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Original Research Paper
Preparation and evaluation of sustained-release diltiazem hydrochloride pellets
Xiaopeng Han, Linan Wang, Yinghua Sun, Xiaohong Liu, Wanjun Liu, Yuqian Du, Lin Li, Jin Sun*
Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China
ARTICLE INFO
ABSTRACT
Article history: Received 3 July 2013 Received in revised form 10 August 2013 Accepted 19 August 2013
Keywords:
Diltiazem hydrochloride Sustained release Pellets
In vitro and in vivo studies
In this study, diltiazem hydrochloride (DTZ) pellets were prepared successfully by extrusion—spheronization method. Then methacrylic acid and ethylcellulose coating formulations were employed to make the DTZ pellets sustained release. The pellets with different coatings were investigated by in vitro dissolution tests. At last, the pellets with the best coating copolymer were subjected to pharmacokinetic studies in beagle dogs. The dissolution profiles of pellets coated with Eudragit® NE30D were similar to Herbesser®, one of the marketed sustained release capsules. In the bioavailability study, the principal phar-macokinetic parameters of self-made pellets and the marketed ones were comparable; the relative bioavailability of DTZ sustained release capsules compared with Herbesser® was 98.5 ± 36.4%. All the data indicated self-made sustained pellets could prolong the release of DTZ, decrease the fluctuation of drug level in vivo, and increase the compliance of patients.
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Introduction
Diltiazem hydrochloride (DTZ), one member of calcium channel blockers, is widely used in the treatment of angina pectoris and hypertension [1]. DTZ is extensively metabolized by the liver and excreted by the kidney. And it is absorbed fraction up to about 80%. However, due to an extensive first-effect, DTZ is subject to an absolute bioavailability of about 40%. The plasma elimination half life following single or
multiple administration is approximately 3-5 h. Frequent administration of immediate release preparations is often recommended to maintain effective blood plasma levels of DTZ. A slow and sustained release of the active ingredient is beneficial to patients to maintain sustainable levels of DTZ in the blood plasma [2,3].
We aimed to develop sustained release capsules of DTZ in multiple-unit pellet system (MUS) by extrusion-spheronization method and coating technique. In comparison to the
* Corresponding author. Tel.: +86 24 23986325, +86 13898882644 (mobile); fax: +86 24 23986320. E-mail address: sunjin0529@yahoo.com.cn (J. Sun).
Peer review under responsibility of Shenyang Pharmaceutical University
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conventional or immediate-release dosage forms, MUS has some unique advantages. In MUS, pellets are often filled into hard gelatin capsules or compressed into tablets [4]. In one single dose of MUS, pellets are rapidly and homogeneously distributed in the gastrointestinal tract (GIT) in spite of feeding or fasting condition, thus reduce the risk of high local concentration and side effects, increase the contract region between drug and the GIT, furthermore, enhance drug absorption and lower the fluctuations of peak plasma. Therefore, MUS could decrease dose frequency and increase patient compliance, improve the safety and efficacy of drug [5-7].
Though there are many approaches to prepare pellets, such as extrusion and spheronization, fluid bed granulation [8], centrifugal granulation [9]. Extrusion-spheronization is one of common strategies to prepare pellets for acquiring modified release systems in pharmaceutical industry since 1970 [10], and the method consists of two basic processes of extrusion and spheronization. Pellets prepared by the method of extrusion-spheronization have some advantages, such as high sphericity, compact structure, low hygroscopicity, narrow particle size distribution and smooth surface [11,12].
In this study, we attemptto apply extrusion-spheronization, simply and easily industrialized preparation method to prepare uncoated pellets, followed by coating process using methacrylic or ethylcellulose copolymers to achieve the sustained release, which have the similar pharmacokinetic characteristic to Herbesser®. Herbesser® was a commercially available DTZ sustained release capsules. Many factors have been studied to adjust the drug release rate by different coating formulations. The dissolution tests are performed in different media, the profiles of dissolution from the commercial one and self-made are compared by similar factors method, and the performances in vivo from commercial one and self-made formulation are carried out in beagle dogs.
