Transdermal Drug Delivery Systems Biology Essay

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High blood pressure is known as 'silent killer' as it is causing a considerable damage to blood vessels, heart, brain and kidneys, without any noticeable symptoms. Hypertension is a major risk factor for cardiovascular disease. Approximately 7.6 million premature deaths worldwide were attributed to high blood pressure in the year 2001. Hypertension is an increasingly important medical and public health issue. More than half of people 60-69 years of age and approximately three-fourths of those 70 years of age and above are affected. The prevalence of hypertension increases with increasing age. The age related rise in Systolic Blood pressure is major cause for an increase in both prevalence and incidence of hypertension with increasing age. Now a day's even the prevalence of hypertension in children and adolescents appear to be increasing which leads to cardiovascular diseases and with other disorders. This is due in part to the increasing prevalence of childhood obesity as well as growing awareness of this disease. It is now established that hypertension is detectable in children and adolescents and is not uncommon. Population changes in health-related behaviors, including the childhood obesity epidemic, indicate that the rates of hypertension in the young are increasing. Many people are successfully treated for hypertension using -blockers. - blockers reduce blood pressure by inhibiting the secretion of renin and by decreasing the heart rate and contractility. Bisoprolol which belongs to the category of - blockers was selected as an antihypertensive drug in the present investigation. Bisoprolol is a cardio selective beta blocker, devoid of intrinsic sympathomimetic and membrane-stabilizing properties. Bisoprolol fumarate (BF) is effective in reducing blood pressure (BP) with beneficial cardiac effects in patients with hypertension. Many elderly people have difficulty taking medicines because of their reduced swallowing capability. Even young patients especially adolescents were not willing to take medications and skip their doses. So following dosage forms were made in order to overcome the above problems.

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1.2 TRANSDERMAL DRUG DELIVERY SYSTEMS

Over the past two decades, there have been significant advances in the science of controlled transdermal systemic drug delivery, but the concept of systemic therapy via the skin is not a recent innovation. The potential of using intact skin as a part of drug administration to the human body has been recognized long back as evidenced by development and extensive use of medicated plasters for many decades. Historically, the medicated plasters could be viewed as the first application of the idea of transdermal drug delivery, bringing medication into close contact with the skin, through which drug is delivered transdermally.

The use of the skin as a route of delivery into the systemic circulation was not commercially or scientifically exploited, until agents such as nitroglycerin and salicylates dispelled the notion that the skin was largely impermeable, simply because these agents were shown to be therapeutically effective. Drug concentrations in plasma and duration of action are not reliably predictable for several reasons, most of which are patient dependent. Dosage frequency, amount and area of application can affect therapeutic efficacy, but the most significant factor is the inter- and intra- individual variation in skin permeability.

1.3 ORAL THIN/DISINTEGRATING FILMS (OTFs)

Orally disintegrating systems have emerged as a niche amongst the oral drug delivery systems due to the highest component of compliance they enjoy especially in the geriatrics and pediatrics patients. In addition, patients who cannot swallow large quantity of water due to dysphagia, motion sickness, repeated emesis during chemotherapy and mental disorders prefer these medications. OTFs offer fast accurate and dosing in safe, efficacious format that is convenient and portable, without requiring use of water. However, Research is particularly focused in developing OTFs has been aimed at investigating different excipients as well as techniques to meet the requirements of formulating these dosage forms with mechanical strength sufficient to with stand the usage of handling and capable of disintegrating within a few seconds on contact with saliva.

The main objectives of the present study are as follows:

To design and develop novel drug delivery systems, namely transdermal patches and oral thin films of a selected anti hypertensive drug, Bisoprolol fumarate, using different polymers.

To select the suitable penetration enhancer from the selected amino acids.

To choose the best formulations based on the In vitro diffusion studies and In vivo evaluations in the rabbits.

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And finally, to increase the patient compliance especially in geriatric, pediatric and adolescent patients in terms of delivery and with controlled release.

Preformulation studies for Bisoprolol fumarate, like Solubility, Melting point, Partition coefficient and Drug-Excepients studies using FTIR and Differential scanning calorimeter (DSC) were been carried out before optimizing the formulation.

FORMULATION OF TRANSDERMAL PATCHES

The matrix-type transdermal patches of bisoprolol were prepared by using different ratios of Polyvinyl alcohol (PVA) and Polyvinyl Pyrrolidone (PVP) polymers First PVA was dissolved in the hot water at about 70-80°C with stirring then slowly the PVP was mixed thoroughly to obtain uniform solution. Glycerol was used as a plasticizer and then drug was dissolved in the above polymeric solution with stirring, after cooling it to the room temperature. The polymeric solution of drug was poured onto the glass moulds and dried at room temperature in dust free environment. The patches were stored in air tight container at ambient conditions for further evaluation.

