Formulation and Characterization of Transdermal Patches for Controlled Delivery of Cyproheptadine

 

K. Chaitanya Prasad1*, Somesetty Pavani1, Ramya Sri S.2

1Department of Pharmaceutics, Samskruti College of Pharmacy,

Affiliated to JNTUH University, Hyderabad 501301, Telangana, India.

2Department of Pharmacy, University College of Technology, Osmania University,

Hyderabad – 500 007, Telangana, India.

*Corresponding Author E-mail: chaitanyaprasadpharmacy@gmail.com

 

ABSTRACT:

The purpose of this research was to develop a matrix-type transdermal therapeutic system containing drug Cyproheptadine with different ratios of polymeric systems by the Solvent evaporation technique by using Dibutyl phthalate to the polymer weight, incorporated as plasticizer. Dimethylsulphoxide were used to enhance the transdermal permeation of Cyproheptadine. The physicochemical compatibility of the drug and the polymers studied by infrared spectroscopy suggested absence of any incompatibility. Formulated transdermal patches were physically evaluated with regard to thickness, weight variation, drug content, flatness, tensile strength and folding endurance. In-vitro drug studies of formulations were performed by using Franz diffusion cells. The results followed the release profile of Cyproheptadine followed mixed peppas release kinetics. However, the release profile of the optimized formulation F3 (98.51% at 12hr) indicated that the permeation of the drug from the patches was governed by a diffusion mechanism.

 

KEYWORDS: Cyproheptadine, Transdermal drug delivery and solvent evaporation technique.

 

 


INTRODUCTION:

Cyproheptadine hydrochloride (CYP) chemically known as 4-(5H dibenzo[a,d]-cyclohepten-5-ylidene)-1-methyl-piperidine HCl. Cyproheptadine is an antihistamine used to relieve allergy symptoms such as watery eyes, runny nose, itching eyes/nose, sneezing, hives, and itching. It works by blocking a certain natural substance (histamine) that our body makes during an allergic reaction. This medication also blocks another natural substance in your body(serotonin).1

 

Transdermal delivery of drugs through the skin to the systemic circulation provides a convenient route of administration for a variety of clinical indications. Pharmaceutical scientists have accepted the challenge of transdermal drug delivery over the last 25 years.2 Transdermal delivery system is currently available for the treatment of various diseases such as cardiovascular diseases, Parkinson’s disease, Alzheimer’s disease, depression, anxiety and attention deficit hyperactivity disorder (ADHD), skin cancer, female sexual dysfunction, post-menopausal bone loss and urinary incontinence.3 The transdermal route of administration cannot be employed for a large number of drugs, only a small number of drug products are currently available via transdermal delivery. In many cases, a drug's physical properties, including molecular size and polarity, have limited its capacity to be delivered transdermally. Similarly, the biological properties of drug molecules, including dermal irritation and insufficient bioavailability, have been problematic.4 Transdermal drug delivery systems have recently developed to achieve the objective of systemic medication through topical application. The transdermal route of drug delivery is becoming popular because large number of drugs can be delivered and various diseases can be treated after transdermal administration5. The drug input can be terminated at any point of time by removing transdermal patch.6

 

Convenient, patient-friendly option for drug delivery with the potential for flexibility, easily allowing dose changes according to patient needs and the capacity for self-regulation of dosing by the patient.7

 

The statical data showed a market of $ 12.7 billion in the year 2005 which is assumed to increase by $ 21.5 billion in the year 2010 and $ 31.5 billion in the year 2015. Almost all the pharmaceutical companies are developing transdermal drug delivery systems.8 The transdermal route now ranks with oral treatment as the most 6 successful innovative research area in drug delivery, with around 40% of the drug delivery candidate products under clinical evaluation related to transdermal system.9 The transdermal drug delivery system promotes various advantages over conventional injectable and oral methods. 10

 

MATERIALS AND METHODS:

Cyproheptadine Procured From Swiss Garnier Life Sciences Pvt. Ltd. Mehatpur., Provided by Sura Labs, Dilsukhnagar, Hyderabad.  Eudragit-L100 and Eudragit-S100 procured from Yarrow-Chem products, Mumbai. Eudragit RSPO and Dichloromethane Procured From Accord labs, Secunderabad. Dibutyl phthalate procured from Karnataka Fine Chem Laboratory Chemicals (Bengaluru, India). Dimethylsulphoxide procured from Avantor Performance Materials India Limited (Haryana, India).

 

Preformulation study:

A. Colour, Odour, Taste and Appearance:

The drug sample was evaluated for its Colour, odour and appearance.

B. Melting point determination:

Melting point of the drug sample was determined by capillary method by using melting point apparatus.

C. Determination of solubility:

The solubility of Cyproheptadine was determined by adding excess amount of drug in the solvent.

