Introduction
In the preceding reports, a new technology of thermoplastic coating was developed
and the properties of the coating membrane (H membrane) were evaluated.[1]
[2] This technology consists of following three steps: hot-melt extrusion for membrane,
heat skin coating, and laser melt cutting (abbreviated as HHL; [Fig. 1]). Metformin hydrochloride thermoplastic coated tablets (HHL-METF) and nifedipine
thermoplastic coated tablets (HHL-NIF) were prepared by this technology.
Fig. 1 (A) Schematic illustration of the H membrane preparation and (B) the process of thermoplastic coating.
The traditional metformin hydrochloride osmotic pump tablets (METF-OPTs) such as Fortamet,
and nifedipine osmotic pump tablets (NIF-OPTs) prepared by spraying cellulose acetate
(CA) dissolved in acetone on the surface of tablets are available in the market.[3] Water-soluble METF, an inexpensive oral hypoglycemic agent, widely used in type
II diabetes, has expanded usage due to its other beneficial effects. METF is mainly
absorbed in the upper part of the small intestine after oral administration. It is
taken two to four times a day with a half-life of 0.9 to 2.6 hours. In addition, it
has a stimulating effect on the gastrointestinal tract. Therefore, METF-OPTs with
fewer side effects are developed and marketed abroad.[4]
[5]
[6] Water-insoluble NIF, a commonly used antihypertensive drug, should be taken thrice
a day with a short half-life. Its large peak/trough ratio of blood concentration can
cause significant blood pressure fluctuations, resulting in serious adverse effects.
In clinical practice, NIF-OPTs have been widely used once daily to better control
blood pressure.[7]
In this paper, in vitro drug release profiles of HHL-METF and HHL-NIF were studied
and compared with those of OPTs prepared by the conventional spray coating. The effects
of membrane thickness, polyethylene glycol-1,500 (PEG1500) content, number of orifice,
stirring speed, and release medium on the drug release were investigated, and associated
mechanisms of drug release were also explored.
Materials and Methods
Materials
The standard substances of METF and NIF were purchased from the National Institute
for Food and Drug Control (Beijing, China). The reference listed drug product, METF-OPTs
(Fortamet, 500 mg), was purchased from Watson Laboratories of Florida (Florida, United
States). CA was purchased from Eastman Chemical Company (Kingsport, Tennessee, United
States). Triethyl citrate (TEC) was purchased from Fengyuan Tushan Pharmaceutical
Company (Bengbu, China). PEG1500 was purchased from Nanjing Weier Chemical Company
(Nanjing, China). Metformin hydrochloride tablets core (500 mg/core) and nifedipine
double-layer tablets core (60 mg/core) were gifts from National Pharmaceutical Engineering
Research Center (Shanghai, China). Sodium chloride (NaCl) and methanol were purchased
from National Pharmaceutical Chemical Reagent Co., Ltd. (Beijing, China).
Preparation Method for Thermoplastic Coated Tablets
Preparation of Thermoplastic Coating Membrane
H membranes were prepared by the hot-melt extrusion process according to the preceding
report.[1] The corresponding amounts of CA, TEC, and PEG1500 of the formulation compositions
from [Table 1] were weighed and mixed. The mixture was hot-melt extruded into a plastic strip at
180°C through a twin-screw extruder (Thermo Scientific Process 11, Thermo Fisher Scientific,
United States). The plastic strip was cut into plastic granules using a plastic cutting
machinery (15–80, Zhejiang Good Plastic Machinery Co., Ltd., Hangzhou, China). The
plastic granules were further extruded through a single-screw extruder (Thermo Scientific
HAAKE Rheomex 19/10 OS, Thermo Fisher Scientific, Unites States) at 190°C to obtain
a sheet with thickness of approximately 1 mm. From which, membranes used for thermoplastic
coating with thickness of 100, 80, and 60 μm were further calendered on a double-roller
calender at 170°C.
