Sciresol Sciresol Journal of Pharmaceutical Research 2454-8405 10.18579/jopcr/v17.4.shahla ORIGINAL ARTICLE Design and Evaluation of Transdermal Patches of Nicorandil Nicorandil transdermal patch design & evaluation Hosseini Shahla 1 Sudheer Preethi 1 Department of Pharmaceutics, Krupanidhi College of Pharmacy Bengaluru, Karnataka India 17 4 27 2018 Abstract

Objectives: The purpose of this study was to develop a transdermal patch containing the drug nicorandil with different ratios of Eudragit RL 100 polymeric by solvent casting method.

Methods: The prepared patches were evaluated for physicochemical characterization, thickness uniformity, mass uniformity, drug content uniformity, folding endurance, moisture loss, FTIR, SEM, in vitro release, ex vivo permeation, and stability studies.

Findings: The results of the studies suggest that formulated transdermal patches with good physical properties and drug content were obtained by the solvent casting method. Surface morphological studies indicated uniform distribution of drugs in the polymeric patch formulation. The in vitro diffusion study suggested that drug release was controlled by all six formulations in comparison with the pure drug. The cumulative release of the drug in phosphate buffer pH 6.8 from formulations (F1-F6) ranged between 89.55±0.62- 78.52±0.63% in a 12-hour study. Ex vivo results showed a good correlation with the in vitro study results. About 89.55±0.62% of the drug from (F4=drug: polymer 1:4) permeated through the rat abdominal skin sample over a period of 12 h.

Novelty: Transdermal patches could be a good alternative for controlled drug therapy with nicorandil.

 Keywords Nicorandil Eudragit Transdermal patches Controlled release In vitro release Introduction

The conventional dosage forms, including tablets, capsules, ointments, liquids, and injectable drugs, have been primary means for treating both acute diseases and chronic illnesses, by administering drugs to patients. This type of drug delivery system promotes drug release. To ensure that the drug concentration remains within the therapeutic range required for effective treatment, it is necessary to administer this type of drug delivery system multiple times per day. This results in significant fluctuations in drug levels. Further, the conventional dosage forms used for the control of infection, pain and fertility may cause side effects like nausea, vomiting, gastric irritation, and toxicity if they are consumed for long duration 1.

Thus, the novel drug delivery system points to releasing one or more drugs continuously for a fixed period of time in a predetermined pattern, either systemically or to a specified target organ. Transdermal drug delivery systems (TDDS) are also known as “patches” 2. Transdermal therapeutic systems are a type of self-contained, discrete dosage form that delivers a drug at a controlled rate to the systemic circulation when applied to intact skin. The ability of TDDS to deliver drugs with systemic effects through intact skin while bypassing first-pass metabolism has accelerated transdermal drug delivery research in the field of pharmaceutics. Skin formulations can be classified into two categories according to the target site of action of the drugs. One has systemic action after administration, and the other exhibits localized effects in the skin 3, 4. Transdermal systems are typically designed to administer actives at a constant rate for several hours to days after application to the skin in a manner that approximates zero-order kinetics 5. The advantage of using a transdermal drug delivery route over other types of medication is that it allows for the controlled release of the medication into the patient. This is typically achieved through a porous membrane that covers a reservoir of medication or by melting thin layers of medication embedded in the adhesive. The application of drugs to specific areas of the body is a common method for administering systemically active drugs. These drugs are absorbed into the systemic circulation and transported to their target site to produce a therapeutic effect. This route of administration is often used for drugs that need to be applied directly to a particular area of the body. A self-contained, discrete dosage form which, when applied to intact skin, delivers the drug through the skin at a controlled rate to the systemic circulation. Transdermal delivery offers an advantage over injectable and oral routes because it enhances patient compliance and bypasses the first-pass metabolism.

Nicorandil (N‐[2‐hydroxyethyl] nicotinamide nitrate [ester]) is one of the most emerging molecules belonging to a class of compounds known as potassium channel activators. It is the first therapeutic molecule to hyperpolarize muscle cell membranes and is a potent coronary vasodilator, which exerts its action by arteriodilation and vasodilation. It has an oral bioavailability of approximately 75%, protein binding around 25%, a short half-life of about 1 h, and the usual oral dosage regimen is 5–40 mg taken two-four times a day. The undesirable consequences of nicorandil use may include headaches, and dilation of blood vessels, resulting in flushing, nausea, vomiting, and loss of strength. Oral ulceration has long been recognized as a major side effect of nicorandil treatment, but more recently, it has been associated with ulceration of any region of the gastrointestinal tract, including the perianal area, and may cause withdrawal of nicorandil 6. To promote better patient compliance and decrease the need for regular administration, it would be beneficial to prescribe nicorandil as a TDDS at a single daily dose. Hence, this study involved the development and evaluation of transdermal drug delivery systems containing nicorandil 7, 8, 9, 10.

