Effect of Enzyme Dependent Polymers on the Release Profile of Press Coated Esmeprazole Colon Targeted Tablets

Ashok Thulluru¹*,Nawaz Mahammed², S. Shakir Basha³, K. Siva Jagan Mohan²,

K. Saravanakumar², Ch. S. Phani Kumar⁴

¹Dept. of Pharmaceutics and QA, Shri Vishnu College of Pharmacy (Autonomous), Vishnupur,

Bhimavaram - 534202, W.G. (Dist.), A.P., India.

²Dept. of Pharmaceutics, Sree Vidyanikethan College of Pharmacy, A. Rangampet, Tirupati - 517102,

Chittoor (Dist.), A.P., India.

³Dept. of Pharmaceutical Analysis, Raghavendra Institute of Pharmaceutical Education and Research (Autonomous), K. R. Palli Cross, Chiyyedu (Post) - 515721, Ananthapuramu (Dist.), A.P., India.

⁴Dept. of Pharmaceutics, Adarsa College of Pharmacy, G. Kothapalli-533 285, Gokavaram (Md.),

E.G. (Dist.), India.

*Corresponding Author E-mail: ashokthulluru@gmail.com

ABSTRACT:

The present study was aimed to formulate press‑coated tablets of Esmeprazole for colon targeted delivery (EZCT). Press coated tablets aids to prevent the gastric degradation of drugs, there by improves its oral bioavailability. Various enzyme dependent polymers (pectin, xanthan gum and guar gum) were selected for extending the drug release by press coating the drug incorporated core tablets. Fourier Transform Infrared (FTIR) analysis was performed to check the compatibility of drug and polymers. Core and coating compositions were evaluated for pre‑ and post-compression studies. In vitro release studies were performed in three dissolution media without rat caecal content medium (RCCM) for first 2 h in 0.1 N HCl, next 3 h in pH 6.8 phosphate buffer and then for last 7 h in pH 7.4 phosphate buffer (total 12h). In vitro drug release studies, revealed that the tablets coated with enzyme dependent polymers showed no drug release up to initial 5 h, indicating cid Protection of EZ due to solid dispersion with MgO. The lead formulations with higher conc. (27.8%w/w) of enzyme dependent polymers extends the release of EZ up to 12 h with a better zero order release profile (r² ⁓ 0.999), hence they are selected to perform the dissolution with RCCM, for to simulate the colonic environment. Among all the batches, EZCT9 (27.8% w/w guar gum), drug release kinetics fitted best to the zero order (r²=0.999); its drug release process is predominantly by diffusion and the mechanism of diffusion is by non-Fickian process in with and without RCCM, hence it is selected as optimized one. Optimized formulation (EZCT9) passes the test for stability as per ICH guidelines. Press coated colonic targeted EZ tablets were successfully developed with an aim to increase oral bioavailability and decrease production costs.

KEYWORDS: Press coated tablets, guar gum. xanthan gum, pectin, in vitro dissolution studies.

INTRODUCTION:

Targeted drug delivery to the colon is very much attractive for local treatment of a spread of bowel diseases like (ulcerative inflammatory bowel disease, Chron’s disease) protozoal infection, colonic cancer, and for local treatment of local colonic pathologies, and therefore protein and peptide drugs for the systemic delivery^1-3.

Oral route is most convenient and most popular route however alternative routes for CDDS may be used. The concentration of drug reaching the colon can rely on formulation factors the extent of retrograde spreading and therefore the retention time. Formulations were done to prevent the acidic degradation of drugs by gastric HCl and so as to improve its bioavailability. Various polymers used for CTDD are pH‑dependent (Eudragit L100, Eudragit S100), enzyme‑dependent (Pectin, guar gum, xantham gum), and time‑dependent (HPMC K15M)^4-6. Esomeprazole (EZ) is a classical example of proton pump inhibitor used for the treatment of gastroesophageal reflux disease. It,is chemically known as 5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl] benzimidazol-1-ide. EZ is used to treat and prevent stomach and intestinal ulcers, erosive esophagitis (damage to the esophagus from stomach acid), and other conditions involving excessive stomach acid such as Zollinger-Ellison syndrome. EZ undergoes acid degradation in gastric environment, which can be prevented by enteric coating conventionally or by preparing a solid dispersion with MgO as reported earlier. The acid protected EZ can be colon targeted; by extending the release with enzyme dependent polymers to enhance its oral bioavailability⁷. The aim of the present work was to protect the EZ from acid degradation by preparing a solid dispersion with (MgO and HPMC K15M) and to extend the release of drug up to 12 h by press coating with enzyme dependent polymers [pectin (PT), guar gum (GG) and xanthan gum (XG)] of varying Conc. (13.8, 20.8 and 27.8% w/w) and also to increase the oral bioavailability of EZ by colon targeting.

