AAPS PharmSciTech ( # 2017) DOI: 10.1208/s12249-017-0900-4
Research Article Release Mechanism Between Ion Osmotic Pressure and Drug Release in Ionic-Driven Osmotic Pump Tablets (I) Lizhen Cheng,1 Siqi Gao,1 Defang Ouyang,2 Haiying Wang,1 Yongfei Wang,1 Weisan Pan,1 and Xinggang Yang1,3
Received 5 August 2017; accepted 26 September 2017
The objective of this study was to develop an authentic ionic-driven osmotic pump system and investigate the release mechanism, simultaneously exploring the in vitro and in vivo correlation of the ionic-driven osmotic pump tablet. A comparison of the ionicdriven and conventional theophylline osmotic pump, the influence of pH and the amount of sodium chloride on drug release, the relationship between the ionic osmotic pressure and the drug release, and the pharmacokinetics experiment in beagle dogs were investigated. Consequently, the similarity factor (f2) between the novel and conventional theophylline osmotic pump tablet was 60.18, which indicated a similar drug-release behavior. Also, the release profile fitted a zero-order kinetic model. The relative bioavailability of the ionicdriven osmotic pump to the conventional osmotic pump calculated from the AUC (0-∞) was 93.6% and the coefficient (R = 0.9945) confirmed that the ionic-driven osmotic pump exhibited excellent IVIVC. The driving power of the ionic-driven osmotic pump was produced only by ions, which was strongly dependent on the ion strength, and a novel formula for the ionic-driven osmotic pump was derived which indicated that the drug-release rate was proportional to the ionic osmotic pressure and the sodium chloride concentration. Significantly, the formula can predict the drug-release rate and release characteristics of theophylline ionic-driven osmotic pumps, guiding future modification of the ionic osmotic pump. Abstract.
KEY WORDS: release mechanism; ionic-driven osmotic pump; ionic osmotic pressure; zero-order kinetic model; formula verification; IVIVC.
INTRODUCTION The osmotic drug delivery system was first described by Rose and Nelson in 1955 when they invented the device which controlled the drug release at a constant rate via implantation in vivo, but the device has not been adopted widely due to the great volume and the fact that it is very inconvenient to use (1). Theeuwes published the fundamental theory about osmotic pump in 1975, which established the special position of osmotic pumps in controlled-release preparations. They also described the concept and structure of an elementary osmotic pump, simultaneously simplifying the osmotic pump structure and promoting its industrial production and clinical applications (2–5). The elementary 1
Department of Pharmaceutics, School of Pharmaceutical Science, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China. 2 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences (ICMS), University of Macau, Macau, China. 3 To whom correspondence should be addressed. (e-mail: [email protected])
osmotic pump consisted of a compartment including the drug, osmotic active agents, and semipermeable membrane with a delivery orifice. When the tablet core came into contact with an aqueous environment, the water flowed into the core, and the drug and osmotic agents dissolved. Then, the saturated solution with high osmotic pressure was generated in the tablet core, and the driving force promoted the release of drug and osmotic agents in the saturated solution from orifices at a constant rate (6,7). The driving force of the conventional osmotic pump was supplied by osmotic pressure and swelling pressure. Generally, the osmotic pressure was produced by water-soluble salts (sodium chloride, sodium sulphate, potassium chloride, and sodium bicarbonate), while the swelling pressure was produced by polymers (polyethylene oxide, sodium carboxyl methylcellulose, hydroxyl propyl methyl cellulose, hydroxyl methylcellulose, methylcellulose, polyvinyl pyrollidine, polyacrylamides, and carbopols) (8–12). However, polyoxyethylene has a high viscosity, and its properties are changed after long-term storage; and the high viscosity affected the preparation of the osmotic pump tablet, which has an effect on the stable release of drug (13,14). In addition, the swelling pressure was ignored in conventional elementary osmotic pump drug release. 1530-9932/17/0000-0001/0 # 2017 American Association of Pharmaceutical Scientists
Cheng et al. In order to clarify the drug-release mechanism and overcome the disadvantage of conventional elementary osmotic pump, we designed a novel osmotic pump, the ionic-driven osmotic pump, for which the driving power was the ionic osmotic pressure generated only by the dissolution of the drug and osmotic agents. The ionic-driven osmotic pump closely resembles the elementary osmotic pump of Theeuwes. Compared with the conventional osmotic pump, the advantages of the ionic osmotic pump system are that (a) it overcomes the drawback of lag-time, (b) simplifies the preparation technology, and (c) allows prediction of the drugrelease rate and release characteristics of other ionic-driven osmotic pumps. Importantly, the drug-release mechanism can be described clearly and accurately. In this study, theophylline was selected as a model drug, and it was one of the most widely prescribed drugs for the treatment of asthma and chronic obstructive pulmonary disease (15–17). It is essential that the novel formulation maintains a concentration gradient of the osmotic agent (18– 20). In order to investigate the drug-release mechanism, an ionic-driven osmotic pump tablet was prepared. The study mainly focuses on the influence of the amount of sodium chloride on the drug release, the drug release in vitro and the absorption in vivo, and the relationship between the drugrelease rate and the ionic osmotic pressure. Importantly, it was very important that the drug-release rate can be theoretically predicted using the formula of the ionic-driven osmotic pump, guiding the further development of the ionicdriven osmotic pump. MATERIALS AND METHODS Materials Theophylline (TPL) and acetaminophen were obtained from Yichang Yongnuo Pharmaceutical Co., Ltd., Hubei, China; PEO WSR301 was a gift from Dow Chemical Co. New Jersey, USA; microcrystalline cellulose (MCC) was purchased from Shandong Liaocheng Awa Pharmaceutical Co., Ltd., China. Cellulose acetate (CA) and polyethylene glycol 4000 (PEG 4000, average molecular weight) were supplied by Shenyang Chemical Reagent Company (Shenyang, China); acetonitrile, methyl alcohol, diethyl ether, acetone, sodium chloride, silver nitrate (AgNO 3 ), potassium chromate (K2CrO4), potassium dihydrogen phosphate, sodium hydroxide, anhydrous sodium acetate, acetic acid, and hydrochloric acid (36.5% M) were of analytical grade and obtained from Yuwang Chemical Reagent Co., Shandong, China; distilled water was used throughout the study. The Preparation of Ionic-Driven and Conventional Osmotic Pump Tablet The tablet core formulation of the ionic-driven and conventional theophylline osmotic pump tablet is shown in Table I. The drug and excipients were passed through an 80 mesh sieve, placed in a mortar for uniform mixing, and compressed into tablets. The tablet core was prepared using a single-punch tablet machine with concave punches (diameter 11 mm) (Shanghai no.1 Pharmaceutical Device Co., Shanghai, China).