EFFECT OF PLASTICIZER AND PENETRATION ENHANCER

The best formulation obtained was selected based on the In vitro evaluations using porcine ear skin as a diffusive membrane. In order to find out the effect of plasticizer on the drug release glycerin was replaced with Triethylcitrate (TEC) and further evaluations were carried out. Amino acids were selected and were added to the above optimized formulations and further studies were carried out to know the effect of amino acids as a penetration enhancer.

IN VITRO AND STABILITY STUDIES

A cell fabricated on the lines of Franz diffusion cell with a diffusional area of 2 cm2 was used. The porcine ear skin was collected from local slaughter house. The stratum corneum side of the skin was kept in intimate contact with the release surface of patch under test placed between the two halves of the diffusion cell. The receiver phase was phosphate buffer of pH 7.4 stirred at 500 rpm on magnetic stirrer. The whole assembly was kept at 37 ±0.5°C. The amount of drug permeated was determined by removing an aliquot 1ml samples at appropriate time intervals up to 24 h. Volume was replenished with an equal quantity of pre-warmed receiver solution and the drug diffused was determined spectrophotometrically. Stability studies were done for the best selected patches, which were stored in an aluminum package in a chamber controlled at 40°C and 75% in humidity for 4-8 weeks. The content of Bisoprolol was then determined using HPLC. The patches were also subjected to other physical and diffusion tests.

IN VIVO STUDIES

The experiments were approved by the animal ethical committee at VIT University, Vellore, Tamilnadu, India. (CPCSEA Reg. No-1333/c/10CPCSEA, New Delhi, INDIA). The study was carried out on New Zealand white rabbits. The rabbits were acclimatized for 10 days prior to the conduction of the experiment. The objective of this study was to determine the plasma concentration profile of Bisoprolol fumarate after administration and evaluate the benefits of the transdermal patches in terms of plasma concentration profile. Hair present on the abdominal portion was shaved and removed. Transdermal patches were applied on to the shaved portion of skin of each rabbit and animals were housed in clean cages and maintained in controlled temperature. They were fed with standard diet throughout the study. Blood samples were collected from marginal ear vein at regular intervals in a heparinized centrifuge tubes. The samples were centrifuged immediately and the plasma separated was stored at -20°C till the time of analysis.

3.2 FORMULATION OF ORAL THIN FILMS (OTF)

Films were prepared by mixing PVA, Hydroxypropyl Methylcellulose (HPMC), TEC, Glycerol, Kollicoat SR 30 D, aspartame and mango flavor in water. Ultrasonic defoaming apparatus was used to remove the air bubbles in the solution. The mixture was then coated onto the glass plates to prepare the thin films using the coating apparatus fabricated locally. The obtained film with the basic glass plate was cut without lopping the glass plate into 2cm x 2cm in size, containing 5 mg of the drug. The films were then removed from the glass plates and further evaluations were done.

3.2.1 IN VITRO AND STABILITY STUDIES

Dissolution test was carried out according to the USP II paddle dissolution apparatus. The test solution was 900 mL of freshly deionized water at 37±0.5°C and the rotation rate of 75rpm.Ten-mL aliquots of samples were taken at regular intervals with auto sampler and the same volume of fresh test solution was replenished. One-mL aliquot of the sample was taken in a polyethylene tube and the same volume of internal standard solution (1g/mL Propranolol HCl) was added and the concentration of BF was calculated using HPLC method. Oral thin film pieces cut from both the formulations were stored in an aluminum package in a chamber controlled at 40°C and 75% in humidity for 4-8 weeks. The content of Bisoprolol was then determined using HPLC. The film samples were also subjected to disintegration and dissolution tests.

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3.2.2 IN VIVO STUDIES

The objective of this study was to determine the plasma concentration profile of Bisoprolol fumarate after administration and evaluate the benefits of the oral thin film in terms of plasma concentration profile. The experiments were approved by the animal ethical committee at VIT University, Vellore, Tamilnadu, India. (CPCSEA Reg. No-1333/c/10CPCSEA, New Delhi, INDIA) The study was carried out on New Zeland white rabbits. The rabbits were acclimatized for 10 days prior to the conduction of the experiment. Formulations were applied to the buccal cavity bilaterally. After checking for the complete disintegration of the films the animals were housed in clean cages and maintained in controlled temperature. They were fed with standard diet throughout the study. Blood samples were collected from marginal ear vein at regular intervals in a heparinized centrifuge tubes. The samples were centrifuged immediately and the plasma separated was stored at -20°C till the time of analysis.