2. Materials and methods
2.1. Materials
Diltiazem hydrochloride was purchased from Nanchong Science and Technology Development Co., Ltd (Hubei, China), Herbesser® was purchased from Tianjin Tanabe Seiyaku Co., Ltd (Tianjin, China). Huling® PH 101 (microcrystalline cellulose) was purchased from Zhanwang Pharmaceutical Co., Ltd (Zhejiang, China). Eudragit® NE30D, Eudragit® RS30D and Surelease® were kindly provided by Colorcon (Shanghai, China). HPLC-grade methanol and acetonitrile were purchased from Fisher Scientific (Pittsburgh, PA, USA). All other materials were of analytical grade and used as received.
2.2. Preparation of diltiazem hydrochloride (DTZ) sustained release pellets
Drug-loaded pellets were prepared by the extrusion— spheronization method. The formulation of the cores was as follows: DTZ 125 g; MCC 125 g; HPMC (K4M, 2%) 110 ml, which was used as a binder. The powders were mixed for 30 min before the adhesive was added, then appropriate quantity of binder was added slowly during constant mixing, and the
process continued for a further 20 min. The wet mass was extruded at room temperature, through a die of 0.8 mm diameter and 4 mm in length by 20 rpm equipped with an axial screen extruder (WL350, Wenzhou, China), the extrudate was collected in a container before it was spheronized. About 50 g of extrudate was spheronized at a time, on a spheronizer 40 cm in diameter equipped with a grooved plate, for 2 and 10 min at 2000 and 8000 rpm, respectively. The pellets were dried under conditions at 40 ± 2 °C for 24 h. The 18-24 mesh pellets were chosen for coating.
Eudragit® NE30D, Eudragit® RS30D and Surelease®, three types of aqueous polymeric dispersions, were used for the preparation of sustained release pellets. The formulations were followed as:
Formulation 1 (F1): coated with Eudragit® NE30D, resulting in 6-13% coat loading. Coating suspension includes talc, HPMC (E5) and SDS.
Formulation 2 (F2): coated with Eudragit® RS30D, resulting in 10-25% coat loading. Coating suspension includes talc, TEC and SDS.
Formulation 3 (F3): Surelease®, resulting in 10-30% coat loading.
A fluid-bed bottom spray processor was adopted for the coating of the pellets by using Eudragit® NE30D or Eudragit® RS30D as the coating solution. The coating suspensions were prepared as follows steps: (1) Eudragit® NE30D or Eudragit® RS30D was dripped into the desired volumes of water and agitated by magnetic stirrer at room temperature for at least 30 min; (2) micronized talc was dispersed in water and stirred until no lumps formed; (3) materials (1) and (2) were mixed and stirred, then the HPMC/TEC, SDS were also added into the suspensions. After stirred for at least 1 h, the coating suspensions were spraying onto the pellets. After Surelease® dispersed in water 1 h, the solutions were spraying onto the pellets.
Coating conditions: inlet temperature: 30 °C, outlet temperature: 25-30 °C, spray rate: 2 ml/min, atomization pressure is 0.2 MPa, blast pressure is 0.3 MPa. The final pellets were dried in oven at 40 ° C for 12 h.
2.3. Assay of the drug content
Drug content was determined by the HPLC method. The HPLC system included a LC-AT pump and SPD-10A UV-Vis detector (SHIMADZU Japan). A Kromasil C18 column (5 mm, 200 x 4.6 mm) was used. The mobile phase consisted of sodium acetate-camphor sulfonic acid buffer (dissolve 9.0 g of sodium acetate and 1.2 g of camphor sulfuric acid in 500 ml of water)-acetonitrile-methanol (50:26:24, V/V/V), adjust the pH value to 6.5 with acetic acid, the flow rate was 1.0 ml/min, and the UV detector was set at 240 nm.
From each batch of the coated pellets, a certain amount was taken and milled to fine powders. Then fine powders containing 100 mg drug were weighed and added to a 100 ml volumetric flask containing 70 ml of methanol. After, a 30-min ultrasonic extraction, the solution was diluted with methanol to 100 ml and then filtered through a 0.45 mm membrane. Precisely 5 ml of this solution was transferred to 25 ml volumetric flask and methanol was added to give a volume of
Table 1 - Formulation of uncoated pellets containing different amounts of MCC.