Table I. Basic Formulation of Ionic-Driven (A) and Conventional Theophylline Tablet Core (B)
Formulation
F(A1) F(A2) F(A3) F(A4) F(B)
Amount (mg/tablet) Theophylline
NaCl
PEOWSR 301
MCC
30 30 30 30 30
0 250 450 550 100
0 0 0 0 200
570 320 120 20 170
The coating of the tablet core with cellulose acetate and polyethylene glycol 4000 (CA/PEG4000) was conducted in a traditional coating pan (Shanghai Tianfan Machinery Factory, Shanghai, China). The ratio of CA/PEG4000 was 2:1 (ionicdriven osmotic pump tablet) and 15:4 (conventional osmotic pump tablet). The coating solution was prepared by dissolving cellulose acetate in acetone and PEG 4000 in water, then mixing and stirring until dissolution was completed. The pan rotation rate was set at 35 rpm; the hot air used for drying the tablets during pan coating was 40°C; the spray rate was set at 7 ml/min; and the tablets were dried at 40°C for 12 h in an oven. Finally, the 0.8-mm orifice was drilled using a micro drill bit. In Vitro Dissolution Test The in vitro behavior of the theophylline osmotic pump tablet was continuously recorded using a fully automated dissolution apparatus. The release characteristics of the osmotic pump formulation were determined using the USP 2 paddle method (with sinker) (19,21). Studies carry out in 900 mL 0.1 M hydrochloric acid (HCl, 9 mL HCl added in 1000 mL water, CHCl = 0.1 mol/L), pH 4.5 sodium acetate-acetic acid buffer (18 g sodium acetate and 9.8 mL added and dissolved to 1000 mL water, Csodium acetate = 0.21 mol/L), pH 6.8 phosphate buffer (250 mL potassium phosphate monobasic (0.2 mol/L) and 118 mL sodium hydroxide solution (0.2 mol/L) diluted to 1000 mL, Cpotassium phosphate = 0.051 mol/L), pH 7.4 phosphate buffer (1.36 g potassium phosphate monobasic and 79 mL sodium hydroxide solution (0.1 mol/L) diluted to 200 mL, Cpotassium phosphate = 0.05 mol/L), and water. The dissolution medium temperature was maintained at 37 ± 0.5°C, and the rotation speed was 100 rpm. Five-ml samples were withdrawn and replaced by an equal volume of fresh medium at predetermined intervals of 0.5, 1, 2, 4, 6, 8, 10, and 12 h. Then, the samples were filtered, and the concentration was measured at an ultraviolet (UV) absorbance of 272 nm (22). All experiments were performed in triplicate. The dissolution profiles of each formulation were determined by plotting the percentage cumulative drug release at different times. The difference factor (f1) and the FDA similarity factor (f2) were used to evaluate the similarity of two drug-release profiles [Eqs. (1) and (2)] (23). f1 ¼
∑ni¼1 jRt −T t j ∑ni¼1 Rt
100
ð1Þ
Release Mechanism Between Ion Osmotic Pressure and Drug Release ( f 2 ¼ 50log
1þ
) −0:5 1 100 ∑nt¼1 ðRt −T t Þ2 n
ð2Þ
Where Rt and Tt are the dissolution value at time t of the reference batch and the test batch, respectively; n is the number of time points. The two drug-release profiles were considered similar when f2 was not less than 50. Gastrointestinal Simulation Experiment
Determination of Osmotic Pressure The Preparation of K2CrO4 Indicator and AgNO3 Standard Solution The preparation of K2CrO4 indicator: 5 g K2CrO4 was dissolved in 100 mL water, and AgNO3 solution was added to the solution with stirring until the brick red color disappeared. After 12 h, the solution was filtered to obtain 5% K2CrO4 indicator solution. The preparation of 0.1 mol/L AgNO3 standard solution: 17 g AgNO3 was added in 1000 mL distilled water, stir evenly and obtained the 0.1 mol/L AgNO3 standard solutions (14). Determination of Ionic Osmotic Pressure and the Cumulative Release of NaCl In this study, we determined the osmotic activity of chloride ions instead of directly measuring the osmotic pressure of the system. The osmotic pressure in the tablet core was dependent on the sodium chloride in the tablet core, and the concentration of sodium chloride could be obtained by determination of the chloride ions. Samples of ionic-driven osmotic pump tablet were put into 900 mL water at 37 ± 0.5°C and stirred at 100 rpm. At predetermined intervals (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 h), samples were withdrawn and put in another 900-mL dissolution container. They were then filtered to obtain the first dissolution solution samples, and the chloride ions in the dissolution solution samples were determined using the potassium chromate indicator method (24). A few drops of 5% K2CrO4 indicator were added to the sample solution and titrated with 0.1 mol/L AgNO3 standard solution until the appearance of a brick red color. The principle was as shown in Eqs. (3) and (4):
¼ 1:8 10‐10
Ag2 CrO4
¼ 1:2 10‐12
ð4Þ
Because the solubility of AgCl was lower than the solubility of Ag 2 CrO 4 (K sp,AgCl < K sp, Ag2 CrO4 ), according to the principle of fractional titration, the AgCl white precipitate appeared first; when the Cl− was titrated completely, an Ag2CrO 4 brick red precipitate was formed. In Vivo Evaluation of the Ionic-Driven Osmotic Pump
In this study, the pH of the medium was changed for the same sample to simulate gastrointestinal (GIT) conditions. The samples of ionic-driven osmotic pump were set in 750 mL HCl medium (0.1 mol/L) for 2 h. Then, 250 mL sodium phosphate solution was added into the above 750 mL HCl medium to adjust the pH to 6.8. Next, the sample solution was withdrawn and determined.
Agþ þ Cl‐ ¼ AgCl ðwhite precipitateÞ Ksp ;AgCl
2 Agþ þ CrO2− 4 ¼ Ag2 CrO4 ðbrick red precipitateÞKsp;
ð3Þ
All animal experiments were conducted in accordance with the principles of Laboratory Animal Care and approved by Shenyang Pharmaceutical University Animal Ethical Committee, and the ethical committee approval number of animal studies is SYPU-IACUC2017-1210-501. A randomized, two period crossover design was used to investigate the in vivo properties of the ionic-driven osmotic pump tablet, and the washout period between successive experiments was 1 week. The elimination half-life of theophylline in dogs is about 2 h. Beagle dogs (n = 6, 10 ± 2 kg) were fasted for 12 h before the experiment. According to the schedule of the two period crossover tests, the dogs were given an ionicdriven osmotic pump tablet and an innovator conventional osmotic pump tablet, and blood samples (3 mL) were collected in heparinized tubes at predetermined times (1, 2, 4, 6,7, 8, 9, 10, 12, 14, 16, 24, 36, and 48 h). Then, the collected blood was centrifuged immediately at 4000 rpm for 10 min, and the plasma samples were separated and frozen at − 20°C. For analysis, the plasma was thawed, then, 0.5 mL of each plasma sample was placed in a 10 mL centrifuge tube, followed by 10 μL internal standard solution (acetaminophen/methyl alcohol solution, 200 μg/mL), then, 500 μL acetonitrile, and vortexed for 1 min. Then, 3 mL diethyl ether was added followed by vortexing for 3 min, then centrifuged at 4000 rpm for 10 min. Then, 2.5 mL organic phase was removed and transferred to another centrifuge tube, and the organic solution was dried at 40°C under a stream of nitrogen. Then, it was dissolved in 200 μL methyl alcohol, vortexed for 1 min, and centrifuged at 12000 rpm for 5 min. Finally, 20 μL subnatant was withdrawn for high-performance liquid chromatography (HPLC)-analysis (16). Diamonsil C18 column (4.6 mm × 200 mm, 5 μm) was used to separate the samples at 30°C. The mobile phase was methanol/water (22/78, V/V), and the flow rate of the mobile phase was 1.0 mL/min; and measurements were carried out at 272 nm. In Vivo Data Analysis The theophylline concentrations in plasma versus time data were evaluated using DAS 2.0 software (Mathematical Pharmacology Professional Communities of China, Shanghai, China), which indicated that the absorption fitted single compartment model, and the overall elimination rate constant ke was measured (25). The AUC(0-t)
