INTRODUCTION:
Solid dispersion can be defined as “The dispersion of one or more active ingredients in an inert carrier or matrix at solid state’’(1). Oral drug delivery is the most widely utilized route of administration among all the routes that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage forms. Oral route is considered as most natural, uncomplicated, convenient and safe due to its ease of administration, patient acceptance, and cost-effective(2) manufacturing process(3).
The goal in designing sustained delivery systems(4) is to reduce the frequency of the dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required or providing uniform drug delivery(5,6). A single dose of a drug that is released over a sustained period of time to maintain a near constant or uniform blood level of a drug often translates into better patient compliance, as well as enhanced clinical efficacy of the drug for its intended use(7). There are certain considerations for the preparation of sustained release formulations. If the active compound has a long half-life, it is sustained on its own(8).
Carvedilol is a non-selective beta adrenoreceptor blocker, used in the treatment of hypertension(9). The drug was selected as a model drug for the investigation because this drug has low molecular weight (carvedilol 406.5), undergoes extensive hepatic first-pass metabolism resulting in a low bioavailability (25-35 %) when given by oral route and has low dose (3.25 to 25 mg)(10).
Carvedilol beta-adrenergic receptor blocking ability decreases the heart rate, ocardial contractility, and myocardial oxygen demand. Carvedilol also decreases systemic vascular resistance via its alpha-adrenergic receptor blocking properties.
Solid dispersion is proposed to be formulated as semisolid capsules by fusion method using Gelucire44/4, Polaamer188, Gelatin, PVPK30, PEG600. Gelucire for the formulation of semisolid capsule was based on the following properties as inert semisolid waxy material, amphiphilic in nature, unique emulsifying properties that make it ideal for prompt release formulation(11).
The present study is the preparation of solid dispersion of Carvedilol by solvent free fusion method using Poloxamer188, Gelatin, PVP30 and PEG600.
MATERIALS AND METHODS:
MATERIALS:
Caevedilol was obtained as a kindly gift sample from Divis lab, Vizag, Andhrapradesh, India. Gelucire44/4 was gifted by Gattfose, India. Poloxamer188 was gift sample from Gattfose, India. Gelatin was gift sample from Gattfose, India. PVP30 was gift sample from Euro Drugs. PEG6000 was gift sample from Finer chemicals. HCL was gift sample from Finer chemicals.
METHODOLOGY:
Preformulation studies:
The goals of preformulation studies are to choose the correct form of the drug substance, evaluate its physical and chemical properties, and generate a thorough understanding of the material's stability under the conditions that will lead to the development of a particular DDS. Preformulation is a science that serves as a big umbrella for the fingerprinting of a drug substance or product both at the early and later stage of development in pharmaceutical manufacturing. The preformulation phase is a critical learning time about candidate drugs. Typically, it begins during the lead optimization phase and continues through predomination and into the early phases of development.Decisions made on the information generated during this phase can have a profound effect on the subsequent development of those compounds(12). The goals of the preformulation study are to establish the necessary physicochemical characteristics of a drug substance, to determine its kinetic release rate profile, to establish its compatibility with different excipients. Hence, preformulation studies on the obtained sample of drug include color, taste, solubility analysis, melting point determination and compatibility studies by FTIR .
Preparation of Solid Dispersion:
The carriers PEG600(13), Poloxamer188, PVPK30 heated on a china dish above their melting (fusion)(14) point and weighed amount of drug was gradually incorporated into molten mass. The mixture was cooled with constant stirring to homogenously disperse the drug into it(15). The cooled mass was crushed in a mortar, passed through a sieve 18 and stored in a desiccator over anhydrous calcium chloride, until use.
Preparation of Carvedilol semisolid capsules:
The semisolid matrix was prepared by the fusion method. In the formulations prepared the release retardants used are poloxamer188, gelucire44/14(16), gelatin, PVPK30, PEG6000 were used. Drug polymer ratios 1:1, 1:2, 1:3 were used to study their effect on release of drug from the capsules prepared (Table 1).
