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3038 Int J Pharm Sci Nanotech Vol 8; Issue 4 October December 2015

Research Paper

Chronomodulated Delivery of Pantoprazole for Nocturnal Hyperacidity P. Mahalakshmi1*, T.N.K. Suriyaprakash2 and S. Lakshmana Prabu3

1,2Department of Pharmaceutics, Al Shifa College of Pharmacy, Kerala – 679 322, India; and 3Department of Pharmaceutical Technology, Anna University of Technology, Tiruchirappalli – 620 024, India.

Received July 7, 2015; accepted August 13, 2015

ABSTRACT

The objective of this work was to design and evaluate an oral site-specific, pulsatile drug delivery system containing Pantoprazole sodium which can be targeted to colon in a pH and time dependent manner, to modulate the drug level in synchrony with the circadian rhythm of nocturnal hyperacidity. Five different composition of Core tablets were prepared by direct compression technique. Based on the release studies of core tablets, nine different compositions of press coated tablets were prepared and analyzed. The press coated tablet further coated by using five different proportions of Eudragit RS PO for providing

consistent, reproducible chronomodulated release profile. Formulation FPC3 is more suitable among the formulations to design pulsatile release formulations of pantoprazole sodium for 6 hours lag time. After this lag time burst release was observed which exhibited sigmodial release pattern and that was considered to be an ideal for the pulsatile drug delivery system. The chronomodulated drug delivery systems for pantoprazole sodium for the treatment of hyperacidity was successfully developed and the release of the drug was sharp and complete after the lag time which is necessary for any pulsatile drug delivery systems.

KEYWORDS: Pantoprazole; HPMC E15; Eudragit RS PO; Chronomodulated delivery; Circadian; Acidity.

Introduction

The oral route of drug delivery is typically considered the favored and the most user-friendly means of drug administration having the highest degree of patient compliance, as a result of which much effort are aimed to identify orally active candidates that would provide reproducible and effective plasma concentration. (Saigal et al., 2009). All the functions in man are highly organized in time as biological rhythms of diverse periods, both in health and in disease. Several enzymatic activities, cellular detoxification and pharmacokinetics vary according to a 24 hr scale of the circadian rhythm

(Qvortrup et al., 2010; Levi F 2002). Maintenance of constant drug level is not desirable for the optimal therapy. A drug should be delivered only when and where it is needed at the minimum required dose (Qureshi et al., 2008). This represents a challenge for those involved in the development of drug delivery systems to make possible the treatment of illness according to these physiological rhythms as a means of improving therapeutic outcomes. One approach is to increase the efficiency of pharmacotherapy for the administration of drugs at times at which they are most effective and best tolerated (Tiwari et al., 2008). The ability to deliver bioactive compounds to patients in a pulsatile release profile has been a major goal in drug delivery research over the last two decades. Based on the relevance of potential therapeutic applications,

variety of design strategies have been formulated in the pursuit of pulsatile release (Anil et al., 2007). Biological rhythms not only impact the function of physiology, but also the pathophysiology of disease (Youan, 2004).

The term “Chrono” refers to the observation that every metabolic event undergoes rhythmic changes in time. Chronotherapy is one of the several approaches to increase efficacy of chemotherapy has been investigated over years. In the chronotherapy, the drug delivery rate is adapted to the circadian rhythms which are endogenous and genetically based and measured along the 24 hr scale. Cellular rhythms can modulate the metabolism of cytotoxic agents and the cellular response to them (Granda TG et al., 2002; Raida et al., 2001). Chronopharmaceutics is clinically relevant, and reliable discipline could delineate a formal and systematic approach to design and evaluation drug delivery system that release a bioactive agents at a rhythm that ideally matches the biological requirements of a given disease therapy (Ohdo, 2010). A circumscribed inflammatory and often suppurating lesion on the skin or an internal mucous surface resulting in necrosis of tissue called ulcer. The proton pump inhibitors are a group of drugs that reduce the secretion of gastric acid, act by irreversibly binding with enzyme H+, K(+)-ATPase of the gastric parietal cells. This reduced secretion of acid in the stomach will aid in the healing of duodenal ulcers (Litalien et al., 2005).