 Methods

The reagents used in this study were of pharma grade or the best possible laboratory reagent (LR) supplied by the manufacturer, and double-distilled water was used in all experiments.

Preformulation studies

Preformulation testing was performed to investigate the physiochemical properties of the drug substance alone and in combination with excipients.

Melting point determination

Melting point determination of the obtained drug samples was performed using the open capillary method. The drug was taken in a glass capillary whose end was sealed by a flame. The capillary-containing drug was dipped in liquid paraffin inside a melting point apparatus. The melting point is a good first indication of the purity of the sample because the presence of a relatively small amount of impurity can be detected by lowering and widening the melting point range.

 Determination of lambda max

A stock solution of 1 mg/ml nicorandil was prepared by dissolving 100 mg of the drug in 100 ml phosphate buffer solution (PBS) at pH 6.8. The stock solution was then diluted to a concentration of 10 µg/ ml. The solution was scanned between 200 nm and 400 nm.

 Calibration curve of Nicorandil in phosphate buffer pH 6 8

A stock solution of 1 mg/ml nicorandil was prepared by dissolving 100 mg of the drug in 100 ml phosphate buffer solution (PBS) at pH 6 .8. The stock solution was diluted to obtain Beer’s concentration range of 5 to 40 mcg/ml. A calibration curve was constructed by plotting the absorbance vs. concentration.

 Formulation of nicorandil loaded patches <xref id="xref-c1777818003645eda75097f7e3bf9210" rid="R235364930938690" ref-type="bibr">11</xref>

A transdermal patch of nicorandil was prepared using the solvent casting method for the formulations shown in Table 1. The weighed quantity of Eudragit was dissolved in 25 ml acetone. To the above solution, the required quantity of nicorandil was added and 0.1 ml of plasticizer was mixed and stirred for 10 min. The drug-polymer solution was cast in a Petri dish and dried at room temperature for 24 hours. An inverted funnel was placed over the Petri dish to prevent air currents. After drying, the patches were peeled from the Petri dish, wrapped in aluminum foil, and preserved in desiccators for further studies.

<bold id="strong-d60b48fd4958467fa1e90449ff896811"/> <bold id="strong-34581ade803e4568bb84dd4a1bdc9d69"> <bold id="strong-1218c4e814fc44bebdd5f38890ea083b">Formulation</bold> </bold>

Ingredients

F1

F2

F3

F4

F5

F6

Nicorandil (mg)

450

450

450

450

450

450

Eudragit RL-100 (mg)

500

1000

1500

2000

2500

3000

Glycerin (mL)

0.5

0.5

0.5

0.5

0.5

0.5

Acetone (mL)

25

25

25

25

25

25
Characterization of patches <xref rid="R235364930938691" ref-type="bibr">12</xref>, <xref rid="R235364930938698" ref-type="bibr">13</xref> Physical appearance

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

 Thickness uniformity <xref id="xref-5f78559401ee49fa86c40b6715bef5e5" rid="R235364930938689" ref-type="bibr">14</xref>

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

 Mass uniformity <xref id="xref-e0f42d5a0a724ecaa9e42df341f1b845" rid="R235364930938699" ref-type="bibr">15</xref>

A patch of size 2×2 cm2 was cut, the weight of each patch was taken individually, and the average weight of the patch was calculated.

 Folding endurance

The folding endurance was measured manually for the prepared patches. A strip of the patch (2×2 cm2) was cut and repeatedly folded at the same place until it broke. The number of times the film could be folded at the same time without breaking gave the value of the folding endurance.

 Percentage moisture loss

The patches were individually weighed and stored in a desiccator containing calcium chloride. The final weight was noted, and there was no change in the weight of the individual patches. The percentage moisture content was calculated as the difference between the initial and final weights with respect to the final weight.

