INTRODUCTION:

Diltiazem hydrochloride (DH) is a water-soluble calcium channel blocker. It is classified as a rate-limiting cardiovascular drug and has a negative inotropic and chronotropic effect with a vasodilator activity. It has been widely used in the management of chronic stable angina, tachycardia and hypertension^1,2. Besides, it has numerous off-label indications, in the treatment of migraine headache, Raynaud phenomenon, and subarachnoid hemorrhage in addition to anal fissure^2,3. A controlled release pharmaceutical formulation is recommended as a promising approach for orally-given DH, due to its short elimination half-life (3-5 h)⁴.

Oral drug delivery is the most clinically acceptable route of administration. However, conventional dosage forms have little control over the drug release characteristics, leading to fluctuated plasma concentrations, therefore, a low availability of the effective concentration at the target site is expected especially in a chronic manner^5-7. In addition to the severe side effects caused by conventional dosage forms of many drug molecules such as nifedipine which leads to the need to develop the controlled release formulations⁸. However, drug release from oral controlled release dosage forms may be affected by biological and physiological factors in addition to the physico-chemical properties of the drug molecule^9,10. These controlled release drug delivery systems can be achieved in several mechanisms, one of them is the principle of osmosis as the delivery force¹¹. Osmotic drug delivery systems may be administered orally or as implantable devices, having single core or multiple cores^12,13. Drug release from these systems is not influenced by the different physiological factors within the GIT and it can provide reproducible kinetics.These osmotic systems typically consist of a tablet core surrounded by a semipermeable membrane with an orifice drilled mechanically or by a laser beam which is called elementary osmotic pump¹⁴. Osmotic pumps development continues with the controlled porosity osmotic pump (CPOP) which were designed to decrease the incidence of excessively localized drug-induced injury due to drug release out of one single orifice towards the intestinal wall¹⁴. The delivery orifices in CPOP tablets are formed by the incorporation of a leachable component in the coating. Once the tablet comes in contact with the biological fluids, the water-soluble osmotic component dissolves, and an osmotic pumping system results^14-16. CPOP tablets also have other pharmaceutical applications related to prolonged release such as colon targeted drug delivery¹⁷. Several osmotic delivery systems of DH was formulated using different techniques^18-20. The major purpose of this research is to develop and optimize CPOP tablets of DH, in addition to evaluate the effect of PEG’s molecular weight as a pore former and coating thickness level on release characteristics.

MATERIALS AND METHODS:

Materials:

DH (99.6%) was obtained from Fleming Laboratories (Telangana, India). Cellulose acetate (CA-320S) was provided from Eastman (USA). Mannitol was purchased from Loba Chemie (Mumbai, India). Polyethylene glycol (6000, 1500 and 400) were obtained from Sisco Research Laboratories (Mumbai, India). Microcrystalline cellulose PH101 was purchased from Patel Chem Specialties (Gujarat, India). Talc and Magnesium Stearate were purchased from S.D. Fine Chem (Mumbai, India). All other chemicals were of analytical grade.

Methods:

Preparation of tablet cores:

The required amounts of all ingredients were weighed accurately in order to prepare two batches of tablet cores as demonstrated in Table (1), and blended manually for 15 minutes. Then talc and magnesium stearate were added and mixed for 5 minutes.

Table 1: Formulations of the tablet cores.

Ingredients	Amounts (mg)
Ingredients	F1	F2
Diltiazem Hydrochloride	90	90
Mannitol	135	135
Microcrystalline Cellulose PH101	118	167
Talc	3.5	4
Magnesium Stearate	3.5	4
Theoretical weight (mg)	350	400
Die diameter (mm)	8	10

The pre-compression mixture was tested for moisture content²¹. Direct compression was applied on a rotatory tablet press (Cadmach Machinery Co. PVT. LTD, Ahmedabad, India) using round standard biconvex punches.