International Journal of Pharmaceutical Sciences and Nanotechnology

Volume 8Issue 4 October – December 2015

MS ID: IJPSN-7-7-15-MAHALAKSHMI

3038

Mahalakshmi et al: Chronomodulated Delivery of Pantoprazole for Nocturnal Hyperacidity 3039

The objective of this work was to design and evaluate an oral site-specific, pulsatile drug delivery system containing Pantoprazole sodium which can be targeted to colon in a pH and time dependent manner, to modulate the drug level in synchrony with the circadian rhythm of nocturnal hyperacidity.

Materials and Methods

Materials

Pantoprazole sodium and HPMC E15 were obtained as gift sample from Madras Pharmaceuticals, Chennai, India. Sodium chloride, Sodium bicarbonate, potassium dihydrogen ortho phosphate, microcrystalline cellulose, starch, gum acacia and talc were obtained from Nice Chemicals Pvt Ltd., Kochi, India. Magnesium stearate was obtained from Kemphasol, Mumbai, India; Isopropyl alcohol and PEG 4000 were obtained from Reachem Laboraotry Chemicals, Chennai, India; Eudragit RS PO from Sigma-Aldrich Cheme, Germany; Ethanol from Micro Fine Chemicals, Delhi, India and PVP from BASF Aktiengesellschaft, Germany.

Methodology

Formulation of core tablets: Five different composition of Core tablets were prepared by direct compression technique. Formulation composition is shown in Table 1.

TABLE 1

Composition of pantoprazole sodium core formulation.

Ingredients (mg) Formulation

F1 F2 F3 F4 F5 Pantoprazole sodium 40 40 40 40 40 Sodium chloride 40 30 20 15 - Micro crystalline cellulose 40 60 60 60 60 Starch 36 26 36 41 96 Sodium bicarbonate 40 40 40 40 - Magnesium strearate 2 2 2 2 2 Talc 2 2 2 2 2 Total weight 200 200 200 200 200

Formulation of press coated tablets: Based on the release studies of core tablets, nine different compositions of press coated tablets were prepared in the ratio of 10%, 20% and 30% of drug: polymer with various binding agents. Press coated tablet compositions are shown in Table 2.

TABLE 2

Composition of press coated tablet.

Ingredients (mg)

Formulation FP1 FP2 FP3 FP4 FP5 FP6 FP7 FP8 FP9 FP10

HPMC E15 100 100 100 200 200 200 200 300 300 300 Guar gum 14 - - - 14 - - 14 - - Acacia - 10 - - - 10 - - 10 - PVP in IPA - - 10 - - - - - - - PVP in hot water

- - - 10 - - 10 - - 10

Development of pulsatile release tablets: The press coated tablet further coated by using five different

proportions of Eudragit RS PO for providing consistent, reproducible chronomodulated release profile.

TABLE 3

Coating composition.

Ingredients (mg) Formulation

FPC1 FPC2 FPC3 FPC4 FPC5

Eudragit RS PO 30 50 70 80 100 PEG 4000 1.5 2.5 3.5 4 5 Talc q.s. q.s. q.s. q.s. q.s. Iso propyl alcohol 50 ml 50 ml 50 ml 50 ml 50 ml

Drug-excipients compatibility studies: Excipients are integral components of almost all pharmaceutical dosage form. Compatibility studies are very important for the successful formulation of any dosage form. Commonly DSC, FT-IR, TLC and UV techniques are used for the determination of drug compatibility. Fourier Transform Infrared Spectroscopy (FTIR) and UV studies were used for the evaluation of physicochemical compatibility and interactions, which helps in the prediction of interaction of the drug with excipients used in the formulation. The earlier reports on drug-excipient interactions recommended that 1:1 ratio of drug and excipient maximizes the possibility of interaction and helps in easier detection of incompatibilities. (Lakshmana Prabu S et al., 2008). Therefore, in the present study 1:1 ratio was used for the preparation of physical mixtures and analyzed for compatibility studies.

Fourier transform infrared spectroscopy: FTIR studies are very helpful in the evaluation of drug–polymer interaction studies. Incompatibility between the drugs and excipients can be predicted based on their characteristic wave numbers. Drug and various polymers were thoroughly mixed with 300 mg of potassium bromide, compressed and the IR spectrum was obtained between 450 and 4000 cm-1 by placing the thin pellet in light path.

