Formulation and Evaluation of Transdermal Drug Delivery Systems of Ivabradine Hydrochloride

 

Vaseeha Banu T.S.¹, Sandhya K.V.² and K.N. Jayaveera³

¹Dept. of Pharmaceutics, M.M.U College of Pharmacy, K.K. Doddi, Ramanagara- 562159. Karnataka

² Dept. of Pharmaceutics, T. John College of Pharmacy, Bannerghatta Road, Bangalore- 560083. Karnataka

³ Dept. of Chemistry, Jawaharlal Nehru Technological University Anantapur, Anantapur- 515002, Andhra Pradesh.

 

ABSTRACT:

Stable angina is characterized by chest discomfort rather than actual pain. The main goal of the treatment is to control symptoms, slow progression of the disease and reduction of major cardiovascular events. Ivabradine HCl (IBH) is a new first specific If channel blocker used to treat stable angina. In our present investigation, an attempt has been made to formulate transdermal drug delivery system of IBH to treat stable angina. The suitability of drug with respect to lower dose, low molecular weight and short half life makes this drug as a suitable candidate for administration via transdermal route. Transdermal films of IBH have been prepared by solvent casting technique using different ratios of varying degree of hydrophilic and hydrophobic polymers namely hydroxypropyl methyl cellulose (HPMC), ethyl cellulose (EC) and polyvinyl pyrrolidine (PVP) (blend ratios viz; 0.5:1.5, 1:1 and 1.5:0.5% w/v). Propylene glycol (30% w/w) and Isopropyl myristate and oleic acid (2:0.5% w/w) was incorporated as plasticizer and permeation enhancer respectively. The effect of polymers on the various physicochemical characteristics and ex-vivo skin permeation studies were evaluated. The formulations exhibited uniform thickness, weight and good uniformity in drug content. Moisture content and moisture absorption were increased for the patches containing higher amount of PVP due to its hydrophilic nature, the results of water vapour transmission rate revealed that the transdermal films were permeable to water vapours. Ex-vivo release studies showed zero order release of the drug from all the patches and the mechanism of release was diffusion mediated. Moreover, the release of the drug was sustained and extended over a period of 24 h in all the formulations. On the basis of technical properties and ex-vivo release formulation F7 emerged as the most satisfactory formulation. The stability studies revealed no morphological changes in formulations and an insignificant variation in drug content. Furthermore the results of skin irritation test revealed that the patches were seemingly free of any skin irritation. Thus it could be concluded that the transdermal films proved to be a promising drug delivery system for IBH with more patient compliance in the treatment of stable angina.

 

 

INTRODUCTION:

Controlled drug release system could be prepared from either pumps or polymers. Polymers are most widely used, due to their smaller size and cost effective.¹ Polymers are the backbone of transdermal drug delivery system. Polymer-based products and pioneering process technologies are playing a very important role in medicine and pharmacy^2,3.  Polymer should provide consistent, effective delivery of a drug throughout the products intended shelf-life or delivery period and have generally recognised-as safe status⁴.

 

Being the largest organ of our body skin plays an important role by offering selective entrance of molecules and preventing access of noxious matters through it. Therefore, the skin as a route for systemic drug administration has become very attractive since the introduction of transdermal therapeutic system in the form of patches. Transdermal patches utilize a natural and passive diffusion mechanism that allows substances to penetrate the skin and enter the blood stream. It offers many advantages over other dosage form, which includes the ability to avoid problems of gastric irritation, pH and emptying rate effects; avoid hepatic metabolism thereby increasing the bioavailability of drug; reduce the risk of systemic side effects by minimising plasma concentrations compared to oral therapy; provide a sustained release of drug at the site of application; rapid termination of therapy by removal of the device or formulation and avoids pain associated with injection ^5,6.

 

Heart rate, a major determinant of angina in coronary disease, is also an important predictor of cardiovascular mortality. Lowering heart rate is therefore one of the most important predictor of cardiovascular mortality. Treatment of lowering heart rate is therefore one of the most important therapeutic approach in cases of stable angina pectoris. In the present study, an I_f channel blocker Ivabradine hydrochloride (IBH) was selected as a model drug. It is the first specific heart rate lowering agent, lowers heart rate at concentration that does not affect other cardiac ionic current and provides an alternative to conventional treatment for patients with stable angina⁷. The purpose of formulating the IBH transdermal film is the suitability of the IBH with respect to low dose (5-7.5 mg), solubility, low molecular weight, half life (2 h), bioavailability (40%) and the drug undergoes extensive hepatic metabolism after oral administration. All these properties prompted the selection of drug for transdermal drug delivery system.

