DSpace at VNU: Pectin HPMC dry powder coating formulations for colon specific targeting tablets of metronidazole

Accepted Manuscript Pectin/HPMC dry powder coating formulations for colon specific targeting tablets of metronidazole Nguyen-Thach Tung, Ph.D., Thi-Minh-Hue Pham, Ph.D., Thanh-Hai Nguyen, ThanhTam Pham, Thi-Quynh Nguyen PII: S1773-2247(16)30073-9 DOI: 10.1016/j.jddst.2016.03.004 Reference: JDDST 177 To appear in: Journal of Drug Delivery Science and Technology Received Date: 12 October 2015 Revised Date: 19 February 2016 Accepted Date: March 2016 Please cite this article as: N.-T Tung, T.-M.-H Pham, T.-H Nguyen, T.-T Pham, T.-Q Nguyen, Pectin/ HPMC dry powder coating formulations for colon specific targeting tablets of metronidazole, Journal of Drug Delivery Science and Technology (2016), doi: 10.1016/j.jddst.2016.03.004 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT Pectin/HPMC dry powder coating formulations for colon specific targeting tablets of metronidazole Nguyen-Thach Tunga*, Thi-Minh-Hue Pham a**, Thanh-Hai Nguyenc, Thanh-Tam Phamb, Thi-Quynh Nguyenb RI PT a b c SC Department of Pharmaceutics, Hanoi University of Pharmacy, Vietnam Department of Pharmaceutics, Thai Nguyen University of Medicine and Pharmacy, Vietnam M AN U School of Pharmacy, Vietnam National University, Vietnam 10 11 12 14 15 TE D 13 *Correspondence to: 17 Nguyen-Thach Tung, Ph.D 18 Hanoi University of Pharmacy 19 13-15 Le Thanh Tong, Hoan Kiem, Vietnam 20 e-mail: nguyenthachtung@hup.edu.vn AC C 21 EP 16 22 **Co-correspondence to: 23 Thi-Minh-Hue Pham, Ph.D 24 Hanoi University of Pharmacy 25 13-15 Le Thanh Tong, Hoan Kiem, Vietnam 26 e-mail: hueptm@hup.edu.vn ACCEPTED MANUSCRIPT ABSTRACT The objective of this study was to develop a dry powder coating technique applied to colon targeting tablets containing metronidazole (MET) by using a pan coater The coating formulation consisted of a polymer mixture (pectin/HPMC) and plasticizer (dibutyl phthalate) Dissolution rate of MET was conducted at pH 1.2, 7.4 and 6.8 in the presence of pectinolytic enzyme The lag time release of MET was simultaneously controlled by enzyme signal in colonic medium and coating level There was a significant correlation between the coating level and lag time release when the ratio of pectin: HPMC was from 1:1 to 3:1 SEM indicated a homogenous coating layer when coated tablets were cured at 100oC The lag time 10 phase of drug release was prolonged one more hour when curing time increased from 24 to 11 72 h at 60oC The in-vitro lag time of optimal formulation was 6.01 h The X-ray imaging 12 study showed the presence of coated tablets in ascending and descending colon after and 13 hour of tablet administration, respectively The obtained dry powder coating technique had 14 potential to prepare pulsatile release systems with long lag time release and without using 15 organic solvent 16 Keywords: dry powder coating · metronidazole · colon targeting tablet · pectin · HPMC · 17 pectinolytic enzyme 21 22 SC M AN U TE D 20 EP 19 AC C 18 RI PT ACCEPTED MANUSCRIPT 1 Introduction In recent years, dry powder coating has emerged as a useful alternative to traditional coating technique in which highly flammable and toxic organic solvents [1-3] like ethanol or dichloromethane are used to dissolve coating polymers In an effort to eliminate solvents from the coating process, a number of studies managed to develop different coating methods such as plasticizer dry powder coating, thermal coating and electrostatic coating [3, 4] Among these methods, plasticizer dry powder coating is the most popular for it does not require specific coating equipment, and the whole coating process can be done on a traditional film coater [1, 3] In plasticizer dry powder coating technology, coating powders 10 and the plasticizer are sprayed onto dosage surface from separate