Table 1: Different formulations are given in following table
|
Formulation code |
Drug: carrier ratio |
Drug (mg) |
EXCIPIENTS (mg) |
|
F1 |
1:1, 1:2, 1:3 |
10 |
Poloxomar-100mg, 200mg, 300mg |
|
F2 |
1:1, 1:2, 1:3 |
10 |
Poloxomar+gelucire44/14100mg, 200mg, 300mg |
|
F3 |
1:1, 1:2, 1:3 |
10 |
Gelucire44/14+gelatin 100mg, 200mg, 300mg |
|
F4 |
1:1, 1:2, 1:3 |
10 |
PVPk30+PEG600 100mg, 200mg, 300mg |
|
F5 |
1:1, 1:2, 1:3 |
10 |
Gelucire44/14+PEG600 100mg, 200mg, 300mg |
EVALUATION OF SUSTAINED RELEASE SEMISOLID CAPSULES:
Following evaluation tests were carried out for the for the capsule
· Assay
· In vitro dissolution studies
· Assay:
Accurately weighed Semisolid
capsule contents equivalent to 10mg drug was taken in a beaker having 100mL of 0.1N HCl heated to 60°C to 70°C, and allowed to cool to room temperature. The lipid was solidified and the drug solution was
filtered through Whatmann filter paper. The sample was analyzed for drug content
by UV spectrophotometer at 241nm
after suitable dilutions. Determinations were
performed in 
triplicate. Percentage yield of each formulation was
calculated(17).
· In vitro Dissolution Studies:
The release of Carvedilol from the SSM capsule was studied by using
900mL of 0.1 N HCl using a USP dissolution basket
assembly at 100 rpm and 37±0.5ºC. An aliquot (5mL) was withdrawn at specific time intervals and drug
content was determined by UV-visible spectrophotometer at 241 nm. An equal volume of fresh dissolution medium
was replaced to maintain the dissolution volume. Dissolution studies were performed 3 times and the mean value were taken. Cumulative
percentage of drug release was calculated using an equation obtained from a standard curve(17).
Kinetic analysis of in vitro release rates of sustained release(18):
The results of in vitro release profile obtained for all the formulations were plotted in modes of data treatment as follows:
1. Zero – order kinetic model – Cumulative percentage drug released Versus time
2. First – order kinetic model – Log cumulative percent drug remaining versus time.
3. Higuchi’s model – Cumulative percent drug released versus square root of time.
4. Higuchi’s model – Cumulative percent drug released versus square root of time versus log time.
RESULTS AND DISCUSSION:
Fourier Transform Infrared spectroscopic studies:
There was no disappearance of any characteristics peak in the FTIR spectrum of drug and the polymers used. This shows that there is no chemical interaction between the drug and the polymers used (Figure 1).
Figure 1: FTIR spectra for optimized formulation Carvedilol + poloxamer
Figure 2: Standard graph of Carvedilol in 0.1N HCl
Table 2: In vitro Cumulative percentage drug release of Carvedilol by using Poloxamer
|
Time |
Cumulative % drug release |
|||
|
F1 |
F2 |
F3 |
||
|
0 |
0 |
0 |
0 |
|
|
0.5 |
43.4 ±1.9 |
39.3 ±6.9 |
37.7 ±3.2 |
|
|
1 |
47.9 ±2.8 |
46.3 ±1.8 |
48.2 ±6.1 |
|
|
2 |
51.1 ±3.6 |
48.1 ±2.1 |
57.5 ±4.0 |
|
|
3 |
53.8 ±2.5 |
50.1 ±3.6 |
60 ±3.5 |
|
|
4 |
56.5 ±2.0 |
52.9 ±3.4 |
63.3 ±3.9 |
|
|
5 |
59.8 ±1.3 |
54.3 ±3.4 |
65.6 ±3.6 |
|
|
6 |
61.3 ±2.4 |
56.4 ±4.2 |
67.8 ±3.7 |
|
|
12 |
64.9 ±2.2 |
64 ±2.3 |
72.8 ±5.8 |
|
|
18 |
66.7 ±2.2 |
70.6 ±2.5 |
77.3 ±2.6 |
|
|
24 |
67.9 ±2.0 |
74.9 ±2.3 |
78.6 ±2.2 |
|
From the above studies Carvedilol formulations with Poloxamer the formulation F3 shows better results when compared with the F1 and F2 (Table 2).