Evaluation of tablet formulations (Bankar et al., (1987))

Evaluation of characteristics of powder blend and tablets: The various characteristics of powder blend like angle of repose, bulk density, tapped density, compressibility index, Hausner’s ratio and drug content were studied. The formulated tablets were evaluated for uniformity of weight, hardness, friability, and drug content. The coated tablets were tested for Percentage weight gain, enteric coating test [USP Gastric Resistance test (Dissolution), Acid uptake testing (Disintegration)] and rupture test.

In vitro dissolution studies: The dissolution studies were performed in triplicate for all the core tablets in a USP XXIII dissolution rate test apparatus (Type II) in phosphate buffer 6.8 for 3 minutes. To verify how the composition of the core and the barriers were interferes with the drug release profile form the cores, the in vitro release behavior of the uncoated cores and press-coated tablets, coated tablets were tested. Five milliliters aliquots were withdrawn at predefined intervals, and the volume of the dissolution medium was maintained by


adding the same volume of fresh prewarmed dissolution medium and the drug release was analyzed.

Enteric Coating Test (USP)

At the conclusion of the coating trials, chrono-modulated Pantoprazole sodium tablets were evaluated for:

(a) USP Gastric Resistance test (Dissolution): The tablets were tested in a USP Dissolution apparatus (Basket type II) at 100 rpm using 0.1N HCl. The liberated Pantoprazole sodium was determined by means of UV- spectrophotometer (Schimadzu – 1700). Failures in this case consisted of tablets that either disintegrated or had softened and become swollen.

(b) Acid uptake testing (Disintegration): In this revised method, six coated tablets were weighed individually and placed in the disintegration basket tubes (Charles et al 2001). Immersed the disintegration basket in 900 mL of 0.1 N HCl and operated the apparatus for 2 hour. The individual tablets that were still intact then were dried with a towel and reweighed. The percent of weight increase was reported as % acid uptake. Tablets that fully disintegrated during the testing were counted as having 100% acid uptake. This method has been reported to provide an accurate measure of acid resistance of the coating, and acid uptake values, within 5% suggest that the tablets would readily pass the acid phase of the delayed-release dissolution testing.

Rupture test (Jain et al,. 2010)

The time at which the outer coating layer starts to rupture is defined as the lag time. It was determined visually by using the USP dissolution apparatus (Basket type II) 900 mL of 0.1 N HCl for initial 2 hour and then media was changed to phosphate buffer pH 6.8, 37±0.5 °C, and 50 rpm.

Effect of paddle speed on the lag time and release characteristics: Coated tablets were subjected to in vitro dissolution study at different paddle speeds (50 and 100 rpm) (Ali et al,. 2008). Effect of paddle speed on release behavior and lag time was observed and analyzed.

SEM for optimized formulation: The tablet was transversely cut and sputtered with gold ion sputter coated under vacuum. Gold coated surface of tablet was evaluated by Hitachi PC based digital scanning electron microscope.

Stability studies: The formulation which showed best in vitro release was selected for stability studies. The accelerated stability studies were conducted according to the ICH guidelines for a period of 6 months.

Results and Discussion

Drug delivery systems are becoming increasingly sophisticated as pharmaceutical scientists need to acquire a better understanding of the physicochemical

and biological parameters pertaining to their performance.

FT-IR and UV studies were performed to investigate chemical interactions between drug and the excipients. Pantoprazole sodium contains chemical functional groups like C-F stretching, C-O stretching, S=O stretching, C=C stretching, C=N stretching, C-O stretching, C-N stretching and C-H out of plane bending; the corresponding wave numbers are 3489, 1655, 1592, 1483, 1372, 1166, 1226 and 817 cm-1 respectively; these characteristic bands were present in the formulation composition. No new bands or shift in characteristic peaks were appeared. IR spectra are shown in Figure 1. In UV technique, the UV spectrum of drug is super impossible with the spectrum obtained with drug excipients mixtures and there is no change in the λmax 293 nm between the drug and drug excipients mixtures. FT-IR and UV results revealed that there is no interaction between the drug and the excipients used in the formulation.

The formulated core tablets were evaluated for its physical properties like thickness, weight variation, hardness, friability, and content uniformity. The average weight of tablets were found to be between 0.199 and 0.208 g; hardness between 2.1 and 3.4 kg/m2; friability between 0.42 and 0.87%; whereas the content uniformity was found to be 98.33 and 101.33% w/w. All the tablets were found to pass the uniformity of weight.

