Formulation and Characterization of Tramadol HCl Transdermal Patch

 

Beedha. Saraswathi*, Dr. T. Satyanarayana, K. Mounika, G. Swathi ,  K. Sravika,

M. Mohan Krishna

Department of Pharmaceutics, Mother Teresa Pharmacy College, Sathupally, Khammam Dist, 507303, India.

*Corresponding Author E-mail: sarru.saraswati@gmail.com

 

ABSTRACT:

Transdermal drug delivery leads direct access to the systemic circulation through the skin which bypasses drugs from the hepatic first pass metabolism leading to increase bioavailability. Tramadol HCl has been selected as model drug because it has low bioavailability. It exhibit all physicochemical characteristics required for the transdermal patch. Transdermal patches of Tramadol HCl were prepared by solvent casting method using different polymers i.e. HPMCK4M, HPMCK15M, HPMCE5.Propyleneglycol was used as plasticizer and methanol was used to dissolve the drug. Water was used as solvent to dissolve the polymer. The prepared formulations were evaluated for drug content uniformity, in vitro diffusion study, thickness, tensile strength, moisture content, folding endurances etc. Amongst all formulation, formulation F3 had more desirable characteristic & shows 88.36% drug release in 12hr. Release kinetic can be described by Higuchi model with anomalous diffusion as a release mechanism. The Transdermal patch formulated from HPMCK4M, HPMCK15M and HPMCE5 showed satisfactory physicochemical properties. The ratios of hydrophilic polymers HPMCK4M, HPMCK15M and HPMCE5 good moisture content property, good tensile strength, folding endurances and in-vitro drug release. So, it can be concluded that such a matrix type patches of HPMCK4M, HPMC K15M and HPMCE5 could be a good carrier in transdermal delivery of Tramadol HCl. FTIR studies showed there were no incompatibilities between drug and other excipients.

 

KEY WORDS: Transdermal patch, Tramadol HCl, HPMC.

 

 


INTRODUCTION:

With the advent of new era of pharmaceutical dosage forms, transdermal drug delivery system (TDDS) established itself as an integral part of novel drug delivery systems. Transdermal patches are polymeric formulations which when applied to skin deliver the drug at a predetermined rate across dermis to achieve systemic effects. Transdermal dosage forms, though a costly alternative to conventional formulations, are becoming popular because of their unique advantages.

 

Controlled absorption, more uniform plasma levels, improved bioavailability, reduced side effects, painless and simple application and flexibility of terminating drug administration by simply removing the patch from the skin are some of the potential advantages of transdermal drug delivery. Development of controlled release transdermal dosage form is a complex process involving extensive efforts. This review article describes the methods of preparation of different types of transdermal patches viz., matrix patches, reservoir type, membrane matrix hybrid patches, drug-inadhesive patches and micro reservoir patches. In addition, the various methods of evaluation of transdermal dosage form have also been reviewed. 1-4

 

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. Continuous I.V5. infusion has been recognized as a superior mode of systemic drug delivery that can be tailored to maintain a constant and sustained drug level within a therapeutic concentration range for as long as required for effective treatment. It also provides a means of direct entry into the systemic circulation of drugs that are subjected to hepatic first-pass metabolism and/or suspected of producing gastro-intestinal incompatibility. Unfortunately, such a mode of drug administration entails certain health hazards and therefore necessitates continuous hospitalization during treatment and requires close medical supervision.6

 

Transdermal drug delivery can closely mimic the slow intravenous infusion, without its potential hazards and also offer another most important advantage in allowing the patient to terminate the drug therapy by simply removing the patch at any desired time if toxicity develops. Drugs like estrogens, testosterone, and nitroglycerine when administered orally will be inactivated by gastrointestinal enzymes or environmental difference. Such drugs can now be delivered directly into systemic circulation by a noninvasive transdermal route. On the contrary, transdermal drug delivery mode is not suitable for all drugs, which may be the reason for the fact that only few drugs have been successfully designed and commercialized by different companies. The skin acts as a formidable barrier to the penetration of drugs and other chemicals; it does have certain advantages which make it an alternative route for systemic delivery of drugs. Transdermal drug delivery system involves the passage of substances from the skin surface through the skin layers, into the systemic circulation. 7-10 The skin has been commonly used as a site for topical administration of drugs, when the skin serves as a port for administration of systemically active drugs. The drug applied topically is distributed following absorption, first into the systemic circulation and then transported to the target tissue, which can be relatively remote from the site of drug application to achieve its therapeutic action.