Cheng et al. was determined by the trapezoidal method, and the AUC (0-∞) was obtained by eqs. (5) and (6): AUCð0‐∞Þ ¼ AUCð0‐tÞ þ CðtÞ =K e
ð5Þ
The Wagner–Nelson method was used to calculate the percentage of the theophylline dose absorbed, Fa: Fa ¼
100 CðtÞ þ ke AUCð0‐tÞ =ke AUCð0‐∞Þ
ð6Þ
different data of test time; these results showed that there was no significant difference among the average release rate. Also, the average release rate at the same tested time in different dissolution media was relatively similar. The result of ionic-driven osmotic pump tablet gastrointestinal (GIT) simulation experiment was shown in Fig. 1c, and the results further indicate that the drug release of ionicdriven osmotic pump tablet was not influenced by the change of gastrointestinal pH. Comparison of Ionic-Driven and Conventional Osmotic Pump Tablet
RESULTS AND DISCUSSION In Vitro Dissolution Test The in vitro release profile of the ionic-driven osmotic pump tablet in different dissolution media was studied. A plot of the cumulative drug release versus time is presented in Fig. 1a. The f1 and f2 in Table II between the drug-release profiles in media of different pH confirmed that the drug release was independent of pH. Figure 1b shows the average release rate of theophylline in 0.1 M HCl, pH 4.5 sodium acetate-acetic acid buffer, pH 6.8 phosphate buffer, pH 7.4 phosphate buffer, and water. Analysis of variance was used to evaluate the differences. The p was higher than 0.05 between
From Fig. 1d, comparing the release profiles in 900 mL water between ionic-driven and conventional theophylline osmotic pump tablets, the in vitro drug-release data were fitted to a zero-order, first-order, and Higuchi model, and the kinetics results of drug release from ionic-driven osmotic pump were shown in Table III. The r value of the regression curve equation indicated the release profile of ionic-driven and conventional theophylline osmotic pump was fitted to a zero-order model. Also, the f1 and f2 between the drugrelease profiles were 6.72 and 60.18, indicating that the ionicdriven and conventional osmotic pump tablets exhibited a similar in vitro behavior. In this study, the coating membrane of ionic-driven and conventional osmotic pump tablet was investigated. The
Fig. 1. a In vitro drug-release profiles of different dissolution medium (n = 3). b Average drug-release rate in different dissolution medium (n = 3). c Ionic-driven osmotic pump tablet gastrointestinal (GIT) simulation profile. d Comparison of the in vitro release profiles of ionic-driven and conventional osmotic pump tablet (n = 3)
Release Mechanism Between Ion Osmotic Pressure and Drug Release Table II. f1 and f2 Value Between the Drug-Release Profiles Under Different ph Value of Medium
Dissolution medium
pH 1.2– pH 4.5
pH 1.2– pH 6.8
pH 1.2– pH 7.4
pH 1.2water
pH 4.5– pH 6.8
pH 4.5– pH 7.4
pH 4.5water
pH 6.8– pH 7.4
pH 6.8water
pH 7.4water
f1 f2
10 55
8 58
3 74
4 68
5 83
10 59
7 69
8 64
4 77
4 77
optimal ratio of CA/PEG4000 was 2:1 (ionic-driven osmotic pump tablet) and 15:4 (conventional osmotic pump tablet), and Fig. 1d showed similar release behavior of ionic-driven and conventional osmotic pump tablets. Simultaneously, the coating membrane formulation of ionic-driven and conventional osmotic pump tablets was exchanged and the result was revealed in Fig. 2. Only about 40% of drug was released from the ionic-driven osmotic tablet, and the problem cannot solve by adjusting the tablet core formulation. It was mainly due to the ionic-driven osmotic pump tablets only have NaCl without PEO in the tablet core, so the water passed through the tablet core in per unit time is very small, and the osmotic pressure produced in tablet core is little. For the conventional osmotic pump tablet, drugrelease rate was too fast to control the drug release at constant rate. Similar coating membrane formulation cannot obtain similar drug-release behavior, so different coating member formulation of ionic-driven and conventional osmotic pump tablet was used. Influence of the Amount of Sodium Chloride on the Drug Release The influence of the amount of sodium chloride on the drug release in vitro and the average osmotic pressure were also investigated in Fig. 3a, b. The cumulative release rate is shown in Fig. 3c. The results showed that the cumulative drug release increased rapidly on increasing the amount of sodium chloride. When the amount of sodium chloride in the tablet core was 0 mg and 250 mg, with the release of drug, the amount of sodium chloride in the tablet core also decreased, and the concentration of sodium chloride was not enough to maintain saturation. Therefore, the osmotic pressure in the tablet core was reduced and it was not possible to maintain constant rate of drug release. When the amount of sodium chloride was 550 mg, the drug-release rate increased rapidly, and the drug release was completed before 10 h. In addition,
the drug-release profile did not fit zero-order kinetics. Therefore, the amount of sodium chloride could not increase infinitely. However, there was an optimum amount of sodium chloride. When the amount of sodium chloride was 450 mg, the system had enough osmotic pressure to promote the drug release, and the profile also exhibited zero-order drug release. Hence, it was concluded that the optimal amount of sodium chloride was 450 mg for the ionic-driven theophylline osmotic pump system. The Theory for the Drug Release by the Ionic-Driven Osmotic Pump Tablet In the drug release from the elementary osmotic pump tablet, when the tablet core comes into contact with the aqueous environment, water passes through the semipermeable membrane and comes into contact with the tablet core. Due to the difference in osmotic pressure inside and outside the membrane, the drug can be released at a constant rate through the delivery orifice. The general drug-release rate can be summarized by the following eq. (7) (26): dm A ¼ Lp ðδ Δ∏−Δ pÞcdrug dt h
ð7Þ
Where A is the membrane area; h is the membrane thinness; Lp is the mechanical permeability; δ is the reflection coefficient; △Π and △p are the osmotic and hydrostatic pressure differences between inside and outside the
Table III. Kinetics of Drug Release From Ionic-Driven Osmotic Pump Tablet (A) and Conventional Osmotic Pump Tablet (B)
AA
BB
Model name
Equation
r
Zero-order model First-order model Higuchi model Zero-order model First-order model Higuchi model
Q = 7.8535t − 0.3713 ln(100-Q) = − 0.1853t + 4.8334 Q = 32.753t1/2 – 27.42 Q = 8.7038t − 5.1309 ln(100-Q) = − 0.2126t + 4.8708 Q = 30.853t1/2 – 21.428
0.9973 0.9769 0.9857 0.9910 0.9711 0.9481
Where t is the tested time; Q is the cumulative drug release at t hours
Fig. 2. Influence of coating solution on drug release of ionic-driven and conventional osmotic pump (n = 3)
Cheng et al.