 Drug content uniformity <xref id="xref-480bfa4b05384fbaa4bfa7038ad5cbde" rid="R235364930938703" ref-type="bibr">16</xref>

The patches were then tested for content uniformity. Patches of size 1 cm2 were cut and placed in a 100 ml volumetric flask. The contents were stirred using magnetic beads for 24 hours to dissolve the patches. Subsequent dilutions were prepared using a phosphate buffer (pH 6.8). The absorbance of the solution was measured against the corresponding blank solution at 260 nm by using a UV-visible spectrophotometer. The experiment was repeated three times to validate the results.

 Drug polymer interaction by Fourier Transform Infrared (FTIR) Spectroscopy

Infrared spectra of the pure drug, physical mixture of drug with polymers, and formulation were obtained using the KBr pellet technique and were recorded in the range of 4000 – 400 cm using an FTIR Spectrophotometer.

 Scanning electron microscopic analysis of Nicorandil patches

The patches were mounted onto stubs using double-sided adhesive tape and sputter-coated with platinum using a sputter-coater. The patches were observed under the SEM at the required magnification at room temperature. The acceleration voltage used was 10 kV, and the secondary electron image was used as a detector.

 In vitro release studies <xref rid="R235364930938696" ref-type="bibr">17</xref>, <xref rid="R235364930938702" ref-type="bibr">18</xref>, <xref rid="R235364930938705" ref-type="bibr">19</xref>

The fabricated patches were cut into 2.5 cm2 and placed on the commercial semi-permeable membrane (regenerated cellulose which was permeable to low molecular weight substances) and attached to the diffusion cell such that the cell’s drug-releasing surface towards the receptor compartment which was filled with phosphate buffer solution of pH 6.8 at 37 ± 1°C. The elution medium was then magnetically stirred. Aliquots (1 mL) were withdrawn at predetermined time intervals and replaced with equal volumes of phosphate buffer (pH 6.8). The drug content of the samples was analyzed using a UV spectrophotometer at 262 nm.

 Ex vivo permeation studies

An ex vivo permeation study was performed on albino rats. The excised skin of albino rats is made free of hair by shaving. The test was conducted on the unbraded skin of the rats. The skin was cleared using a rectified spirit and attached to the selected patch formulation. This was placed between the donor and receptor compartments of the Franz diffusion cell. Aliquots from the receptor compartment were collected and tested for the quantification of drug permeated via the excised skin 20, 21.

 Stability studies <xref id="xref-29394e3f15ce4759b8518f61d97f8c3c" rid="R235364930938705" ref-type="bibr">19</xref>

The purpose of the stability study was to provide evidence of the quality of a drug substance or drug product which varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light. The formulation was selected on the basis of its physicochemical characteristics and drug content. The formulation was subjected to accelerated stability studies according to the International Conference on Harmonization guidelines. The most satisfactory formulation was sealed in aluminum foil and stored at 30 ± 2°C, 65 ± 5% H, 40± 2°C, and 75 ± 5% RH for 4 weeks.

 Results Preformulation Studies <bold id="strong-5a98cb1d6a0842debb8bb8674a2fa373">Melting</bold> <bold id="strong-002c7bd1d6aa4769bac4c5dc92e3533f"> </bold> <bold id="strong-c722491d2bf043a2a7fa3f09c383ea87">point</bold> <bold id="strong-c9ae5d6d45a24a03935e455e3e5637b2"> </bold> <bold id="strong-eb3b8511e85f4732b0612ed8678450de">determination</bold>

The melting point of nicorandil was 92°C which complied with the BP standards, indicating the purity of the obtained drug sample.

 <bold id="strong-bd78a0ef897648409d748561da6affad">lambda max of nicorandil</bold>

The Nicorandil is soluble in water, soluble in alcohol, methyl alcohol, freely soluble in acetone, dimethyl formamide. The lambda max (λmax) of nicorandil was 260 nm in 6.8 Phosphate buffer.

 <bold id="strong-59fde60b53be4797bec4165d8ff437f7">Calibration curve of Nicorandil</bold>

The standard curve yielded a straight line, which indicated that the drug obeyed Beers/Lambert’s range in the concentration range of 5 – 40 µg/mL (Figure 1). The regression co-efficient was found to be 0.9988.