MATERIALS AND METHODS:

Materials:

Esomeprazole was procured as a gift sample from A to Z pharmaceuticals, Chennai. Magnesium oxide [MgO] (Fisher scientific), HPMC K15M (Fisher scientific), Hydrochloric acid (HCl) (Merck), Sodium hydroxide (NaOH) (Fisher scientific), Potassium dihydrogen phosphate (KH₂PO₄) (HI media), Guar gum (Merck), Xanthan gum (HI media), Pectin (HI media), Polyvinylpyrrolidone (PVP) (HI media), Microcrystalline cellulose (MCC) (HI media), Magnesium Stearate (HI media), Talc (Merck).

Methods:

Drug- Excipients compatibility/ FTIR studies:

FTIR spectra of EZ and EZ: polymer (1:1) physical mixtures were recorded out, in the region of 400-4000 cm^-1 at spectral resolution of 2 cm^-1, by the direct sampling method with isopropyl alcohol as solvent, using FTIR instrument (Agilent technologies Cary 630 FT-IR, Japan).⁸

Preparation of pH 1.2 buffer / 0.1 N HCl:

Solutions of any molarity XM may be prepared by diluting 85X mL of hydrochloric acid (Place 21.25mL of hydrochloric acid in a 250mL volumetric flask and then add water up to the mark).⁹

Preparation of pH 6.8 phosphate buffer:

Place 50.0mL of 0.2 M potassium dihydrogen phosphate in a 200mL volumetric flask, add the 22.4mL of 0.2 M sodium hydroxide and then add water to volume. (Weigh accurately about 1.7g of potassium dihydrogen phosphate solution in a 250mL volumetric flask and add 0.22g of sodium hydroxide solution and then add water up to the mark).⁹

Preparation of pH 7.4 phosphate buffer:

Place 50.0mL of 0.2 M potassium dihydrogen phosphate in a 200mL volumetric flask, add the 39.0mL of 0.2 M sodium hydroxide and then add water to volume. (Weigh accurately about 1.7g of potassium dihydrogen phosphate solution in a 250mL volumetric flask and add 0.39g of sodium hydroxide solution and then add water up to the mark).⁹

Standard calibration curve of EZ in various buffers (pH 1.2, pH 6.8 and pH 7.4):

Stock solution-I; (1 mg/mL (or) 1000µg/mL):

50mg of Esomeprazole was dissolved in 10mL of methanol and then volume was adjusted with the respective buffer up to the mark in a 50mL volumetric flask and then placed in a sonicator for 5 min.

Stock solution-II; (10µg/mL):

1mL of the stock solution-I was taken into a 100mL volumetric flask and then add respective buffers were added up to the mark.

Working dilutions (2, 4, 6, 8 and 10µg/mL):

2, 4, 6, 8 and 10mL of the stock solution-II was taken into a 10mL volumetric flask and then add respective buffers were added up to the mark, to obtain the series of working dilutions 2, 4, 6, 8 and 10µg/mL respectively. The standard calibration curve was plotted by taking conc. (µg/mL) on X-axis and absorbance at λ_max on Y-axis. Conc. vs absorbance values of EZ in different buffers and the linearity of standard curve with regression coefficient (r²).¹⁰

Preparation of solid dispersion:

Weigh accurately 500mg of EZ and 500mg of HPMC K15M and 500.1mg of MgO in 1:1:1.1 ratio and added to 70mL 1:1 of methanol and distilled water in a 100mL beaker, mix the dispersion with the help of homogenizer and spray dried to obtain solid dispersion.¹¹

Preparation of EZCTs:

Core tablets:

Weighed accurate quantities of SD, CCS, and lactose were passed through # 30 ASTM sieve and blended in a poly bag for 5 min, it was lubricated with # 60 ASTM sieve passed talc and magnesium stearate by mixing in the same poly bag for 2 min. Compressed to obtain core tablets.

Coating composition granules:

Gum [PT/ GG/ XG], MCC and lactose were triturated it in a mortar with a pestle for 5 min. 5% w/v PVP K30 alcoholic solution was added and needed to obtain wet mass. The wet mass is passed through # 20 ASTM sieve to get wet granules, which are dried in a hot air oven at 60 °C for 1 h. Dried granules were passed through # 30 ASTM sieve. Finally lubricated with # 60 ASTM sieve passed talc and magnesium stearate by mixing in the poly bag for 2 min.