Table 1
Membrane composition and thickness of HHL-METF
|
HHL-METF
|
Membrane composition (g)
|
Thickness (μm)
|
|
CA
|
TEC
|
PEG1500
|
|
M10–100
|
65
|
25
|
10
|
100
|
|
M10–80
|
80
|
|
M10–60
|
60
|
|
M10–60 (nonorifice)
|
60
|
|
M15–80
|
60
|
25
|
15
|
80
|
|
M5–80
|
70
|
25
|
5
|
80
|
Abbreviations: CA, cellulose acetate; HHL-METF, metformin hydrochloride thermoplastic
coated tablets; PEG, polyethylene glycol; TEC, triethyl citrate.
Preparation of Coated Tablets
HHL-METF and HHL-NIF were prepared by the HHL method (refer to the preceding report[1]) using different thermoplastic coating membranes with compositions shown in [Tables 1] and [2]. In (M10–100), M represented METF, 10 represented the 10% PEG1500 content in H membrane
used for coating, and 100 represented 100 μm membrane thickness. In (N15–100), N represented
NIF, 15 represented the 15% PEG1500 content in H membrane used for coating, and 100
represented 100 μm membrane thickness. All tablets listed in [Tables 1] and [2] except (M10–60 nonorifice) were laser drilled with an orifice. Typical examples
of thermoplastic coated tablets are shown in [Fig. 2]. As can be seen in [Fig. 2], HHL-METF was a single-chamber thermoplastic coated tablet and HHL-NIF was a double-chamber
thermoplastic coated tablet.
Table 2
Membrane composition and thickness of HHL-NIF
|
HHL-NIF
|
Membrane composition (g)
|
Thickness (μm)
|
|
CA
|
TEC
|
PEG1500
|
|
N15–100
|
60
|
25
|
15
|
100
|
|
N10–100
|
65
|
25
|
10
|
100
|
|
N5–100
|
70
|
25
|
5
|
100
|
Abbreviations: CA, cellulose acetate; HHL-NIF, nifedipine thermoplastic coated tablets;
PEG, polyethylene glycol; TEC, triethyl citrate.
Fig. 2 Typical examples of thermoplastic coated tablets prepared by the HHL method: HHL-METF
(white) and HHL-NIF (yellow). HHL, technology of thermoplastic coating; HHL-METF,
metformin hydrochloride thermoplastic coated tablets; HHL-NIF, nifedipine thermoplastic
coated tablets.
Determination of Release Profiles
Release Profiles of HHL-METF
The release experiments were performed according to the first method (basket method)
of dissolution and release assay (0931) of Chinese Pharmacopoeia (volume IV, 2015
edition). The release medium in the automatic dissolution tester (6,300 type, Distek
Company, United States) was 900 mL water or NaCl solution (0.9%, w/v) maintained at
(37 ± 0.5)°C. The stirring speed was 50 or 100 rpm. Each time, 5 mL of release medium
was withdrawn at 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours, respectively, and used as
test samples. In addition, the standard substance of METF was accurately weighed,
dissolved and diluted to approximately 30 μg/mL with water, and used as the standard
solution. The test samples and the standard solution (0.5 μL each) were accurately
injected into high-pressure liquid chromatograph (HPLC, H-class, Waters, United States).
The column was Waters Acquity UPLC Bridged Ethylene Hybrid (BEH) C18 (2.1 × 50 mm,
1.7 μm, Waters) with the column temperature maintained at 30°C. A 0.05% sodium heptane
sulfonate solution was first adjusted to pH 4.0 with 10% phosphoric acid and then
the adjusted 0.05% sodium heptane sulfonate solution:acetonitrile (84:16) was used
as the mobile phase at a flow rate of 0.4 mL/min.[8] The detection wavelength was at 233 nm. According to the external standard method,
the cumulative release percentages at different time points were calculated from recorded
chromatograms by peak area. The corresponding release rates were then calculated.
Release Profiles of HHL-NIF
The experiment was performed according to the first method (basket method) of dissolution
and release assay (0931) of Chinese Pharmacopoeia (volume IV, 2015 edition). The release
medium in the automatic dissolution tester (6,300 type, Distek Company, United States)
was 900 mL sodium dodecyl sulfate solution (1%, pH = 1.2) maintained at (37 ± 0.5)°C.
