Antianginal Transdermal Drug Delivery System: Formulation and Evaluation

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

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

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

³Jawaharlal Nehru Technological University Anantapuramu, Anantapuramu- 515002, Andhra Pradesh.

ABSTRACT:

Lercanidipine Hydrochloride (LH) is a calcium channel blocker used to treat hypertension along with chronic stable angina related to myocardial ischemia characterised by chest discomfort rather than actual pain. The main goal of the treatment of stable angina pectoris is to control symptoms, slow progression of the disease and reduction of major cardiovascular events. In our present investigation an attempt has been made to formulate transdermal drug delivery system of LH to treat angina pectoris. Transdermal films of LH have been formulated by solvent casting technique using three different polymers hydroxy propyl 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), of varying degrees of hydrophilicity and hydrophobicity. Propylene glycol (PG 30% w/w) and dimethyl sulfoxide (DMSO 7% w/w) was incorporated as plasticizer and permeation enhancer respectively. The prepared films were evaluated for various physicochemical parameters and ex-vivo drug release through rat abdominal skin using Franz diffusion cell. The patch containing combination of HPMC:PVP shown maximum water vapour transmission rate, % moisture absorption and % moisture loss, which could be attributed to the hydrophilic nature of both the polymers. Ex-vivo data revealed that the released pattern from all the patches followed zero order; moreover it was sustained and extended over a period of 24 hours in all formulations. F7 emerged as the most satisfactory formulation by permeating drug upto 88.94%. Further the best formulation F7 was subjected to skin irritation studies, the results revealed that the F7 has no erythema and oedema.

KEYWORDS: Antianginal drug, DMSO, PVP, HPMC, EC

INTRODUCTION:

There has been increased interest and challenges in the delivery of an active ingredient through the skin. Transdermal drug delivery systems (TDDS) are a class of novel drug delivery systems, which are going worldwide accolade as evidenced by the numerous scientific documents being published¹. Delivery of drugs into systemic circulation via skin has generated a lot of interest during the last decade, as TDDS offers many advantages over the conventional dosage forms and oral controlled release delivery system. TDDS avoids hepatic first pass metabolism, decrease in frequency of administration, reduction in gastrointestinal side effects and improves patient compliance. In this type of dosage forms peak plasma levels of drug are reduced, leading to the decreased side effects and increase the therapeutic value for many drugs by avoiding specific problems associated with the drug.

Inspite of several advantages offered by transdermal route, only a limited number of drugs are administered transdermally because of the formidable barrier nature of stratum corneum. To overcome these problems vehicles, chemical penetration enhancers has been attempted in the development of TDDS².

Most of the chronic diseases have genetic, hereditary cause or lifestyle borne like hypertension, asthma, diabetes, addiction etc. It is desirable, from the standpoint of pharmacodynamics to maintain the drug concentration in plasma within a therapeutic effective range for long periods³. However, even if the drug is well absorbed orally, it will run through entero-hepatic cycle. In some cases it decreases the systemic availability of drug as it undergoes hepatic first pass metabolism. This effect will establish a significant difference between claimed and attained bioavailability of drug moiety⁴_.

Lercanidipine HCl (LH), a novel lipophilic and vasoselective dihydropyridine, calcium antagonist is effective as antihypertensive and antianginal agent ^{5, 6}. Lercanidipine HCl is poorly absorbed after oral administration with peak plasma concentrations observed within three hours. Bioavailability of this drug about 44% and extensively metabolised in liver. The half life is about 4.6 hours. Lercanidipine HCl due to its low therapeutic dose (2.5-20mg) and substantial biotransformation in liver becomes an ideal candidate for development of TDDS ^{7, 8}.

In this study we have attempted to develop TDDS of LH for the treatment of angina pectoris

MATERIALS AND METHODS:

Lercanidipine HCl (LH) was obtained as a gift sample from Aurobindo Pharmaceuticals, Hyderabad. Hydroxy Propyl Methyl Cellulose (HPMC) from NR Chemicals, Mumbai, Ethyl Cellulose (EC) and Propylene Glycol (PG) from Ranchem, New Delhi and Polyvinyl pyrrolidine (PVP) and Dimethyl Sulfoxide (DMSO) from S.D Fine Chemicals, Mumbai, India. All other ingredients used were of analytical grade.