EVALUATION OF TRANSDERMAL PATCHES

IN VITRO DRUG DIFFUSION AND STABILITY STUDIES

The in vitro drug diffusion behavior of the prepared transdermal patches are presented in the form of tables and figures and discussed in detail. From the results it was clearly noted that amino acids showed penetration for bisoprolol through skin and as the concentration of PVP is increased the release behavior and pattern can be controlled. As formulations which contains low concentration of PVP the drug release from the polymer matrix is much faster compared to that of formulations in which PVP concentration is high. Cysteine and Lysine showed good penetration through porcine ear skin among the amino acids chosen. When it comes to the effect of plasticizer, TEC showed good diffusion when compared to that of glycerin, this may be due to the high binding effect of glycerin to the drug and as well as the percentage of glycerin is high when compared to TEC to give the good plasticity for the patches. Both the patches showed good stability studies for eight weeks.

IN VIVO STUDIES

The results of the in vivo pharmacokinetic studies presented in the form of tables, graphs and chromatograms are discussed. Finally, there was considerable variability to transdermal drug permeation found in the parameters obtained from permeation profiles across rabbit skin. Since the tactics to improve the diffusion are either reducing the barrier properties of the skin or increasing the diffusion properties of the drugs, the use of appropriate penetration enhancers seemed to be necessary to increase their permeation capacity across the skin. Results showed that there are significant changes in the pharmacokinetic parameters in both the formulations. The formulation which contains cysteine showed good therapeutic window when compared to the lysine and skin irritation studies revealed that there was no reddening of the skin without any inflammation after a day, at the site where the transdermal patches were applied.

EVALUATION OF ORAL THIN FILMS

IN VITRO DRUG DIFFUSION AND STABILITY STUDIES

All the formulations showed rapid disintegration. The in vitro drug release behavior of the prepared transdermal patches are presented in the form of tables and figures and discussed in detail. The data reveal that the dissolution rates of the films depend upon the polymers used. The release of the drug in the dissolution media seems to the function of the polymer concentration as well as the nature of the polymeric material. The hydrophilic polymers, HPMC and PVA present in one of the formulation absorb water quickly and swell up thus releasing the drug immediately from the matrix. The release of the drug from other formulation is slow as it contains Kollicoat SR 30 D. The slower drug release from the formulation may be attributed to the higher PVAc content. Further, PVP, a highly flexibility polymer incorporated into the coating dispersion as a stabilizer, is highly soluble in water. When the film comes into contact with the dissolution media, it dissolves and acts as a pore-forming agent. The drug, therefore, dissolves and diffuses out through the pores at a controlled rate. Thus formulation contains kollicoat SR 30 D shows controlled release behavior. The physical characteristics and content uniformity of the samples are almost similar for eight weeks.

IN VIVO STUDIES

The drug concentrations in rabbit plasma were evaluated by HPLC. Results show the time course of changes in the drug concentrations after oral administration to rabbits. The pattern of changes for plasma concentrations is different for the two groups with slightly but not significantly higher in the formulation which contains Kollicoat SR 30 D. From the in vivo studies it may be concluded that Cmax for the formulation which contains PVA and HPMC is high when compared to other formulation and more over the t1/2 of the Kollicoat SR 30 D formulation is higher when compared to the other formulation. These findings show that Kollicoat SR 30 D formulation has good controlled release behavior when compared to that of other formulation which contains PVA and HPMC.

Two novel drug delivery systems for Bisoprolol fumarate were designed using different polymers and are evaluated in terms of Physical, In vitro and In vivo studies. Here an attempt was made to prepare the transdermal patches and oral thin films to improve the patient compliance both in geriatric and pediatric hypertensive patients. In case of transdermal patches, In vitro drug diffusion behaviour clearly shows that the formulations which contain TEC as plasticizer showed good diffusion when compared to glycerin. Cysteine and Lysine showed good penetration enhancers both in the case of In vitro and In vivo studies. Oral thin films show good physical properties and more over it shows rapid disintegration. The results revealed that the formulation which contains Kollicoat SR 30 D showed good controlled release behaviour when compared to the other formulation which contains HPMC. All the formulations showed good stability for eight weeks in the case of drug release, content uniformity and other physical evaluations.

These findings, taken together, suggest that the Bisoprolol fumarate transdermal patches can give good therapeutic effect in the management of hypertension in pediatric and adolescent patients. More over the oral thin films containing bisoprolol fumarate is potentially useful in managing the hypertension to the patients suffering from dysphagia or aphagia and also in the case of geriatric patients who shows unwillingness towards the intake of tablets.