Uncoated pellets 1 2 3 4 5
DTZ (%) 30 40 50 60 80
MCC (%) 70 60 50 40 20
Binder HPMC (2%) HPMC (2%) HPMC (2%) HPMC (2%) HPMC (2%)
Angles of repose (0) 16 ± 1 16 ± 1 17 ± 2 25 ± 3 40 ± 2
1 h dissolution (%) 100.12 ± 5.36 101.02 ± 1.46 99.21 ± 4.94 99.93 ± 4.12 101.23 ± 1.68
100 ml. 20 ml of the solution was injected for analysis. All samples were analyzed in triplicate.
2.4. In vitro dissolution tests
The release of diltiazem hydrochloride (DTZ) from pellets was investigated based on ChP 2010 Type 2 dissolution apparatus (paddle method) and all the release tests were conducted in triplicate. In this case, the 900 ml medium was kept at 37 ± 0.5 °C and the rotating speed was 100 rpm. 0.1 M HCl solution, pH 4.5 sodium acetate buffer, pH 6.8 and pH 7.2 phosphate buffers, and purified water were used as dissolution media. The capsules containing the drug pellets equivalent to 90 mg DTZ were used in all dissolution tests. At each predetermined time point, a 5 ml aliquot of dissolution medium was withdrawn and replaced by the same volume of fresh medium. The total volume of medium was kept at 900 ml. The sample solution was filtered through 0.45 mm filtration membrane and analyzed using a UV spectrophotometer (Beijing Rayleigh Analytical Instrument Co.) at 240 nm.
2.5. Bioavailability studies
2.5.1. In vivo studies
The sustained pellets of DTZ were filled into hard gelatin capsules for the pharmacokinetic parameters studies. Meanwhile, Herbesser® was served as the control. The experimental protocol was admitted by the university ethics committee for the use of experimental animals and conformed to the guideline for care and use of laboratory animals. The study was based on single-dose, open-label, randomized two-way crossover design with wash out period of one week. The six male beagle dogs were divided into 2 groups. After 12 h of fasting, 90 mg of DTZ test and reference preparations were orally administered to test and reference group dogs under fasted conditions, respectively. Venous blood samples (5 ml) were collected 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 24 and 36 h after dosing and immediately centrifuged. Plasma samples were kept frozen at -20 ° C until assay. Diltia-zem hydrochloride in plasma was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
100 ml of plasma was mixed with 50 ml of internal standard (verapamil solution) and 50 ml of mobile phase solution. The solution vortexed for 1 min, 100 ml of acetonitrile added to precipitate the proteins in the plasma. After centrifugation (10,000 rpm) for 10 min, 5 ml aliquot of supernatant was directly injected into the high performance liquid chroma-tography system.
Chromatographic conditions [13]: ACQUITY UPLCTMBEH C18 column (1.7 mm, 50 mm x 2.1 mm, Waters Corp, Milford, MA, USA); mobile phase consisted of acetonitrile: 8 mM
ammonium acetate (70:30, v/v); flow rate 0.2 ml/min; UV detector wave length 240 nm.
2.5.2. Data analysis
The concentrations of DTZ in plasma were calculated, and all the data were processed by DAS 2.0 statistical software. The area under the mean plasma concentration-time curves from zero to time (AUC0-36 h) and (AUC0-N) was calculated.
3. Results and discussion
In this study, DTZ sustained release pellets were prepared by the extrusion/spheronization method, and then were subjected to coating with methacrylic acid copolymers (Eudragit NE30 or Eudragit RS30) or derivative of ethylcellulose (Sure-lease). The in vitro release studies showed that the dissolution profiles of the pellets coated with Eudragit NE30D were similar to the commercially available DTZ sustained release capsules. In vivo study, the principal pharmaceutical parameters showed that the profiles of DTZ from self-made and the marketed one were comparable.
3.1. Formulation and process parameters optimization
3.1.1. Effect of amount of MCC
Formulations of the uncoated pellets are described in Table 1 and the release profile of DTZ in water in 1 h is shown in Fig. 1. The drug release behavior was similar from different formulations. At 5 min, the accumulative release of the uncoated pellets was about 80% and reached 100% at 20 min. That is to say, DTZ could be completely released from the uncoated
Release Time (min)
Fig. 1 - In vitro release profiles of DTZ from the uncoated pellets in water at 1 h (each point represents the mean ± SD, n > 3).