Press coated tablets:

Tablets were compressed by placing half of the coating composition at bottom, core tablet at the centre and remaining half of the coating composition at top in the die cavity, with an avg. wt. of 180 mg and avg. hardness of 6 kg/cm². Formulation table of EZCTs was tabulated in (Table 1).

Table 1: Formulation Table of EZCTs

Ingredients*	EZCT1	EZCT2	EZCT3	EZCT4	EZCT5	EZCT6	EZCT7	EZCT8	EZCT9
Core Tablet
EZ: HPMC K15M, MgO (1:1:1.1) SD	62	62	62	62	62	62	62	62	62
CCS	4	4	4	4	4	4	4	4	4
Lactose	12.4	12.4	12.4	12.4	12.4	12.4	12.4	12.4	12.4
Mg. Stearate	0.4	0.4	0.4	0.4	0.4	0.4	0.4	0.4	0.4
Talc	1.2	1.2	1.2	1.2	1.2	1.2	1.2	1.2	1.2
Total	80	80	80	80	80	80	80	80	80
Coating composition
*Intra-granular*
Pectin	25	37.5	50	-	-	-	-	-	-
Xanthan gum	-	-	-	25	37.5	50	-	-	-
Guar gum	-	-	-	-	-	-	25	37.5	50
MCC	15	15	15	15	15	15	15	15	15
Lactose	58	45.5	33	58	45.5	33	58	45.5	33
5% w/v PVP K30-Ethanolic soln.	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.
*Extra-granular*
Mg. Stearate	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
Talc	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
Total	180	180	180	180	180	180	180	180	180

EZ= Esmeprazole, SD=Solid dispersion, CCS=Crosscarmellose sodium, MCC=Microcrystalline cellulose and PVP=Polyvinyl pyrrolidone. *Quantities mentioned in mg per tablet.

Evaluation studies:

The formulated tablets were evaluated for the following pre-compression, post- compression and in vivo dissolution studies.

Pre-compression parameters:¹²

Angle of repose:

Fixed funnel method was used to determine the angle of repose. A funnel was fixed with its tip at a given height ‘h’ above a flat horizontal surface to 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 the funnel. The angle of repose was then calculated by:

θ = Tan^-1 (h/r) Eq. No. (1)

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

Bulk density (BD):

It is a ratio of mass of powder to bulk volume. The bulk density depends on particle size distribution, shape and cohesiveness of particles. Accurately weighed quantity of powder was carefully poured into graduated measuring cylinder through large funnel and volume was measured, which is the initial bulk volume. Then it is expressed in gm/cm³ and is given by:

D_b = M / V₀Eq. No. (2)

Where, M = mass of powder, V₀ = bulk volume of the powder

Tapped density (TD):

Ten gram of powder was introduced into a clean, dry 100 mL measuring cylinder. The cylinder was then tapped 100 times from a constant height and the tapped volume was read. It is expressed in gm / cm³ and is given by:

D_t = M / V_t Eq. No. (3)

Where, M = mass of powder, V_t = tapped volume of the powder.

Carr’s index (CI):

Carr’s index is an indication of the compressibility of a powder. It is expressed in percentage and is given by:

CI = (D_t – D_b / D_t)x 100 Eq. No. (4)

Where D_t =Tapped density, D_b=Bulk density

Hausner’s ratio:

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

HR= TD/BD Eq. No. (5)

Post compression studies:^13,14

Avg. wt. and wt. variation:

20 tablets were selected and weighed collectively and individually. From the collective weight, average weight was calculated. Each tablet weight was then compared with average weight to assure whether it was within permissible limits or not. Not more than two of the individual weights deviated from the average weight by more than 5% for 600 mg tablets and none by more than double that percentage.

Avg wt = wt of 20 tablets / 20 Eq. No. (6)

%wt variation=Avg wt- wt of each tablet x 100 Eq. No. (7)

Avg wt

Thickness:

Control of physical dimensions of the tablet such as thickness is essential for consumer acceptance and tablet uniformity. The thickness of the tablet was measured using digital Vernier calipers.

Hardness:

The Monsanto hardness tester was used to determine the tablet hardness. The tablet was held between affixed and moving jaw. 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 the hardness of the tablet.

Friability:

Roche friabilator was used to measure the friability of the tablets. Ten tablets were weighed collectively and placed in the chamber of the friabilator. In the friabilator, the tablets were exposed to rolling, resulting from free fall of tablets within the chamber of the friabilator. It was rotated at a rate of 25 rpm. After 100 rotations (4 minutes), the tablets were taken out from the friabilator and intact tablets were again weighed collectively. The percent friability was determined using the following formula.