The stirring speed was 100 rpm. Each time, 5 mL of release medium was withdrawn at
0.5, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 16, and 24 hours, respectively, and used as test
samples. In addition, the standard substance of NIF was accurately weighed, dissolved
with methanol, and diluted to approximately 40 μg/mL with release medium, and used
as the standard solution. The test sample and the standard solution (0.5 μL each)
were accurately injected into high-pressure liquid chromatograph (HPLC, H-class, Waters,
United States). The column was Thermo Hypersil BDS C18 (4.6 × 50 mm, 2.4 μm, Thermo)
with the column temperature maintained at 30°C. Methanol:acetonitrile:water (25:25:50)
was used as mobile phase at a flow rate of 1.0 mL/min.[9] The detection wavelength was 235 nm. According to the external standard method,
the cumulative release percentages at different time points were calculated from recorded
chromatograms by peak area. The corresponding release rates were then calculated.
Comparison of Release Profiles
The “similarity factor” f
2 was used to compare the drug release profiles, which was calculated according to
the following equation:
where n is the total number of sampling times; Rt
and Tt
are the cumulative drug release percentage at time point t for two different samples, respectively.[10] If f
2 is larger than 50 (between 50 and 100), the two release profiles of tablets are considered
to be similar.
Fitting of Drug Release Models
The release data of HHL-METF and HHL-NIF were fitted with drug release models by calculating
the correlation coefficient R
2 [11] of zero-order, first-order and the Higuchi square-root of time release equations,
respectively.
Results and Discussion
Specificity Assay for Release Profile Determination
Specificity Assay of METF
The METF standard solution, the test samples of (M10–80) at different time points
(1, 4, 8, and 16 hours) in water and the test sample of (M5–80) at 20-hour in NaCl
solution (0.9%, w/v) were assayed on the high-pressure liquid chromatograph, and the
results are shown in [Fig. 3]. METF was baseline separated without interferences, and no new impurity peak was
detected within 20 hours indicating that the specificity of the assay met the requirements.
Fig. 3 High-pressure liquid chromatograms of METF standard solution and test samples of
HHL-METF at different release time points. 1, METF standard solution; 2, M10–80 water
medium–1-hour; 3, M10–80 water medium–4-hour; 4, M10–80 water medium–8-hour; 5, M10–80
water medium–16-hour; 6, M5–80 NaCl medium–20-hour. HHL-METF, metformin hydrochloride
thermoplastic coated tablets; METF, metformin hydrochloride.
Specificity Assay of NIF
The NIF standard solution and the test samples of (N10–100) at 1, 4, 8, and 16 hours
were analyzed on the high-pressure liquid chromatograph. The results are shown in
[Fig. 4]. NIF was baseline separated without interferences, and no new impurity peak was
detected within 16 hours indicating that the specificity of the assay met the requirements.
Fig. 4 High-pressure liquid chromatograms of NIF standard solution and test samples of HHL-NIF
at different release time points. 1, N10–100–1-hour; 2, N10–100–4-hour; 3, N10–100–8-hour;
4, N10–100–16-hour; 5, NIF standard solution. HHL-NIF, nifedipine thermoplastic coated
tablets; NIF, nifedipine.
Factors Affecting the Drug Release
Effect of Membrane Thickness on Drug Release
Based on the method, discussed in section “Release Profiles of HHL-METF,” HHL-METF
coated with membranes of different thicknesses [100 μm (M10–100), 80 μm (M10–80),
and 60 μm (M10–60)] were tested for METF release at a stirring speed of 50 rpm in
water. The results are shown in [Fig. 5]. It was seen that, at any given time, the cumulative drug release percentage decreased
as the coating membrane thickness increased.
Fig. 5 Effect of membrane thickness on the release profiles of HHL-METF (n = 6). HHL-METF, metformin hydrochloride thermoplastic coated tablets.