The solubility was determined in distilled water and phosphate buffer pH 7.4. The procedure can be detailed as follows.

 

Saturated solution of Cyproheptadine prepared using 10 ml. of distilled water/ phosphate buffer pH 7.4 in 25 ml volumetric flasks in triplicate. Precaution was taken so that the drug remains in medium in excess. Then by using mechanical shaker, the flasks were shaken for 48 hours. The sample withdrawn (1 ml after filtration) was diluted with appropriate medium and analyzed by using UV spectrophotometer at 286 nm and 288 nm for phosphate buffer and distilled water respectively.

 

Formulation of drug incorporated transdermal patches:

Solvent evaporation technique:

The matrix-type transdermal patches containing Cyproheptadine were prepared using different concentrations of Ethyl Cellulose, HPMC and Eudragit RSPO polymers. The polymers in different concentrations were dissolved in the respective solvents. Then the drug was added slowly in the polymeric solution and stirred on the magnetic stirrer to obtain a uniform solution. Dibutyl phthalate was used as plasticizers. Then the solution was poured on the Petri dish having surface area of 78 cm2 and dried at the room temperature. Then the patches were cut into 2x2 cm2 patches. Drug incorporated for each 2x2 cm2 patch. The formulation table is given in table no.

 

Table 1: Formulation of Cyproheptadine patches

INGREDI-ENTS

FORMULATION CHART

F1

F2

F3

F4

F5

F6

F7

F8

F9

Cypro-heptadine

4

4

4

4

4

4

4

4

4

Ethyl Cellulose

30

60

90

-

-

-

-

-

-

HPMC

-

-

-

30

60

90

-

-

-

Eudragit RSPO

-

-

-

-

-

-

30

60

90

PEG-400 (ml)

10

10

10

10

10

10

10

10

10

Chloroform

10

10

10

10

10

10

10

10

10

Dimethyl-sulphoxide (ml)

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

Dibutyl

phthalate* (ml)

8

8

8

8

8

8

8

8

8

 

RESULTS AND DISCUSSION:

Initially the drug was tested by UV to know their significant absorption maximum which can be used for the diffusion study of the drug.

 

Figure 1: Standard calibration curve of Cyproheptadine

 

Preformulation study:

Totally, nine formulation trials were done with the aim to achieve the successful matrix type Cyproheptadine transdermal patches. The blend trials prepared for the drug was evaluated for various physical parameters and content uniformity of drug by UV.

 

A. Colour, odour, taste and appearance:

Table 2: Results of identification tests of drug

Parameter

Cyproheptadine

Color

White

Odor

Odorless

Taste

Bitter

Appearance

A white powder

 

B. Melting point determination:

Table 3: Results of melting point determination tests of drug

Drug

Reported melting point

Cyproheptadine

112.3-113.3 0C

 

C. Determination of solubility:

Table 4: Solubility Determination

Solvent

Drug solubility(mg/ml)

Distilled water

0.00206 mg/mL

 

Evaluation of Patch:

The formulations F1 to F9 were varying in thickness when compared to other formulations which is due to the variation in the polymer concentration. Which shows the increase in polymer concentration increases the thickness of patch. For all other formulations it was found to be in between 0.042±0.001 to 0.050±0.001mm.

 

All formulations from F1 to F9 Shows weight variation in between 86±1.53 to 98±1.91mg.

 

Folding endurance from formulations F1 to F9 was found to be in between 70 ± 0.58 to 70 ± 0.58 which can withstand the folding of the skin.

 

All formulations showed % drug content from 95.91 ±6.29 to 99.35 ±2.48.

 


Table 5: Evaluation of patches

Formulation Code

Average weight(mg)

Thickness (mm)

Folding endurance

Flatness

(%)

Flatness

% Drug Content

F1

120±5.93

0.056±0.004

70 ± 5.16

96

Transparent

95.26 ±2.10

F2

119±1.64

0.052±0.002

76 ± 1.52

98

Transparent

98.90 ±0.36

F3

118±0.13

0.059±0.001

72 ± 6.90

98

Transparent

99.83 ±6.29

F4

116±2.60

0.051±0.006

78 ± 0.16

94

Transparent

96.16 ±9.15

F5

119±1.89

0.053±0.004

75 ± 5.72

96

Transparent

98.97 ±4.48

F6

120±6.14

0.055±0.003

71 ± 2.53

96

Transparent

97.43 ±9.99

F7

117±2.79

0.056±0.004

76 ± 7.10

94

Transparent

98.82 ±3.15

F8

119±1.36

0.057±0.001

70 ± 9.98

97

Transparent

98.97 ±2.27

F9

118±0.42

0.054±0.004

71 ± 4.43

97

Transparent

97.34 ±7.60

 

In vitro diffusion study:

All the formulation in vitro diffusion study was carried out by using Franz type diffusion cell under specific condition such as temp maintained at 32 ± 0.5oC. The diffusion was carried out for 12 h and 5 ml sample was withdrawn at an interval of 1 h.