 

MATERIALS AND METHODS:

IBH was obtained as a gift sample from Ind Swift (Chandigarh India), Hydroxy Propyl Methyl Cellulose (HPMC) from NR Chemicals, Mumbai, Ethyl Cellulose (EC) and Propylene Glycol (PG) from Rankem, New Delhi and Polyvinyl pyrrolidine (PVP), Isopropyl myristate (IPM) and oleic acid (OA) from SD fine chemicals Mumbai India and all other ingredients were of analytical grade.

 

Fabrication of transdermal film ^{8, 9}

Solvent casting technique was employed for fabrication of transdermal films. To prepare polymeric solution for transdermal film, 2% w/v concentration of polymer was taken. Polymers were dissolved in ethanol with the help of magnetic stirrer for 30 min. Drug was then dissolved separately in the solvents with help of magnetic stirrer for 30 min, propylene glycol (PG), IPM and OA were used as plasticizer and permeation enhancer respectively, was added to the drug solution and mixed with the help of magnetic stirrer for another 30 min. The solution containing drug with PG, IPM and OA was added to the polymer solution and the whole solution was stirred for 30 min using magnetic stirrer. Then the solution was sonicated to ensure the uniform distribution, and then the solution was casted in flat surfaced petridish. The films were dried at room temperature, to avoid rapid evaporation of solvent.  The petridish was covered with the inverted funnel for 48 h. The dried films were taken out and packed in an aluminium foil covering, which is used as backing membrane. The dried films were stored in desiccators for a week until further evaluation.

 

Evaluation of transdermal patches

Physical appearance ¹⁰

The prepared patches were physically examined for colour, clarity and surface texture. 

 

Thickness uniformity¹¹

The  thickness of patches was  measured  by  using  electronic  caliper,  with  a  least count  of  0.01mm.  Thickness  was  measured  at  three  different  points  on  the  film  and average readings were taken.

 

Uniformity of weight¹²

The patch of size 2x2 cm was cut and weight of each patch was taken individually, the average weight of the patch was calculated. 

 

Drug content uniformity ^{10, 13}

The patches were tested for the content uniformity. The patches of size 2 cm² was cut and placed in a 100 ml volumetric flask. The contents were stirred using a magnetic bead to dissolve the patches. Subsequent dilutions were made with phosphate buffer (pH 7.4).  The  absorbance  of  the  solution  was  measured  against  the corresponding blank  solution  at  286  nm  using  UV-visible  spectrophotometer.  The experiment was repeated three more time to validate the result

 

Tensile strength ^{14, 15}

Tensile strength was measured using modified analytical two pan balance method. The patch of 20 mm width and 50 mm length were cut and clamped between two clamps on one side, until the patch breaks weight were added to the pan on other side. The required weight to break the patch was taken as a measure of tensile strength of the patch.

 

Folding endurance ^{11, 16, 17}

The folding endurance was measured manually for the prepared patches. A strip of patch  (2  x  2  cm )  was  cut  and  repeatedly  folded  at  the  same  place  till  it  broke.  The number  of  times  the  film  could  be  folded  at  the  same  place  without  breaking  gave  the value of folding endurance.

 

Percentage moisture loss ^{17, 18}

Three patches from each batch were weighed individually and the average weight was calculated. This weight was considered as Initial weight. Then all the patches were kept in a desiccators containing activated Silica at normal room temperature for 24 h. The final weight was noted when there was no further change in the weight of individual patch. The percentage moisture absorption was calculated as a difference between initial and final weight with respect to final weight.

 

% Moisture content = [(Initial weight – Final weight)/ Final weight] X 100

Percentage moisture uptake ¹⁹

 

The  patches  were  weighed  accurately  and  placed  in  a  desiccators  where  a  humidity condition  of  80-90%  RH  was  maintained  by  using  saturated  solution  of  potassium Chloride. The patches were kept until uniform weight was obtained, then taken out and weighed. The percentage of moisture uptake was calculated as the difference between final and initial weight with respect to initial weight.    