spraying nozzles The 11 dosage surface will be wetted by the plasticizer and bounded with the coating polymers The 12 continuous film coating layers will be formed by interaction of plasticizer and polymer 13 powder after curing at a predetermined time and temperature [5, 6] M AN U SC RI PT The plasticizer dry powder coating technology is mainly applied in colonic release 15 systems because the coated tablets can effectively prolong the lag time release of drugs For 16 example, in a study by Pearnchob [7], pellets containing propranolol hydrochloride were 17 coated in a fluidized bed with micronized ethyl cellulose particles, Eudragit RS particles and 18 shellac The results showed that Eudragit RS and ethylcellulose powders could delay drug 19 release for at least hours with coating level of 15% Similarly, Kablitz and Urbanetz [8] 20 used a mixture of the enteric polymer HPMCAS and a plasticizer TEC/Myvacet to coat 21 theophylline pellets After curing the obtained pellets at 55oC for 0.75h, the coated pellets 22 could inhibit under 10% drug release in pH 1.2 Generally speaking, several kinds of coating 23 polymers have been employed to prepare colonic drug delivery systems However, the fact 24 that these polymers control drug release either by pH changes in the gastro-intestinal tract or 25 by the time erosion of coating layer also had disadvantages such as lack of site specificity and 26 high inter/intra subject variability [9] Meanwhile, pectin, one kind of polysaccharides, shows 27 high potential in colonic drug delivery system since it is able to effectively control drug 28 release in colon tract Under the impact of pectinase, a colonic enzyme, pectin is degraded 29 and promotes drug release time in colon Pectin was successfully used as a coating layer for 30 colonic targeting tablets in compression coated tablets [10] However, when it comes to dry 31 powder coating technique in pan coater, the use of pectin alone is insufficient to maintain the 32 consistency of the coated tablet before it reaches colon medium Because of the quick AC C EP TE D 14 ACCEPTED MANUSCRIPT solubility of pectin in water, the maximum lag time of pectin-coated tablets was around hours Consequently, a powder mixture of pectin and another polymer (hydroxypropylmethyl cellulose, Eudragit) has been developed for a colon-specific delivery system [9].The reason for this is the improved mechanical strength of the tablet wall around a drug core thanks to the presence of a high molecular polymer (HPMC, Eudragit) in coating layer [11, 12] The combination of pectin and HPMC successfully produced zero-order release kinetics for matrix tablet system containing prednisolone [13] RI PT In the present study, metronidazole (MET) is chosen as the model drug for preparation of colon targeting tablets because this antibiotic is the preferred choice for mild-to-moderate 10 Clostridium difficile colitis [14] If metronidazole is administered in conventional tablet 11 dosage form, the amount of metronidazole for local action in the colon is minimum and 12 unwanted systemic effects still occur Therefore, the objective of this study is to develop and 13 apply a dry powder coating technique for colon targeting tablets containing metronidazole by 14 using a pan coating apparatus with a powder mixture of pectin and HPMC 15 Materials and methods 17 2.1 Materials TE D 16 M AN U SC Metronidazole was obtained from Shanghai Fine Chemicals Co., Ltd (China) Pectin 104 19 was supported by CP Kelco (U.S.A) Hydroxypropyl methylcellulose (HPMC K100M and 20 HPMC E6) were purchased from Dow Chemical Company (U.S.A) Dibutyl phthalate, 21 triethyl citrate, polyethylene glycol 400 were purchased from Beijing Chemical Reagent 22 Factory (China) Enzyme pectinex was supplied by Sigma-Aldrich Co LLC (U.S.A) Water 23 was purified by reverse osmosis and was filtered in