Galantamine hydrobromide is formulated in tablets and capsules prescribed through oral delivery for the treatment of Alzheimer’s disease. However, oral delivery of drugs can cause severe side effects such as nausea, vomiting, and gastrointestinal disturbance. Transdermal delivery of galantamine hydrobromide could avoid these unwanted side effects. In this work, galantamine hydrobromide was formulated in gel drug reservoir which was then fabricated in the transdermal patch. The in vitro drug release studies revealed that the drug release from the donor chamber to receptor chamber of Franz diffusion cell was affected by the amount of polymer, amount of neutralizer, amount of drug, types of permeation enhancer, and amount of permeation enhancer. Visual observations of the gels showed that all formulated gels are translucent, homogeneous, smooth, and stable. These gels have pH in the suitable range for skin. The gel also showed high drug content uniformity. Hence, this formulation can be further used in the preparation of transdermal patch drug delivery system.
Galantamine hydrobromide is a tertiary alkaloid, which is isolated from various plant species such as
Chemical structure of galantamine hydrobromide [
Transdermal patch is a system that delivers drugs to the targeted cells or organs by passing through the human biggest organ, skin. The drug molecules will then enter the blood circulation system and then the targeted sites. Transdermal patch drug delivery provides many advantages. Firstly, drug-loaded patch allows longer treatment time for diseases. Thus, patients need less frequent dosing compared to other drug administration methods. Transdermal drug delivery contributes to lesser side effects such as nausea, vomiting, and gastrointestinal disturbance. Patch can also be removed easily and immediately if any side effects are detected. It is also patient friendly especially for unconscious patient, nauseated patient, and the patient with swallowing difficulties [
There were some requirements for the compositions used in the gel drug reservoir for transdermal patch. The polymer used for the preparation of gel drug reservoir must be stable, compatible with drugs and other components in gel, inexpensive, and easily fabricated into desired products and provides effective controlled drug release. The penetration enhancers should have reversible impact on skin, not irritating, nontoxic, compatible with formulation, odourless, and colourless. For drug molecules used in gel drug reservoir, they should have low molecular weight (less than 1000 g/mol), low partition coefficient (
Carbopol is a synthetic, highly cross-linked, and hydrophilic polymer [
Galantamine hydrobromide was purchased from Xi’an Yiyang Bio-Tech (Xi’an City, China). Carbopol 940 was bought from Fisher Scientific (Waltham, MA, USA). Triethanolamine, propylene glycol, sodium chloride, potassium chloride, monopotassium phosphate, disodium monohydrogen phosphate, and sodium hydroxide were obtained from Merck (Darmstadt, Germany). Trifluoroacetic acid and acetonitrile were obtained from Avantor Performance Materials (Center Valley, PA, USA). All chemicals were of reagent or analytical grade and were used without further purification.
The gel-type drug reservoir was prepared by dissolving carbopol and galantamine hydrobromide in deionized water at 75°C. Triethanolamine which acts as the neutralizer was added to the drug/polymer mixture. This mixture was stirred until homogenized gel formulation is obtained. Permeation enhancer was then added to the gel formulation. Continuous stirring was performed until the formation of a translucent gel. The final gel formulation was examined so that there were no formation of crystals and no phase separations.
The drug release from drug-loaded gels was performed by collecting samples (0.5 mL) from the Franz diffusion cells at time intervals of 1, 2, 3, 4, 5, 6, 7, and 8 h. Each time withdrawal of samples will be replenished by 0.5 mL fresh phosphate buffer into the receptor compartment to maintain the same initial volume. The samples taken out from the receptor compartment were then analyzed by using HPLC. Amount of drug permeated was calculated using previous calculated standard calibration curve. The effects of each composition in the formulation on drug release were investigated by changing the percentage of polymer, neutralizer, drug, and enhancer as well as the types of enhancers.
The galantamine hydrobromide analysis was studied by using Waters 1525 HPLC system with Waters 2489 UV/VIS detector. The isocratic HPLC system consists of Agilent Eclipse XDB RF C18 column (5
Data were expressed as mean ± S.D. of three replicates. Statistical analysis was performed by one-way analysis of variance (ANOVA) with
The physical appearance, homogeneity, texture, and stability of the selected gel formulations were studied by visual observations.
In order to test the pH of the formulated gels, the gels were first diluted using deionized water in the dilution factor of 100 (gel : deionized water = 1 : 100). After the suspensions were formed, the pH of each suspension was tested by using pH meter (Mettler Toledo, Delta 320).