Table 2 - The effect of disc speed on pellet physical characteristics.
Disc speed (rpm) 1000 2000
10,000
18-24 mesh cut yield (%) Roundness Sphericity (q) Bulk density (g/ml) Friability (%)
74 ± 2.3 2
40.2 ± 1.3 0.77 ± 0.1 0.43 0.11
84 ± 4.3 4
22.3 ± 2.5 0.79 ± 0.3 0.45 0.12
87 ± 4.1 4
24.5 ± 3.6 0.81 ± 0.2 0.46 0.12
87 ± 3.3 4
23.3 ± 4.3 0.82 ± 0.1 0.43 0.1
76 ± 1.3 4
24.6 ± 2.7 0.81 ± 0.2 0.45 0.1
pellets within 20 min. The formulation of the uncoated pellets includes DTZ and microcrystalline cellulose (MCC). MCC acts as fillers and disintegrants enhancing the dissolution rates of the pellets. In addition, the solubility of diltiazem HCl is 565 mg/ml in water, indicating dissolution of the drug is not limit by solubility [14]. MCC not only plays an important role in the process of disintegration, but also influences the process of granulation. Probably acting as "molecular sponge" [15] and "crystallite-gel" [16], MCC is considered as one of the most common extru-sion-spheronization ingredients, making the pellets with such desirable characteristics as good sphericity, low friability, narrow particle size distribution and smooth surface properties. When drug-loading was 80%, the angle of repose was about 40°, and pellets were highly friable with irregular shapes like dumbbell and short bar. However, when drug-loading was 30%, the angle of repose was about 16°, and pellets were extremely flexible with a good sphericity. Given that only the difference among C1-C5 formulation was the amount of MCC, the results suggested that the amount ratio between drug and MCC had a significant effect on the process of extrusion and spheroniza-tion. In order to get the desirable drug-loading and good physical characteristics of pellets, we chose uncoated-pellets drug-loading was 50%.
3.1.2. Influence of rotational speed
The method of extrusion/spheronization consists of five procedures: preparation the damp mass-wet granulation; screening the wet mass into cylinders - extrusion; breaking up the extrudate and rounding off the particles into spheres -spheronization; drying the pellets [17]. Some process parameters influence the morphologic characteristic and rheological parameters of the pellets. For example, high concentration of adhesive (5%, HPMC) resulted in severely overwetted masses that could not be extruded or spheronized. By Contrast, low concentration of adhesive (1%, HPMC) led to dry masses which could not be extruded. Among five procedures, we particularly investigated the rotational speed of disc effect on the physical characteristic of pellets, including shape of pellets, hardness, size, sphericity, porosity of pellets. When the rotational speed was low, most of pellets were short cylindrical resulting from the minor shearing force which leads to breaking short cylindrical into the compact breads. In comparison, when the rotational speed was high, the centrifugal force made the pellet cracking resulting of the formation of powders, as well as the adhesions of pellets bringing about wide size distribution. As shown in Table 2, it can be seen that different rotational speeds had notable influence the morphologic characteristic and size distribution of pellets. When the rotational speed was 1000 rpm, the pellets were dumb-bell, low fluidity. When the rotational speed ranged from 2000 to 10,000 rpm, 18-24 mesh cutyield was
higher than 80%, high fluidity, narrow size distribution. In order to get desirable characteristic of pellets, we chose rotational speed 2000 rpm for 2 min to cut off the extrudate, and then the speed rose up to 8000 rpm gradually, which was continued 10 min to get the final pellets.
3.1.3. Influence of different coating formulations The profiles of DTZ released from the sustained pellets with different coating formulation in water are shown in Fig. 2, and it can be seen from Fig. 2 that different coating formulations and coating weight gains had a significant influence of the release of DTZ from the coated pellets. In general, Eudragit® NE30D and Eudragit® RS30D coating suspension successfully prolonged the release in water, however, the coating of Surelease® did not properly control the dissolution and more than 40% of drug-loading was released in 2 h. Even with 30% coating weight gain, DTZ was released about 50% in 2 h, 20% higher than that of Herbesser®. Therefore, the coating polymers of Eudragit® NE30D and Eudragit® RS30D were better for prolonging the release of DTZ.