<bold id="strong-1ca73b7e421040ff840fb64addadfeb3"/> <bold id="strong-7835306c4de64df0930483fafeed816c"/> <bold id="strong-2dd78b848faa4d9fae44b42ec35162dd">Standard</bold> <bold id="strong-0c2a07bd43f845fb8eb72e0068f1a464"> </bold> <bold id="strong-cd68ee65ffb14c6ca17bf352aa4bc0dd">calibration</bold> <bold id="strong-f16ded55d04645608ee2b0b2a86abd01"> </bold> <bold id="strong-7dcdde18bd624835b76f09117d3ba82c">curve</bold> <bold id="strong-8a11475bdba245688f293a4843a3f50a"> </bold> <bold id="strong-7770f85365504cd7bdb02d109be6b22c">for nicorandil</bold> <bold id="strong-f647b05966ae408eb7de0137c5cb91a7"> </bold> <bold id="strong-864d6ebb3d3f42868f76c76bdce0735d">in</bold> <bold id="strong-a76dc4eba58847c8a42bf1ce76e21920"> </bold> <bold id="strong-8bacedcbf7194383babc3d67bd8d6341">Phosphate</bold> <bold id="strong-07ac600fca8746729f36c8ffb1777f31"> </bold> <bold id="strong-9bf0a02ddf1246d69de4cb66f2aea2d1">buffer</bold> <bold id="strong-131c4fd9c1f74f55bca18f7508ff69bc"> </bold> <bold id="strong-3b6d040649be4b749f0d372ff4af58e0">pH</bold> <bold id="strong-a0f6a25e85f948c6a46f1fe912661a61"> </bold> <bold id="strong-2abc1b90dcc34f50931c1ec4bf591a47">6.8</bold> <bold id="strong-2b303a41adee49e99f1f86c60a9b2fad"> </bold> <bold id="strong-15d86010709d46b196f594d539104322">at</bold> <bold id="strong-314a3177c80d4ba492b85ce424bd1422"> </bold> <bold id="strong-82497e1d0d1a4b0db4aac49b50aff9b1">260nm</bold> Characterization of patches

The characterization of the patches is presented in Table 2. The drug content varied from 99.28 + 0.12 to 99.41 + 0.21%.

<bold id="strong-7bd9a72811d04b49ad573355dc778614">Evaluation of</bold> <bold id="strong-10f0dbae488a404fa07498ef4c60bd73"> </bold> <bold id="strong-2c099129008f4ea1a9cfc7fc6b1db915">patches</bold>

Formula code

Physical appearance

Thickness (mm)

Mass uniformity (mg)

Folding endurance

Drug content uniformity (%)

Moisture loss (%)

F1

Clear

0.35±0.51

12.23±1.11

125±0.32

99.28±0.12

7.486±0.185

F2

Clear

0.37±0.84

18.25±0.98

128±1

99.30±0.14

5.216±0.271

F3

Clear

0.38±0.78

24.78±0.67

131±0.88

99.35±0.17

6.48±0.248

F4

Clear

0.40±0.56

30.67±1.08

134±0.5

99.36±0.19

9.17±0.258

F5

Clear

0.42±0.65

35.76±0.99

136±0.98

99.37±0.2

6.813±0.0750

F6

Clear

0.43±0.56

41.23±0.67

140±0.67

99.41±0.21

4.55±0.227
Drug polymer interaction (FTIR) study

The spectra of nicorandil, polymers, and the physical mixture of nicorandil and polymers showed that all characteristic peaks of nicorandil were present in the combination spectrum, thus indicating compatibility of the nicorandil and polymer (Figure 2, Figure 3).

<bold id="strong-28c3efe1e233406d967d07994e795f04">FTIR</bold> <bold id="strong-94cc42f2649947fe8497eb1f08e29c05"> </bold> <bold id="strong-2ff01aedb7934804b5abfe9ef211ee2a">Spectrum</bold> <bold id="strong-cf7565fc7dfd47e8bdaf55e7395b6861"> </bold> <bold id="strong-5602387b50204d259e395fdbf68a9ac8">of</bold> <bold id="strong-78fc2695226d44a1bb05a0ecfc1ef229"> </bold> <bold id="strong-557458151d5e4b8c9deea85887a813ab">Nicorandil</bold> <bold id="strong-906419aae69d4d65a004202cdf57008d"> </bold> <bold id="strong-133334a44d3444dbae5d2948f7cfa9f3">pure</bold> <bold id="strong-612b7cd54ae14ac09f8632a2e4539d10"> </bold> <bold id="strong-bd45501a3d124478b60c0529aff516cb">drug</bold>