Fig. 3. a Influence of sodium chloride amount on the drug release of ionic-driven osmotic pump tablet (n = 3). b Influence of sodium chloride amount on the average osmotic pressure of osmotic pump tablet (n = 3). c The cumulative release rate of sodium chloride (n = 3). d Cumulative release profiles of 450 mg sodium chloride (n = 3)
membrane, respectively; and c is the concentration of drug in the solution. For the control system, if △Π > > △p. Lpδ is replaced by constant k. The simplified eq. (8) is as follows: dm kA ¼ Δ∏cdrug dt h
ionic-driven osmotic pump tablet in Fig. 4. So, the following eq. (9) applies: dm kA
ð∏TPL þ ∏NaCl Þin −ð∏TPL þ ∏NaCl þ ∏medium Þout cdrug ¼ dt h
ð9Þ
ð8Þ
For the ionic-driven osmotic pump tablet, the tablet core is composed of drug, sodium chloride, and microcrystalline cellulose (MCC). Because MCC is insoluble in water, the osmotic pressure in the tablet core (Π) is generated by two different materials: drug and sodium chloride, and schematic diagram describing the process of the drug release from the
To determine the optimal formulation for the ionicdriven osmotic pump tablet, the release characteristic of sodium chloride was investigated systematically. The cumulative release of 450 mg NaCl is shown in Fig. 3d. The release rate of sodium chloride was at a consistent value before 6 h. It can also be concluded that the concentration of sodium chloride was maintained at saturation. At a later period, the
Fig. 4. Schematic diagram describing the process of the drug release from the ionic-driven osmotic pump tablet
Release Mechanism Between Ion Osmotic Pressure and Drug Release release rate of sodium chloride was decreased, so the ionic osmotic pressure in the tablet core was also decreased, but it was sufficient to drive the drug release from the osmotic pump tablet. Figure 5a, b shows the results of the average ionic osmotic pressure and the average drug-release rate at each tested time. The profile of the average osmotic pressure basically followed the average drug-release rate. In addition, the ratio of the average drug-release rate and the average ionic osmotic pressure is shown in Fig. 5c, and the result showed that the average drug-release rate was proportional to the average ionic osmotic pressure. Therefore, it can be concluded the drug release was dependent on the osmotic pressure in the tablet core. From Fig. 3c, it was found that the average osmotic pressure profile was related to the release of sodium chloride in the tablet core. Sodium chloride was released at a constant rate, and the concentration of sodium chloride was maintained at saturation before 6 h, so, the osmotic pressure did not change. However, after 6 h, the average osmotic pressure declined gradually because the sodium chloride concentration in the osmotic pump tablet core could not maintain saturation for drug
release. Nonetheless, the osmotic pressure in the later period was only reduced slowly and drug release was still promoted. The data for the average osmotic pressure produced by drug and sodium chloride are shown in Table IV. In addition, the osmotic pressure in the dissolution medium was 0.32 Mpa (pH 1.2), 0.68 Mpa (pH 4.5), 0.38 Mpa (pH 6.8), 0.46 Mpa (pH 7.4), and 0 Mpa (water). This showed that ΠNaCl,in > > ΠTPL,in and ΠNaCl,in > > Πmedium. The osmotic pressure caused by 30 mg theophylline was only 0.22 MPa, so ΠNaCl,in > > Πout. Therefore, the ionic osmotic pressure produced by sodium chloride was the main driving force of drug release. So, the simplified eq. (10) was: dm kA cdrug ¼ ∏ dt h NaCl
ð10Þ
Regarding the osmotic pressure, it depends on the number of solute particles per unit volume. Equation (11) applies (27): ð11Þ
∏ ¼ csolution RT
Where csolution is the solution concentration; R is the perfect gas constant; and T is the thermodynamic temperature. Substituting Eq. (11) into Eq. (10) gives in Eq. (12): dm kA ¼ RTcdrug ðcNaþ Þðccl− Þ dt h
ð12Þ
According to eq. (12), the theoretical value of the osmotic pressure was 3.0256 Mpa, while the experimental value of the average osmotic pressure was 2.7564 Mpa, and, according to eq. (12), it can be described as follows (eq. 13): dm kA ¼ 2:7564 cdrug dt h
ð13Þ
Then, the experimental value of osmotic pressure was used to verify the correctness of eq. (12). The fitting relation coefficient (r) of eqs. (12) and (13) was 0.995. Therefore, eq. (12) can be used to predict the release rate of theophylline. In addition, eq. (12) is also applicable to drugs whose property was same to theophylline, and it can be applied to predict the release rate and release characteristics of theophylline ionicdriven osmotic pump tablets. Table IV. The Average Osmotic Pressure Produced by Theophylline and Sodium Chloride Respectively in Tablet Core (n = 3)
Fig. 5. a Average osmotic pressure of optimal ionic-driven osmotic pump tablet (n = 3). b Average drug-release rate of optimal ionicdriven osmotic pump tablet (n = 3). c The ratio of average drugrelease rate and ionic osmotic pressure (red: theoretical value; black: experimental value)
Time/h
1
2
4
6
8
10
12
ΠTPL/Mpa ΠNaCl/Mpa
0.12 25.78
0.11 25.20
0.11 25.20
0.12 26.67
0.13 23.67
0.13 16.50
0.12 11.28
Cheng et al. Table V. Pharmacokinetic Parameters of Tested and Reference Formulations in Beagle Dogs (n = 6)
Formulation
Reference
Testing
t0.5 (h) Cmax (μg/mL) Tmax, average (h) SUM (Tmax) AUC(0-t) (μg/mL h)
9.979 ± 3.283 3.979 ± 1.255 12.725 ± 4.258 31.0 80.585 ± 21.163
11.889 ± 4.654 3.243 ± 0.778 12.667 ± 2.733 47.0 71.663 ± 24.928
All the data was presented in the form of mean ± SD
In Vivo Investigation and IVIVC The main pharmacokinetic parameters (t0.5, Cmax, Tmax, AUC(0-∞)) are given in Table V, and the in vivo pharmacokinetic profiles of theophylline in beagle dogs from the ionicdriven and conventional osmotic pump tablets are shown in
Fig. 6a. Tmax was analyzed using the Wilcoxon rank sum test. According to the two overall rank sum test table, when n is 6, the critical value of T was T1 (26), T2 (50). The SUM (reference) and SUM (testing) were between T1 and T2, it indicated there was no significant difference of the Tmax. The profiles show that the ionic-driven and conventional osmotic pump tablets are characterized by peak blood levels at 12 h. Also, the plasma concentration increased gradually. The relative bioavailability of the ionic-driven osmotic pump tablet to the conventional osmotic pump calculated from AUC(0-∞) was 93.6%. The IVIVC of the ionic-driven osmotic pump tablet was calculated using the Wager-Nelson method. The regression equation was Ft = 0.9861Fa + 6.949, the regression profile was shown in Fig. 6b, and the correlation coefficient (R) was 0.9945, which indicated that the ionic-driven osmotic pump tablet exhibited an excellent correlation of IVIVC. CONCLUSION In this study, an ionic-driven osmotic pump tablet was developed, and its release mechanism and IVIVC were examined. The driving force of the ionic-driven osmotic pump was produced only by the ionic osmotic pressure. Also, the ionic osmotic pressure was strongly dependent on the amount of sodium chloride. For an optimal ionic-driven osmotic pump formulation, the amount of sodium chloride was 450 mg, and the average osmotic pressure and average drug-release rate were 2.7564 Mpa and 2.26 mg/h, respectively. The relationship between the drug-release rate and the ionic osmotic pressure was investigated and the novel formula was obtained and verified for the ionic-driven osmotic pump system. Finally, eq. (12) was obtained which showed that the drug-release rate was proportional to ionic osmotic pressure or the concentration of sodium chloride. Importantly, it was highly significant that the drug-release rate can be predicted by the formula of the ionic-driven osmotic pump, and eq. (12) is also helpful for modifying the ionic-driven osmotic pump formulation. The pharmacokinetic parameters showed the bioequivalence of the ionic-driven and conventional osmotic pump tablets, and the IVIVC of ionic-driven osmotic pump was excellent. In addition, the manufacturing process was simpler, and the formula can predict the formulation. So, the ionicdriven osmotic pump is a promising system for controlling drug release. ACKNOWLEDGEMENTS This work was supported by the program of supporting career development of young and middle-aged teachers from Shenyang Pharmaceutical University (ZQN2015011). COMPLIANCE WITH ETHICAL STANDARDS
Fig. 6. a In vivo pharmacokinetics profiles of theophylline in beagle dogs from the ionic-driven and conventional osmotic pump tablet (n = 6). b IVIVC model linear regression plots of percentage absorbed in vivo versus percentage released in vitro from ionicdriven osmotic pump tablet
All animal experiments were conducted in accordance with the principles of Laboratory Animal Care and approved by Shenyang Pharmaceutical University Animal Ethical Committee, and the ethical committee approval number of animal studies is SYPU-IACUC-2017-1210-501.