Table 3: In vitro Cumulative percentage drug release profile of carvedilol formulations with Gelicire44/14+PEG6000
|
Time |
Cumulative % drug release |
||
|
F1 |
F2 |
F3 |
|
|
0 |
0 |
0 |
0 |
|
0.5 |
74.3 ± 2.2 |
75.6 ± 1.6 |
75.9 ± 1.7 |
|
1 |
76.6 ± 2.1 |
78.8 ± 0.9 |
84.4 ± 2.1 |
|
2 |
79.7 ± 2.7 |
86.6 ± 1.5 |
87 ± 1.7 |
|
3 |
84.5 ± 2.0 |
89.5 ± 0.6 |
90 ± 1.4 |
|
4 |
87 ± 1.3 |
91.8 ± 1.0 |
94.6 ± 2.2 |
|
5 |
90.1 ± 1.8 |
96.5 ± 2.0 |
97.9 ± 1.2 |
From the above studies Carvedilol formulation with Gelucire44/14+PEG6000 F3 shows better immediate release when compared with the other formulation ratios of F1 and F2 (Table 3).
Table 4: In vitro Cumulative percentage drug release of Carvedelol by usingPVPK30+PEG6000:
|
Time |
Cumulative % drug release |
||
|
F1 |
F2 |
F3 |
|
|
0 |
0 |
0 |
0 |
|
0.5 |
65.4 ±1.9 |
76.6 ± 1.5 |
72.5 ± 1.1 |
|
1 |
76.6 ±2.4 |
80.9 ± 3.0 |
74.9 ± 0.9 |
|
2 |
83.7 ±1.9 |
85.7 ± 2.3 |
77.8 ± 1.4 |
|
3 |
85.3 ±1.9 |
89 ± 1.7 |
81.9 ± 2.8 |
|
4 |
89.9 ± 2.2 |
92.5 ± 2.2 |
85.8 ± 1.4 |
|
5 |
92.7 ±3.6 |
96.2 ± 2.8 |
90 ± 1.8 |
From the above studies Carvedilol formulation with the PVPK30+PEG6000 of F2 shows better immediate release when compared to the other formulation ratios of F1and F3 (Table 4).
Table 5: In vitro Cumulative percentage drug release of Carvedilol by using Gelucire 44/14+Gelatin:
|
Time |
Cumulative % drug release |
||
|
F1 |
F2 |
F3 |
|
|
0 |
0 |
0 |
0 |
|
0.5 |
75.5 ± 1.1 |
74.5 ± 2.3 |
77.6 ± 1.2 |
|
1 |
77.4 ± 1.1 |
76.7 ± 2.5 |
79.9 ± 1.2 |
|
2 |
80.9 ± 2.3 |
78.9 ± 2.1 |
82.9 ± 1.5 |
|
3 |
84.4 ± 1.9 |
81.8 ± 2.4 |
86.5 ± 1.9 |
|
4 |
86.2 ± 1.8 |
84 ± 2.7 |
91.4 ± 3.9 |
|
5 |
88.5 ± 1.3 |
89.4 ± 2.9 |
95.4 ± 3.8 |
From the above studies Carvedilol formulation with Gelucire 44/14+gelatin of F3 shows better immediate release when compared to the other formulation ratios of F1and F2 (Table 5).
Table 6: In vitro Cumulative percentage drug release of Carvedilol by using Poloxamer+Gelucire44/14:
|
Time |
Cumulative % drug release |
|||
|
F1 |
F2 |
F3 |
||
|
0 |
0 |
0 |
0 |
|
|
0.5 |
73.2 ±1.1 |
84.8 ±1.5 |
84.7 ±1.9 |
|
|
1 |
74.7 ±1.5 |
87.4 ±2.1 |
87.4 ±1.7 |
|
|
2 |
77.1 ±1.6 |
91.1 ±2.2 |
90.4 ±2.2 |
|
|
3 |
79.8 ±1.9 |
94.1 ±2.9 |
93.2 ±1.8 |
|
|
4 |
81.9 ±2.3 |
95.5 ±2.9 |
95.9 ±1.3 |
|
|
5 |
85.4 ±3.7 |
96.8 ±2.0 |
98.2 ±1.1 |
|
From the above studies Carvedilol formulations with poloxamer+gelucire 44/14 F3 shows better immediate release when compared with the other formulation ratios of F1 and F2 (Table 6).