 

Table 6: In vitro drug permeation of Cyproheptadine containing different concentrations of Ethyl Cellulose

Time (hr)

F1

F2

F3

F4

F5

F6

F7

F8

F9

0

0

0

0

0

0

0

0

0

0

1

27.42

25.69

21.41

32.26

27.92

22.92

36.54

30.14

25.30

2

34.39

30.09

27.69

48.78

32.65

30.36

46.41

38.79

31.26

3

47.60

42.16

38.34

55.36

43.89

37.61

55.05

46.23

36.71

4

56.51

50.65

44.61

67.23

54.32

44.53

61.60

52.90

43.82

5

67.62

63.19

50.08

76.98

62.87

51.88

67.35

57.44

50.19

6

78.37

70.67

58.39

87.46

67.90

64.46

75.12

64.15

56.53

7

85.26

78.76

64.56

95.68

75.36

71.87

89.28

73.20

64.75

8

96.78

86.54

71.98

98.14

82.77

79.29

95.46

77.38

72.89

9

99.82

92.34

86.18

 

89.53

86.14

96.65

83.02

79.93

10

 

98.54

90.14

 

97.91

92.49

 

92.11

85.42

11

 

 

95.34

 

 

96.73

 

98.97

90.82

12

 

 

98.51

 

 

 

 

 

95.36


The formulations F7 to F9 were prepared by different concentrations of Eudragit RSPO (30, 60, 90mg) the drug release or drug permeation from the patch was dependence on the concentration of polymer in the matrix. The 30mg (F7) concentration of polymer was showed maximum drug release 96.65 within 9 hours. The 60mg (F8) concentration of polymer was showed maximum drug released at 11 hours 98.97 %. The 90mg (F9) concentration of polymer was showed less drug release 95.36 at 12 h.

 

Among all 9 formulations F3 formulation showed good drug permeation from the patch.

Among all in vitro evaluation parameters F3 formulation passed all evaluation parameters.

 

Kinetic models for Cyproheptadine

 

Figure 2: Graph of peppas release kinetics

 

From the above data the optimized formulation followed peppas release kinetics model rule.

 

Compatibility studies:

IR SPECTROSCOPY:

 

FTIR Spectrum of pure Cyproheptadine drug

 

FTIR of Optimized formulation

 

The compatibility studies of the drug with excipients indicate no characteristic visual changes and no additional peaks were observed during FT-IR studies.

 

CONCLUSION:

The method of preparation of transdermal patches of Cyproheptadine presented in this research work is simple.

 

Transdermal patches were prepared by using Eudragit grade polymers like Ethyl Cellulose, HPMC and Eudragit RSPO. Considering solubility of drug and polymer, the solvent system of Chloroform and Dimethylsulphoxide was chosen. Dibutyl phthalate was used as a plasticizer.

 

All formulation also showed good physicochemical properties like thickness, weight variation, drug content, flatness, folding endurance, Flatness, % drug content and in vitro drug release and the values were found to be within the acceptable limits.

 

The in-vitro release data showed that drug release from the patch formulation have been affected by types of polymer and concentration of polymer.

 

The formulation F3 containing Ethyl Cellulose showed good mechanical and physicochemical properties were selected as a suitable formulation for further studies.

 

The transdermal patches of Cyproheptadine were prepared using the different types of polymers in different concentration with permeation enhancer  and  plasticizer  was  found  to  be completely  compatible  with  the  drug  molecule  and  the designed formulation release the drug in a sustained fashion over a prolonged period of time.

 

Based on the in vitro release studies, formulation F3 were considered as the best formulations.

 

The formulation F3 showed a maximum release and permeation of drug for longer time period up to 12 h. Hence, it can be concluded that Cyproheptadine can be successfully formulated as the transdermal patch that can release the drug for an extended period of time up to 12 hours in a sustained manner. Such a drug delivery system can be used to avoid the side effects associated with the therapy and can safely deliver the drug with better patient compliance.

 

Based on the observations, it can be concluded that the attempt of formulation and evaluation of the Cyproheptadine patches was found to be successful in the release of the drug for an extended period of 12 hrs.

 

ACKNOWLEDGEMENT:

Thе Authors arе thankful to Principal, Department of Pharmacy, Samskruti College of Pharmacy, Hyderabad, for extending the support to carry out the research work. Finally, the authors express their gratitude to the Sura Labs, Dilsukhnagar, Hyderabad, for providing research equipment and facilities.

 

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Received on 08.10.2022         Accepted on 11.11.2022        

Accepted on 01.12.2022        ©A&V Publications all right reserved

Research J. Topical and Cosmetic Sci. 2022; 13(2):71-75.

DOI: 10.52711/2321-5844.2022.00012