Coating weight gain had a significant effect on DTZ release. Clearly, with higher coating weight gain, the DTZ pellets showed slower release rate. For coating with Eudragit® NE30D, when coat-loading was about 12.5%, only 80% of DTZ was released from the pellets at 24 h. Compared to the coating level of 6.5%, more than 80% of drug was released at 5 h. The release profiles of pellets coated by Eudragit® NE30D and Eudragit® RS30D, respectively, were comparable. When comparing Fig. 2A and B, it was found that 8.5% coating weight gain of Eudragit® NE30D and 15% coating weight gain of Eudragit® RS30D were better similar to Herbesser®. But for Eudragit® RS30D, the release rate of DTZ from 15% coat-loading was faster than Herbesser®, and nearly 70% of DTZ was released from the pellets at 5 h. When increasing the coating weight gain to 20%, nearly 55% of DTZ was released from the pellets at 5 h. When the coating weight gain was 8.5%, the accumulative release percent of DTZ from the pellets coated with Eudragit® NE30D was nearly 60%, very similar to the release rate of
Table 3 - Analog analysis of the home-made sustained release capsules and reference capsules in different media (n > 3).
Medium f2
Water 72 ± 2
pH 1.0 67 ± 3
pH 4.5 68 ± 4
pH 6.8 66 ± 2
pH 7.2 68 ± 3
-H —1—6.50% —1—8.50% —H-10.50% -*-12.50%
£ 100
H 10.00% 25.00% 30.00%
Time (h)
« ■3
10.00% -A-15.00%
20.00%
Time (h)
Fig. 2 - Release profiles from the coated pellets with different coating polymers and coating weight gains. (A) Eudragit® NE30D (B) Eudragit® RS30D (C) Surelease®, H-Herbesser® (each point represents the mean ± SD, n £ 3).
Herbesser®. In order to avoid the burst release at the initial stage of the dissolution, we chose Eudragit® NE30D as the coating polymer, coat weight gain of 8.5%, and the final coating formulation included sodium dodecylsulfate (1% of Eudragit® RS30D, w/w) as antistatic agents and talc (20% of Eudragit® RS30D, w/w) as antiadherent.
3.2. Drug release comparison
Dissolution profiles of home-made preparations and marketed sustained-release capsules were compared in various
media, including 0.1 M HCl, pH 4.5 NaAc-HAc buffers, water, pH 6.8 and pH 7.2 phosphate buffer solutions. The dissolution profiles of self-made pellets and Herbesser® are shown in Fig. 3. From the dissolution results, the self-made pellets shown slower release rates than that of the marketed ones in 0.1 M HCl and pH 4.5 NaAc-HAc buffer solution, while in the higher pH such as pH 6.8 and pH 7.2 phosphate buffer solutions, the different release rates were present. In general, there were nearly no various profiles of dissolution from the self-made pellets in various media, resulting from the nonsensitive to pH of Eudragit® NE30D.
l2o loo
water O.lM HCl pH=4.5 pH=6.8 pH=7.2
loo so
water O.lM HCl pH=4.5 pH=6.S pH=7.2
Time (h)
Fig. 3 — The effect of pH values on the release profile of marketed and self-made sustained-release capsules. A: Herbesser® B: home-made (each point represents the mean ± SD, n > 3).
The similarity factors which are calculated between the market formulation and self-made preparing are presented in Table 3. Similar index was calculated by the similarity factor (f2) [18]:
/2 = 50 x log
1 +1 x£(Rt - Tt)2
where n is the number of dissolution sample, and Rt and Tt are the percentages of the Herbesser® and self-made pellets drug release, respectively. The valve of f2 value is between 0 and 100. If f2 of control and test preparation is between 50 and 100, then these two preparations drug release are similar. From the data of Table 3, the results of f2 in different medium were all more than 50, indicating that self-made sustained release pellets and Herbesser® have similar drug release profiles.
3.3. Drug release mechanism
The drug-release data was fitted according to different models in attempt to elucidate the release mechanism. The kinetic
Table 4 - Models for drug release fitting and correlation
coefficients.