<bold id="strong-c8a400180fbe41b085f97048363eade7"/> <bold id="strong-f363e7f9f6e44c78b145c337762f79fd">FTIR</bold> <bold id="strong-eab1f9386e7549bfb3e5c1e67da67b1e"> </bold> <bold id="strong-fdafbe6ccd2f40c58937c354951bca23">Spectrum</bold> <bold id="strong-136e6bce2b994458a0f3b61c355c4b14"> </bold> <bold id="strong-63f452f055624631a92009b5ab3a7ac6">of</bold> <bold id="strong-f6ccefa3cfea4e7cb698c2d22722e7ac"> </bold> <bold id="strong-c4739b30c3a6468a824f01380a341809">physical</bold> <bold id="strong-ebbfd8062f584fc29bb5163ab4ea6a5b"> </bold> <bold id="strong-993527b0e91e49fea0c5116c47cb6df0">blend</bold> Surface morphology of Nicorandil patches

The SEM analysis revealed the surface morphology (Figure 4, Figure 5). SEM photographs of nicorandil patches indicated a uniform distribution of drug particles in the patches, and slight surface precipitation of the drug may be accounted for by unentrapped drug particles. The patches had a slightly uneven surface texture.

<bold id="s-ed462a0947ce"/> <bold id="s-e20e51fe3739"/> <bold id="s-a241553c7103">SEM</bold> <bold id="s-06e521538010"> </bold> <bold id="s-6c516f62ec48">photograph of</bold> <bold id="s-d112d74f774f"> </bold> <bold id="s-7ceba49cbc0f">Nicorandil</bold> <bold id="s-7bbd78cd3f11"> </bold> <bold id="s-43cf1d656e50">patches<bold id="strong-569bd9588b06464e9588a7b33f1b1a74"/><bold id="strong-269a2994bfad45a791e815dd43926e90"/></bold> <bold id="strong-e67fe641700e4e54ad3d643c2a61df55"/> <bold id="strong-235cfa7f3d7946ef84777310a816971e"/> <bold id="strong-595ad209de1442c7aca914721c9cffae">SEM</bold> <bold id="strong-54c47a6015b94756a1bd0d3dd84d7abe"> </bold> <bold id="strong-782c6c8675814f828054e075274ca236">photograph of</bold> <bold id="strong-f3942981e2224680a170fd92156a7931"> </bold> <bold id="strong-c309f9acd55c44b185d6e6960b3e7809">Nicorandil</bold> <bold id="strong-182efbe5da82474dac3dfff657e0dcd5"> </bold> <bold id="strong-92d8cb740071489eaa9e2c13173add07">patches</bold> In vitro release study

The in vitro performance of the nicorandil patches showed prolonged and controlled release of the drug from all formulations (Table 3 and Figure 6).

<bold id="strong-4fc08c66471c4ccb96864b2866208774"/><bold id="strong-49b530abb872443ba2a78cc9d9897cbb">In-vitro</bold><bold id="strong-918f85aa975541508b439aa7dd429742"> release data</bold> <bold id="strong-96e2ad0b6c4c4d429056baaf843beb4e">from</bold><bold id="strong-c8be243ede8f41f0beef1dfb749cfe8b"> </bold><bold id="strong-ac937a9361ff4ebe9df8b4a2bc197684">Nicorandil</bold><bold id="strong-731b88027578405dbc77630853815f15"> </bold><bold id="strong-35f94323c1b14208aba0c54b0bb04744">patches</bold>

% Cum. Drug release*

Time (hr)

