Pulsatile Multiparticulate Drug Delivery System for Metoprolol Succinate

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develop a time-controlled release formulation of metoprolol succinate based on a ... Metoprolol succinate layered on sugar pellets (74% w/w) layered with 20% ...
Arch Pharm Res Vol 34, No 3, 369-376, 2011 DOI 10.1007/s12272-011-0303-0

Pulsatile Multiparticulate Drug Delivery System for Metoprolol Succinate Swati C. Jagdale1,2, Sachin M. Chede2, Ram Gulwady3, Bhanudas S. Kuchekar2, Pradeep D. Lokhande4, Tejas P. Shah5, and Anuruddha R. Chabukswar6 1

MAEER’s Maharashtra Institute of Pharmacy, Pune 411 038, Maharashtra, India, 2MAEER’s Maharashtra Institute of Pharmacy, Pune 411 038, Maharashtra, India, 3Sanmour Pharm Pvt Ltd., Ghodbandar Road, Owala, Thane West, 4 Department of Chemistry, University of Pune, Pune Maharashtra, India, 5Cognizant Technology Solutions, Powai, Mumbai-76, and 6Department of Pharmaceutical Chemistry, MAEER’s Maharashtra Institute of Pharmacy, Pune 411 038, Maharashtra, India (Received March 10, 2010/Revised June 18, 2010/Accepted July 16, 2010)

Cardiovascular diseases and their treatment pose a great challenge. Many instances of cardiovascular disease occur in the early morning hours. Hence, the objective of this study was to develop a time-controlled release formulation of metoprolol succinate based on a pulsatile multiparticulate (pellets) drug delivery system. The formulation was intended to be administered in the evening at 22:00 hours to evaluate symptoms of cardiovascular disease that are experienced in the early morning hours (from 04:00 to 06:00). Drug layering followed by a swelling layer and finally by an insoluble coat application was done using a Sanmour fluid bed processor. Metoprolol succinate layered on sugar pellets (74% w/w) layered with 20% (w/w) ion doshion resin P-547 and coated with 15% (w/w) ethocel with the addition of 20% castor oil showed a lag time of 4 h and was then followed a sigmoidal release pattern with more than 95% drug having been released by the 10th h. Key words: Pulsatile release, Ion doshion resin, Ethyl cellulose, Castor oil

INTRODUCTION Pulsatile drug delivery systems have many advantages over conventional (immediate release) and prolongedrelease (sustained-release) formulations. Frequency of drug administration is minimised by pulsatile drug delivery. Patient compliance is improved due to lower peak concentrations, which reduces the adverse effects elicited by conventional drug delivery systems (Troy, 2004). In the case of cardiovascular disease, several vital functions such as blood pressure, heart rate, stroke volume, cardiac output and blood flow of the cardiovascular system are subject to circadian rhythms. Capillary resistance and vascular reactivity are higher in the morning and decrease later in the day (Bussemer Correspondence to: Swati C. Jagdale, Assistant Professor and Head, Department of Pharmaceutics, MAEER’s Maharashtra Institute of Pharmacy, Pune 411 038, Maharashtra, India Tel: 91-988-1478118 E-mail: [email protected]

et al., 2001). Coronary infarction as well as angina pectoris attacks are predominant in the early morning hours. The onset of nonfatal and fatal myocardial infarctions predominate between 05:00 and 11:00 am. A similar circadian time pattern has been shown for sudden cardiac death, stroke, ventricular arrhythmias and arterial embolism. He onset of angina attacks in variant angina peaks in the early morning, around 4:00 am. Thus, it appears that the early morning hours are the one associated with greatest cardiovascular risk. Cardiovascular diseases follow chronopharmacological behaviours. Metoprolol succinate has a short half life (3-7 h) and a high first pass effect, and night time dosing is required (Ritschel and Forusz, 1994; Ueda et al., 1994; Lemmer, 1999; Bussemer and Bodmeier, 2001). Pulsatile release is useful for targeting drugs that cause irritation to the stomach and are susceptible to degrada-tion in the stomach, as well as drugs that lead too the development of biological tolerance, or drugs with an extensive first-pass metabolism (e.g., b-blockers; Bussemer and