house All other reagents were of 24 analytical grade commercial products and purchased from Beijing Chemical Reagent Factory 25 (China) 26 2.2 Preparation of drug loaded tablets AC C EP 18 27 The core tablets containing 200 mg MET per tablet were obtained by wet granulation 28 Metrodinazole (80%), sodium croscarmellose (4%) and Avicel® PH101 (10%) were mixed in 29 a blender for 10 minutes A binder solution of PVP 15% in ethanol was added to the mixture 30 to make wet granules These granules were then dried in oven at 60oC for 10h The dried ACCEPTED MANUSCRIPT granules were then blended for more minutes with magnesium stearate (1%) and colloidal silicon dioxide (1%) The core tablets (diameter: mm, biconvex, round, hardness: 6-9 kp, average tablet weight: 250 mg) were compressed using a single punch tablet press (Korsch, Germany, Model 1975) 2.3 Coating of drug-loaded tablets RI PT The process was conducted in coating pan The formulations for the coating with dry polymer powder (pectin 104, HPMC K100M) and plasticizers were shown in Table The coating powder was ground, mixed and sieved through different sieves prior to coating process The plasticizer mixture was prepared by emulsifying dibutyl phthalate (DBP) or 10 triethyl citrate (TEC) or solubilizing polyethylene glycol (PEG 400) into adhesive solution 11 (HPMC E6 in water) The powder (polymer plus talc) and a plasticizer mixture were 12 fed/sprayed separately onto drug-loaded tablets in a coating pan (Erweka, Germany, Model 13 DKE) The coating process was performed using a batch size of 500 g, with the following 14 parameters: inlet temperature: 50-60oC, plasticizer feed rate: 10 -15 ml/min, rotation speed of 15 pan: 100 – 120 rpm, atomizing air pressure: 1.2 bar, spray nozzle diameter: 1.2 mm, powder 16 feed rate: 8-10 g/min The coating level (weight gain) of the coated tablets was determined by 17 the weight difference between the coated and uncoated tablets TE D M AN U SC After the coating process, the coated tablets were dried for 10 in pan coater to 19 stabilize the coating prior to the curing process The size and hardness of coated tablets were 20 around 10 mm, and 18 – 20 kp, respectively The coated tablets were then oven-cured at 21 different conditions: 60oC/24h, 60oC/72h, 100oC/24h to determine the effect of curing 22 temperatures and curing duration on properties of tablet Besides, the coated tablets cured at 23 60oC/72h were put into stability chamber at 40oC/75% relative humidity for and months 24 to study the effect of short-term stability test on the drug content and dissolution rate of MET 25 2.4 HPLC analysis AC C 26 EP 18 The amounts of MET in core tablets and coated tablets were analyzed by a HPLC method 27 which was described in USP 30 Briefly, ten tablets were ground, transferred to a suitable 28 volumetric flask Add methanol and shake by mechanical means for 30 minutes Dilute with 29 methanol to volume and allow the solution to stand until the insoluble materials have settled 30 Withdraw ml supernatant into a 100 ml volumetric flask and dilute with mobile phase to 31 volume, mix and filter through membranes 0.45 µm (Satorius, Germany, Model Minisart RC ACCEPTED MANUSCRIPT 25) The filtered solution was injected onto the column for analysis The HPLC system consisted of an isocratic pump (Agilent, U.S.A., Model G1311C), a manual injector (Agilent, U.S.A., Model G1328C), a column thermostat (Agilent, U.S.A., Model G1316A), a multi- wavelength detector (Agilent, U.S.A., Model G1315D) Detector output was integrated and digitalized using Agilent ChemStation software (Agilent, U.S.A., Model 1200 Series HPLC system) The column used was a C18 column (Zorbax SB, 4.6ì150 mm, àm particle size, Agilent, U.S.A.) The mobile phase consisted of methanol:water (20:80, V/V) Its flow rate was 1.2 mL/min and detector wavelength was 254 nm The total