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Research Article Release Mechanism Between Ion Osmotic Pressure and Drug Release in Ionic-Driven Osmotic Pump Tablets (I) Lizhen Cheng,1 Siqi Gao,1 Defang Ouyang,2 Haiying Wang,1 Yongfei Wang,1 Weisan Pan,1 and Xinggang Yang1,3
Received 5 August 2017; accepted 26 September 2017
The objective of this study was to develop an authentic ionic-driven osmotic pump system and investigate the release mechanism, simultaneously exploring the in vitro and in vivo correlation of the ionic-driven osmotic pump tablet. A comparison of the ionicdriven and conventional theophylline osmotic pump, the influence of pH and the amount of sodium chloride on drug release, the relationship between the ionic osmotic pressure and the drug release, and the pharmacokinetics experiment in beagle dogs were investigated. Consequently, the similarity factor (f2) between the novel and conventional theophylline osmotic pump tablet was 60.18, which indicated a similar drug-release behavior. Also, the release profile fitted a zero-order kinetic model. The relative bioavailability of the ionicdriven osmotic pump to the conventional osmotic pump calculated from the AUC (0-∞) was 93.6% and the coefficient (R = 0.9945) confirmed that the ionic-driven osmotic pump exhibited excellent IVIVC. The driving power of the ionic-driven osmotic pump was produced only by ions, which was strongly dependent on the ion strength, and a novel formula for the ionic-driven osmotic pump was derived which indicated that the drug-release rate was proportional to the ionic osmotic pressure and the sodium chloride concentration. Significantly, the formula can predict the drug-release rate and release characteristics of theophylline ionic-driven osmotic pumps, guiding future modification of the ionic osmotic pump. Abstract.
KEY WORDS: release mechanism; ionic-driven osmotic pump; ionic osmotic pressure; zero-order kinetic model; formula verification; IVIVC.
INTRODUCTION The osmotic drug delivery system was first described by Rose and Nelson in 1955 when they invented the device which controlled the drug release at a constant rate via implantation in vivo, but the device has not been adopted widely due to the great volume and the fact that it is very inconvenient to use (1). Theeuwes published the fundamental theory about osmotic pump in 1975, which established the special position of osmotic pumps in controlled-release preparations. They also described the concept and structure of an elementary osmotic pump, simultaneously simplifying the osmotic pump structure and promoting its industrial production and clinical applications (2–5). The elementary 1
Department of Pharmaceutics, School of Pharmaceutical Science, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China. 2 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences (ICMS), University of Macau, Macau, China. 3 To whom correspondence should be addressed. (e-mail: [email protected])
osmotic pump consisted of a compartment including the drug, osmotic active agents, and semipermeable membrane with a delivery orifice. When the tablet core came into contact with an aqueous environment, the water flowed into the core, and the drug and osmotic agents dissolved. Then, the saturated solution with high osmotic pressure was generated in the tablet core, and the driving force promoted the release of drug and osmotic agents in the saturated solution from orifices at a constant rate (6,7). The driving force of the conventional osmotic pump was supplied by osmotic pressure and swelling pressure. Generally, the osmotic pressure was produced by water-soluble salts (sodium chloride, sodium sulphate, potassium chloride, and sodium bicarbonate), while the swelling pressure was produced by polymers (polyethylene oxide, sodium carboxyl methylcellulose, hydroxyl propyl methyl cellulose, hydroxyl methylcellulose, methylcellulose, polyvinyl pyrollidine, polyacrylamides, and carbopols) (8–12). However, polyoxyethylene has a high viscosity, and its properties are changed after long-term storage; and the high viscosity affected the preparation of the osmotic pump tablet, which has an effect on the stable release of drug (13,14). In addition, the swelling pressure was ignored in conventional elementary osmotic pump drug release. 1530-9932/17/0000-0001/0 # 2017 American Association of Pharmaceutical Scientists
Cheng et al. In order to clarify the drug-release mechanism and overcome the disadvantage of conventional elementary osmotic pump, we designed a novel osmotic pump, the ionic-driven osmotic pump, for which the driving power was the ionic osmotic pressure generated only by the dissolution of the drug and osmotic agents. The ionic-driven osmotic pump closely resembles the elementary osmotic pump of Theeuwes. Compared with the conventional osmotic pump, the advantages of the ionic osmotic pump system are that (a) it overcomes the drawback of lag-time, (b) simplifies the preparation technology, and (c) allows prediction of the drugrelease rate and release characteristics of other ionic-driven osmotic pumps. Importantly, the drug-release mechanism can be described clearly and accurately. In this study, theophylline was selected as a model drug, and it was one of the most widely prescribed drugs for the treatment of asthma and chronic obstructive pulmonary disease (15–17). It is essential that the novel formulation maintains a concentration gradient of the osmotic agent (18– 20). In order to investigate the drug-release mechanism, an ionic-driven osmotic pump tablet was prepared. The study mainly focuses on the influence of the amount of sodium chloride on the drug release, the drug release in vitro and the absorption in vivo, and the relationship between the drugrelease rate and the ionic osmotic pressure. Importantly, it was very important that the drug-release rate can be theoretically predicted using the formula of the ionic-driven osmotic pump, guiding the further development of the ionicdriven osmotic pump. MATERIALS AND METHODS Materials Theophylline (TPL) and acetaminophen were obtained from Yichang Yongnuo Pharmaceutical Co., Ltd., Hubei, China; PEO WSR301 was a gift from Dow Chemical Co. New Jersey, USA; microcrystalline cellulose (MCC) was purchased from Shandong Liaocheng Awa Pharmaceutical Co., Ltd., China. Cellulose acetate (CA) and polyethylene glycol 4000 (PEG 4000, average molecular weight) were supplied by Shenyang Chemical Reagent Company (Shenyang, China); acetonitrile, methyl alcohol, diethyl ether, acetone, sodium chloride, silver nitrate (AgNO 3 ), potassium chromate (K2CrO4), potassium dihydrogen phosphate, sodium hydroxide, anhydrous sodium acetate, acetic acid, and hydrochloric acid (36.5% M) were of analytical grade and obtained from Yuwang Chemical Reagent Co., Shandong, China; distilled water was used throughout the study. The Preparation of Ionic-Driven and Conventional Osmotic Pump Tablet The tablet core formulation of the ionic-driven and conventional theophylline osmotic pump tablet is shown in Table I. The drug and excipients were passed through an 80 mesh sieve, placed in a mortar for uniform mixing, and compressed into tablets. The tablet core was prepared using a single-punch tablet machine with concave punches (diameter 11 mm) (Shanghai no.1 Pharmaceutical Device Co., Shanghai, China).