Table 7: Correlation coefficient (R2) of different kinetic models for optimized formulation F3 by using poloxamer
|
|
Time (hr) |
Zero order |
First order |
Higuchi |
Korsemeyer-peppas |
|
F1 |
24 |
0.364 |
0.530 |
0.613 |
0.530 |
|
F2 |
24 |
0.542 |
0.779 |
0.763 |
0.972 |
|
F3 |
24 |
0.449 |
0.680 |
0.709 |
0.941 |
DISCUSSION:
Capsule(19) is more flexible compare to matrix tablets. Moreover, sustained release capsules have unique advantage of lessening dose dumping when compared with the matrix tablets(20). The purpose of this research was to develop sustained release capsules of Carvedilol by using different ratios of hydrophilic polymers such as Poloxamer188, Gelucire44/14, PVPK30, Gelatin, PEG6000. In - vitro drug release studies were conducted in 0.1N HCl and the results revealed that the release of the Carvedilol from different formulations varies with characteristics and composition of polymers as shown in graphs 3, 4, 5, 6, 7, 8. The formulations were prepared with different excipients for both immediate and sustained release. From which formulation of the Carvedilol with Poloxamer in 1:3 ratio shows better sustained release when compared to the all the formulations with different excipients. So that the formulation of the Carvedilol with the poloxamer in the ratio of 1:3 considered as the optimized formulation for sustained release. And the triplicate study was conducted to that formulation and percentage yield of the each formulation was calculated. The influence of poloxamer (lutrol) include in lipid matrice composed of lanolin on their dissolution performance was studied. The addition of the hydrophilic polymer poloxamer increased the amount of Carvedilol release(21). As the Carvedilol and lanoline are hydrophobic in nature the poloxamer aids in the release of drug(22). In the formulations of the Carvedilol with Gelucire44/14+PEG6000 the formulation F3 shows better immediate release because the Gelucire44/14 and PEG6000 are hydrophilic nature they aid in better immediate release of hydrophobic drug. In the formulations of the Carvedilol with PVPK30+PEG6000 the formulation F2 shows better immediate release because PVPK30 and PEG6000 are hydrophilic nature they aid in better immediate release of the hydrophobic drug. In the formulations of the Carvedilol with Gelatin+Gelucire44/14 the formulation F3 shows better immediate release because gelatin and gelucire44/14 are hydrophilic in nature they aid in better immediate release of hydrophobic drug. In the formulations of the Carvedilol with Poloxamer+ Gelucire44/14 the formulation F3 shows better immediate release because Poloxamer and Gelucire44/14 are hydrophilic nature they aid in better immediate release of the hydrophobic drug. Formulations subjected to curve fitting analysis showed that the formulations best fit for korsemeyer Peppas model with diffusion and erosion mechanism.
CONCLUSION:
The study was carried out to develop the sustained release formulations by using different excepients to reduce the frequency of dosing in chronic therapy. The main of the study was the development of the sustained release capsules and the effect of the different excipients on the in vitro release. The formulations of the Carvedilol was successfully prepared by fusion method using different excipients such as Poloxamer188, Gelucire44/14, PEG6000, gelatin, PVPK30. They are added individually and in combinations. In vitro drug release studies showed that the drug release from the Carvedilol formulation by using Poloxamer188 in the ratio of 1:3 showed maximum sustained release During 24hrs study. The results reveal that the excipient such as poloxamer 188 shows sustained release among all the formulations by using Gelucire44/14, gelatin, PVPK30, and PEG6000.
ACKNOWLEDGEMENT:
We thankful to the Management of Vaagdevi College of Pharmacy for providing the facilities to carry out this research work.
CONFLICT OF INTEREST:
None of the authors of this manuscript have any financial interest that has influenced the results or interpretation of this manuscript.
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Received on 05.03.2020 Modified on 19.05.2020
Accepted on 24.06.2020 © RJPT All right reserved
Research J. Pharm. and Tech. 2021; 14(2):752-756.
DOI: 10.5958/0974-360X.2021.00131.1