run time for a sample was about 10 All operations were carried out at ambient temperature SC 10 RI PT 2.5.In vitro drug release studies The coated tablets containing 200 mg MET were evaluated for drug release by the method 12 developed by Turkoglu et al [11] The dissolution rate of MET from samples into medium 13 was studied using the dissolution apparatus type (Vankel Varian, U.S.A, Model 7010) A 14 quantity of 900 ml dissolution medium of 0.1 M HCl was used for hours The dissolution 15 medium was adjusted to pH 7.4 by potassium dihydrophosphat and sodium hydroxid for the 16 next hours Finally, the dissolution medium was adjusted to pH 6.8 by 0.1 M HCl and 17 supplemented with ml pectinolytic enzyme for the last hours The temperature was 18 maintained at 37 ± 0.5oC The rotation speed was 100 rounds per minute (rpm) Five 19 milliliters of aliquot were withdrawn at predetermined time intervals of hour and filtered 20 through membranes 0.45 µm (Satorius, Germany, Model Minisart RC 25) The medium was 21 replenished with ml of fresh medium each time Withdrawn samples were analyzed by a 22 UV spectrophotometer (Hitachi, Japan, Model U-1800) at 378 nm 23 2.6 Scanning electron microscopy TE D EP AC C 24 M AN U 11 The morphology of the surfaces and cross-sections of the coated tablets were examined 25 prior to and after curing by scanning electron microscopy The surfaces and cross-sections of 26 the coated tablets were obtained by cutting the tablets with a razor blade The dried pieces 27 were fixed on a plate using adhesive tape and coated with gold for 240s These samples were 28 then observed by a scanning electron microscope (Hitachi, Japan, FESEM S4800) 29 2.7 X-ray imaging studies ACCEPTED MANUSCRIPT To determine the existence of coated tablets in colon, X-ray imaging technique was used All of metronidazole was replaced by barium sulfate, a radiopaque material Three healthy male beagle dogs, between 10–12 kg body weight, were used for X-ray imaging studies After an overnight fast, each subject was administered one optimized tablet containing barium sulfate with 200 mL water Abdominal radiographs were taken after 0, 6, and h 2.8 Data analysis RI PT The experiment was run triplicates The data were expressed as mean ± standard deviation and analyzed for statistical significance by one-way ANOVA using Excel (Microsoft, U.S.A.) The release data was fitted to different mathematical models (Higuchi, Hopfenberg, 10 Korsmeyer–Peppas, Weibull, and Hixson–Crowell) The most suitable mathematical model 11 was accepted when correlation coefficient was over 0.9 and Akaike information criterion 12 (AIC) was the lowest The lag time release (tlag) and t50% of MET from the coated tablets were 13 calculated from the chosen mathematical model The data analysis of release models was 14 conducted using Mathcad - Software version 14.0 (Mathsoft PTC, U.S.A, Version 14.0) 15 Results and discussion TE D 16 M AN U SC A dry powder coating process using a powder mixture of HPMC and pectin was 18 investigated to prepare colon targeting tablets containing metronidazole This process was 19 conducted on the sugar coating pan This technique was an alternative solution to the 20 traditional film coating because of the avoidance of organic solvents The two main 21 components of the coating formulation were coating plasticizers and polymers 22 3.1 Screening of plasticizers for coating layer AC C 23 EP 17 Different kinds of plasticizer (DBP, TEC and PEG 400) having different water solubility 24 were investigated A plasticizer concentration of 40% based on the total amount of polymers 25 was used for dry powder coating The coating level of tablets was fixed at 100% w/w in 26 comparison with the core tablets All of the obtained tablets were cured under the same 27 condition at 60oC in 24h The drug contents in tablets prior to and after