% Moisture absorption = [(Final weight – Initial weight)/ Initial weight] x 100

 

Water vapor transmission rate (WVTR) ^{20, 21} 

For this study vials of equal diameter were used as transmission cells.  These cells were washed thoroughly and dried in an oven.  About  1 g  of fused calcium chloride was taken  in  cells and the polymeric patches  measuring 3.14 cm² area  were  fixed  over  the  brim  with  the  help  of  an  adhesive.  The  cells  were  weighed  accurately  and  initial  weight  was recorded, and  then kept  in a closed desiccator containing  saturated solution  of  potassium chloride  to maintain 80-90% RH.  The cells were taken out and weighed after 72 h. The amount  and  rate  of  water  vapor  transmitted  was  calculated  by  the  difference  in  weight using the formula. Water vapour transmission rate is usually expressed as the number of grams of moisture gained/72 h/cm^2.

 

Ex-vivo permeation studies: ⁹

Male rats weighing 105-120 g, free from any visible signs of disease were selected. Using a depilatory preparation the hairs of the male rat was removed by scissor. The prepared skin was washed with pH 7.4 phosphate buffer and tied on the donor compartment with transdermal patch. Patch was placed in such a way that the stratum corneum was faced towards donor compartment while the dermis towards receptor compartment containing 100 ml of pH 7.4 phosphate buffer. At fixed time interval samples were withdrawn and replaced with the same receptor fluid. After 24 hours sampling, absorbance was taken at 286 nm against blank pH 7.4 phosphate buffer using UV spectrophotometer.

 

Primary skin irritation test: ⁹

This test was done by modifying the method describes by Draize and his colleagues in 1994, based on scoring method. Scores are assigned from 0 to 4 based on the severity of erythema or oedema formation. The safety of patch decreases with an increase in scoring.

 

Newzeland white rabbits, each weighing 1.5 to 2.0 kg were used in this study (n=4 in each group). They were housed in cages in the animal house under controlled temperature and light conditions. They were fed a standard laboratory diet and had access to water ad libitum. The dorsal surface of the rabbit was cleared and the hair was removed by shaving. The skin was cleared with rectified spirit. The control patch (without any drug group I), and experimental patch (F7, group II) were applied to the shaved skin of rabbits and secured using 3 M Micropore”- medical adhesive tape. A 0.8% v/v aqueous solution of formaldehyde was applied as a standard irritant (group III). Its effect was compared with the test. The animals were observed for any sign of erythema and oedema

   

Stability studies:

The best formulations were subjected to stability studies at 25⁰C/ 60% RH, 30⁰C/ 65% RH and 40⁰C/ 75% RH for 90 days in a stability chamber (Thermo Lab., Mumbai, India). These samples were analyzed UV Spectrophotometrically and checked for changes in physicochemical parameters and drug release at an interval of 15 days.

 

RESULTS AND DISCUSSION:

Transdermal films of IBH were prepared by solvent casting method. Different polymers were used viz HPMC, EC and PVP (2%), they were used as combination in different ratios. PG as plasticizer (30% w/w) and IPM and OA (2: 0.5% w/w) were used as permeation enhancer. The selection of polymer combinations that produces transparent, smooth, flexible, substantive and desired thickness films of IBH were chosen. The physicochemical evaluation data given in Table No. 2 revealed, that there were no physical changes in-terms of appearance, colour and flexibility at room temperature at which the films were stored.

 

Flatness studies of the prepared films were performed to judge any constriction in the films and whether it has smooth surface, as these properties are important in an ideal patch. The results of the study revealed that none of the prepared films had any differences in strip length before and after their cuts. The values of flatness was much near to 100% in all the formulated films, indicating good uniformity of the polymers throughout the formulated films and these formulations could maintain uniform surface when they were applied onto skin.

 

The thickness of the films were found to be in the range of 0.022 to 0.024 mm, low standard deviation values ensure the uniformity of the films prepared by solvent casting method. The prepared films should have ability to withstand rupture and maintain their integrity with skin folding when used. This could be identified by folding endurance.  It was measured manually and the results revealed that the prepared films had above said qualities. The value of folding endurance was found to be higher for the patches with the combination of HPMC and PVP.