Fabrication of transdermal film ^{9, 10}

Solvent casting technique was employed for fabrication of transdermal films. Composition of LH transdermal films were shown in table 1. Accurately weighed quantities of drug and polymer were dissolved in ethanol at room temperature, PG as plasticizer (30%w/w) and DMSO as permeation enhancer (7%w/w) were added into the polymeric solution while continuously starring on magnetic stirrer for 30 min. The solution was poured into flat surfaced petridish and the solvent was allowed to evaporate at room temperature. An inverted funnel was placed over the petridish to prevent fast evaporation of the solvent. Films of 2 cm² containing 15 mg of LH were cut and packed in an aluminium foil covering.

Evaluation of transdermal patches:

Physical appearance ¹¹

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

Thickness uniformity¹²

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

Uniformity of weight¹³

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

Drug content uniformity ^{11, 14}

The patches were tested for the content uniformity. The patches of size 2 cm² were 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 236 nm using UV-visible spectrophotometer. The experiment was repeated three more time to validate the result

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	DMSO% W/W
F1	0.5:1.5	-	-	30	7
F2	1:1	-	-	30	7
F3	1.5:1.5	-	-	30	7
F4	-	0.5:1.5	-	30	7
F5	-	1:1	-	30	7
F6	-	1.5:1.5	-	30	7
F7	-	-	0.5:1.5	30	7
F8	-	-	1:1	30	7
F9	-	-	1.5:1.5	30	7

Drug loaded in each 2 cm² = 15mg,

Tensile strength ^{15, 16}

Tensile strength was measured using modified analytical two pan balance method. A patch of 20 mm width and 50 mm length was 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^12,17,18

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 was broken. The number of times the film could be folded at the same place without breaking gave the value of folding endurance.

Percentage moisture loss ^{18, 19}

Three patches from each batch were weighed individually and the average weight was calculated. This weight was considered as an Initial weight. Then all the patches were kept in a desiccator containing activated Silica at normal room temperature for 24hr. 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 uptake²⁰

The patches were weighed accurately and placed in a desiccator where a humidity condition of 80-90% RH was maintained by using saturated solution of potassium chloride. The patches were kept until uniform weight is 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) ^{21, 22}

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 3.14cm² 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 hrs. The amount 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 hr/cm^2.

Ex-vivo permeation studies¹⁹:

Male rats weighing 105-120 gm, free from any visible sign of disease were selected. the hair on abdominal region was removed using a depilatory preparation one day prior to experiment. On the day of experiment, animals were sacrificed by cervical dislocation and the abdominal skin was excised. The fatty material adhered to the dermis was carefully peeled off, 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 donar compartment while the dermis towards receptor compartment containing 100 ml of pH 7.4 phosphate buffer. At fixed time intervals the samples were withdrawn and replaced with receptor fluid. After 24 hours of sampling absorbance were measured at 236 nm against blank pH 7.4 phosphate buffer by UV spectrophotometer.

Primary skin irritation test ¹⁰.

This test is 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.

The test was performed on six healthy rabbits weighing around 1.2 to 1.5 kg. the dorsal surface of the rabbits was cleared and the hair was removed by shaving. The skin was cleaned with rectified spirit. The patche (F7) was placed over the skin with the help of adhesive tape. They were removed after 24 hrs and the skin was examined for any untoward reaction. No signs of erythema, edema or ulceration was observed.

