify the release of drug and the polymers present in the core tablet regulate drug release in burst release followed by controlled manner. This type of tablet could be described as a pulsatile system in which the top cover layer consists of swellable and rupturable polymer layer and the inner part of a conventional tablet acting as a drug reservoir. The sequential changes observed during dissolution studies for the core-in-cup tablet was depicted in the figure. A similar behavior was noticed in all the formulations. The release profiles had a typical pulsatile shape. It is clear that in all cases minimum drug release occurs during the lag time followed by rapid release phase. At the stage of rapid release, the release of celecoxib is faster and terminates from the cup. These results suggest that apart from the drug solubility the top cover layer also plays a significant role in modifying the lag time and the drug release. The polymer properties and the quantity of the polymer material contained in this layer control the performance and the function of the system. The in vitro drug release suggest that core-in-cup tablet prepared with ethyl cellulose and sodium alginate shows higher lag time than that of remaining formulations due to more swelling delaying rupturing properties of sodium alginate and ethyl cellulose.

 

Figure 5: Comparative dissolution profiles of core tablet and core-in-cup tablets.

 

Figure 6: Mechanism of drug release from press coated core-in-cup tablet.

ACKNOWLEDGEMENT:

The authors are thankful to _{Shasun Laboratories, Himachal Pradesh} for providing Celecoxib as a gift sample. Authors are also grateful to principal and management of V.L. College of pharmacy for providing facilities for carryout the research work.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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