Corresponding author: Svitlana Gubar ( gubarsn@ukr.net ) Academic editor: Maya Georgieva
© 2021 Tatyana Shyteyeva, Svitlana Gubar, Nataliia Smielova, Elena Bezchasnyuk, Liana Budanova.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Shyteyeva T, Gubar S, Smielova N, Bezchasnyuk E, Budanova L (2021) The analysis of the permeability process of calcium antagonists in developing transdermal forms with a cardiovascular effect. Pharmacia 68(1): 189-193. https://doi.org/10.3897/pharmacia.68.e37632
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Aim. The aim of the work was to evaluate the possibility of using calcium antagonists, namely, nifedipine and amlodipine besylate, while conducting transdermal delivery, that included the analysis of in vitro permeability process as a primary preformulation stage of pharmaceutical development of a transdermal dosage form, determination of qualitative and quantitative characteristics of a permeability process and the expediency analysis of development of a therapeutic transdermal system (TTS) with a cardiovascular effect.
Materials and methods. The active pharmaceutical ingredients (API) of nifedipine and amlodipine besylate. The study has been carried out in vitro by a dialysis method using a modified diffusion device of the Valia-Chien design.
Results. Character analysis, description of the mathematical model and definition of the kinetic parameters in the process of permeability of the studied medicinal products (MP) of nifedipine and amlodipine besylate allowed to evaluate their potential for creating TTS as being positive and appropriate. The implemented methodological approaches allow to substantiate the further algorithm for the development of cardiovascular TTS with the mentioned API.
Nifedipine, amlodipine besylate, in vitro permeability, a transdermal therapeutic system
Cardiovascular diseases, in particular, ischemic heart disease and arterial hypertension are the main causes of disability and mortality among the population. Nowadays, a numerical increase in the incidence of this type of pathology may be present. The pharmacotherapy of the mentioned pathological states usually requires a long time, an individual approach and a complex adjustment, taking into account all the parts of the pathological process.
The first line of the medicinal products in treating hypertensive disease includes calcium antagonists, which show antianginal and antihypertensive properties. Among the groups of the calcium channel blockers the medicinal products of 1,4-dihydropyridine type- nifedipine and amlodipine are widely spread.
Nifedipine is a short-acting calcium antagonist, widely known in the world of medical practice. Its main drawback is a short-duration half-life period, which takes only 2–4 hours. For these purposes, nifedipine requires an increase in the number of administration during the day and it is accompanied by the occurrence of side effects. After oral administration, it undergoes an intensive metabolism, which leads to a decrease in bioavailability (40–60%) (Oparin et al. 1998).
The next calcium antagonist generations of the dihydropyridine group differ from nifedipine by a longer effect. A vivid representative of the third generation is amlodipine, characterized by asufficiently high bioavailability (64–80%) and slight fluctuations in the maximum and minimum concentration in the blood within 24 hours (
The design of modern innovative dosage forms (DF) for the medicinal products of this group are based on seeking an alternative way of the delivery of active ingredients (
Only the oral formulations of nifedipine and amlodipine besylate are currently presented in the pharmaceutical market and none of them are presented in transdermal forms. Nevertheless, a number of scientists have been carrying out research and development of the transdermal forms of these medicinal products for a long time (
The modern approach to the problems of transdermal DF design involves a detailed and comprehensive study of the various biopharmaceutical aspects of their development. The experimental research should be directed to the determination of the target quality profile of a medicinal product. For optimal therapeutic effect with transdermal administration of the product it is necessary to take into account physico-chemical properties of the active substance, the influence of the excipients, which are part of the combinations, and the skin condition. With the aim of defining a more rational approach for developing TTS a pharmaceutical consideration of a transdermal product should be preceded by preformulation studies of the medicinal products permeability in vitro through the membrane. The main advantage of such research is a possibility of a control over the experiment conditions and, therefore, the possibility to control changes in permeability due to the influence of different factors (
In this context, the aim of our work is to study in vitro the process of calcium antagonist permeability, nifedipine and amlodipine besylate, and determining their application perceptiveness in the creation of transdermal patches with cardiovascular effect.
The API of nifedipine (Suchem Laboratories company, India) and аmlodipine besylate (Hetero Drugs Limited company, India) have been chosen as the objects of the study.
Nifedipine (Fig.
Amlodipine (in the besylate form) (Fig.
The study of the permeability of the chosen API through a semipermeable membrane was carried out in vitro by a dialysis method using a modified diffusion device of the Valia-Chien design, which was earlier described in paper (
The qualitative characteristics of the permeability process were determined with Fick’s law, which describes diffusion processes, including the active substance transfer through the skin or membrane.
The assessment of the permeability process of the studied substances through a semipermeable membrane was conducted according to the determined values of the flux Is, permeability coefficient Кр and the diffusion delay time Θ. The experiment results have been presented in Table
According to the obtained results of the API quantity, Хi and its concentration Сi in a dialysis sample (Table
The qualitative criteria of permeability of API with cardiovascular effect through a semipermeable membrane in a dialysis sample.