F = (W_initial) - (W_final)/ (W_initial) X 100 Eq. No. (8)

Assay:

Five tablets were selected randomly and average weight was calculated. Tablets were crushed in a mortar individually and accurately weighed amount of tablet triturate from each blend was taken. Then, samples were transferred to 100 mL volumetric flask, diluted with pH 6.8 PBS and agitated for 30 min. Sample (1 mL) was withdrawn and after appropriate dilution assayed by UV Spectrophotometric at 295 nm.

Swelling index (SI):

Measurement of hydration rates of formulation were carried out, after the immersion of the tablets in the test medium to relate the observed phenomena of drug release with the rates of polymer hydration. Weighed tablets were placed in the baskets of the dissolution apparatus rotating at 50 rpm, with the dissolution medium of simulated gastric fluid for model drug at 37±0.5^oC. After 1, 2, 3, 4, 5, 6, 7 and 8 h, each dissolution basket containing the sample was withdrawn, blotted to remove excess water and weighed on an analytical balance. The experiment was performed in triplicate for each time point. The SI was estimated at each time point by the following equation.

SI = (W_w- W_i) / W_{i X 100}Eq. No. (9)

Where,

SI= swelling index,

W_w = wt of the hydrated sample and

W_i = wt of initial dry sample

Preparation of 4 % w/v rat caecal content medium (RCCM):

The protocol (SVCP/IAEC/I-012/2018-19 dated on 01/04/2019) for animal studies was approved by the Institutional Animal Ethics Committee (IAEC) of Sree Vidyanikethan College of Pharmacy, Tirupati and is in accordance with guidance of committee for the purpose of Control and Supervision of Experiments on Animals (CPCSEA), Ministry of Social Justice and Empowerment, Govt. of India. Male albino rats weighing 150 to 200 g were kept on a normal diet and administered 1 mL of 1% w/v solution of the selected gums (GG, XG and PT) in water. This treatment was continued for 7 days to induce the specific enzyme responsible for degradation of selected gums in vivo. 30 min before the dissolution studies began, the anesthetized rats were sacrificed, the rat abdomen was opened, ligatures were made before and after the caecum and the caecum was removed under anaerobic conditions. The caecum bag was opened and its contents were weighed and homogenized, then suspended in pH 7.4 PBS to give the 4 % w/v conc. of caecal contents. The suspension was centrifuged at 2000 rpm for 10 min at 4ºC to disrupt the bacterial cells followed by sonication. The resultant mixture was centrifuged at 2000 rpm for further 20 min. As the environment of caecum is anaerobic, all operations were performed in a CO₂ atmosphere.¹⁵

In vitro dissolution studies (without and with RCCM):

In vitro drug release studies of EZCTs were carried out using a USP type I dissolution test apparatus (paddle, 100 rpm, 37 ± 0.5°C) in 900 mL of dissolution medium (pH 1.2 HCl buffer for first 2 h, pH 6.8 PBS for next 3 h and pH 7.4 PBS without or with 4 % w/v RCCM for next 7 h). At predetermined intervals, 5 mL of samples were withdrawn through a 0.45 μm nylon filter discs, by replacing with the same amount of fresh respective medium and after suitable dilution they were assayed spectrophotometrically at 295 nm.^16,17

In vitro drug release kinetic studies (without and with RCCM)):

The in vitro drug release data of all batches were fitted into zero order, first order, Higuchi and Korsemeyer- Peppas models to ascertain the drug release kinetics. The regression coefficient (r²) of the kinetic model plots were analyzed using MS EXCEL 2007. The drug release from the matrix tablets whether depends on drug’s concentration or not was explained by zero and first order.¹⁸ Higuchi model describes whether the drug release is predominantly by diffusion or not. The Korsemeyer- Peppas model further explains the mechanism of diffusion.^19,20 The respective models were defined by the equations below.

Zero order: Q_t= Q₀+ K₀t Eq. No. (10)

First order: LogQ = log Q₀-K₁t / 2.303 Eq. No. (11)

Higuchi model: Q_t= K_Ht^1/2Eq. No. (12)

Korsemeyer-Peppas model: M_t /M_∞ = K tⁿEq. No. (13)

Where Q_tis the amount of drug dissolved at time, t; Q₀is the initial amount of drug in the solution at time t=0, Q is the amount of drug remaining at time, t; Mt/M∞ is the fraction of drug released at time, t and n is diffusion exponent. K₀, K₁, K_H and K refer to the rate constants of respective kinetic models.