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Bodmeier, 2003). Pulsatile drug delivery systems (DDS) are characterized by a rapid drug release after a predetermined lag time and can be classified as single unit (e.g. tablet or capsule) or multiparticulate (e.g. pellet) systems (Pozzi et al., 1994). Most of the pulsatile drug delivery systems contain a drug reservoir surrounded by a barrier that erodes and/or dissolves or ruptures. Upon the ingress of water, the swellable layer expands, resulting in the film rupturing and subsequent rapid drug release (Wilding and Davis, 1994; Sungthongjeen et al., 2004). In the case of hard and/or soft gelatin capsules, the lag time and completeness of release was independent of the capsules content, and was influenced, in the case of tablets, to a remarkable extent by the core composition (Bussemer et al., 2003a). The properties of the swelling layer as well as the composition and thickness of the outer membrane have been reported as major factors affecting rupturing and release parameters (Bussemer et al., 2003b). Multiparticulate systems (e.g. pellets) offer various advantages over single unit systems. These advantages include no risk of dose dumping, flexibility of blending units with different release patterns, as well as short and reproducible gastric residence times (Gazzaniga et al., 1995; Bussemer et al., 2003c). Here we present a “time controlled explosion system (TES)” as a rupturable, multiparticulate, pulsatile DDS. The drug was layered on an inner core, followed by a swellable layer and then a water-insoluble polymer membrane as a top layer (Dashevsky and Mohamad, 2006). Despite the advantages of aqueous coatings over organic ones (lower raw material costs, environmentally friendly, etc.), so far only organic coatings have been described (at least for rupturable pulsatile delivery systems) (Leopold, 1999; Barbara et al., 2004). Our pulsatile multiparticulate DDS, which was coated with an aqueous dispersion of Aquacoat® ECD, cross-linked carboxymethyl cellulose (AcDiSol®) was used as the swelling agent. The objective of the present work was to develop and evaluate a pulsatile multiparticulate (DDS). A rupturable pulsatile DDS consists of (i) a drug core; (ii) a swelling layer, containing a superdisintegrant and a binder; and (iii) an insoluble, water-permeable polymeric coating. Upon ingress of water, the swellable layer expands, resulting in the rupturing of the outer membrane with subsequent rapid drug release. Drug loaded pellets have been coated usingion doshion resin P-547 layers as a superdisintegrant and further coated with ethyl cellulose (Ethocel), an insoluble, water-permeable polymeric coating. For achieving the desired pulsatile release profile, changes in the concentration of the

S. C. Jagdale et al.

superdisintegrant and the outer polymeric coating according to % weight gain were made on a trial and error basis.