Evaluation of tablet cores:

a) Mechanical resistance tests:

10 tablet cores were assessed for hardness using hardness tester (TBH200, Erweka, Germany). There are no pharmacopeial criteria for hardness test results²². 20 tablet cores were subjected to friability test using the apparatus (FAB-2, Logan Instruments Corp.USA). Friability is considered acceptable if it is up to 1%²³.

b) Weight uniformity:

20 tablet cores were weighed individually using an analytical balance (Radwag WAS 220/X, Radom, Poland), and subjected to the pharmacopeial weight uniformity test.

c) Drug content uniformity:

10 tablet cores were tested for their drug content individually²³. Each core was finely powdered, dispersed in phosphate buffer (pH 7.4) in a 100ml volumetric flask and sonicated using (ELMA Transsonic 460/H Ultrasonic Bath, Germany)²⁴. Aliquots were taken, diluted appropriately and filtered through 0.45µm membrane filters. These solutions were analyzed by UV-Visible spectrophotometer (JascoV-530/VIS-spectrophotometer/Japan). The results were evaluated according to the pharmacopeial criteria²³.

Coating of tablet cores:

Cellulose acetate (3%) was dispersed in the solvent mixture (75% acetone: 25% distilled water) and sonicated until it completely dissolved followed by the addition of PEG. The coating process was performed in a conventional coating pan (Erweka AR 402, Heusenstamm, Germany), the pan speed was set to 120 rpm, with a spray rate of 3 ml/min and the coating solution was applied manually on the tablet cores bed. Table (2) demonstrates the coating characteristics of the prepared formulations of CPOP tablets of DH.

Evaluation of CPOP tablets:

a) Assessment of the film coating thickness and weight gain:

10 randomly picked tablets were subjected to thickness measurement and weight gain tests before and after coating. Digital electronic caliper was used to determine thickness. The coating thickness was calculated according to equation (1) and weight gain was expressed in percentage according to equation (2):

Coating thickness (µm) = (average thickness of coated tablet – average thickness of tablet core)/2 (1)

Weight gain%=

(weight gain (mg)/initial weight (mg))* 100 (2)

Table 2: Coating characteristics of the prepared CPOP tablets.

Weight gain (%)*	Thickness (µm)*	CA: PEG	PEG Mw	Formula code
2.49 ± 0.25	80 ± 7.7	4:1	PEG6000	C1
2.96 ± 0.23	94 ± 8.2	4:1	PEG6000	C2
0.82 ± 0.19	31 ± 3.8	4:1	PEG400	C3
1.40 ± 0.15	56 ± 7.8	4:1	PEG400	C4
2.76 ± 0.12	76 ± 8.7	4:1	PEG400	C5
2.85 ± 0.18	93 ± 8.1	4:1	PEG400	C6
5.91 ± 0.40	183 ± 11.4	4:1	PEG400	C7
5.49 ± 0.30	184 ± 9.8	4:1	PEG400 + PEG6000 (1: 1)	C8
4.60 ± 0.24	178± 8.3	4:1	PEG1500	C9
5.23 ± 0.24	186 ± 11.0	4:1	-	C10

*expressed in mean ± standard deviation

Table 3: Results of evaluation of tablet cores.

F2	F1	Test
0.10 ± 10.03	7.99 ± 0.07	Diameter (mm) (n=10)*
4.54 ± 0.08	4.69 ± 0.07	Thickness (mm) (n=10)*
8.48 ± 1.37	1.19 ± 0.46	Hardness (kpa) (n=10)*
0.23 %	Tablets were broken	Friability (%) (n=20)
398.95 ± 6.24	-	Weight variation (mg) (n=20)*
100.16 ± 3.19	-	Content uniformity (%) (n=10)*

*Results were expressed in mean ± standard deviation

In vitro drug release:

a) Effect of coating thickness:

Based on dissolution profiles of C1 and C2 shown in figure (1), both of them had an extended release profile up to 12 hours with burst release, as the cumulative released drug exceeded the pharmacopeial limits at 3 hours’ point, which decreased significantly (p-value=0.006) in C2 in comparison with C1 along with increased coating thickness (p-value=0.000), in addition to significant less overall cumulative released drug (p-value=0.022). Besides, according to the dissolution profiles of formulations demonstrated in figure (2), the release rate and burst release were found to be inversely related to coating thickness which is attributed to decreased water penetration rate^{25, 26}. The burst release was eliminated in C7, which is significantly less than C3, C4 and C5 (p-value=0.000). However, increasing thickness did not affect the overall released drug (p-value=0.554 at 12 hours’ point). These results were in accordance with the findings of other researchers.