Accelerated stability studies of the optimized EZCT:

were carried according to an international; conference on harmonization (ICH) guidelines. 20 tablets were packed in each 10 cc HDPE bottle and sealed thermally and were placed in a humidity chamber (nsw-175, Narang scientific work, India) maintained at 45°C±2°C and 75% ± 5% RH. Up to 3 months, at the end of every month the respective samples were withdrawn and evaluated for post compression studies. The consolidated results of post compression studies on accelerated stability samples of optimized EZCT9; expect Avg. Wt. (n=20) and friability test (n=1), the other was carried out in triplicate (n=3) and the result as (mean±SD) were tabulated in (table). In vitro dissolution profiles of initial and accelerated stability samples of optimized EZCT9 were represented graphically.²¹

RESULTS AND DISCUSSION:

Drug-excipient compatibility/ FTIR studies:

The FTIR spectrum of pure EZ showed the broad peak at 3217.01 cm^-1 corresponds to C=N group. The peak at 108.32 cm^-1 corresponds to C=S boding. The peaks at 1613.2 cm^-1 and 1581.2 cm^-1 indicate the presence of carbonyl group. The drug and polymers employed were found to be compatible as similar peaks were observed with minor differences in the spectra of EZ + polymer(s) (1:1 ratio physical mixtures).²² The comparative FTIR spectra of EZ, EZ+β-CD and EZ+polymer(s) (1:1 ratio physical mixtures) were shown in (Fig.1).

Fig. 1: FTIR spectrum of A. EZ+ MgO; B. EZ+ HPMCK15M; C. EZ+PT; D. EZ+ XG; and E. EZ+GG

Standard calibration curves:

In three buffer solutions (pH 1.2 HCl, pH 6.8 and pH 7.4 PBS) the standard curve is showing linearity with a regression coefficient (r² > 0.999) and obeys Beer’s law in the conc. range of 0-20 μg/mL. Std. cal. curve for the estimation of EZ in various selected buffers by spectrophotometric method was shown in Fig.2.

Fig. 2: Std. cal. curve for the estimation of EZ in (A) 0.1 N HCl, (B) pH 6.8 PBS and (C) pH 7.4 PBS by spectrophotometric method

Pre-compression studies:

The angle of repose of the directly compressible blend of core tablets of EZCTs are is 21°.21’; CI and HR were found to be as 13.30% and 1.15 respectively, indicating excellent flow and compressibility properties of the blend. The angle of repose of all the coating compositions prepared by non-aqueous wet granulation are ranging between 20°.13’+0.08 to 25.26°+0.07’; CI and HR were found to be in the range of 12.97 to 15.81% and 1.14 to 1.14 respectively, indicating excellent flow and compressibility properties of the blends. Results of pre-compression studies of core tablet and coating composition of EZCT are tabulated in (Table 2).

Table 2: Results of pre-compression studies of core tablet and coating composition of EZCT

Core Tablet
F. Code	AR (°) n=3	BD (g/cm³) n=3	TD (g/cm³) n=3	CI* (%)	HR* ( )
Same for all	21.21+0.07	0.486+0.001	0.565+0.002	13.30	1.15
Coating Composition
F. Code	AR(°) n=3	BD (g/cm³) n=3	TD (g/cm³) n=3	CI* (%)	HR* ( )
EZCT1	20.13+0.08	0.476+0.001	0.547+0.002	12.97	1.14
EZCT2	20.92+0.07	0.483+0.001	0.557+0.001	13.30	1.15
EZCT3	21.33+0.09	0.487+0.001	0.564+0.002	13.40	1.16
EZCT4	22.46+0.08	0.493+0.002	0.572+0.001	13.80	1.16
EZCT5	24.09+0.10	0.502+0.002	0.583+0.002	13.90	1.16
EZCT6	24.33+0.06	0.513+0.002	0.596+0.001	14.58	1.16
EZCT7	25.26+0.07	0.493+0.002	0.583+0.002	15.20	1.15
EZCT8	25.24+0.10	0.470+0.002	0.565+0.002	15.81	1.16
EZCT9	24.33+0.06	0.457+0.002	0.553+0.001	15.35	1.17

AR=Angle of repose, BD=Bulk density, TD= Tapped density, CI=Carr’s index and HR=Hausner’s ratio. * CI and HR are calculated from the mean values of BD and TD of respective batches.