Model Equation r
Zero-order model Qt = 8.1736 + 8.8219t 0.9620
First-order model ln(100 - Qj) = —0.1855t + 4.6067 0.9970
Higuchi Qt = 33.571t172 — 16.847 0.9910
RitgerePeppas log Qt = 0.7228log t + 1.2703 0.9827
models consist of zero order [19], first order [20], Higuchi model [21] and Ritger—Peppas model [22]. The optimum values for the parameters present in each equation were determined by linear or non-linear least-squares fitting methods. As shown in Table 4, the first-order model was best fitted for the home-made sustained release pellets.
Many modes of drug release from the extend-control pellets were first-order model, which releases the drug from the dosage form at the constant rate, reducing the fluctuation of druglevel in the blood, maintain blood concentration of drug at
l40.00
"g l20.00
loo.oo
Reference Test
JS 20.00
20 Time (h)
Fig. 4 - Average diltiazem plasma concentration-time curves of the reference and test capsules (each point represents the mean ± SD of 6 dogs).
Table 5 - Pharmacokinetic parameters of test and reference preparations.
T1/2 (h) Cmax (ng/ml) Tmax (h) AUC0-36 (ng h/ml) AUC0-n (ng h/ml)
Reference 4.2 ± 1.9 85.0 ± 55.1 4.5 ± 1.9 761.1 ± 528.4 767.3 ± 535.5
Test 4.9 ± 1.9 100.0 ± 66.4 3.5 ± 0.8 824.9 ± 523.6 838.4 ± 601.2
desirable level for an extended period. In order to obtain first order drug release profiles, different technologies can be used, such as, hydrophilic or matrix systems with channel forming agents and barrier membrane coated multiparticulate systems. Eudragit® NE30D was one of low permeability, pH independent swelling coating polymers. It was assumed that some drives, as follows, to obtain the first order drug release profiles for Eudragit® NE30D: (1) Concentration gradient. Once the film was in contact with water, the film swelled, and water slowly permeated into the core of pellets, and the drug was dissolved, thus, the saturable solution of drugs within the coating. Drug molecules diffused down the concentration gradient, and finally released into the outer medium. (2) Channel effect. The influx water induced swelling of membrane and expanded the copolymer network; the compact membrane was converting into un-continuous one, leading to the pore for the water molecule and drug molecule freely influx and efflux the pellet film. In addition, a number of aqueous channels were formed across the film once the pellets are in contact with water, and acted as the release gate for the drug.
3.4. Bioavailability
The in vivo pharmacokinetic behavior of self-made sustained and commercial available capsules (Herbesser®) were investigated following oral administration of 90 mg of DTZ to six healthy beagle dogs. Mean plasma concentration-time curves after administration of test and control preparation were shown in Fig. 4. There main bioavailability parameters are listed in Table 5. The mean relative bioavailability of DTZ self-made sustained pellets to Herbesser®, which was calculated from the AUC0-36 of DTZ, was 98.5 ± 36.4%. The average peak concentration (Cmax) of the reference (85.0 ± 55.1 ng/ml) was slightly lower than that of the test (100.0 ± 66.4 ng/ml), AUC0-n of test and reference were 767.3 ± 535.5 ng h/ml, and 838.4 ± 601.2 ng h/ml, respectively. From the data of main bioavailability parameters, it could conclude that the phar-macokinetic profiles of self-made pellets and marketed ones in vivo were comparable.
4. Conclusion
The DTZ sustained release pellets were successful prepared. The formulation of the uncoated pellets included MCC, binders and DTZ. The uncoated pellets achieved good sphericity, low friability, narrow particle size distribution and smooth surface. It was found that the rotational speed has a significant effect on the physic characteristics of pellets prepared by extrusion and spheronization method. The coating polymer Eudragit® RS30D and coating weight gain 8.5% could prepare the desired DTZ sustained-release pellets, which had similar release profiles to the marketed Herbesser® with f2
more than 60. From the bioavailability studies, it was obvious that the home-made sustained pellets could prolong the release of DTZ and has comparable in vivo pharmacokinetic performance to the marketed Herbesser®.
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