Drug content analysis was used to determine the uniform distribution of galantamine hydrobromide in the gels. The gels were diluted using deionized water with dilution factor of 100 (gel : deionized water = 1 : 100) prior to the drug content analysis. The mixtures were vortexed for 5 mins in order to ensure homogeneous mixing of gels and deionized water. Then, the mixtures were subjected to the centrifugation at 1000 rpm for 20 mins. The drug content of each gel formulation was determined by using HPLC.
Figure
Drug release profile of gel drug reservoirs with different carbopol 940 percentage (mean ± S.D.;
Figure
Drug release profile of gel drug reservoirs with different triethanolamine percentage (mean ± S.D.;
Figure
Drug release profile of gel drug reservoirs with different galantamine hydrobromide percentage (mean ± S.D.;
The effects of different types of penetration enhancers on drug release were investigated by changing the enhancers used in gels, namely, Brij 30, glycerine, linoleic acid, propylene glycol, and Brij 97. The enhancer which provides the best enhancement effect was then investigated on the effects of enhancer content on the drug release. Figure
Drug release percentage at 8 h and enhancement ratio of each enhancer.
Enhancer types | Drug release percentage at 8 |
Enhancement ratio |
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Brij 30 | 39.54 ± 0.20 | 29.18 |
Glycerine | 38.04 ± 0.53 | 28.07 |
Linoleic acid | 13.17 ± 0.24 | 9.72 |
Propylene glycol | 43.95 ± 0.60 | 32.44 |
Brij 97 | 27.04 ± 0.12 | 19.96 |
Control | 1.35 ± 0.00 | — |
Percentage of drug release at 8 h from different gel formulations (mean ± S.D.;
Factors | Weight percentage (% w/w) | Drug release percentage at 8 h (%) |
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Carbopol amount | 0.50 |
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1.00 | 32.47 ± 0.23 | |
2.00 | 17.79 ± 0.08 | |
5.00 | 12.48 ± 0.05 | |
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Triethanolamine amount | 1.00 | 66.42 ± 0.51 |
3.00 |
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5.00 | 1.37 ± 0.00 | |
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Galantamine hydrobromide amount | 1.00 | 14.71 ± 0.04 |
3.00 |
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5.00 | 97.94 ± 0.50 | |
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Propylene glycol amount | 0.00 | 1.35 ± 0.00 |
1.00 | 1.37 ± 0.01 | |
5.00 | 26.33 ± 0.24 | |
10.00 |
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Drug release profile of gel drug reservoirs with different types of enhancer (mean ± S.D.;
Propylene glycol showed the highest drug release when compared to other penetration enhancers. Figure
Drug release profile of gel drug reservoirs with different propylene glycol percentage (mean ± S.D.;
Theoretically, gels with higher drug release give higher amount of drug penetration through human skin. Hence, three galantamine hydrobromide-loaded gel formulations (F1, F2, and F3) that provide the highest drug release were selected for further physical studies. Table
Three gel formulations with the highest percentage of drug release.
Formulation code | F1 | F2 | F3 |
---|---|---|---|
Carbopol 940 (% w/w) | 0.50 | 0.50 | 0.50 |
Triethanolamine (% w/w) | 3.00 | 1.00 | 3.00 |
Galantamine hydrobromide (% w/w) | 3.00 | 3.00 | 5.00 |
Propylene glycol (% w/w) | 10.00 | 10.00 | 10.00 |
Table
Gels characteristics.
Formulation code | F1 | F2 | F3 |
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Appearance |
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Transparency | Translucent | Translucent | Translucent |
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Homogeneity | Highly homogeneous |
Highly homogeneous |
Highly homogeneous |
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Stability | No phase separation | No phase separation | No phase separation |
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Texture | Smooth | Smooth | Smooth |
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pH | 7.80 ± 0.01 | 7.06 ± 0.01 | 7.45 ± 0.02 |
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Drug content (%) | 93.79 ± 1.92 | 96.67 ± 1.60 | 95.72 ± 1.81 |
Formulation without drug.
pH values of F1, F2, and F3 formulations were stated in Table
Table
The gel drug reservoirs were successfully prepared by adding galantamine hydrobromide in the gels. The
High performance liquid chromatography
Ultraviolet/visible
Standard deviation
Analysis of variance.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The first author would like to thank his supervisor, co-supervisors and friends who gave a lot of guidance and helps during his experiments. Special thanks are due to Professor Dr. Mahiran Basri, who provides good working environments for the research works.