RESULTS AND DISCUSSIONS:

The solvent casting technique was used to prepare the transdermal films of LH. It was found that prepared films were transparent, smooth, thin and flexible. The physicochemical evaluation data revealed that there were no physical changes in terms of appearance, colour and flexibility at room temperature at which the films were stored. An ideal patch must be developed in a way so that it should have smooth surface which should not constrict for a given period of time. The result of flatness is shown in table 2, where low value of standard deviation indicates the uniformity of the patches. It was also clear from the flatness study that none of the formulation had much difference in the strip length before and after cutting. The flatness observed for almost all the patches was much closer to 100% which indicates a very little constriction in the film which in turn was the characteristic of smooth and flat surface of the patches and these formulations maintained uniform surface when they were applied on skin for evaluation.

The thickness of the transdermal films were found to be in the range of 0.024-0.026 mm among which the film prepared with polymer EC: PVP (0.5:1.5) had least thickness.

The folding endurance indicates the measurement of the ability of the patches to withstand the breaking or cracking during its usage. The folding endurance was measured manually and the results revealed that the patches had sufficient integrity. The value of folding endurance was found to be higher for the patches prepared with the combination of HPMC and PVP.

The tensile strength tells the strength of a patch while it is subjected for a tension. From the experiment it was found that the patch prepared with combination of PVP: HPMC (1.5:0.5) had highest tensile strength.

The data related to moisture content provides the information about the stability of the prepared formulation, especially when the inherent moisture present in the formulation may influence the stability of the dosage form and if the drug is sensitive to water. The results of the moisture content studies for all the formulations are shown in table 2. The data reveals that there was a small variation for all the formulations evaluated however there was an increase in moisture content with increase ratio of the hydrophilic polymer. The transdermal films were found to contain low moisture which in turn could help the patches to remain stable for a longer period of time. Moisture uptake also influences the stability of the dosage form. Low moisture uptake protects the material from the microbial contamination. So for transdermal patches it is necessary to determine the percentage moisture uptake of the matrices. The experimental data (Table 2) reflects that the moisture uptake of the transdermal patch was low which could also reduce the bulkiness of the film.

As expected the WVTR was found to be more for the formulations containing the hydrophilic polymer PVP. It may be attributed due to the fact that because of the more affinity of the films prepared with hydrophilic polymer PVP towards moisture.

A transdermal patch allows controlling the overall release pattern of the active molecule through an adequate and appropriate selection of the polymer, permeation enhancer, plasticizer with their combination and concentration. The various mechanistic pathways were generated due to the blend of the polymers to maintain the desired steady release of the drug from the patches. In vitro release profile is an important aspect for the evaluation of transdermal patches because it can predict that how a drug molecule will act in vivo. It is also required to approximately estimate the duration and rate of drug release. From the drug release pattern, it can be stated that the rate of drug release was rapid during the first two hours period which might be due to the rapid dissolution of the drug on skin surface, which in turn can prove useful for the dermal penetration of the drug. The drug release study of the formulations was found to show the release of drug loaded patches in the range of 77.96-88.94% as the concentration of hydrophobic polymer was decreased the amount of drug release was increased. This inversely proportional characteristic of the drug-polymer resembled the pattern like release unlike. This may be the result of the initial rapid dissolution of the hydrophilic polymers when the patch was in contact with the skin which in turn results the accumulation of high amount of the drug on the surface of the skin thus leads to the saturation with drug molecules.