MATERIALS AND METHODS Materials Sugar pellets (400-600 microgram) were obtained from Micoropellets. Metoprolol succinate USP was obtained from Polydrug. Ion doshion resin P-547 was obtained from Doshion Ltd. Ethyl cellulose was from Colorcon; starch from Universal Starch; castor oil from S D Fine Chemicals; talc from Luzenac; titanium dioxide from Kronos; isopropyl alcohol was from Thomas Banker; methylene chloride was from Thomas Banker. All other ingredients were of analytical grade and were used as received. Preparation of a pulsatile multiparticulate DDS A pulsatile multiparticulate drug delivery system consists of (i) a drug core; (ii) a swellable layer, containing a superdisintegrant and a binder; and (iii) an insoluble, water-permeable polymeric coating. For achieving the desired pulsatile release profile, changes in the concentrations of the components of the swelling layer and the outer polymeric coating according to % weight gain were made on a trial and error basis as shown in the formula in Table I. Drug layering A hydro-alcoholic system was preferred for the drug layering process. Metoprolol Succinate USP was layered on sugar pellets using a 15% (w/v) solution, in isopropyl alcohol/water (50:50 w/w mixture). Drug layering was done using a Sanmour Fluid Bed Processor Roto Insert Change part to achieve a 74.58% weight gain. The layering conditions were: batch size 300 g, inlet temperature 60oC, product temperature 40oC-42oC, outlet temperature 36oC-38oC, disk rpm 5.4, spray gun nozzle diameter 1.0 mm, atomization air pressure 1.8 bar, spray rate 11 g/min/ gun, final drying at 40oC for 10 min. Layering of swelling layer Drug-containing pellets were layered with a 5% (w/ w) suspension of ion doshion resin (P-547) as a superdisintegrant, starch as a coating aid and disintegrant, and PVP K-30 as a binder, in methylene chloride/isopropyl alcohol (65:35 w/w). Coating of the pellets was done in a Sanmour Fluid Bed Processor RI Change to achieve the required weight gain for different release profiles. The process conditions were: batch size 300 g, inlet temperature 60ºC, product

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Table I. Formulation development for T to C4 Stage I 1 2 3 4 5

II 1 2 3 4 5

III 1 2 3 4

Formula (mg)

T

Drug Layering NPS (400-600 90.5 microgram) Metoprolol Succinate 47.5 PVP-K30 8 Talcum 6 Titanium Dioxide 6 158 Weight gain (%w/w) 74.58 Coating of Swellable Layer Resin 10 Starch 10 PVPK-30 4 Talcum 5 Titanium Dioxide 5 192 Weight gain (%w/w) 20 Coating of Ethyl Cellulose Ethyl Cellulose 25 Castor oil 7 Talcum 4 Titanium Dioxide 2 TOTAL 230 Weight gain (%w/w) 20

A1

A2

A3

A4

B1

B2

B3

B4

C1

C2

C3

C4

90.5

90.5

90.5

90.5

90.5

90.5

90.5

90.5

90.5

90.5

90.5

90.5

47.5 47.5 47.5 47.5 47.5 47.5 8 8 8 8 8 8 6 6 6 6 6 6 6 6 6 6 6 6 158 158 158 158 158 158 74.58 74.58 74.58 74.58 74.58 74.58

47.5 8 6 6 158 74.58

47.5 47.5 8 8 6 6 6 6 158 158 74.58 74.58

47.5 8 6 6 158 74.58

47.5 8 6 6 158 74.58

47.5 8 6 6 158 74.58

10 10 4 5 5 192 20

10 10 4 5 5 192 20

18 5.5 3 1.5 220 15

25 7 4 2 230 20

10 10 4 5 5 192 20

10 10 4 5 5 192 20

31.57 37.87 8.84 10.6 5.05 6.29 2.54 3.24 240 250 25 30

temperature 40oC-42oC, outlet temperature 36oC-38oC, disk rpm 5.4, spray gun nozzle diameter 1.0 mm, atomization air pressure 1.8 bar, spray rate 14 g/min/ gun, final drying at 40oC for 10 min.

Coating with ethyl cellulose The pellets layered with the swelling layer were then coated with ethyl cellulose solution (Ethocel), in methylene chloride/ isopropyl alcohol (65:35 w/w) with 5% (w/w) solids content and plasticized with 20% (w/ w) castor oil by stirring for 30 min; 10% talc was added. Plasticizers and talc amounts were based on the total solids content of the solution. Coating was done in a Sanmour Fluid Bed Processor RI Change part to achieve the required weight gain for different release profiles under following conditions: batch size 300 g, inlet temperature 60oC, product temperature 40oC-42oC, outlet temperature 36oC-38oC, disk rpm 5.4, spray gun nozzle diameter 1.0 mm, atomization air pressure 1.2 bar, spray rate 12 g/min/gun, final drying at 40oC for 10 min. Physical evaluation of pellets Appearance: This was checked with the help of visual inspection.