In vitro release studies were performed for 3 minutes and the release results are shown in Figure 2. Upon contact of the core tablet with the dissolution medium, the formulation releases CO2 that builds up the pressure within the tablet. The core erodes and ultimately explodes with immediate release of drug (surge release). At the end of 2.5 minutes F1 and F3 releases 99% of drug, but the hardness of F1 was not sufficient enough to withstand further press coating of tablets. So F3 was chosen as best formulation and used for press coating. F3 release pattern which were shown in Figure 3.

Nine press coated formulations were prepared. The dried powder mixtures were tested for powder properties like angle of repose (between 21.13 and 30.57°), bulk density (between 0.39 and 0.53 g/cc), tapped density (between 0.53 and 0.66 g/cc), percentage compressibility index (between 14.28 and 26.41 g/cc) and Hausner’s ratio (between 1.15 and 1.25). The evaluation results revealed that all the powder mixture had good flow properties.

The average weight of tablets were found to be between 0.398 and 0.408 g; hardness between 3.2 and 7.4 kg/m2; friability between 0.56 and 0.927%; whereas the content uniformity was found to be 97.66 and 99.43% w/w. All the tablets were found to pass the uniformity of weight.

All the press coated tablets were subjected to dissolution study and the release results are shown in Figure 4 observed that all the formulations have shown reproducible drug release with distinct lag time. When compare to the other formulations, formulation FP6 had shown results in achieving a maximum of 99.6% drug release over a time period of 4 hours. The lag time of tablet decreased with increasing level of swelling layer.


As the amount of swelling agent increased, it exerted more pressure over the outer layer resulting in rapid rupturing of the tablet.

From the above release studies press coated formulation FP6 was selected for enteric coating using Eudragit RS PO as the weight gain ratio of 3%, 5%, 7%, 8% and 10% w/w. The acid uptake test result shows that the 3% weight gain fails for the test; whereas other formulation passes for the acid uptake test results are shown in Table 4. Water uptake performance test was performed and the values were found to be between 20.31% and 23.35% w/w.

In vitro release studies (Figure 5) were carried out for the coated tablets. Cumulative % drug release was observed before the lag time. The release was found to be 98.2% and 99.69%. The release before completion of lag time was found to be 99.27%, 98.02% and 98.22% for formulation FPC3, FPC4 and FPC5 respectively. Increasing the coating level of Eudragit RS PO shows a decrease in the dissolution rate of drug. This may be due to increasing the coat concentration made the coat more

impermeable and drug release was retarded. As the coat ruptures slows, drug dissolution through it was facilitated. Thus this study clearly indicated that formulation FPC3 is more suitable among the formulations to design pulsatile release formulations of pantoprazole sodium for 6 hours lag time. After this lag time burst release was observed which exhibited sigmodial release pattern and that was considered to be an ideal for the pulsatile drug delivery system.

Drug release from the device, need to be independent of agitation intensity of the release media. The cumulative percentage of drug released from the device was found to be 98.89% and 99.13% for 50 and 100 rpm respectively (Figure 6). The results revealed no drastic change in release profile in different rotational speed, as it predicts no change in the performance of the system as increased gastric motility.

The SEM images clearly demonstrated the various layers core, inner swelling and outer polymer layer; which are shown in Figure 7a and 7b.

Fig. 1. IR Spectra of drug, excipients and formulation composition.


Fig. 3. Release pattern of Pantoprazole sodium core.

Fig. 4. Comparative dissolution profile of press coated tablet formulation.

Fig. 5. Comparative dissolution profile of coated tablet formulation.

Fig. 2. Comparative dissolution profile of core tablet formulation.


Fig. 6. Effect of paddle speed on the dissolution profile of optimized formulation.

Fig. 7a. SEM of optimized formulation surface coated with Eduragit RS PO.

Fig. 7b. SEM-Showing three layers.

Stability studies were carried out at 40 °C and 25 °C

and tested for its physical properties and in vitro release studies, stability study results revealed that the prepared formulation was stable in the stress condition.

Conclusions

The chronomodulated drug delivery system for pantoprazole sodium for the treatment of hyperacidity was successfully developed. The system was found to be


satisfactory interms of release of the drug after a lag time. The release of the drug was sharp and complete after the lag time which is necessary for any pulsatile drug delivery systems.

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Address correspondence to: P.Mahalakshmi, Assistant Professor, Al Shifa College of Pharmacy, Poonthavanam Post, Kizhattur, Kerala- 679325, India. Tel: 08157997654; E-mail: [email protected]

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