preparation process 28 were all evaluated by HPLC method and these data were used to calculate the cumulative 29 metronidazole release The drug content in core tablets was 103.6 ± 0.28 (%) And, the drug 30 contents in coated tablets using DBP, TEC and PEG 400 were 102.0 ± 3.54 (%), 104.8 ± 2.89 ACCEPTED MANUSCRIPT (%) and 102.1 ± 1.80 (%), respectively These data indicated that the drug content of MET was insignificantly changed after preparation process (p > 0.05) This result was in agreement with that in previous studies [15, 16] which reported that MET was a stable drug Based on these drug contents, drug release of MET from coated tablets was determined and as shown in Figure 1, metronidazole released from coated tablets followed the order PEG 400 > TEC > DBP after hour Only the coated tablets using DBP as plasticizer could release lower than 10% after hour, and over 85% after hour which was suitable with sigmoidal release model Time points from to 10 hour were utilized to fit the different release kinetics models And the coated tablet using DBP as plasticizer was chosen as model tablet for 10 determination of release kinetics Among the five release kinetics, only Weibull model was 11 the most suitable mathematical model because the correlation coefficient was the highest 12 (0.999) and the AIC was the lowest (14.971) (Table 2) Other kinetics may have the 13 correlation coefficient over 0.9 but the AIC value was not satisfied When calculating the 14 release kinetics with dissolution data from other coated tablets, the Weibull model was 15 always the most suitable kinetics and this model was chosen to determine the lag time of the 16 coated tablets ANOVA test indicated that the lag time release of tablets using DBP (tlag = 4.3 17 ± 0.02 h) was significantly different to those using TEC (tlag = 4.07 ± 0.41 h) and PEG 400 18 (tlag = 1.92 ± 0.16 h) (p < 0.05) The water solubility of plasticizers decreased in the order of 19 PEG 400 > TEC > DBP thus MET easily leaked out of tablets with the more hydrophilic 20 plasticizers (PEG 400, TEC) Besides, the hydrophilic plasticizers made the dissolution 21 profiles of MET highly variable This may result from the inhomogenous coating layer of the 22 tablets using PEG 400 and TEC (Figure 2) In contrast, the tablets using a hydrophobic 23 plasticizer (DBP) could obtain a smooth surface and a sigmoidal pattern of drug release with 24 lag time of 4.3 h This was in agreement with the result of Klar et al [17] The study 25 suggested that the hydrophobic plasticizers promoted capillary forces between the 26 hydrophilic polymer particles (HPMCAS) and vice versa Consequently, a good plasticizer 27 could accelerate the adhesion of this polymer on the cores and enhance the coating efficiency 28 This plasticizer was not taken up by the coating polymer but remained on the polymer’s 29 surface [17] In the present study, DBP, also a hydrophobic plasticizer, was assumed to 30 promote capillary forces between hydrophilic HPMC particles This plasticizer did not go 31 deeply inside the coating layer but functioned as a liquid lubricant between the tablet and 32 coating pan surfaces Meanwhile, PEG 400 and TEC that were more hydrophilic than DBP 33 migrated deeply inside the coating layer, resulting in the inhomogeneity of the coating layer, 34 especially in the case of PEG 400 AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT Table Release kinetics models, correlation coefficient, Akaike information criterion and tlag of dry coating tablets using 40% dibutyl phthalate as plasticizer and 100% coating level AIC tlag 0.999 14.971 4.3 49.405 4.9 44.242 4.8 51.558 4.9 ‫ = )ݐ(ܥ‬1 − ݁ Higuchi ‫ܭ = )ݐ(ܥ‬ு (‫ ݐ‬− ‫ݐ‬௟௔௚ )ଵ/ଶ 0.649 ‫ = )ݐ(ܥ‬1 − [1 − (Kఉ (t − t ௟௔௚ )]ଷ 0.89 ‫ ݐ(ܽ = )ݐ( ܥ‬− ‫ݐ‬௟௔௚ )௡ 0.733 Korsmeyer-Peppas Hopfenberg ‫ = ) ݐ( ܥ‬1 − [1 − ݇ଵ ‫ݐ‬൫‫ ݐ‬− ‫ݐ‬௟௔௚ ൯]௡ [21] 0.944 