Effect of PEG1500 Content on Drug Release
Based on the method, discussed in section “Release Profiles of HHL-METF,” HHL-METF
coated with membranes of different PEG1500 content [(15% (M15–80), 10% (M10–80), and
5% (M5–80)] was tested for METF release at a stirring speed of 50 rpm in water. The
results are shown in [Fig. 6]. Similarly, based on the method, discussed in section “Release Profiles of HHL-NIF,”
HHL-NIF coated with membranes of different PEG1500 content [15% (N15–100), 10% (N10–100),
and 5% (N5–100)] was tested for NIF release at a stirring speed of 100 rpm in sodium
dodecyl sulfate solution (1%, pH = 1.2). The results are reported in [Fig. 7]. In both cases, it was clear that at any given time, the cumulative drug release
percentage increased with increasing PEG1500 content. This is consistent with the
known effect of porogen content on drug release from traditional OPTs based on spray
coating membranes.
Fig. 6 Effect of PEG1500 content on the release profiles of HLL-METF (n = 3). HHL-METF, metformin hydrochloride thermoplastic coated tablets.
Fig. 7 Effect of PEG1500 content on the release profiles of HHL-NIF (n = 3). HHL-NIF, nifedipine thermoplastic coated tablets.
Effect of Release Orifice (with or without) on Drug Release
Based on the method, discussed in section “Release Profiles of HHL-METF,” (M10–60)
and (M10–60 nonorifice) were tested for the METF release in water at a stirring speed
of 50 rpm. The results are shown in [Fig. 8]. The METF release profiles of both thermoplastic coated tablets with and without
a laser-drilled orifice were indeed similar, as confirmed by a similarity factor f
2 of 75. This suggested that micropores in the membrane generated by the leaching of
PEG1500 were large enough for releasing METF. Consistent with the preceding report,[2] in HHL-METF, water absorption was caused by the osmotic mechanism, and the release
of water-soluble METF through micropores in the membrane was triggered by diffusion
mechanism due to high concentration of METF. The results showed that HHL-METF could
control the drug release by adjusting the content of water-soluble PEG1500 in the
membrane, similar to the ordinary microporous OPTs. The preparation process of microporous
OPTs is relatively simple without the need for laser drilling. In addition, microporous
OPTs can release drugs through multiple micropores distributed over the entire OPT
surface in vivo, rather than pumping concentrated drug solution through one or two
orifices, and, therefore, it should be safer with less adverse reactions than OPTs
with orifices.[12]
Fig. 8 Effect of release orifice (with or without) on the release profiles of M10–60 (n = 6).
Effect of Stirring Speed on Drug Release
Based on the method, discussed in “Release Profiles of HHL-METF,” METF release from
(M15–80), (M10–80), and (M5–80) was determined in water at stirring speeds of 50 and
100 rpm, respectively. The results are shown in [Fig. 9]. Where it was seen that the stirring speeds studied had little effect on the METF
release, as demonstrated by the similarity of release profiles from the three thermoplastic
coated tablets at the two stirring speeds, confirmed by their similarity factor f
2 being 60, 68, and 83, respectively (all > 50). It was, therefore, confirmed that
the drug release from thermoplastic coated tablets was not affected by the stirring
speed.
Fig. 9 Effect of stirring speed on the release profiles of various HHL-METF (n = 3). HHL-METF, metformin hydrochloride thermoplastic coated tablets.
Effect of Release Medium on Drug Release
Based on the method, discussed in “Release Profiles of HHL-METF,” METF release from
(M15–80) and (M5–80) was determined at a stirring speed of 50 rpm in 900 mL water
and NaCl solution (0.9%, w/v), respectively. The results are summarized in [Fig. 10]. The effect of release medium on the release profile of (M15–80) membrane was not
significant with a calculated f
2 of 59. The reason was that, although the osmotic pressure difference in the release
medium of NaCl solution (0.9%, w/v) was reduced compared with the osmotic pressure
difference in water, the change of osmotic pressure difference in NaCl solution (0.9%,
w/v) was not large enough to affect the rate of water influx into the (M15–80) core.