15 15 6 7.5 7.5 209 30

15 15 6 7.5 7.5 209 30

15 15 6 7.5 7.5 209 30

15 15 6 7.5 7.5 209 30

20 20 8 10 10 226 40

20 20 8 10 10 226 40

20 20 8 10 10 226 40

20 20 8 10 10 226 40

18 5.5 3 1.5 237 15

25 7 4 2 247 20

31.57 8.84 5.05 2.54 257 25

37.87 10.6 6.29 3.24 267 30

18 5.5 3 1.5 254 15

25 7 4 2 264 20

31.57 8.84 5.05 2.54 274 25

37.87 10.6 6.29 3.24 284 30

Loss on drying: The moisture content of pellets can be affected by changes in the formulation and/or process. It is essential to determine the moisture content for each batch that is evaluated. Bulk density: The density of pellets can be affected by changes in the formulation and by coating process. The density of the pellets was measured using a 100 mL graduated cylinder for all batches. Sieve analysis: We placed 100 g of sample in a lab sifter containing the required mesh sieves (# 16, # 18, # 20, # 24 and # 30) and calculated retention of the pellets. Assay Pellets were crushed with the help of a mortar and pestle. We determined the amount of crushed power of the pellets that was equivalent to 47.5 mg of metoprolol succinate, and a solution of this compound in 100 mL pH 6.8 phosphate buffer was prepared. Five mL of solution was removed and diluted to 50 mL with pH 6.8 phosphate buffer. Absorbance was measured at 280 nm and drug content was calculated. Drug release The pellets from each formulation were processed in

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a USP paddle apparatus (Dissolution Test Apparatus, Electro Lab, TDT-08L) (900 mL pH 6.8 phosphate buffer, 37oC, 100 rpm, n = 3). Three milliliter samples were withdrawn at predetermined time points and analyzed by UV absorption at λ = 280 nm for metoprolol succinate (UV Spectrophotometer UB Varian Cary 100 scan EL 08053091). The lag time was determined by extrapolation of the upper part of the release profile to the time (X) axis. Stability testing of the best formulation Temperature dependent stability studies were carried out on the optimized batches B1 and B2. They were packed in low density polyethylene (LDPE) bags enclose in high density polyethylene (HDPE) containers and stored under the following conditions for a period as prescribed by ICH guidelines for accelerated studies. (I) 2 ± 30oC and RH 65 ± 5% (II) 2 ± 40oC and RH 75 ± 5% The pellets were withdrawn after periods of 7, 14, 21 days and 1, 2, and 3 months and analyzed for physical characteristics (appearance, moisture content, bulk density), using a dissolution study and a percentage assay.

Fig. 1. % Drug content of batches T to C4.

RESULTS Physical evaluation All formulation batches of the multiparticulate pulsatile drug delivery system for metoprolol succinate were analysed for physical parameters and the results are shown in Tables II & III.

Fig. 2. Metoprolol succinate release from control batch T.

Assay study Drug content of all formulation batches of the multiparticulate pulsatile drug delivery system for metoprolol succinate are shown in Fig. 1.

Stability testing Results of stability studies for batches B1 and B2 are shown in Tables IV-VII.

Drug release Metoprolol succinate release from the control batch T is shown in Fig. 2. Metoprolol succinate release from drug stores layered on sugar pellets up to the weight gain of 74.58% (w/w), layered with 20% (w/w) ion doshion resin P-547, and coated with 30% (w/w) ethocel with the addition of 20% castor oil showed lag times of 5 to 6 h. This was then followed by a delayed release profile with more than 90% of drug release having occurred by the 18th h. According to the release profile of the control batch, changes were made in the formula to get the required pulsatile release profile. Metoprolol succinate release from batches A1 to A4 are shown in Fig. 3. Metoprolol succinate release from batches B1 to B4 is shown in Fig. 4. Metoprolol

succinate release from batches C1 to C4 is shown in Fig. 5.