b) Effect of PEG’s molecular weight on drug release:

The release rate was significantly influenced by the molecular weight of PEG as shown in figure (3). Drug release rate was slower along with molecular weight of PEG was reduced. Although the drug release was affected by the coating thickness with both PEG6000 and PEG400 as pore formers, PEG6000 achieved less controlled release compared to PEG400 as presented in figure (3-a). When comparing both C2 and C6, which had the same CA: PEG ratio and coating thickness (p-value=0.726), but different PEG molecular weight, it was concluded that C6 showed significantly less burst release than C2, as 26.47% of drug released after 3 hours against 35.18% respectively (p-value=0.005) in addition to significant less drug released at 6 and 9 hours. Same results when comparing C1 and C5 as shown in figure (3-a).

Fig 1: Comparative dissolution profiles of C1 and C2.

Fig 2: Comparative Dissolution Profiles for CPOP tablets (C3 – C7)

These results may be attributed to water-affinity of PEG which depends on molecular weight that is related to the average number of oxyethylene groups, higher molecular weight of PEG may achieve more water-solubility and lead to the formation of more porous regions in the coating film structure²⁶.Same results are concluded from figure (3-b) when comparing the dissolution profiles of C7, C8 and C9 which were coated to the same thickness level (p-value=0.322). The drug release was more controlled with slower rate along with lower molecular weight of PEG, as well as, using a mixture of PEG400 and PEG6000 (C8) caused the drug release rate to increase comparing to PEG400 formulation (C7).

Figure (4) demonstrates the comparative dissolution profiles of C7 and C10 which have the same thickness level (p-value=0.533). It was found that there were significant differences at every time point (as p-value ranged between 0.000-0.006). It can be concluded that the addition of a pore former is essential to achieve an acceptable release rate. On the other hand, considering the concept of osmosis, the semipermeable membrane allows only water molecules to pass through, while the coating layer which allows the drug molecules to pass is an incomplete semipermeable membrane, although no PEG was added as in the case of formulation C10. These results may be interpreted due to the presence of water in the solvent mixture²⁶.

c) Effect of pH on drug release:

There were no significant differences between dissolution profiles of C7 when medium pH was changed at 9 and 12 hours. However, significant difference was found at the initial stage, as well as, the cumulative released drug exceeded the pharmacopeial limit at 3 hours’ point. This result may be attributed to the chemical properties of the drug molecule (pka=7.7), therefor, its solubility increases in acidic medium whereas decreases in higher pH, which interprets that the drug release rate decreased gradually in higher pH²⁷. Whereas the drug release profile was not affected by pH change according to several other studies¹².

Figure 4: Comparative dissolution profiles of C7 and C10.

Fig 5: Comparative dissolution profiles of C7 in different-pH media.

Surface morphology:

As shown in Figure (6) the surface of C7 tablet exhibits smooth non-porous structure before coming in contact with the dissolution medium (a), while it showed porous regions after the dissolution study (b) due to leaching of the pore former (PEG400) and the surface became microporous, as a result, drug would possibly release through these delivery ports.

Figure 6: Microscopic images of formulation C7 tablet before (a) and after (b) dissolution study.

CONCLUSION:

CPOP tablets of DH were designed in this research, using cellulose acetate as a semipermeable coating membrane and PEG6000, PEG400 and PEG1500 as leachable additives, by applying the techniques of direct compression and spray coating. As a result, increased coating thickness and higher PEG’s molecular weight accompanied with more controlled and less burst release. Besides, drug release was influenced partially by pH-change of the dissolution medium.

ACKNOWLEDGMENTS:

The authors would like to thank Zein Pharma (Tartous, Syria) for providing many excipients and laboratory facilities in order to carry out this research work, Human Pharma (Tartous, Syria) and Barakat (Aleppo, Syria), for providing other excipients and diltiazem hydrochloride.

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Received on 19.10.2021 Modified on 20.12.2021

Research J. Pharm. and Tech 2022; 15(9):4043-4047.

DOI: 10.52711/0974-360X.2022.00678