 

Advantages of Transdermal patches:

·         Provide relatively steady and sustained drug concentration in plasma in contrast to conventional systems where peaks and troughs are a common feature.

·         Variability due to factors such as pH intestinal motility, food intake, etc, which make vast difference in the bioavailability of the drugs given through oral route, are not existent.11

·         The hepatic first pass metabolism is avoided.

·         A constant rate of absorption is possible in a vast variety of adverse patient population.

·         Ease of administration and patient convenience.

·         Drug input terminable by mere removal of the Transdermal patches.

·         Drugs that cause gastro intestinal upset can be good candidates for Transdermal delivery because this method avoids direct effects on stomach and intestine.

·         Increased therapeutic value due to avoidance of hepatic first pass effect, gastro intestinal irritation and low absorption problem.12-16

·         Drugs that are having short biological half-life can be given by this therapeutic systems and it also reduces dosing frequency.

·         Transdermal patches are used for cessation of tobacco smoking.

·         Another advantage is convenience, especially notable in patches that require only once weekly application. Such a simple dosing regimen can aid in patient adherence to drug therapy.17-20

 

Disadvantages of Transdermal patches:

·         Can be used only for drugs, which require very small plasma concentrations for action.

·         Local irritation and arythmea are possible. Enzymes in epidermis or derived from micro organisms present on the skin may denature the drugs.20-25

·         Another significant disadvantage of Transdermal drug delivery is that skin is less permeable because it serves as protective barrier for the entry of foreign particles.

·         In order to maintain constant release states, transdermal patches must contain surplus of active drug.26-27

 

MATERIALS AND METHODS:

Tramadol HCl is procured from KP Labs, Hyderabad HPMC K4M, HPMC K15M, HPMC E5, Propylene glycol, Methanol, Glycerin are the gifted samples from Sree Srinivasa Scientifics, Hyderabad.

 

Preparation of Transdermal patches:

Transdermal patches containing Tramadol HCl were prepared by solvent casting method using varying ratios of different grades of polymers and plasticizers in different concentrations as shown in the table 1.

 

Procedure for patch preparation:

The Matrix type Transdermal patches of Tramadol Hydrochloride was prepared by the Solvent casting method as described by Hemangi J. Patel et al: 2001. Briefly, Solution I was prepared by dissolving polymers HPMCK-4M, HPMCK-15M, HPMCE5 in different ratios in water and was allowed to stir for 2 hours and kept for overnight swelling. Solution II was prepared by dissolving the accurately weighed quantity of Tramadol Hydrochloride in methanol. Then the drug solution added slowly to the polymer solution and stirred on a magnetic stirrer to obtain uniform solution. Propylene glycol was used as a plasticizer. Then the solution was poured on the Petri dish having the area of 18.8cm2 and dried at room temperature. Then the patches were cut into 2X1cm2 patches. Drug incorporated for each patch was 100 mg. The dried patches were wrapped in butter paper and stored in a closed container away from light and in cool place.


 

Formulation design:

Table 1:Composition of formulation:

Formulation code

F1

F2

F3

F4

F5

F6

F7

F8

F9

Tramadol Hcl(mg)

100

100

100

100

100

100

100

100

100

HPMC K4M(mg)

25

50

100

---

---

---

---

---

---

HPMC K15M(mg)

---

---

---

25

50

100

---

---

---

HPMC E5(mg)

---

---

---

---

---

---

50

100

200

Methanol(ml)

 5

 5

 5

 5

 5

 5

 5

 5

 5

Oleic acid(ml)

  1

  1

  1

  1

  1

  1

  1

  1

  1

Propylene glycol(ml)

 2

 2

 2

 2

 2

 2

 2

 2

 2

Water(ml)

10

10

10

10

10

10

10

10

10

Glycerin(ml)

 1

 1

 1

 1

 1

 1

 1

 1

 1

 


EVALUATION STUDIES:

Compatibility studies by FTIR:

The drug and excipient compatibility studies were carried out by FTIR study. The study showed peaks for the corresponding functional groups in Tramadol HCl. When the study was carried out with the combination of Tramadol HCl and polymers, there was no major changes in the peaks. Hence there was no interaction with the polymers. The results were shown below

 

 

 

Figure 1: FTIR Spectra of Tramadol and FTIR

 

Spectra of optimised formulation:

The FTIR studies of pure drug and the optimised formulation were performed as shown in figure1. The results was found to be there is no interaction with the pure drug and other excipients and shown compatibility with each other.

 

Physical appearance:

All the Transdermal patches were visually inspected for colour, clarity, flexibility.