DISCUSSION Metoprolol succinate release from batches A1 to A4 is shown in Fig. 3. Metoprolol succinate release from drug layered on sugar pellets up to a weight gain of 74.58% (w/w), layered with 20% (w/w) ion doshion resin P-547 and coated with 15% (w/w) ethocel with the addition of 20% castor oil showed a lag time of 4 h and then followed a sigmoidal release pattern with more than 90% drug release by the 10th h. As the concentration of the ethyl cellulose coating increased from 20 to 30% (w/w), the lag time increas-ed to 5 h. This was followed by a delayed release profile, with more than 95% drug released by the 18th h. Fig. 4 indicates metoprolol succinate release from drug layered on sugar pellets upto the weight gain of

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Table II. Physical evaluation of the pellets for T to A4 Batch No.

Sr. No.

Physical parameters

1

Appearance

2 3

Loss on drying (%) Bulk density (g/cc) Above 16 # Pellet sieve 16-20 # Analysis 20-24 # (% fraction) 24-30 # Below 30 #

4

T

A1

A2

A3

A4

White to off White to off White to off White to off White to off white colour white colour white colour white colour white colour spherical pellets spherical pellets spherical pellets spherical pellets spherical pellets 2.56 2.65 2.83 2.30 2.17 0.74 0.72 0.72 0.73 0.74 9.71 5.84 5.35 5.45 5.41 45.83 37.38 37.69 37.51 37.58 43.18 55.44 55.36 55.48 55.37 1.17 0.86 0.64 0.89 0.79 0.0 0.0 0.0 0.0 0.0

Table III. Physical evaluation of the pellets for B1 to C4 Sr. No.

1

2 3

4

Physical Parameters

Batch No. B1

B2

B3

B4

C1

C2

C3

C4

White to off White to off White to off White to off White to off White to White to off White to off white white white white white off white white colour white colour Appearance colour colour colour colour colour colour spherical spherical spherical spherical spherical spherical spherical spherical pellets pellets pellets pellets pellets pellets pellets pellets Loss on drying (%) 2.34 2.66 2.84 2.74 1.84 2.52 2.49 2.37 Bulk density (g/cc) 0.72 0.74 0.72 0.73 0.73 0.73 0.74 0.74 Above 16 # 10.04 9.81 10.50 9.26 13.24 13.29 13.46 13.78 44.96 45.93 45.99 45.90 33.26 33.39 33.33 33.15 Pellet sieve 16-20 # analysis 20-24 # 43.14 43.17 43.27 43.28 49.68 49.85 49.90 49.93 (% fraction) 24-30 # 9.09 1.18 1.11 1.21 3.13 2.99 3.57 3.68 Below 30 # 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

Table IV. Stability data for B1 at 2 ± 30oC/65 ± 5% RH Tests

Initial

7 days

14 days

21 days

1 month

Stability Date

2/04/09 White to off white colour spherical pellets 2.32 100.33

9/04/09 White to off white colour spherical pellets 2.87 99.18

16/04/09 White to off white colour spherical pellets 2.36 100.27

23/06/09 White to off white colour spherical pellets 2.33 98.36

30/04/09 White to off white colour spherical pellets 2.56 99.39

0.72

0.74

0.72

0.73

0.73

Appearance LOD (%) Assay (%) Bulk density (g/cc)

74.58% (w/w), layered with 30% (w/w) ion doshion resin P-547 and coated with 15% (w/w) ethocel with addition of 20% castor oil. There was a lag time of 4 h followed by a sigmoidal release pattern with more than 90% drug released by the 8th h. As the concentration of the ethyl cellulose coating increased from 20 to 30% (w/w), there was no significant change in the lag time or the subsequent drug release profile. As the coating level of ethyl cellulose increased up to

2 month

3 month

30/05/09 30/06/09 White to off White to off white white colour colour spherical spherical pellets pellets 2.75 2.44 99.59 99.27 0.73

0.72

30% (w/w), there was a slightly delayed release after an initial lag time of 4 h, with more than 95% drug released by the 12th h. Fig. 5 indicates metoprolol succinate release from drug layered on sugar pellets up to the weight gain of 74.58% (w/w), layered with 40% (w/w) ion doshion resin P-547 and coated with 15% (w/w) ethocel with the addition of 20% castor oil. The lag time was 2 h with more than 90% of the drug released by the 8th h.