 

The tensile study indicates the strength and elasticity of the film, reflected by the parameters, tensile strength and percentage elongation. A soft and weak polymer is characterized by a low tensile strength and percentage elongation; a hard and brittle polymer is defined by a moderate tensile strength and low percentage elongation; a soft and tough polymer is characterized by a moderate tensile strength and high percentage elongation; where as a hard and tough polymer characterized by high tensile strength and percentage elongation. Hence it is predicated that a suitable transdermal film should have a relatively high tensile strength and percentage elongation. The result of these mechanical properties reveals that the films in combination of HPMC: PVP (0.5: 1.5) exhibited highest values of tensile strength and percentage elongation. It also observed that as the concentration of PVP increased the tensile strength and percentage elongation also increased, this observation indicates that the patch was strong, flexible and not brittle, which might be attributed to the addition of the plasticizer PG (30%w/w).

 

Table No. 1: Composition of the transdermal patches

Formulation Code	HPMC:EC % W/V	EC:PVP %W/V	HPMC:PVP % W/V	PG %W/W	IPM:OA % W/W
F1	0.5:1.5	-	-	30	2: 0.5
F2	1:1	-	-	30	2: 0.5
F3	1.5:1.5	-	-	30	2: 0.5
F4	-	0.5:1.5	-	30	2: 0.5
F5	-	1:1	-	30	2: 0.5
F6	-	1.5:1.5	-	30	2: 0.5
F7	-	-	0.5:1.5	30	2: 0.5
F8	-	-	1:1	30	2: 0.5
F9	-	-	1.5:1.5	30	2: 0.5

Drug loaded in each 2 cm² = 7 mg, HPMC = hydroxy propylmethyle cellulose, EC= ethyl cellulose, PVP= polyvinyle pyrrolidine, PG= propylene glycol, Isopropyl myristate (IPM) and oleic acid (OA)

 

Table No 2: Physicochemical evaluation of the prepared transdermal patches of IBH

Formulation code	flatness	Weight variation (mg)	Thickness (mm)	Folding enduranec	Drug content (%)	Tensile strength (gm/10cm2	Percentage elongation
F1	99.23 ±0.12	11.18 ±0.20	0.022±0.002	132 ±9.8	99.24±0.53	15.21±0.38	10±0.056
F2	99.45 ±0.21	10.72±0.63	0.024±0.003	129±10.4	98.36±0.26	15.18±0.23	09±0.024
F3	98.71±0.52	10.83±0.45	0.023±0.006	137±8.5	97.48±0.54	15.34±0.36	10±0.036
F4	99.65±0.31	10.56±0.25	0.024±0.002	136±10.5	96.32±0.23	15.48±0.39	11±0.054
F5	99.41±0.14	10.74±0.45	0.023±0.006	138±12.5	98.52±0.47	15.24±0.24	12±0.014
F6	99.74±0.10	10.93±0.24	0.024±0.008	136±10.6	98.12±0.15	15.32±0.54	10±0.045
F7	99.97±0.12	10.54±.023	0.022±0.004	145±10.7	97.48±0.48	15.56±0.41	13±0.064
F8	99.78±0.11	10.12±0.41	0.022±0.003	140±10.5	99.43±0.41	15.27±0.24	11±0.046
F9	99.82±0.15	10.87±0.22	0.023±0.001	142±10.8	98.68±0.42	15.38±0.36	12±0.036

 

Figure 1: Comparison of moisture absorption, moisture content and WVTR of formulation F1-F3

 

Figure 2: Comparison of moisture absorption, moisture content and WVTR of formulation F4-F6

 

Figure 3: Comparison of moisture absorption, moisture content and WVTR of formulation F7-F9

 

Figure 4: Comparison of ex- vivo release of formulation F1-F9

 

 

The results of moisture absorption and moisture content of all the formulation varied to a small extent in all the patches. The moisture content and moisture absorption in the patches range from 2.638 ±0.56 to 2.862 ± 0.35 and 2.308 ± 0.28 to 3.214 ± 0.41 respectively. The results revealed that the moisture content and moisture absorption was found to increase with increasing concentration of hydrophilic polymers viz PVP and HPMC. The presence of small amount of moisture would help the patches to remain stable and from being completely dried and brittle. Along with these properties, it also protect the formulations from microbial contamination and also reduce bulkiness of films.