 

a. Weight of the patch:

Drug loaded patches (4x4 cm2) were tested for uniformity of weight. The patches were found uniform. The average weight of the patch found was found to be in the range of 102.3 to 121.7 mg. as the polymer content increase, the weight of the patch also increased.

 

b. Thickness of the patch:

All the patches have uniform thickness throughout. Average thickness was found to be in the range of 0.11 to 0.30mm. As the polymeric content increases, the thickness of the patch also increases.

 

c. Moisture content:

Moisture content in F1 to F10 were found to be in the range of 3 to 7%.

 

d. Drug content determination:

It was determined for all formulation by UV spectrophotometer method. The data obtained from triplicate studies were analyzed for mean and standard deviation. The results of content uniformity indicated that the drug was uniformly dispersed. Recovery was possible to the tune of 90.13% to 101.29 %.

 

e. Folding endurance:

Folding endurance measures the ability of patch to withstand rupture. Patch did not show any cracks even after folding for more than 300 times. Hence it was taken as the end point. Folding endurance did not vary when the comparison was made between plain patch and drug loaded patch.

 

In vitro drug release studies:

The drug release profiles of Transdermal patches of Tramadol HCl and their release data was shown in table no 3 & 4. The drug release was governed by the amount of matrix forming polymer. An increase in polymer concentration causes an increase in the viscosity of the gel as well as for mation of a gel layer with a longer diffusion path. This could cause a decrease in the effective diffusion coefficient of the drug and therefore a reduction in the drug release rate however, the difference is insignificant among the formulations. Formulation F3 showed maximum drug release (88.36%), whereas formulation F9 showed lowest release of (62.46%) among the series. Data of the in vitro diffusion release was fit into different equations and kinetic models to explain the release kinetics of Tramadol HCl from transdermal patches. The kinetic models used were zero-order equation, first-order equation, and Korsemeyer Peppas models. The drug release profile of F3 showed highest linearity with Higuchi mechanism release as the R2 value was found to be 0.970.


 

Table 2: Result of Evaluation Parameters of Batch F1-F9

Code

Average Weight (mg)

Mean Thickness (mm)

Moisture Content (%)

Drug Content (%)

Folding Endurance

F1

102.3±2.510

0.110±0.013

3 ± 0.957

101.29%±0.5

300 ± 2.33

F2

104.3±3.491

0.140±0.036

4 ± 0.942

98.35%±0.58

310 ± 0.66

F3

108.6±3.055

0.274±0.026

3 ± 0.642

97.37%±0.62

317 ± 1.66

F4

109.6±2.605

0.255±0.032

5 ± 0.744

99.71%±0.07

322± 0.51

F5

111.0±3.605

0.231±0.012

4 ± 0.956

97.95%±0.08

300 ± 2.33

F6

114.5±4.601

0.294±0.021

4 ± 0.749

90% ±0.56

305 ± 1.66

F7

117.4±2.331

0.294±0.022

7 ± 0.442

99.90%±0.75

302 ± 1.34

F8

119.2±4.461

0.294±0.036

6 ± 0.882

96.13%±0.05

307 ± 2.66

F9

121.3±3.071

0.302±0.042

5 ± 0.242

98.5% ±0.38

311 ± 1.03


 

Table No 3: In vitro diffusion release data of factorial batch F1 to F5

Time

F1

F2

F3

F4

F5

0

0

0

0

0

0

0.5

23.25±0.04

24.67±0.03

25.64±0.06

23.68±0.02

22.91±0.03

1

30.24±0.06

31.91± 0.05

32.47±0.02

26.42± 0.05

26.42± 0.08

2

33.52± 0.04

34.31± 0.09

38.72±0.08

31.67± 0.06

29.41± 0.05

3

36.47± 0.01

37.85± 0.01

43.65±0.04

33.91± 0.07

32.35± 0.04

4

39.51± 0.05

41.86± 0.07

46.12±0.05

35.49±0.08

35.73± 0.09

5

41.38± 0.02

45.83± 0.05

49.71±0.01

38.18± 0.09

38.94± 0.04

6

43.56±0.08

49.72± 0.02

53.84±0.08

41.58± 0.04

42.82± 0.01

7

49.48± 0.06

53.64± 0.08

58.86±0.07

44.82± 0.05

46.57± 0.06

8

56.37± 0.07

57.49± 0.05

62.38±0.04

49.47± 0.01

52.41± 0.05

9

60.31± 0.05

63.42± 0.04

68.48±0.06

55.58± 0.02

57.22± 0.02

10

63.65± 0.06

68.31± 0.06

75.56±0.03

63.35± 0.03

64.86± 0.08

11

68.87± 0.07

73.49± 0.04

79.58±0.06

68.68± 0.07

68.54± 0.07

12

71.56± 0.08

75.49± 0.08

88.36±0.03

69.97± 0.04

71.62± 0.05

 