FI

F2

F3

F4

F5

F6

Pure drug

0

0

0

0

0

0

0

0

0.5

16.22± 0.23

15.86± 0.66

16.01± 0.36

13.25± 0.54

10.1± 0.46

9.10±0.45

35.55± 0.54

1

22.04± 0.88

18.64± 0.56

19.01± 0.54

19.27± 0.47

17.84± 0.53

16.83±0.52

48.31± 0.67

2

29.45± 0.65

26.15± 0.78

27.2± 0.71

27.53± 0.33

23.72± 0.36

22.70±0.33

82.52± 0.25

3

36.55± 0.75

36.88± 0.64

35.82± 0.49

35.62±0.65

30.11± 0.29

29.10±0.28

95.42± 0.66

4

44.11± 0.66

41± 0.81

42.22± 0.57

39.53± 0.45

37.86± 0.78

36.85±0.68

-

5

49.55± 0.89

46.01± 0.67

47.15± 0.66

44.02± 0.58

42.01± 0.32

41.01±0.22

-

6

56.64± 0.67

57.26± 0.39

56.57± 0.59

50.21± 0.66

48.01± 0.36

47.01±0.26

-

7

63.26± 0.55

60.54± 0.81

59.26± 0.81

55.9± 0.39

52.01± 0.52

51.01±0.42

-

8

71.88± 0.48

65.31± 0.66

62.54± 0.54

63± 0.57

58.88± 0.45

57.78±0.35

-

9

79.82± 0.58

70.33± 0.54

68.8± 0.67

72.22± 0.77

65.21± 0.71

64.11±0.61

-

10

83.55± 0.69

74.41± 0.67

71.56± 0.58

76± 0.53

70.33± 0.54

69.33±0.51

-

11

86.45± 0.73

78.94± 0.55

76.32± 0.66

79.12± 0.45

75.01± 0.63

74.01±0.53

-

12

89.55± 0.62

87.66± 0.12

85.02± 0.26

82.79± 0.42

78.52± 0.62

77.42±0.52

-

All the values are expressed a mean ± SD Standard deviation (n=3)

<bold id="strong-997dd041b8d94bd28db4e8306cde88bd"/> <bold id="strong-b100f89eb99a4ebd904236e6c3b3c1ff"/> <bold id="strong-8eb2f7a14ca1460eb61fe6d85d42bb8e">In-vitro</bold> <bold id="strong-886c64d312324a22a8250c6d6003d07d"> </bold> <bold id="strong-24e01618d2984b1caf1a5e87b194e374">release </bold> <bold id="strong-fc2f57b703124d348d925ac4cda5ab61">profile</bold> Ex vivo permeation study of selected formula F4

Ex vivo permeation studies of the selected formulation (F4) were performed using excised rat abdominal skin samples. An ex vivo permeation study of the selected formulation was carried out and compared with that of the pure drug, and the results were found to be in good agreement with those of the in vitro release study (Table 4 and Figure 7).

<bold id="strong-277c01293ab647c192701a7cf8f7664f">Ex-vivo</bold> <bold id="strong-716e4eca1de8446981e916690381981a"> </bold> <bold id="strong-66e83b3d14d649a6b5ed3a892c9a9f60">permeation</bold> <bold id="strong-2c520d59818a462db5569d7945fe4e1c"> </bold> <bold id="strong-f423184f535c4afe942ca507cb977b65">study</bold> <bold id="strong-18fa03e9497f4a7ab0fedde1a1b32ca2"> </bold> <bold id="strong-e5b825f9aa5b4c828e91da512b0d6abe">of</bold> <bold id="strong-3cf96cb1c9824cfabf6dd842b663060c"> </bold> <bold id="strong-6e7df305ab4d47e3bae63db0b9cf46e8">optimized</bold> <bold id="strong-e75f649885ce45c2adce49e7a24a569f"> </bold> <bold id="strong-7723769b09214bc5b38158ff4ed5d275">formula</bold> <bold id="strong-f59c0bc81c334aa1be9f5909c39f4394"> </bold> <bold id="strong-6b092a3c588146928019e7b42c571149">F4</bold>

Time (hrs)

%CDR

Nicorandil (pure)

F2

0.5

4.11± 0.004

10.24 ± 0.008

1

7.53± 0.002

17.32 ± 0.012

2

10.34± 0.012

22.56 ± 0.006

3

13.52± 0.016

29.12 ± 0.031

c4

18.16± 0.008

33.43 ± 0.022

5

22.52± 0.006

37.15 ± 0.009

6

26.92± 0.004

42.54±0.001

7

33.17± 0.012

49.15 ± 0.042

8

40.23± 0.024

54.21 ± 0.056

9

43.42± 0.034

60.89 ± 0.014

10

48.26± 0.012

68.55 ± 0.008

11

51.53± 0.006

75.41 ± 0.010

12

59.15± 0.005

88.11 ± 0.024
<bold id="s-3495a16435f3">Comparative Ex-vivo permeation profile</bold> Stability studies

The selected formulation (F4) was subjected to accelerated stability studies at 25°C ± 2°C / 60% ± 5% RH and 40°C ± 2°C / 75% ± 5% RH, as shown in Table 5.