Table I. Basic Formulation of Ionic-Driven (A) and Conventional Theophylline Tablet Core (B)
Formulation
F(A1) F(A2) F(A3) F(A4) F(B)
Amount (mg/tablet) Theophylline
NaCl
PEOWSR 301
MCC
30 30 30 30 30
0 250 450 550 100
0 0 0 0 200
570 320 120 20 170
The coating of the tablet core with cellulose acetate and polyethylene glycol 4000 (CA/PEG4000) was conducted in a traditional coating pan (Shanghai Tianfan Machinery Factory, Shanghai, China). The ratio of CA/PEG4000 was 2:1 (ionicdriven osmotic pump tablet) and 15:4 (conventional osmotic pump tablet). The coating solution was prepared by dissolving cellulose acetate in acetone and PEG 4000 in water, then mixing and stirring until dissolution was completed. The pan rotation rate was set at 35 rpm; the hot air used for drying the tablets during pan coating was 40°C; the spray rate was set at 7 ml/min; and the tablets were dried at 40°C for 12 h in an oven. Finally, the 0.8-mm orifice was drilled using a micro drill bit. In Vitro Dissolution Test The in vitro behavior of the theophylline osmotic pump tablet was continuously recorded using a fully automated dissolution apparatus. The release characteristics of the osmotic pump formulation were determined using the USP 2 paddle method (with sinker) (19,21). Studies carry out in 900 mL 0.1 M hydrochloric acid (HCl, 9 mL HCl added in 1000 mL water, CHCl = 0.1 mol/L), pH 4.5 sodium acetate-acetic acid buffer (18 g sodium acetate and 9.8 mL added and dissolved to 1000 mL water, Csodium acetate = 0.21 mol/L), pH 6.8 phosphate buffer (250 mL potassium phosphate monobasic (0.2 mol/L) and 118 mL sodium hydroxide solution (0.2 mol/L) diluted to 1000 mL, Cpotassium phosphate = 0.051 mol/L), pH 7.4 phosphate buffer (1.36 g potassium phosphate monobasic and 79 mL sodium hydroxide solution (0.1 mol/L) diluted to 200 mL, Cpotassium phosphate = 0.05 mol/L), and water. The dissolution medium temperature was maintained at 37 ± 0.5°C, and the rotation speed was 100 rpm. Five-ml samples were withdrawn and replaced by an equal volume of fresh medium at predetermined intervals of 0.5, 1, 2, 4, 6, 8, 10, and 12 h. Then, the samples were filtered, and the concentration was measured at an ultraviolet (UV) absorbance of 272 nm (22). All experiments were performed in triplicate. The dissolution profiles of each formulation were determined by plotting the percentage cumulative drug release at different times. The difference factor (f1) and the FDA similarity factor (f2) were used to evaluate the similarity of two drug-release profiles [Eqs. (1) and (2)] (23). f1 ¼
∑ni¼1 jRt −T t j ∑ni¼1 Rt
100
ð1Þ
Release Mechanism Between Ion Osmotic Pressure and Drug Release ( f 2 ¼ 50log
1þ
) −0:5 1 100 ∑nt¼1 ðRt −T t Þ2 n
ð2Þ
Where Rt and Tt are the dissolution value at time t of the reference batch and the test batch, respectively; n is the number of time points. The two drug-release profiles were considered similar when f2 was not less than 50. Gastrointestinal Simulation Experiment
Determination of Osmotic Pressure The Preparation of K2CrO4 Indicator and AgNO3 Standard Solution The preparation of K2CrO4 indicator: 5 g K2CrO4 was dissolved in 100 mL water, and AgNO3 solution was added to the solution with stirring until the brick red color disappeared. After 12 h, the solution was filtered to obtain 5% K2CrO4 indicator solution. The preparation of 0.1 mol/L AgNO3 standard solution: 17 g AgNO3 was added in 1000 mL distilled water, stir evenly and obtained the 0.1 mol/L AgNO3 standard solutions (14). Determination of Ionic Osmotic Pressure and the Cumulative Release of NaCl In this study, we determined the osmotic activity of chloride ions instead of directly measuring the osmotic pressure of the system. The osmotic pressure in the tablet core was dependent on the sodium chloride in the tablet core, and the concentration of sodium chloride could be obtained by determination of the chloride ions. Samples of ionic-driven osmotic pump tablet were put into 900 mL water at 37 ± 0.5°C and stirred at 100 rpm. At predetermined intervals (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 h), samples were withdrawn and put in another 900-mL dissolution container. They were then filtered to obtain the first dissolution solution samples, and the chloride ions in the dissolution solution samples were determined using the potassium chromate indicator method (24). A few drops of 5% K2CrO4 indicator were added to the sample solution and titrated with 0.1 mol/L AgNO3 standard solution until the appearance of a brick red color. The principle was as shown in Eqs. (3) and (4):
¼ 1:8 10‐10
Ag2 CrO4
¼ 1:2 10‐12
ð4Þ
Because the solubility of AgCl was lower than the solubility of Ag 2 CrO 4 (K sp,AgCl < K sp, Ag2 CrO4 ), according to the principle of fractional titration, the AgCl white precipitate appeared first; when the Cl− was titrated completely, an Ag2CrO 4 brick red precipitate was formed. In Vivo Evaluation of the Ionic-Driven Osmotic Pump
In this study, the pH of the medium was changed for the same sample to simulate gastrointestinal (GIT) conditions. The samples of ionic-driven osmotic pump were set in 750 mL HCl medium (0.1 mol/L) for 2 h. Then, 250 mL sodium phosphate solution was added into the above 750 mL HCl medium to adjust the pH to 6.8. Next, the sample solution was withdrawn and determined.
Agþ þ Cl‐ ¼ AgCl ðwhite precipitateÞ Ksp ;AgCl
2 Agþ þ CrO2− 4 ¼ Ag2 CrO4 ðbrick red precipitateÞKsp;
ð3Þ
All animal experiments were conducted in accordance with the principles of Laboratory Animal Care and approved by Shenyang Pharmaceutical University Animal Ethical Committee, and the ethical committee approval number of animal studies is SYPU-IACUC2017-1210-501. A randomized, two period crossover design was used to investigate the in vivo properties of the ionic-driven osmotic pump tablet, and the washout period between successive experiments was 1 week. The elimination half-life of theophylline in dogs is about 2 h. Beagle dogs (n = 6, 10 ± 2 kg) were fasted for 12 h before the experiment. According to the schedule of the two period crossover tests, the dogs were given an ionicdriven osmotic pump tablet and an innovator conventional osmotic pump tablet, and blood samples (3 mL) were collected in heparinized tubes at predetermined times (1, 2, 4, 6,7, 8, 9, 10, 12, 14, 16, 24, 36, and 48 h). Then, the collected blood was centrifuged immediately at 4000 rpm for 10 min, and the plasma samples were separated and frozen at − 20°C. For analysis, the plasma was thawed, then, 0.5 mL of each plasma sample was placed in a 10 mL centrifuge tube, followed by 10 μL internal standard solution (acetaminophen/methyl alcohol solution, 200 μg/mL), then, 500 μL acetonitrile, and vortexed for 1 min. Then, 3 mL diethyl ether was added followed by vortexing for 3 min, then centrifuged at 4000 rpm for 10 min. Then, 2.5 mL organic phase was removed and transferred to another centrifuge tube, and the organic solution was dried at 40°C under a stream of nitrogen. Then, it was dissolved in 200 μL methyl alcohol, vortexed for 1 min, and centrifuged at 12000 rpm for 5 min. Finally, 20 μL subnatant was withdrawn for high-performance liquid chromatography (HPLC)-analysis (16). Diamonsil C18 column (4.6 mm × 200 mm, 5 μm) was used to separate the samples at 30°C. The mobile phase was methanol/water (22/78, V/V), and the flow rate of the mobile phase was 1.0 mL/min; and measurements were carried out at 272 nm. In Vivo Data Analysis The theophylline concentrations in plasma versus time data were evaluated using DAS 2.0 software (Mathematical Pharmacology Professional Communities of China, Shanghai, China), which indicated that the absorption fitted single compartment model, and the overall elimination rate constant ke was measured (25). The AUC(0-t)