The effect of release medium on the release curve of (M5–80) was slightly significant
and the cumulative drug release slightly slowed down in NaCl solution (0.9%, w/v).
Nevertheless, the release profiles of (M5–80) in water and NaCl solution (0.9%, w/v)
were still similar (f
2 = 53).
Fig. 10 Effect of different release medium on the release profiles of HHL-METF (n = 3). HHL-METF, metformin hydrochloride thermoplastic coated tablets. NS, NaCl solution
(0.9%, w/v)
NaCl solution (0.9%, w/v) does not significantly affect drug release because the ion-molar
concentration of NaCl solution (0.9%, w/v) is 0.3077 mol/L. The solubility of METF
is 346 mg/mL. Its ion-molar concentration is 4.178 mol/L, which is much larger than
the ion-molar concentration of NaCl solution (0.9%, w/v). Therefore, basing on the
Van't Hoff equation, the osmotic pressure difference is barely changed in the presence
of NaCl solution (0.9%, w/v), indicating that the influence of NaCl solution (0.9%,
w/v) on the osmotic pressure difference would be small enough to be ignored.
Comparison with Reference Listed Drug Product
According to the method, discussed in section “Release Profiles of HHL-METF,” METF
release from (M10–100) and (M10–80), (M10–60 nonorifice), and reference listed drug
product Fortamet was determined at a stirring speed of 100 rpm in water. The results
are shown in [Fig. 11]. The similarity factor (f
2) between (M10–80) and Fortamet was 61, indicating the release profiles of these two
tablets were similar.
Fig. 11 Comparison of the release profiles between HHL-METF and Fortamet (n = 3). HHL-METF, metformin hydrochloride thermoplastic coated tablets.
Visualization of Drug Release
Photographs of (N5–100) at 0, 8, and 24 hours during release test are shown in [Fig. 12]. The push layer of the HHL-NIF expanded during the release process and facilitated
the NIF release from the orifice. After 24 hours, the volume of HHL-NIF increased
slightly due to the softness and ductility of the H membrane. Its release profile
was consistent with that of the conventional push and pull OPTs.[13]
Fig. 12 Photographs of N5–100 at 0, 8, and 24 hours during release test.
Mechanism of Drug Release
Fitting of Drug Release Models
The release data of HHL-METF and HHL-NIF were fitted with drug release models of zero-order,
first-order, and the Higuchi square-root of time release equations. The results are
shown in [Tables 3] and [4]. Based on 24-hour fitting, the releases of Fortamet, (M5–80), and (N5–100) were
nearly zero-order. Whereas for 12-hour fitting, the releases of Fortamet, (M10–100),
(M10–80), (M5–80), (M10–60), (N5–100), and (N10–100) were nearly zero-order. Thus,
tablets coated by the HHL method could achieve zero-order in vitro drug release by
adjusting the content of the membrane thickness and PEG1500.
Table 3
Correlation coefficient R
2 of fitting drug release from HHL-METF to various models
|
Tablets
|
Zero-order
|
First-order
|
Higuchi's model
|
|
24-hour
|
12-hour
|
24-hour
|
12-hour
|
24-hour
|
12-hour
|
|
Fortamet
|
0.956
|
0.978
|
0.907
|
0.972
|
0.993
|
0.995
|
|
M10–100
|
0.938
|
0.996
|
0.979
|
0.952
|
0.972
|
0.951
|
|
M10–80
|
0.883
|
0.997
|
0.979
|
0.943
|
0.956
|
0.972
|
|
M10–60
|
0.779
|
0.956
|
0.976
|
0.978
|
0.904
|
0.991
|
|
M15–80
|
0.694
|
0.904
|
0.907
|
0.989
|
0.840
|
0.968
|
|
M5–80
|
0.985
|
0.988
|
0.955
|
0.957
|
0.965
|
0.925
|
|
M10–60 (nonorifice)
|
0.710
|
0.913
|
0.967
|
0.980
|
0.854
|
0.975
|
Abbreviation: HHL-METF, metformin hydrochloride thermoplastic coated tablets.