API | Number of a chosen sample, n | Sampling time, t, h | API quantity in a dialysis sample, Хi∙10-4, g | API concentration in a dialysis sample, Сi∙10-3, mg/ml | Specific flux of API, Qt∙10-2, mg/cm2 |
---|---|---|---|---|---|
Nifedipine | 1 | 1 | 30,771 | 113,9666 | 74,1470 |
2 | 2 | 28,539 | 105,7000 | 142,9157 | |
3 | 3 | 31,751 | 117,5962 | 219,4241 | |
4 | 4 | 28,727 | 106,3962 | 288,6458 | |
5 | 5 | 27,725 | 102,6851 | 355,4529 | |
Amlodipine besylate | 1 | 1 | 45,090 | 167,0000 | 108,6507 |
2 | 2 | 45,839 | 169,7740 | 219,1060 | |
3 | 3 | 46,097 | 170,7296 | 330,1831 | |
4 | 4 | 47,584 | 176,2370 | 444,8434 | |
5 | 5 | 48,010 | 177,8148 | 560,5301 |
The statistical equivalence of the obtained data was evaluated on the basis of a study of samples with experimental values, organized in ascending order. Changes in the variant Хi of the received samples can be considered insignificant if the values of their extreme variants do not exceed the limit values of the confidence interval, calculated by the maximum permissible half-width of the confidence interval (max Δx). The value max Δx was defined on the basis of the relative uncertainty of quantitative analysis of the given API (∆Аs) (equation 1) based on the relative tolerance of API quantitative content in TTS В = 25 % according to the State Pharmacopoeia of Ukraine (SPhU) requirements (State Pharmacopoeia of Ukraine).
max Δx = 0.32 · B = 0.32 · 25 = 8.0% (1)
The limit values of the confidence interval were determined by equations 2 and 3:
– the upper limit
(2)
– the lower limit
(3)
The convergence estimation results of experimental values of process parameters ofthe examined APIpermeability through a membrane have been presented in Table
The research results of the convergence estimation of experimental values of process parameters of permeability in vitro.
Estimation parameters | Selection of values in the dialysis sample | ||
API content (Хi∙10-4, g) | API concentration (Сi ∙10-3, mg/ml) | API flux (Is∙10-2, mg/сm2h) | |
Nifedipine | |||
Selection variants, Xi | 27,725 | 102,6851 | 66,8072 |
28,539 | 105,7000 | 68,7687 | |
28,727 | 106,3962 | 69,2217 | |
30,771 | 113,9666 | 74,1470 | |
31,751 | 117,5962 | 76,5084 | |
Х̄ | 29,503 | 109,2688 | 71,0906 |
Хlow | 27,142 | 100,5273 | 65,4034 |
Хhigh | 31,863 | 118,0103 | 76,7778 |
Amlodipine besylate | |||
Selection variants, Xi | 45,090 | 167,0000 | 108,6506 |
45,839 | 169,7740 | 110,4554 | |
46,097 | 170,7296 | 111,0771 | |
47,584 | 176,2370 | 114,6602 | |
48,010 | 177,8148 | 115,6867 | |
Х̄ | 46,524 | 172,3111 | 112,1060 |
Хlow | 42,802 | 158,5262 | 103,1375 |
Хhigh | 50,246 | 186,0960 | 121,0745 |
According to the results, presented in Table
According to the results, presented in Table
Metrological characteristics of the method for determining the quantitative parameters of API permeabilityin the dialysis sample.
m | ν | Xi∙10-4 | Х̄ ∙10-4 | S2 | S̄ | P | t(P,ν) | Confidence interval, ΔХ∙10-4 | ε, % |
---|---|---|---|---|---|---|---|---|---|
Nifedipine | |||||||||
5 | 4 | 27,725 | 29,503 | 2,839 | 0,7535 | 0,95 | 2,78 | 29,503±2,0946 | 7,10 |
28,539 | |||||||||
28,727 | |||||||||
30,771 | |||||||||
31,751 | |||||||||
Amlodipine besylate | |||||||||
5 | 4 | 45,090 | 46,524 | 1,510 | 0,5495 | 0,95 | 2,78 | 46,524±1,5277 | 3,28 |
45,839 | |||||||||
46,097 | |||||||||
47,584 | |||||||||
48,010 |
As a result, one can take the position that nifedipine and amlodipine besylate permeability through a semipermeable membrane from the solution in the model conditions of the experiment occurs at a constant rate.
The graphic interpretation of the in vitro permeability process of the tested substances through a semipermeable membrane and the statistical analysis parameters of the obtained results are presented in Figure
It has been observed that in all experiments the obtained kinetic equations have the form of a general linear regression (Y = A + B × X). For the obtained kinetic equations, within the time of the experiment, the correlation coefficient (R2) was not less than 0,999.
The main quantitative characteristics of the permeability process of the studied API in vitro, calculated on the basis of a statistical analysis, have been presented in Table
According to the obtained results (Table
The kinetic parameters of the permeability process of API with cardiovascular effect in vitro through a semipermeable membrane.
API | API steady-state flux, Is, mg/cm2h | Time of diffusion delay, Θ, min | Permeability coefficient, Кр, cm/h | Linear correlation coefficient, r |
---|---|---|---|---|
Nifedipine | 0,7083 | – 3,06 | 0,075 | 0,9997 |
Amlodipine besylate | 1,1295 | 3,28 | 0,124 | 0,9999 |
In the result of the carried out research it was defined that nifedipine and amlodipine besylate permeability process in the simulative conditions is characterized by uniform velocity. Based on the statistical analysis, the linear dependence of this process was confirmed. The obtained quantitative values of thesteady-state fluxvelocity and the coefficient of permeability indicate the potential of the selected substances in overcoming membrane barriers, and allowto predict a positive assessment of the acceptability of the selected API for the use in the design of TTS.