Cheng et al. was determined by the trapezoidal method, and the AUC (0-∞) was obtained by eqs. (5) and (6): AUCð0‐∞Þ ¼ AUCð0‐tÞ þ CðtÞ =K e
ð5Þ
The Wagner–Nelson method was used to calculate the percentage of the theophylline dose absorbed, Fa: Fa ¼
100 CðtÞ þ ke AUCð0‐tÞ =ke AUCð0‐∞Þ
ð6Þ
different data of test time; these results showed that there was no significant difference among the average release rate. Also, the average release rate at the same tested time in different dissolution media was relatively similar. The result of ionic-driven osmotic pump tablet gastrointestinal (GIT) simulation experiment was shown in Fig. 1c, and the results further indicate that the drug release of ionicdriven osmotic pump tablet was not influenced by the change of gastrointestinal pH. Comparison of Ionic-Driven and Conventional Osmotic Pump Tablet
RESULTS AND DISCUSSION In Vitro Dissolution Test The in vitro release profile of the ionic-driven osmotic pump tablet in different dissolution media was studied. A plot of the cumulative drug release versus time is presented in Fig. 1a. The f1 and f2 in Table II between the drug-release profiles in media of different pH confirmed that the drug release was independent of pH. Figure 1b shows the average release rate of theophylline in 0.1 M HCl, pH 4.5 sodium acetate-acetic acid buffer, pH 6.8 phosphate buffer, pH 7.4 phosphate buffer, and water. Analysis of variance was used to evaluate the differences. The p was higher than 0.05 between
From Fig. 1d, comparing the release profiles in 900 mL water between ionic-driven and conventional theophylline osmotic pump tablets, the in vitro drug-release data were fitted to a zero-order, first-order, and Higuchi model, and the kinetics results of drug release from ionic-driven osmotic pump were shown in Table III. The r value of the regression curve equation indicated the release profile of ionic-driven and conventional theophylline osmotic pump was fitted to a zero-order model. Also, the f1 and f2 between the drugrelease profiles were 6.72 and 60.18, indicating that the ionicdriven and conventional osmotic pump tablets exhibited a similar in vitro behavior. In this study, the coating membrane of ionic-driven and conventional osmotic pump tablet was investigated. The
Fig. 1. a In vitro drug-release profiles of different dissolution medium (n = 3). b Average drug-release rate in different dissolution medium (n = 3). c Ionic-driven osmotic pump tablet gastrointestinal (GIT) simulation profile. d Comparison of the in vitro release profiles of ionic-driven and conventional osmotic pump tablet (n = 3)
Release Mechanism Between Ion Osmotic Pressure and Drug Release Table II. f1 and f2 Value Between the Drug-Release Profiles Under Different ph Value of Medium
Dissolution medium
pH 1.2– pH 4.5
pH 1.2– pH 6.8
pH 1.2– pH 7.4
pH 1.2water
pH 4.5– pH 6.8
pH 4.5– pH 7.4
pH 4.5water
pH 6.8– pH 7.4
pH 6.8water
pH 7.4water
f1 f2
10 55
8 58
3 74
4 68
5 83
10 59
7 69
8 64
4 77
4 77
optimal ratio of CA/PEG4000 was 2:1 (ionic-driven osmotic pump tablet) and 15:4 (conventional osmotic pump tablet), and Fig. 1d showed similar release behavior of ionic-driven and conventional osmotic pump tablets. Simultaneously, the coating membrane formulation of ionic-driven and conventional osmotic pump tablets was exchanged and the result was revealed in Fig. 2. Only about 40% of drug was released from the ionic-driven osmotic tablet, and the problem cannot solve by adjusting the tablet core formulation. It was mainly due to the ionic-driven osmotic pump tablets only have NaCl without PEO in the tablet core, so the water passed through the tablet core in per unit time is very small, and the osmotic pressure produced in tablet core is little. For the conventional osmotic pump tablet, drugrelease rate was too fast to control the drug release at constant rate. Similar coating membrane formulation cannot obtain similar drug-release behavior, so different coating member formulation of ionic-driven and conventional osmotic pump tablet was used. Influence of the Amount of Sodium Chloride on the Drug Release The influence of the amount of sodium chloride on the drug release in vitro and the average osmotic pressure were also investigated in Fig. 3a, b. The cumulative release rate is shown in Fig. 3c. The results showed that the cumulative drug release increased rapidly on increasing the amount of sodium chloride. When the amount of sodium chloride in the tablet core was 0 mg and 250 mg, with the release of drug, the amount of sodium chloride in the tablet core also decreased, and the concentration of sodium chloride was not enough to maintain saturation. Therefore, the osmotic pressure in the tablet core was reduced and it was not possible to maintain constant rate of drug release. When the amount of sodium chloride was 550 mg, the drug-release rate increased rapidly, and the drug release was completed before 10 h. In addition,
the drug-release profile did not fit zero-order kinetics. Therefore, the amount of sodium chloride could not increase infinitely. However, there was an optimum amount of sodium chloride. When the amount of sodium chloride was 450 mg, the system had enough osmotic pressure to promote the drug release, and the profile also exhibited zero-order drug release. Hence, it was concluded that the optimal amount of sodium chloride was 450 mg for the ionic-driven theophylline osmotic pump system. The Theory for the Drug Release by the Ionic-Driven Osmotic Pump Tablet In the drug release from the elementary osmotic pump tablet, when the tablet core comes into contact with the aqueous environment, water passes through the semipermeable membrane and comes into contact with the tablet core. Due to the difference in osmotic pressure inside and outside the membrane, the drug can be released at a constant rate through the delivery orifice. The general drug-release rate can be summarized by the following eq. (7) (26): dm A ¼ Lp ðδ Δ∏−Δ pÞcdrug dt h
ð7Þ
Where A is the membrane area; h is the membrane thinness; Lp is the mechanical permeability; δ is the reflection coefficient; △Π and △p are the osmotic and hydrostatic pressure differences between inside and outside the
Table III. Kinetics of Drug Release From Ionic-Driven Osmotic Pump Tablet (A) and Conventional Osmotic Pump Tablet (B)
AA
BB
Model name
Equation
r
Zero-order model First-order model Higuchi model Zero-order model First-order model Higuchi model
Q = 7.8535t − 0.3713 ln(100-Q) = − 0.1853t + 4.8334 Q = 32.753t1/2 – 27.42 Q = 8.7038t − 5.1309 ln(100-Q) = − 0.2126t + 4.8708 Q = 30.853t1/2 – 21.428
0.9973 0.9769 0.9857 0.9910 0.9711 0.9481
Where t is the tested time; Q is the cumulative drug release at t hours
Fig. 2. Influence of coating solution on drug release of ionic-driven and conventional osmotic pump (n = 3)
Cheng et al.