<bold id="strong-7af3d4ec7ade46f2b311f17e5e2fb7c7"/> <bold id="strong-26421cfa9d4344e0b476373fe43920e3"> <bold id="strong-1331d1af85d248679aeb67dacb45b403">The</bold> </bold>

No. of days

25 °C ± 2 °C / 60% ± 5% RH

40 °C ± 2 °C / 75% ± 5% RH

Physical Appearance

Average % drug content

Physical Appearance

Average % drug content

0

No Change

99.01

No Change

98.55

15

No Change

99.12

No Change

98.11

30

No Change

98.88

No Change

98.45

45

No Change

98.99

No Change

98.13

60

No Change

98.96

No Change

98.19
Discussion

The development of a transdermal patch is a suitable method to increase bioavailability. In the present study, we aimed to develop and evaluate transdermal patches of nicorandil for controlled drug delivery systems to prevent unwanted systemic side effects. Five formulations were prepared using Eudragit RL 100 as a polymer. A different transdermal patch formulation was observed for the evaluation parameters, and the F4 formulation was found to be the best formulation. The prepared nicorandil patches were evaluated for their appearance, uniformity, thickness, SEM analysis, drug content, in vitro release kinetics, and ex vivo permeation. The compatibility of the drug-polymer was checked using FTIR spectroscopy.

All patches were thin, elastic, smooth, flexible, and transparent; their uniformity and thickness were within the acceptable range. FTIR spectroscopy was performed to determine the compatibility between nicorandil and the Eudragit polymer used for the preparation of nicorandil patches. Characteristic peaks in the region were observed for combinations of drugs and polymers which were identical to those of the pure drug. This confirmed that there was no interaction between the drug and polymers.

F4 which contained 450 mg of nicorandil and 1500 mg of Eudragit RL-100, showed drug release for 12 h. Patches F4 were prepared by incorporating permeation enhancers and showed promising results. Transdermal skin irritation was tested in rats and no significant irritation was observed. SEM analysis showed that the patches had a slightly uneven surface texture. The in vitro performance of the nicorandil patches showed prolonged and controlled release of the drug from all formulations. An ex vivo permeation study of the selected formulation was carried out and compared with that of the pure drug, and the results were found to be in good agreement with those of the in vitro release study.

 Conclusion

In this study, controlled nicorandil patches were developed to reduce side effects by regulating drug release through the skin. This was effectively accomplished using the solvent method with varying concentrations of Eudragit RL100. The F4 formulation exhibited a strong correlation with the in vitro drug release profile compared to that of the pure drug. Therefore, it can be inferred that the transdermal delivery system of nicorandil serves as a favourable alternative to oral and parenteral drug therapy because of its non-invasive and patient-friendly nature, resulting in sustained therapy over an extended duration.