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Table V. Stability data for B1 at 2 ± 40oC/75 ± 5% RH Tests

Initial

7 days

14 days

21 days

1 month

2 month

3 month

Stability Date

2/04/09

9/04/09

16/04/09

23/06/09

30/04/09

30/05/09

30/06/09

Appearance

White to off white colour spherical pellets

White to off white colour spherical pellets

White to off white colour spherical pellets

White to off white colour spherical pellets

White to off white colour spherical pellets

White to off white colour spherical pellets

White to off white colour spherical pellets

LOD (%)

2.24

2.46

2.69

2.62

2.57

2.85

2.39

Assay (%)

98.15

99.36

99.47

99.58

99.69

100.77

99.85

Bulk density (g/cc)

0.73

0.72

0.72

0.73

0.72

0.74

0.72

Table VI. Stability data for B2 at 2 ± 30oC/65 ± 5% RH Tests

Initial

7 days

14 days

21 days

1 month

2 months

3 month

Stability Date

2/04/09

9/04/09

16/04/09

23/06/09

30/04/09

30/05/09

30/06/09

White to off white colour spherical pellets

White to off white colour spherical pellets

White to off white colour spherical pellets

White to off white colour spherical pellets

White to off white colour spherical pellets

White to off white colour spherical pellets

White to off white colour Appearance spherical pellets LOD (%)

2.45

2.57

2.78

2.45

2.85

2.34

2.49

Assay (%)

99.73

99.65

99.57

98.48

99.33

99.26

99.14

Bulk density (g/cc)

0.73

0.74

0.74

0.73

0.72

0.74

0.72

Table VII. Stability data for B2 at 2 ± 40°C/75 ± 5% RH Tests

Initial

7 days

14 days

21 days

1 month

2 month

3 month

Stability Date

2/04/09 White to off white colour spherical pellets 2.39 99.11

9/04/09 White to off white colour spherical pellets 2.76 99.23

16/04/09 White to off white colour spherical pellets 2.56 100.17

23/06/09 White to off white colour spherical pellets 2.99 98.28

30/04/09 White to off white colour spherical pellets 2.76 99.56

30/05/09 White to off white colour spherical pellets 2.23 99.72

30/06/09 White to off white colour spherical pellets 2.63 99.86

0.74

0.72

0.72

0.73

0.73

0.74

0.72

Appearance LOD (%) Assay (%) Bulk density (g/cc)

As the concentration of the ethyl cellulose coating increased from 20 to 25% (w/w), a delayed release was observed after an initial lag time of 3 h, with more than 95% of drug release by the 10th h. As the coating level of ethyl cellulose increased up to 30 % (w/w), we observed a slightly delayed release after an initial lag time of 3 h, with 100% drug release by the 12th h. From Tables IV–VII we saw that there were no

significant changes in the evaluated parameters as well as in the drug release profile for batches stored at 30oC/65% RH and 40oC/75% RH (+/−5%) when compared with the initial batch; therefore, the optimiz-ed batches B1 and B2 are said to be stable. As the concentration of the swelling layer increases from 30% to 40%, it shows a change in lag time from 4 to 3 h, with a sigmoidal release pattern; more than

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375

ethyl cellulose (Ethocel) and water insoluble plasticizer castor oil is required. The lag time was controlled by coating level. Thus it is possible to obtain a timelag of 4 to 5 h with different core composition with different release kinetics. These studies can be used as a platform for developing pulsatile multiparticulate drug delivery systems to relieve the suffering of cardiovascular patients at the hours of greatest risk.