Fig. 3. a Influence of sodium chloride amount on the drug release of ionic-driven osmotic pump tablet (n = 3). b Influence of sodium chloride amount on the average osmotic pressure of osmotic pump tablet (n = 3). c The cumulative release rate of sodium chloride (n = 3). d Cumulative release profiles of 450 mg sodium chloride (n = 3)
membrane, respectively; and c is the concentration of drug in the solution. For the control system, if △Π > > △p. Lpδ is replaced by constant k. The simplified eq. (8) is as follows: dm kA ¼ Δ∏cdrug dt h
ionic-driven osmotic pump tablet in Fig. 4. So, the following eq. (9) applies: dm kA
ð∏TPL þ ∏NaCl Þin −ð∏TPL þ ∏NaCl þ ∏medium Þout cdrug ¼ dt h
ð9Þ
ð8Þ
For the ionic-driven osmotic pump tablet, the tablet core is composed of drug, sodium chloride, and microcrystalline cellulose (MCC). Because MCC is insoluble in water, the osmotic pressure in the tablet core (Π) is generated by two different materials: drug and sodium chloride, and schematic diagram describing the process of the drug release from the
To determine the optimal formulation for the ionicdriven osmotic pump tablet, the release characteristic of sodium chloride was investigated systematically. The cumulative release of 450 mg NaCl is shown in Fig. 3d. The release rate of sodium chloride was at a consistent value before 6 h. It can also be concluded that the concentration of sodium chloride was maintained at saturation. At a later period, the
Fig. 4. Schematic diagram describing the process of the drug release from the ionic-driven osmotic pump tablet
Release Mechanism Between Ion Osmotic Pressure and Drug Release release rate of sodium chloride was decreased, so the ionic osmotic pressure in the tablet core was also decreased, but it was sufficient to drive the drug release from the osmotic pump tablet. Figure 5a, b shows the results of the average ionic osmotic pressure and the average drug-release rate at each tested time. The profile of the average osmotic pressure basically followed the average drug-release rate. In addition, the ratio of the average drug-release rate and the average ionic osmotic pressure is shown in Fig. 5c, and the result showed that the average drug-release rate was proportional to the average ionic osmotic pressure. Therefore, it can be concluded the drug release was dependent on the osmotic pressure in the tablet core. From Fig. 3c, it was found that the average osmotic pressure profile was related to the release of sodium chloride in the tablet core. Sodium chloride was released at a constant rate, and the concentration of sodium chloride was maintained at saturation before 6 h, so, the osmotic pressure did not change. However, after 6 h, the average osmotic pressure declined gradually because the sodium chloride concentration in the osmotic pump tablet core could not maintain saturation for drug
release. Nonetheless, the osmotic pressure in the later period was only reduced slowly and drug release was still promoted. The data for the average osmotic pressure produced by drug and sodium chloride are shown in Table IV. In addition, the osmotic pressure in the dissolution medium was 0.32 Mpa (pH 1.2), 0.68 Mpa (pH 4.5), 0.38 Mpa (pH 6.8), 0.46 Mpa (pH 7.4), and 0 Mpa (water). This showed that ΠNaCl,in > > ΠTPL,in and ΠNaCl,in > > Πmedium. The osmotic pressure caused by 30 mg theophylline was only 0.22 MPa, so ΠNaCl,in > > Πout. Therefore, the ionic osmotic pressure produced by sodium chloride was the main driving force of drug release. So, the simplified eq. (10) was: dm kA cdrug ¼ ∏ dt h NaCl
ð10Þ
Regarding the osmotic pressure, it depends on the number of solute particles per unit volume. Equation (11) applies (27): ð11Þ
∏ ¼ csolution RT
Where csolution is the solution concentration; R is the perfect gas constant; and T is the thermodynamic temperature. Substituting Eq. (11) into Eq. (10) gives in Eq. (12): dm kA ¼ RTcdrug ðcNaþ Þðccl− Þ dt h
ð12Þ
According to eq. (12), the theoretical value of the osmotic pressure was 3.0256 Mpa, while the experimental value of the average osmotic pressure was 2.7564 Mpa, and, according to eq. (12), it can be described as follows (eq. 13): dm kA ¼ 2:7564 cdrug dt h
ð13Þ
Then, the experimental value of osmotic pressure was used to verify the correctness of eq. (12). The fitting relation coefficient (r) of eqs. (12) and (13) was 0.995. Therefore, eq. (12) can be used to predict the release rate of theophylline. In addition, eq. (12) is also applicable to drugs whose property was same to theophylline, and it can be applied to predict the release rate and release characteristics of theophylline ionicdriven osmotic pump tablets. Table IV. The Average Osmotic Pressure Produced by Theophylline and Sodium Chloride Respectively in Tablet Core (n = 3)
Fig. 5. a Average osmotic pressure of optimal ionic-driven osmotic pump tablet (n = 3). b Average drug-release rate of optimal ionicdriven osmotic pump tablet (n = 3). c The ratio of average drugrelease rate and ionic osmotic pressure (red: theoretical value; black: experimental value)
Time/h
1
2
4
6
8
10
12
ΠTPL/Mpa ΠNaCl/Mpa
0.12 25.78
0.11 25.20
0.11 25.20
0.12 26.67
0.13 23.67
0.13 16.50
0.12 11.28
Cheng et al. Table V. Pharmacokinetic Parameters of Tested and Reference Formulations in Beagle Dogs (n = 6)
Formulation
Reference
Testing
t0.5 (h) Cmax (μg/mL) Tmax, average (h) SUM (Tmax) AUC(0-t) (μg/mL h)
9.979 ± 3.283 3.979 ± 1.255 12.725 ± 4.258 31.0 80.585 ± 21.163
11.889 ± 4.654 3.243 ± 0.778 12.667 ± 2.733 47.0 71.663 ± 24.928
All the data was presented in the form of mean ± SD
In Vivo Investigation and IVIVC The main pharmacokinetic parameters (t0.5, Cmax, Tmax, AUC(0-∞)) are given in Table V, and the in vivo pharmacokinetic profiles of theophylline in beagle dogs from the ionicdriven and conventional osmotic pump tablets are shown in
Fig. 6a. Tmax was analyzed using the Wilcoxon rank sum test. According to the two overall rank sum test table, when n is 6, the critical value of T was T1 (26), T2 (50). The SUM (reference) and SUM (testing) were between T1 and T2, it indicated there was no significant difference of the Tmax. The profiles show that the ionic-driven and conventional osmotic pump tablets are characterized by peak blood levels at 12 h. Also, the plasma concentration increased gradually. The relative bioavailability of the ionic-driven osmotic pump tablet to the conventional osmotic pump calculated from AUC(0-∞) was 93.6%. The IVIVC of the ionic-driven osmotic pump tablet was calculated using the Wager-Nelson method. The regression equation was Ft = 0.9861Fa + 6.949, the regression profile was shown in Fig. 6b, and the correlation coefficient (R) was 0.9945, which indicated that the ionic-driven osmotic pump tablet exhibited an excellent correlation of IVIVC. CONCLUSION In this study, an ionic-driven osmotic pump tablet was developed, and its release mechanism and IVIVC were examined. The driving force of the ionic-driven osmotic pump was produced only by the ionic osmotic pressure. Also, the ionic osmotic pressure was strongly dependent on the amount of sodium chloride. For an optimal ionic-driven osmotic pump formulation, the amount of sodium chloride was 450 mg, and the average osmotic pressure and average drug-release rate were 2.7564 Mpa and 2.26 mg/h, respectively. The relationship between the drug-release rate and the ionic osmotic pressure was investigated and the novel formula was obtained and verified for the ionic-driven osmotic pump system. Finally, eq. (12) was obtained which showed that the drug-release rate was proportional to ionic osmotic pressure or the concentration of sodium chloride. Importantly, it was highly significant that the drug-release rate can be predicted by the formula of the ionic-driven osmotic pump, and eq. (12) is also helpful for modifying the ionic-driven osmotic pump formulation. The pharmacokinetic parameters showed the bioequivalence of the ionic-driven and conventional osmotic pump tablets, and the IVIVC of ionic-driven osmotic pump was excellent. In addition, the manufacturing process was simpler, and the formula can predict the formulation. So, the ionicdriven osmotic pump is a promising system for controlling drug release. ACKNOWLEDGEMENTS This work was supported by the program of supporting career development of young and middle-aged teachers from Shenyang Pharmaceutical University (ZQN2015011). COMPLIANCE WITH ETHICAL STANDARDS
Fig. 6. a In vivo pharmacokinetics profiles of theophylline in beagle dogs from the ionic-driven and conventional osmotic pump tablet (n = 6). b IVIVC model linear regression plots of percentage absorbed in vivo versus percentage released in vitro from ionicdriven osmotic pump tablet
All animal experiments were conducted in accordance with the principles of Laboratory Animal Care and approved by Shenyang Pharmaceutical University Animal Ethical Committee, and the ethical committee approval number of animal studies is SYPU-IACUC-2017-1210-501.
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