Figure 1: Comparison of % moisture absorption of formulation F1 –F3

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

Formu lation code	Weight variation (mg)	% Flatness	Thickness (mm)	Folding endurance	Tensile strength Gm/10Cm^2	Percent elongation	Drug content (%)	Moisture content (%)	Moisture absorption (%)	WVTR
F1	26.50 ± 0.40	99.12 ±0.25	0.025 ± 0.003	102 ± 10.8	15.44 ± 0.42	10 ± 0.072	96.54 ± 0.56	2.506	2.643	0.01692
F2	26.43 ± 0.20	98.32 ±0.15	0.026 ± 0.002	105 ± 6.5	15.13 ± 0.23	9 ± 0.023	96.98 ± 0.23	2.134	2.574	0.01680
F3	26.87 ± 0.16	99.10 ±0.14	0.026 ± 0.006	95 ± 8.6	14.96 ± 0.32	9 ± 0.045	97.35 ± 0.11	1.983	2.321	0.01676
F4	25.95 ± 0.12	98.17 ±0.25	0.024 ± 0.003	119 ± 10.6	15.58 ± 0.85	11 ± 0.052	98.37 ± 0.24	2.632	2.528	0.01704
F5	26.22 ± 0.15	100.0 ±0.19	0.025 ± 0.002	110 ± 12.3	15.36 ± 0.56	10 ± 0.051	97.95 ± 0.32	2.628	2.632	0.01706
F6	26.68 ± 0.12	99.25 ±0.56	0.026 ± 0.005	111 ± 8.5	14.32 ± 0.68	10 ± 0.025	96.58 ± 0.10	2.114	2.136	0.01694
F7	25.83 ± 0.19	100.0 ±0.29	0.025 ± 0.006	124 ± 10.3	15.86 ± 0.28	11 ± 0.041	98.69 ± 0.31	2.642	2.864	0.01718
F8	25.98 ± 0.36	98.23 ±0.43	0.025 ± 0.002	124 ± 11.5	14.89 ± 0.27	10 ± 0.036	98.96 ± 0.15	2.598	2.802	0.01717
F9	26.34 ± 0.15	99.52 ±0.15	0.026 ± 0.005	116 ± 8.9	15.64 ± 0.42	10 ± 0.054	97.42 ± 0.21	2.631	2.624	0.01790

Figure 2: Comparison of % moisture absorption of formulation F4 –F6

Figure 3: Comparison of % moisture absorption of formulation F7 –F9

Figure 4: Comparison of WVTR of formulation F1 –F3

Figure 5: Comparison of WVTR of formulation F1 –F3

Figure 6: Comparison of WVTR of formulation F1 –F3

Figure 7: Percentage drug release of F7

CONCLUSION:

LH holds good promise for administration via transdermal route for the treatment of angina pectoris. The various physico chemical parameters that were evaluated helped to realize the suitability and usefulness of LH to be formulated as a transdermal film with different concentration and blends of the polymers. The effect of permeation enhancer (DMSO) and plasticizer (PG) used to prepare the transdermal film were found to be satisfactory. HPMC, EC and PVP polymer blends have the potential to formulate transdermal films as they have good film forming properties like flatness, thickness, folding endurance and moreover mechanical strength. However in a generalised manner a conclusion can be drawn that the selection of a particular polymer blend can vary the diffusion of the drug in a significant manner. Thus there may be an opportunity to modify the formulation composition like the ratio of polymer and permeation enhancer to get the optimum release for a longer period of time. Considering the experimental data polymer based transdermal patches containing permeation enhance i.e. DMSO can emerge as an efficient tool in drug delivery system for the treatment of angina pectoris, however the pharmacokinetic and pharmacodynamic evaluation of these formulations at pre clinical and clinical level is necessary to establish these findings.

REFERENCES:

1. Sanap G. S., Dama G. Y., Hande A.S., Karpe S. P., Nalawade S. V., Kakade R. S., Jadhav G. Y. Prepartion of transdermal monolithic system of idapamide by solvent casting method and the use of vegetable oils as permeation enhancer. Int. J. of Green Pharmacy 2008; 129-133.

2. Mamatha T., Venkateshwara R., Mukkanti K., Ramesh G. Tansdermal drug delivery systems for atomoxetine hydrochloride invitro and ex vivo evaluation current trends in biotechnology and pharmacy. 2009; 3(2): 1-16.

3. Sharad K., Govil. Transdermal drug delivery system, Drug Delivery Devices by Praveen tyle, 1987: 386-417.

4. Chien, w. Yie, Novel drug delivery systems, Marcel and Dekker Inc., New York, 1987; 2-3, 149-153, 185-193.

5. Giuseppe S., Silvia P. S., Cristina G. Cardiovascular safety of Lercanidipine in patients with angina pectoris: a review of six randomised clinical trials. Current therapeutic research 2001; 62(1): 3-15.