REFERENCES

Fig. 3. Metoprolol succinate release from batches A1 to A4.

Fig. 4. Metoprolol succinate release from batches B1 to B4.

Fig. 5. Metoprolol succinate release from batches C1 to C4.

95% drug release had occurred by the 10th h. To achieve pulsatile drug release profile, swelling agent ion doshion resin (P-547) minimum 30% (w/w) layering amount, coating of about 15-25% (w/w) with

Barbara, S., Stefaan, S., and Demeester, J., Programmed polymeric devices for pulsed drug delivery. Pharm. Res., 21,1732-1740 (2004). Bussemer, T. and Bodmeier, R., Review of pulsatile drug delivery. Am. Pharm. Rev., 4, 24 (2001). Bussemer, T., Otto, I., Bodmeier, R., Schoenwald, R. D., and Smolen, V. F., Pulsatile drug-delivery systems. Crit. Rev. Ther. Drug Carrier Syst., 18, 433-458 (2001). Bussemer, T. and Bodmeier, R., Formulation parameters affecting the performance of coated gelatin capsules with pulsatile release profiles. Int. J. Pharm., 267, 59-68 (2003). Bussemer, T., Dashevsky, A., and Bodmeier, R., A pulsatile drug delivery system based on rupturable coated hard gelatin capsules. J. Control. Release, 93, 331-339 (2003a). Bussemer, T., Peppas, N., and Bodmeier, R., Evaluation of the swelling, hydration and rupturing properties of the swelling layer of a rupturable pulsatile drug delivery system. Eur. J. Pharm. Biopharm., 56, 261-270 (2003b). Bussemer, T., Peppas, N., and Bodmeier, R., Time-dependent mechanical properties of polymeric coatings used in rupturable pulsatile release dosage forms. Drug Dev. Ind. Pharm., 29, 623-630 (2003c). Dashevsky, A. and Mohamad, A., Development of pulsatile multiparticulate drug delivery system coated with aqueous dispersion Aquacoat® ECD. Int. J. Pharm., 318, 124-131 (2006). Gazzaniga, A., Busetti, C., and Moro, L., Evaluation of low viscosity HPMC as retarding coating material in the preparation of time-based oral colon specific delivery systems. Proc. Int. Symp. Control. Rel. Bioact. Mater., 22, 242-243 (1995). Lemmer, B., Chronopharmacokinetics: implications for drug treatment. J. Pharm. Pharmacol., 51, 887-890 (1999). Leopold, C., Coated dosage forms for colon-specific drug delivery. Research focus, 2, 197-204 (1999). Pozzi, F., Furlani, P., Gazzaniga, A., Gazzaniga, A., Davis, S. S., and Wilding, I. R., The time clock® system: a new oral dosage form for fast and complete release of drug after a predetermined lag time. J. Control. Release, 31, 99-108 (1994). Ritschel, W. A. and Forusz, H., Chronopharmacology: a review of drugs studies. Meth. Find. Exp. Clin. Pharmacol., 16, 57-75 (1994).

376

Sungthongjeen, S., Puttipipatkhachorn, S., Paeratakul, O., Dashevsky, A., and Bodmeier, R., Development of pulsatile release tablets with swelling and rupturable layers. J. Control. Release, 95, 147-159 (2004). Troy, M., Timing drug availability with therapeutic need. Specialitypharma, 2, 44-47 (2004).

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Ueda, S., Yamaguchi, H., and Kotani, M., Development of a novel drug release system, time controlled explosion system (TES). Chem. Pharm. Bull., 42, 359-363 (1994). Wilding, I. R. and Davis, S. S., Enteric coated timed released systems for colonic targeting. Int. J. Pharm., 111, 99-102 (1994).