Table 4
Correlation coefficient R
2 of fitting drug release from HHL-NIF to various models
|
Tablets
|
Zero-order
|
First-order
|
Higuchi's model
|
|
24-hour
|
12-hour
|
24-hour
|
12-hour
|
24-hour
|
12-hour
|
|
N15–100
|
0.675
|
0.878
|
0.833
|
0.940
|
0.841
|
0.941
|
|
N10–100
|
0.757
|
0.924
|
0.897
|
0.976
|
0.906
|
0.976
|
|
N5–100
|
0.925
|
0.998
|
0.990
|
0.977
|
0.970
|
0.955
|
Abbreviation: HHL-NIF, nifedipine thermoplastic coated tablets.
Mechanism of Drug Release
The release rate of common OPTs or microporous OPTs is calculated according to [Eq. (1)]
[14]
[15]
[16]:
where dm/dt is the quantity of drug released over time, A is the surface area of the coating, K is the permeability value of membrane, π is the osmotic pressure difference between the tablet core and the surrounding solution,
c is the drug concentration pumped out of the tablet core, and h is the thickness of the tablet coating. According to Eq. 1, the release rate is inversely
proportional to the membrane thickness and proportional to the membrane permeability.
The release rates of METF coated tablets and NIF coated tablets are shown in [Figs. 13] and [14], where the following three aspects were noted:
Fig. 13 Release rate-time profiles of HHL-METF. HHL-METF, metformin hydrochloride thermoplastic
coated tablets.
Fig. 14 Release rate-time profiles of HHL-NIF. HHL-NIF, nifedipine thermoplastic coated tablets.
(1) the release rate of (M10–80) was slower than that of (M10–60) but faster than
that of (M10–100), indicating the release rate was inversely proportional to the membrane
thickness.
(2) The release rate of (N10–100) was slower than that of (N15–100) but faster than
that of (N5–100), indicating that the release rate was proportional to the PEG1500
content in membrane. In the above equation, K represents the permeability value of the osmotic membrane which encompasses the influence
by the PEG1500 content of the membrane. The higher the PEG1500 content of membrane
was, the larger the K value, the faster the release rate.
(3) For (N5–100), the release rate from 1.5 to 16 hours was constant at 3.26 ± 0.64 mg/h,
and the cumulative drug release percentage of nifedipine reached 78.8% within 14.5 hours.
For (M5–80), the release rate was constant at 22.03 ± 1.95 mg/h from 6 to 16 hours,
and maintained a constant release during 10 hours, indicating that the release rates
of both tablets were zero-order at certain time. It could be summarized that the drug
release rule of the H membrane coated tablets, followed the above equation (Eq. 1),
and was consistent with that of conventional spray coating OPTs and microporous OPTs.
The prepared thermoplastic coating membrane of this study is a semipermeable membrane.
The drug solubility, membrane thickness, and the PEG1500 content are all key factors
affecting the constant release of the drug.
One of the key factors affecting the release of OPTs relates to the coating membrane.
In the HHL method, the properties of the coated membrane are easily controlled by
the PEG1500 content and membrane thickness. It is easy to control these factors by
precisely weighing the amount of PEG1500 and adjusting the distance of the calender
roller to obtain the desired thickness, irrespective whether it is the laboratory-scale
or larger-scale production. However, the traditionally spray coating osmotic tablets
have the disadvantages of needing to sample coated tablets from time to time and peel-off
the coated membrane to measure the thickness which is cumbersome to operate. In addition,
in the proposed thermoplastic coating, the membrane thickness can be maintained uniform
in large-scale production using plastic industry's calendering film process. Therefore,
the HHL method with good reproducibility is easier to produce an ideal controlled
release membrane for further thermoplastic coating than the conventional spray coating
of OPTs.
Spray coating, which is generally used for OPTs coating, has many problems, such as
using a large amount of organic solvent, environment pollution, safety risk, dust
generation, and complicated operation, etc. The HHL method described here is not only
free from organic solvents and dust generation, but also avoids the drug instability
caused by solvent migration into the core during spray coating.