Table No 4: In vitro diffusion release data of factorial batch F6 to F9

Time

F6

F7

F8

F9

0

0

0

0

0

0.5

22.34±0.05

18.67±0.02

13.85±0.04

14.65±0.01

1

24.54± 0.01

20.22± 0.03

18.45± 0.02

18.52± 0.06

2

28.62± 0.02

26.21± 0.08

24.49± 0.04

23.46± 0.05

3

31.22± 0.08

29.41± 0.06

27.76± 0.08

26.39± 0.03

4

36.47± 0.06

31.81± 0.07

30.46± 0.09

29.85± 0.02

5

40.45± 0.04

34.42± 0.04

34.97± 0.07

31.74± 0.08

6

44.47± 0.07

38.44± 0.06

38.85± 0.06

35.73± 0.07

7

51.48± 0.02

41.48± 0.03

41.67± 0.05

39.46± 0.05

8

54.72± 0.06

43.49± 0.08

44.27± 0.01

43.49± 0.06

9

59.93± 0.05

46.59± 0.01

49.49± 0.04

47.72± 0.08

10

68.43± 0.04

57.6± 0.06

54.72± 0.08

52.49± 0.04

11

71.37± 0.06

60.22± 0.05

59.37± 0.07

56.61± 0.08

12

74.91± 0.08

63.44± 0.04

67.88± 0.01

62.46±0.04


 

 

Figure No 2: Comparison of drug release of polymer HPMCK4M(F1,F2,F3) formulations

 

 

Figure No 3: Comparison of drug release of polymer HPMCK100M(F4,F5,F6 formulations)

 

 

Figure No 4: Comparison of drug release of polymer HPMCE5(F7,F8,F9 formulations)

KINETICS OF INVITRO DRUG RELEASE (CURVE FITTING ANALYSIS):

To study the drug release kinetics of Transdermal patch of Tramadol HCl, different kinetic equations were applied to interpret the release from matrices .the linear nature of curves obtained for zero-order and first-order, Higuchi and Korsemeyer –Peppas model demonstrated by very close and higher R2 values suggests that the release from the formulations may follow any one of these models. The kinetic in vitro dissolution profile of best formulation(f3) were fitted into zero, first, Higuchi and Peppas equations. They showed highest linearity with Higuchi order release.

 

COMPARISION OF OPTIMIZED FORMULATION WITH THE MARKETED FORMULATION:

Drug release profile of optimized transdermal patch and the marketed capsules (Tramacip 100mg) was compared and the drug release of the marketed formulation was found to be 72% due to its hepatic first pass metabolism. And the drug release of the optimized transdermal patch was found to be 88%. The marketed capsules administration is in the form of oral route and its shows hepatic first pass metabolism and should avoid to the kidney patients. The marketed formulations also shows problem when the dose exceed 100mg daily so mostly the marketed oral formulation are modified and formulated in to the patch which shows advantages over oral marketed formulation.

 

CONCLUSION:

Good correlation was observed between drug release and drug permeation study in-vitro. It can be concluded that such a patches of HPMCK4M, HPMC K15M and HPMCE5 could be a good carrier in transdermal delivery of Tramadol HCl. It may also concluded that adhesion of transdermal drug delivery device to skin membrane leads to an increased drug concentration gradient at the absorption site and therefore improved bioavailability of systemically delivered drug All the formulated Transdermal patches were visually inspected for color, clarity, flexibility, checked for flatness, physical parameters such as Physical appearance, Flatness, Weight variation, Thickness, Folding endurance, Drug content, Moisture uptake, Moisture content and all the results were found to be within the pharmacoepial limits. The prepared Tramadol HCl Transdermal patches were evaluated for In-vitro permeation studies using dialysis membrane, among all the 9 formulations F3 formulation was shown 88.36% cumulative drug release within 12 hours. The kinetics of In-vitro permeation studies using dialysis membrane for F3 formulation was plotted and the F3 formulation followed the Higuchi mechanism of drug release. Drug release profile of optimized transdermal patch and the marketed capsules (Tramacip 100mg) was compared and shows advantages over oral marketed formulation.

 

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Received on 07.09.2017          Accepted on 08.11.2017         

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2018; 8 (1):23-28 .

DOI:  10.5958/2231-5713.2018.00004.1