 References Chien Y W Concepts and system design for rate-controlled drug delivery in Novel drug delivery systems 1992 2 1 38 Marcell Dekker Inc New York Bhowmik Avit Kumar Cabral Pedro Cyclone Sidr Impacts on the Sundarbans Floristic Diversity Earth Science Research 2013 2 62 79 1927-0550, 1927-0542 Canadian Center of Science and Education https://dx.doi.org/10.5539/esr.v2n2p62 Jain NK Jain NK Advances in controlled and novel drug delivery CBS publishers & distributors 2008 1 470 Allen V Loyd Nicholas G Popovich N G Ansel Howard C Pharmaceutical dosage forms and drug delivery systems 8 2005 298 299 https://rudiapt.wordpress.com/wp-content/uploads/2017/08/ansels-pharmaceutical-dosage-forms-and-drug-delivery-systems-10th-ed.pdf Pratibha V Mahavir C Ashwini G Mangesh P K Transdermal delivery: A recent trend in treatment of chronic diseases BioMedRx 2013 1 5 473 482 https://www.researchgate.net/publication/339738615_Transdermal_Delivery_A_Recent_Trend_in_Treatment_of_Chronic_Diseases Hiremath J G Valluru R Jaiprakash N Katta S A Matad P P Pharmaceutical aspects of nicorandil International Journal of Pharmacy and Pharmaceutical Science 2010 2 4 24 33 https://www.innovareacademics.in/journal/ijpps/Vol2Issue4/785.pdf Frydman Armand M. Chapelle Philip Diekmann Herbert Bruno René Thebault Jean J. Bouthier Jean Caplain Henri Ungethuem Wolfgang Gaillard Claude Liboux Aimé Le Renard Alain Gaillot Jean Pharmacokinetics of nicorandil The American Journal of Cardiology 1989 63 21 J25 J33 0002-9149 Elsevier BV https://dx.doi.org/10.1016/0002-9149(89)90201-4 Jani R K Patel J K A review on delivery of antihypertensive drugs through trans-dermal systems International Journal of Pharmacology and Clinical Sciences 2012 1 1461 74 https://ijpcsonline.com/files/files/37-288.pdf Rastogi V Pragya P U A brief view on antihypertensive drugs delivery through transdermal patches International Journal of Pharmaceutical Sciences and Research 2012 3 7 1955 1955 https://ijpsr.com/bft-article/a-brief-view-on-antihypertensive-drugs-delivery-through-transdermal-patches/ Selvam R P Singh A K Sivakumar T Transdermal drug delivery systems for antihypertensive drugs-A review International Journal of Pharmaceutical and Biomedical Research 2010 1 1 1 8 Verma P R P Iyer Sunil S Controlled Transdermal Delivery of Propranolol Using HPMC Matrices: Design and In-vitro and In-vivo Evaluation Journal of Pharmacy and Pharmacology 2010 52 2 151 156 0022-3573 Oxford University Press (OUP) https://doi.org/10.1211/0022357001773797 Aqil M. Sultana Yasmin Ali Asgar Dubey Kiran Najmi A. K. Pillai K. K. Transdermal Drug Delivery Systems of a Beta Blocker: Design, In Vitro, and In Vivo Characterization Drug Delivery 2004 11 1 27 31 1071-7544, 1521-0464 Informa UK Limited https://dx.doi.org/10.1080/10717540490265225 Shin Sang-Chul Shin Eun-Young Cho Cheong-Won Enhancing Effects of Fatty Acids on Piroxicam Permeation Through Rat Skins Drug Development and Industrial Pharmacy 2000 26 563 566 0363-9045, 1520-5762 Informa UK Limited https://dx.doi.org/10.1081/ddc-100101269 Gupta S P Jain S K Effective and controlled transdermal delivery of metoprolol tartarate Indian Journal of pharmaceutical sciences 2005 67 3 346 350 https://www.ijpsonline.com/articles/effective-and-controlled-transdermal-delivery-of-metoprolol-tartarate.pdf Pongjanyakul Thaned Prakongpan Sompol Priprem Aroonsri Acrylic Matrix Type Nicotine Transdermal Patches: In Vitro Evaluations and Batch-to-Batch Uniformity Drug Development and Industrial Pharmacy 2003 29 8 843 853 0363-9045, 1520-5762 Informa UK Limited https://dx.doi.org/10.1081/ddc-120024180 Nalluri Buchi N. Milligan Caitlin Chen Jianhong Crooks Peter A. Stinchcomb Audra L. In Vitro Release Studies on Matrix Type Transdermal Drug Delivery Systems of Naltrexone and Its Acetyl Prodrug Drug Development and Industrial Pharmacy 2005 31 9 871 877 0363-9045, 1520-5762 Informa UK Limited https://dx.doi.org/10.1080/03639040500271944 Tipre Dnyanesh N. Vavia Pradeep R. Formulation Optimization and Stability Study of Transdermal Therapeutic System of Nicorandil Pharmaceutical Development and Technology 2002 7 3 325 332 1083-7450, 1097-9867 Informa UK Limited https://dx.doi.org/10.1081/pdt-120005729 Aggarwal G Dhawan S Development, fabrication and evaluation of transdermal drug Delivery System- A review Pharmainfo.net 2009 Mishra A N Jain N K Transdermal Drug Delivery Controlled and Novel Drug Delivery 2004 101 118 https://www.scribd.com/document/668313752/Controlled-and-Novel-Drug-Delivery-by-N-K-Jain-1st-Editn-Reprint Bergh Benedicte A.I van den Bouwstra Joke A Junginger Hans E Wertz Philip W Elasticity of vesicles affects hairless mouse skin structure and permeability Journal of Controlled Release 1999 62 3 367 379 0168-3659 Elsevier BV https://dx.doi.org/10.1016/s0168-3659(99)00168-6 Ghosh Tapash K. Adir Joseph Xiang Si‐Ling Onyilofur Samuel Transdermal Delivery of Metoprolol II: In-Vitro Skin Permeation and Bioavailability in Hairless Rats Journal of Pharmaceutical Sciences 1995 84 2 158 160 0022-3549 Elsevier BV https://dx.doi.org/10.1002/jps.2600840207