M AN U * ೌ SC Weibull Hixson-crowell ష(೟ష೟೗ೌ೒ )್ R2 RI PT Equation* Model AC C EP TE D 16 42.149 4.9 ACCEPTED MANUSCRIPT Table Effect of amount of dibutyl phthalate on tlag, and t50% of MET from colon targeting tablets tlag (h) 40 4.3 30 4.1 20 3.5 5.7 5.4 SC t50% (h) RI PT DBP (%) AC C EP TE D M AN U 17 ACCEPTED MANUSCRIPT 120 RI PT SC 90 M AN U 60 30 0 10 EP AC C Time (hour) TE D Cumulative metronidazol release (%) DBP TEC PEG 400 Fig Effect of kinds of plasticizer: dibutyl phatate (DBP), triethyl citriate (TEC) and polyethylene glycol 400 (PEG 400) on dissolution profile of metronidazole (Mean ± S.D, n=3) 18 ACCEPTED MANUSCRIPT Plasticizers Surface Side SC RI PT PEG 400 AC C EP DBP TE D M AN U TEC Fig Images of coated tablets using different plasticizers (PEG 400, TEC and DBP) 19 ACCEPTED MANUSCRIPT 120 Coating level 50% Coating level 75% Coating level 100% Coating level 130% Coating level 150% RI PT 80 60 40 SC Cumulative metronidazol release (%) 100 0 M AN U 20 10 Time (hour) a) R² = 0.902 R² = R² = 0.374 AC C EP Tlag (hour) R² = 0.946 TE D Pectin : HPMC = 1:1 Pectin : HPMC = 2:1 Pectin : HPMC = 3:1 Pectin : HPMC = 4:1 30 60 90 120 150 180 Coating level (%) b) Fig a) Effect of coating level on release profile of metronidazole, b) correlation of coating level versus tlag with different ratios of pectin: HPMC (Mean ± S.D, n=3) 20 ACCEPTED MANUSCRIPT 120 Pectin:HPMC=1:1 Pectin:HPMC=2:1 Pectin:HPMC=3:1 Pectin:HPMC=4:1 Cumulative metronidazol release (%) 100 RI PT 80 60 20 0 10 M AN U Time (hour) SC 40 a) 12 Pectin : HPMC = 1:1 Pectin : HPMC = 2:1 Pectin : HPMC = 3:1 TE D EP Tlag (hour) AC C 3 4 Pectinase (ml) b) Fig a) Effect of different ratios of pectin: HPMC on release profile of metronidazole; b) effect of amount of enzyme pectinase on tlag of with different ratios of pectin: HPMC (Mean ± S.D, n=3) 21 RI PT ACCEPTED MANUSCRIPT 10 SC Tlag (hour) M AN U el ev gl TE D n ati Co 150 120 ) (% 90 P:H=1:1 R P:H=2:1 P:H=4:1 MC tin: HP c e P f atio o AC C EP 60 P:H=3:1 Fig Response surface plot displays effect of the ratio of pectin: HPMC and coating level on tlag 22 ACCEPTED MANUSCRIPT 120 RI PT 90 SC 60 30 0 10 EP AC C TE D Time (hour) M AN U Cumulative metronidazol release (%) < 90 µm < 125 µm < 180 µm < 250 µm 10 Fig Effect of size of coating powder on release profile of metronidazole (Mean ± S.D, 11 n=3) 12 23 ACCEPTED MANUSCRIPT Surface of coated tablet Cross-section of coated tablet Uncured Cured 60oC/24h Cured 60oC/24h Cured 100oC/24h AC C EP Cured 100oC/24h TE D M AN U SC RI PT Uncured Fig Effect of curing conditions on the morphology of surface and cross-section of coated tablets 24 ACCEPTED MANUSCRIPT 120 RI PT 90 SC 60 30 0 8 10 Time (hour) TE D EP AC C M AN U Cumulative metronidazol release (%) Uncured o Cured 60 C, 24h Cured 100oC, 24h 10 Fig Effect of curing temperature on release profile of metronidazole (Mean ± S.D, n=3) 11 25 ACCEPTED MANUSCRIPT SC 90 M AN U 60 30 0 6 10 Time (hour) EP 2 AC C RI PT Cured 60oC, 24 h Cured 60oC, 72 h Cured 60oC, 72 h and 40oC/75% RH, month Cured 60oC, 72 h and 40oC/75% RH, month TE D Cumulative metronidazol release (%) 120 Fig Effect of curing duration (60oC at 24 and 72h) and short-term storage on release profile of metronidazole (Mean ± S.D, n=3) 10 26 ACCEPTED MANUSCRIPT 6h 8h EP AC C TE D M AN U SC RI PT 0h Fig 10 X-ray images of colon targeting tablets containing metronidazole throughout the GI tract at different time points 10 27 ACCEPTED MANUSCRIPT References [1] S Bose, R.H Bogner, Solventless pharmaceutical coating processes: a review, Pharm Dev Technol, 12 (2007) 115-131 [2] A.H Lau, N.P Lam, S.C 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Germany, Model 1975) 2.3 Coating of drug-loaded tablets RI PT The process was conducted in coating pan The formulations for the coating with dry polymer powder (pectin 104, HPMC K100M) and plasticizers