 

The permeability characteristics of the patches could be determined by WVTR studies. The results of this study revealed that all the formulations are permeable to water vapour. The release of drug from the transdermal patch could be controlled by appropriately selecting polymers and their blends and right choice of permeation enhancer. It is well known that using blends of the polymers one could achieve desired steady state along with controlled/ sustained drug release from the patches. The literature reveals that diffusion is the main mechanism by which drug release from the transdermal patch, and it is governed by two steps. The first step depends on the rate of hydration of polymer which involves changes in the entanglement of individual drug molecules at the matrix surface. The later step involves the movement of the drug molecule from the surface to the bulk of the in vitro fluid via diffusion membrane. In vitro profile plays an important tool to predict both the behaviour of the drug in vivo and the reproducibility of the rate and duration of drug release, thereby eliminating the risks of hazards of molecules of transdermal drug delivery system because of direct experimentation in the living system.

 

Figure 4 shows the release profiles of IBH from transdermal patch. Formulations F7 and F8 exhibited greatest (92.34 ± 12.32 and 91.86 ± 16.57 respectively) where as the lowest value was (85.23±36.98), it was observed that as the concentrations of hydrophilic polymers increased in the formulations, the drug release rate increased substantially, however with a very nominal decrease in formulation F8. It is also observed that the hydrophobic polymer (EC) resists the release of hydrophilic drug IBH, where as the addition of hydrophilic polymers PVP and HPMC increase the release of IBH from transdermal patch. Initially there was burst release, which was useful for dermal penetration of drug and this might be due to hydrophilic polymer which does not have interaction with hydrophilic drug. Whereas the EC that account for the slow release of drug may be due to the interaction of hydrophilic drug with hydrophobic polymer. Further it has been observed that with increase in concentration of PVP increase rate of drug release was observed.

 

This may be due to prevention of crystallization of drug and rise in solubility of the drug by the addition of PVP. The data of in vitro release was fit into different equations and kinetic models used include zero order equation, first order equation, Higuchi and Korsemeyer- Peppas models. The results revealed that all the formulations followed first order equation better than zero order as the R value of the formulations was found to approach unity. Higuchi plot was drawn which confirms diffusion as prominent mechanism by giving R value near to unity (data shown in Table No 3).  To confirm the above said fact, peppas plot was plotted which confirms diffusion mechanism involving non fickian diffusion. The results of the skin irritation studies are shown in Table 04.

 

The score assigned in accordance with the Draize scoring criteria, revealed that primary dermal irritation index value was zero and the film is free from any sign of erythema and oedema.

 

Stability study of the best formulations was carried out. The results after stability period are given in Table 6.  The data after stability period of evaluation parameters were found to be same as those of patch, before the stability period. Hence stability studies indicate that the formulation is quite stable at accelerated conditions.

 

CONCLUSION:

A recent approach to drug delivery is to deliver the drug into systemic circulation at predetermined rate using skin as a site of application. A transdermal films delivers the drug in such a manner that, it maintains the blood concentration of the drug within the therapeutic window ensuring that drug levels neither fall below the minimum effective concentration nor exceed the minimum toxic dose.

 

Stable angina is a chronic condition that often requires control of symptoms, slow progression of the disease and reduction of major cardiovascular events. IBH is a specific I_f channel blocker which holds good promise for administration via transdermal route for the treatment of stable angina. The various parameters that were evaluated helps us to understand the suitability and usefulness of IBH to be formulated as transdermal films with different ratios of polymers. Based on the various physicochemical characterisation and ex-vivo release pattern, formulation (F7) containing HPMC: PVP in ratio of 0.5:1.5 emerged as the best formulation.

 

Thus in this radiant, it could be concluded that IBH could be administered transdermally over a period of 24 hrs. IBH transdermal drug delivery system could be used as an efficient drug delivery tool for treating stable angina as long term therapy to control the symptoms and reducing the risk of cardiac events.

 

Table No 3: Kinetic profile of transdermal patches of IBH (F1-F9)

 

Table No 4: Skin irritation scores of F7 transdermal patch of IBH

Erythema scale: 0, none; 1, slight; 2, well defined; 3, moderate; 4, scar formation.

Oedema  scale: 0, none; 1, slight; 2, well defined; 3, moderate; 4, scar formation

 

Table No 5: Classification of irritation according to primary dermal irritation index (PDI)

 

 

 

Table No 6: results of F7 after stability period

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Received on 14.11.2013       Modified on 05.12.2013

Accepted on 12.12.2013      © RJPT All right reserved