Table 3: Results of post-compression studies of EZCT

F. Code	Avg. wt. (mg) n=3	Thickness (mm) n=3	Hardness (kg/cm²) n=3	Friability (%) n=1*	SI at 3 h (%) n=3	Assay (%) n=3
EZCT1	177+0.09	4.08+0.12	6.08+0.12	0.52	24±1.89	96.38+0.09
EZCT2	176+0.11	4.83+0.23	5.83+0.23	0.58	27±1.24	98.23+0.11
EZCT3	176+0.10	4.66+0.23	5.66+0.23	0.59	28±1.12	97.57+0.14
EZCT4	176+0.13	4.66+0.23	5.78+0.21	0.63	30±0.98	95.78+0.10
EZCT5	177+0.09	5.47+0.11	6.47+0.11	0.64	29±1.16	97.46+0.13
EZCT6	178+0.13	4.17+0.14	6.17+0.14	0.48	32±1.25	96.57+0.09
EZCT7	176+0.10	4.16+0.12	6.16+0.12	0.50	31±0.99	98.29+0.13
EZCT8	176+0.10	4.66+0.23	6.27+0.15	0.53	32±0.86	97.76+0.10
EZCT9	179+0.10	4.66+0.23	6.17+0.14	0.57	33±0.99	89.16+0.12

SI=Swelling index, *Friability test was conducted on 10 tablets (n=1) from each batch.

Fig. 4: In vitro dissolution profiles of selected (F3, F6 and F9) EZCTs with rat caecal content medium

In vitro drug release kinetics (without and with RCCM):

Among all the batches, EZCT9 (with 27.8% w/w GG), drug release kinetics fitted best to the zero order (as zero order, r²=0.996 without and r²=0.998 with RCCM), indicating the drug release from the matrix does not depends on drug’s conc. Drug release process is predominantly by diffusion when Higuchi’s, r² > 0.9 (r²=0.957 without RCCM and r²=0.951 with RCCM); and the mechanism of diffusion is by non-Fickian when Korsemeyer-Peppa’s diffusion coefficient (n) is 0.45 < n < 0.89 for cylindrical shape, (n=0.787 without RCCM and n=0.771 with RCCM).^28-30 Results of in vitro drug release kinetics of AZCTs without and with RCCM were tabulated in (Table 4).

Table 4: Results of in vitro drug release kinetics of EZCT without and for selected formulations with rat caecal content

All formulations without rat caecal content
F. Code	Zero	First	Higuchi	Krosmeyer-Peppas
F. Code	r²	r²	r²	r²	n
EZCT1	0.896	0.954	0.988	0.981	0.492
EZCT2	0.919	0.964	0.984	0.972	0.654
EZCT3	0.976	0.985	0.916	0.996	0.975
EZCT4	0.896	0.926	0.973	0.982	0.440
EZCT5	0.921	0.952	0.983	0.979	0.512
EZCT6	0.975	0.995	0.957	0.998	0.825
EZCT7	0.895	0.937	0.974	0.960	0.365
EZCT8	0.919	0.958	0.984	0.977	0.403
EZCT9	0.996	0.982	0.957	0.998	0.787
Selected formulations with rat caecal content
F. Code	Zero	First	Higuchi	Krosmeyer-Peppas
F. Code	r²	r²	r²	r²	n
EZCT3	0.986	0.974	0.916	0.995	0.969
EZCT6	0.985	0.980	0.956	0.997	0.822
EZCT9	0.998	0.840	0.951	0.998	0.771

r²=Regression coefficient, n=Diffusion exponent.

Accelerated stability studies:

As there were no significant differences in post compression studies (wt. variation, thickness, hardness, friability, SI at 3 h and in vitro dissolution studies) of initial and accelerated stability samples of optimized EZCT9 up to 3 months in the 10 cc HDPE pack, it passes the test for stability as per ICH guidelines. Results of accelerated stability studies of optimized EZCT9 were tabulated in (Table 5). Comparative in vitro dissolution profiles of initial and accelerated stability samples of optimized EZCT9 without RCCM were shown in (Fig.5) reveals there was no significant change. Comparative FTIR spectra of EZ (pure drug) and accelerated stability samples of optimized EZCT9 were shown in (Fig.6) reveals there is no significant change in the functional groups of the EZ due to interaction with polymers and other excipients used in the formulation.^31,32

Fig 5: In vitro dissolution plots of accelerated stability samples of optimized EZCT9 without RCCM

Fig 6: Comparative FT-IR spectra of A. EZ (pure drug); B. 1M; C. 3M- Accelerated stability samples of optimized EZCT9

CONCLUSION:

The prepared EZCTs pass the drug-excipient, pre- and post- compression studies. Protection of EZ from acid degradation was evident from the dissolution profiles, due to preparation of solid dispersion of EZ with MgO and HPMC K15M. All formulations with various Conc. (13.8, 20.8 and 27.8% w/w) of enzyme dependent polymers (GG/XG/PT) are able to extend the release up to 12 h of EZ; in vitro dissolution studies without RCCM. Among all formulations, the batches with highest conc. (27.8%w/w) of enzyme dependent polymers (GG/XG/PT) extends the release of EZ up to 12 h with a better zero order release profile (r² ⁓ 0.999), hence they are selected to perform the dissolution with RCCM, for to simulate the colonic environment. Among all the batches, EZCT9 (27.8% w/w GG), drug release kinetics fitted best to the zero order (r²=0.999); its drug release process is predominantly by diffusion and the mechanism of diffusion is by non-Fickian process in with and without RCCM, hence it is selected as optimized one. Optimized formulation (EZCT9) passes the test for stability as per ICH guidelines. The gastric acid deagration of EZ was protected, by preparing a solid dispersion with and the release of EZ was extended up to 12 h by formulating press coated tablets with enzyme dependent polymer guar gum at a conc. of 27.8% w/w. Colon targeting of gastric acid deagration protected EZ will increase its bioavailability, due to colonic absorption and this method acts an alternative approach to conventional enteric coating and thereby reducing the production costs.

ACKNOWLEDGEMENT:

The authors are thankful to Padmashree. Dr. M. Mohan Babu garu, Chairman and visionary, Sree Vidyanikethan Educational Trust, Tirupati, Dr. Anna Balaji, Principal; Sree Vidyanikethan College of Pharmacy, Tirupati, for providing us the required facilities and being a constant support to carry out this research work. The authors are also thankful to Management, Director and Principal of Shri Vishnu College of Pharmacy (Autonomous), Bhimavaram; for accepting to utilize the facility of FTIR.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

1. Mihir K. Patel, Amit Roy, Sanjib Bahadur, Shashank Kukreja, Monika Bhairam. Colon Targeted Drug Delivery: Approaches and Newer Technology. Res. J. Pharm. and Tech. 2012; 5(9): 1154-60.

2. Akhil Gupta, Anuj Mittal , Alok Kumar Gupta. Colon Targeted Drug Delivery Systems-A Review. Asian J. Pharm. Res. 2011; 1(2): 25-33.

3. Vijaya Kumar V., Raghuram N., K. Hari Krishna, K. Rajyalakshmi, Y. Indira Muzib. A review on colonic drug delivery System. Res. J. Pharma. Dosage Forms and Tech. 2011; 3(4): 122-9.

4. Rajendra Jangde. Colonic Drug Delivery of New Approaches. Res. J. Pharma. Dosage Forms and Tech. 2011; 3(6): 241-6.

5. Rajendra Jangde. Microsponges for colon targeted drug delivery system: An overview. Asian J. Pharm. Tech. 2011; 1(4): 87-93.

6. Babli Thakur, Vinay Pandit, Mahendra Singh Ashawat, Pravin Kumar. Natural and Synthetic Polymers for Colon Targeted Drug Delivery. Asian J. Pharm. Tech. 2016; 6(1): 35-44.

7. Chandile Govind Kishanrao, S.N. Sri Harsha, D. Yashwanth Kumar, K.S.S.N. Neelima and U.Sambamoorthy. Formulation and Evaluation of Colon Specific Matrix Tablets of Esomeprazole. Int J Current Trends Pharm Res. 2013; 1(4): 217-24.

8. Prasanta Kumar Choudhury, Padala Narasimha Murthy, Suvakanta Dash, Rana Mazumder, Dhruba Sankar Goswami. Formulation and In-Vitro Evaluation of Ethyl Cellulose Microspheres by Novel Quasiemulsification Method for Colonic Delivery of Metronidazole. Res. J. Pharma. Dosage Form. and Tech. 2010; 2(4): 295-300.

9. Indian Pharmacopoeia. Govt. of India Vol-I. Ghaziabad: Ministry of Health and Family Welfare, Published by The Indian Pharmacopoeia Commission. 2007; pp. 1319-1320.

10. Mohammadi Begum, Pamulreddy and B. Rajkamal. Formulation and Evaluation of Colon Specific Drug Delivery of Press Coated Esomeprazole Tablet. Der Pharmacia Sinica. 2016; 7(4): 32-43.

11. Roshan Pradhan, Tuan Hiep Tran, Sung Yub Kim, Kyu Bong Woo, Yong Joo Choi, Han-Gon Choi, Chul Soon Yong and Jong Oh Kim. Preparation and characterization of fast dissolving flurbiprofen and esomeprazole solid dispersion using, spray drying technique. Int J Pharm. 2016; 502(1-2): 38-46.

12. Lachman L, Liberman H, Kanig J. Editors. The theory and practice of industrial Pharmacy, Varghese Publishing House, Mumbai, 1991; 3^rded: pp.150-2.

13. Indian Pharmacopoeia. Govt. of India, Vol-II. Ghaziabad: Ministry of Health and Family Welfare, Published by The Indian Pharmacopoeia Commission. 2007; pp. A-145 to A-169.