6. Sasaki T., Maruyam H., Kase Y., Takeda S., Aburada M. Antianginal effects of Lercanidipine on vasopressin or methacholine induced angina model in rats. Bio. Pharm Bull 2005; 28(5): 811-816.

7. Barachielli M., Dolfini E., Farina P., Leoni B., Targa G., Vinaccia V., Tajana A. Clinical pharmacokinetics of Lercanidipine. Journal of cardiovascular pharmacology. 1997; 29(P) S1-S15.

8. James S., Kalus and Michael W. G. Alongacting dihydropyridine calcium channel blocker for treatment of hypertension 2002; 37: 234-238.

9. Dang P.M., Manavi F.V., Gadag A.P., Mastiholimath V.S., Jagdeesh T. Formulation of transdermal drug delivery device of Ketotifen Fumarate Indian Journal of Pharmaceutical Science 2003; 65(3): 239-243.

10. Jayaprakash S., Halith M.S., Firthouse P.U.M., Yasim M. Prepartion and evaluation of Celecoxib transdermal patches. Pakistan Journal of Pharmaceutical Science. 2010; 23(3): 279-283.

11. Sanap GS, Dama GY, Hande AS, Karpe SP, Nalawade SV, Kakade RS, et al. Preparation of transdermal monolithic systems of indapamide by solvent casting method and the use of vegetable oils as permeation enhancer. Int J Green Pharm 2008; 2:129-33

12. Murthy TEGK, Kishore VS. Effect of casting solvent on permeability of antihypertensive drugs through ethyl cellulose films. J Sci Ind Res 2008; 67:147-50.

13. Patel HJ, Patel JS, Desai BG, Patel KD. Design and evaluation of amlodipine besilate transdermal patches containing film former. Int J Pharma Res Dev 2009; 7:1-12.

14. Rao V, Mamatha T, Mukkanti K and Ramesh. Transdermal drug delivery system for atomoxetine hydrochloride–in vitro and ex vivo evaluation. Current Trends in Biotechnology and Pharmacy 2009; 3(2):188-96.

15. Kulkarni RV, Mutalik S, Hiremath D. Effect of plasticizers on the permeability and mechanical properties of eudragit films for transdermal application. Ind J Pharm Sci 2002; 64(1):28-31.

16. Panigrahi L, Ghosal SK. Formulation and evaluation of pseudolatex transdermal drug delivery system of terbutaline sulphate. Ind J Pharm Sci 2002; 64:79-82.

17. Murthy TEGK and Kishore VS. Effect of casting solvent and polymer on permeability of propranolol hydrochloride through membrane controlled transdermal drug delivery system. Indian J Pharm Sci 2007; 69(5):646-50.

18. Subramanian K, Sathyapriya LS, Jayaprakash S, Prabhu RS, Abirami A, Madhumitha B et al. An Approach to the formulation and evaluation of transdermal DDS of isoxsuprine HCl. Int J Pharm Sci Tech 2008; 1(1):22-8.

19. Sankar V, Johnson DB, Sivanand V, Ravichandran V, Raghuraman, S, Velrajan G et al. Design and evaluation of nifedipine transdermal patches. Indian J Pharm Sci 2003; 65(5):510-5.

20. Shinde AJ, Garala KC, More HN. Development and characterization of transdermal therapeutics system of tramadol hydrochloride. Asian J Pharm 2008; 2:265-69.

21. Devi KV, Saisivam S, Maria GR, Deepti PU. Design and evaluation of matrix diffusion controlled transdermal patches of verapamil hydrochloride. Drug Dev Ind Pharm 2003; 29(5):495-503.

22. Pandit V, Khanum A, Bhaskaran S, Banu V. Formulation and evaluation of transdermal films for the treatment of overactive bladder. Int J Pharm Tech Res 2009; 1(3):799-804.

Received on 23.08.2013

Modified on 20.09.2013

Accepted on 27.09.2013

© A&V Publication all right reserved

Research Journal of Pharmaceutical Dosage Forms and Technology. 5(6): November-December, 2013, 320-326