14. United States Pharmacopoeia 26 and National Formulary 21, Published by The United States Pharmacopoeial Convention, Rockville, 2003; PP. 1457-60.

15. Sinha VR, Mittal BR, Bhutani KK, Kumria R. Colonic drug delivery of 5-fluorouracil: an in vitro evaluation. Int J Pharm. 2004; 269(1): 101-08.

16. Yang L. Biorelevant dissolution testing of colon specific delivery system activated by colonic microflora. J Control Rel. 2008; 125(2): 77-86.

17. Yang L, Chu JS, Fix JA. Colon specific drug delivery: new approaches and in vitro/in vivo evaluation. Int J Pharm. 2002; 235(1-2): 1-15.

18. Gautam Singhvi, Mahaveer Singh. Review: In vitro Drug Release Characterization Models. Int J Pharm Studies Res. 2011; 2(1): 77-84.

19. Higuchi T. Rate of release of medicaments from ointment bases containing drugs in suspension. J Pharm Sci. 1961; 50: 874–75.

20. Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA. Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm. 1983; 15(1): 25-35.

21. http://www.ich.org/fileadmin/Public_Web_Site/ABOUT_ICH/Organisation/SADC/Guideline_for_Stability_Studies.pdf

22. Achin Jain, MN Ravi Teja, Laxman Pariyani, V Balamuralidhara and N Vishal Gupta. Formulation and Evaluation of Spray-Dried Esomeprazole Magnesium Microspheres. Trop J Pharm Res. 2013; 12 (3): 299-304.

23. Dhruv Malik, Inderbir Singh. Formulation and evaluation of press coated tablets of esomeprazole for colonic delivery. Asian J Pharm. 2012; 6(4): 252-8.

24. J.W. Skoug, M.V. Mikelsons, C.N. Vigneron, N.L. Stemm. Qualitative evaluation of the mechanism of release of matrix sustained release dosage forms by measurement of polymer release. J Control Rel. 1993; 27: 227-5.

25. L.S. Wan, P.W. Heng, L.F. Wong. Relationship between swelling and drug release in a hydrophilic matrix, Drug Dev Ind Pharm.1993; 19: 1201-10.

26. Masheer Ahmed Khan. Effect of Swelling and Drug Release Relationship of Sustained Release Matrices containing different Grades of Hydroxypropyl Methylcellulose. Res J Pharma Dosage Form. and Tech. 2013; 5(4): 232-6.

27. Mughal MA, Iqbal Z, Neau SH. Guar Gum, Xanthan Gum, and HPMC can define release mechanisms and sustain release of Propranolol Hydrochloride. AAPS Pharm SciTech. 2011; 12(1): 77-87.

28. Vijayakumar V. Alange, Raghavendra V. Kulkarni. Colon Targeted Drug Delivery through functionally modified Natural Biopolymers. Res J. Pharm. and Tech. 2017; 10(6): 1853-7.

29. P.S. Salve. Development and in vitro evaluation of colon targeted drug delivery system using natural gums. Asian J. Pharm. Res. 2011; 1(4): 91-101.

30. Asma Sulthana, B. Ramu, G. Srikanth, Bigala Rajkamal. Formulation and evaluation of colon specific tinidazole matrix tablets. Res. J. Pharm. Dosage Form. and Tech. 2016; 8(3): 167-172.

31. G.R. Prasanna Laxmi and G. Srikanth. Formulation and Evaluation of Colon Specific Drug Delivery of Press Coated Esomeprazole Tablets. J Drug Del Ther. 2019; 9(1): 9-19

32. RJ Garala, SV Shirolkar, AD Deshpande, AD Kulkarni. Colon Targeted Drug Delivery System of Prednisolone by Press Coating Technique: Effect of Different Grades of Hydroxyethylcellulose in Coat. Res. J. Pharm. and Tech. 2011; 4(3): 405-10.

Received on 13.12.2019 Modified on 26.02.2020

Research J. Pharm. and Tech. 2020; 13(12):6186-6194.

DOI: 10.5958/0974-360X.2020.01079.3

Time (Months)	Avg. wt. (mg) n=3	Thickness (mm) n=3	Hardness (kg/cm²) n=3	Friability (%) n=1*	SI at 3 h (%) n=3	Assay (%) n=3
1M	178±1.11	4.22±0.044	6.18±0.213	0.2	33±0.99	99.60±0.85
2M	177±0.95	4.09±0.19	5.99±0.98	0.2	34±0.84	98.01±0.16
3M	176±0.09	5.81±1.27	5.63±0.15	0.15	34±0.67	97.23±0.34