Formulation Development and In vitro Evaluation of Transdermal Patches of Tramadol HCl

 

G. Vasavi, P. Naga Haritha*, B. Chandrashekar

Department of Pharmaceutics, St.Pauls college of Pharmacy, Turkayamjal, Hyderabad, Telangana, India.

 

ABSTRACT:

In the present research work an attempt was made to prepare and evaluate the transdermal patches of Tramadol HCl, a centrally acting opiod analgesic drug. Formulations were made by using different ratios of rate controlling polymers like Eudragit RL100, hydroxyl propyl methyl cellulose 6 cps and ethyl cellulose. Poly ethylene glycol 400 is used as plasticizer and Tween 80 as penetration enhancer. The patches were prepared by solvent evaporation technique using liquid paraffin as lubricant. The study examines the influence of polymers ratio on physicochemical properties and drug release potential of transdermal films. In the pre formulation studies, solubility, partition coefficient and melting point were determined to assess its application for transdermal delivery. The FTIR studies confirmed that there is no incompatibility present between drug and excipients. The patches were evaluated for their appearance, weight uniformity, and thickness uniformity, drug content uniformity, folding endurance, invitro diffusion and stability studies. Based on the evaluation studies F10 formulation was optimised. The drug release was extended for 12 hrs showing drug release of 94.19%. The release kinetics data for optimised formulation has revealed that the patch is best fit in to higuchi model with fickian type of diffusion. The optimised formulation was subjected to accelerated stability studies for 6 months and the results found to be stable with respect to drug content, drug release as well as physical changes.

 

 

 

INTRODUCTION:

At present, the most common form of delivery of drugs is the oral route. While it has an advantage of easy administration, it also has significant drawbacks namely poor bioavailability due to hepatic metabolism and the tendency to produce rapid blood level spikes, leading to a need for high and/or frequent dosing, which can be cost prohibitive and inconvenient ¹.

 

To overcome these difficulties there is a need for the development of new drug delivery system; which will improve the therapeutic efficacy and safety of drugs by more precise (i.e site specific), spatial and temporal placement within the body thereby reducing both the size and number of doses.²New drug delivery systems are also essential for the delivery of novel, genetically engineered pharmaceuticals (i.e. peptides, proteins) to their site of action, without incurring significant immunogenicity or biological inactivation.²² One of the methods most often utilized has been transdermal delivery- meaning transport of therapeutic substances through the skin for systemic effect. Closely related is percutaneous delivery, which is transport into target tissues, with an attempt to avoid systemic effects.^2-3

 

Transdermal drug delivery systems (patches) are dosage forms designed to deliver a therapeutically effective amount of drug across a patient’s skin⁴ also defined as medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Actually, transdermal drug delivery is a transport process of drugs through a multi-laminar structure, e.g. from the patch to stratum corneum then to the viable epidermis, and finally penetrating into the blood.²³In contrast to oral administration (e.g. swallowing a pill), the most convenient way of drug administration, the transdermal route does not suffer from drug degradation in the gastrointestinal tract and reduced potency through first-pass metabolism (i.e. in the liver). In addition, oral-specific side-effects like liver damages are avoided, which are seen for example with common drugs like estradiol (estrogen) or paracetamol.^5,6

 

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.²⁴ In the product development the focus must be on the rationality of drug selection based on pharmacokinetic parameters and physicochemical properties of the drug. Physiochemical factors such as solubility, crystallinity, molecular weight <400, polarity, melting point <200, partition coefficient Log P (octanol-water) between -1.0 to 4 must be considered.⁷

 

Tramadol HCl is centrally acting opioid analgesic, selected for formulation into transdermal patches, because of short biological half-life (6 hrs), to avoid hepatic first-pass metabolism, decrease gastric irritation, frequency of administration, to increase systemic bioavailabity, to maintain seadyplasma drug concentration and to improve patient compliance.^25-27 Transdermal drug delivery in comparison to conventional pharmaceutical dosage forms, offers many advantages, including improved systemic bioavailability of active pharmaceutical ingredients, such as improving patient compliance in long term therapy, by-passing first pass metabolism, sustaining drug delivery, maintaining a constant and prolonged drug level in plasma, minimizing inter and intra patient variability, fewer administration frequency, longer duration of therapeutic action, reduction of side effects and steady drug delivery profile etc. ^{8, 28, 29.}When tramadol is administered orally it has many serious side effects including hallucinations, dizziness, headache, diarrhea, constipation, difficulty in breathing, dryness of mouth, swelling of eyes & face, difficulty in swallowing, nausea, vomiting, these symptoms can be overcome by preparing tramadol as transdermal patch .

 

MATERIALS AND METHODS:

Tramadol HCl was obtained as a gift sample from Hy-Gro chemicals Pharmtek Ltd, Hyderabad, polymers like Hydroxy Propyl Methyl Cellulose 6 cps is obtained from Dr. Reddy's Laboratories Ltd. And Eudragit RL 100and Ethyl cellulose are obtained as gift samples from Evonik Degussa Pvt Ltd. The other excipients like Polyethylene glycol 4000, Glycerin, Tween 80, Acetone, Liquid Paraffin, Sodium hydroxide and Potassium dihydrogen Orthophosphate are purchased fromS D Fine Chemicals. All the chemicals used were of analytical grade.

 

Experimental work:

The Tramadol HCl transdermal patches were prepared by solvent evaporation method using liquid Paraffin as lubricant. Total 10 formulations were prepared by changing the ratios of the polymers. (Table 1) All the polymers were dissolved in solvent system one by one in a boiling tube. The resulting homogenous solution was set aside for about 6hrs allowing the polymers to swell after ultra sonication which aids to remove the air bubbles.Then the drug was slowly added to the solution in little quantities by uniform stirring. Finally plasticizer and penetration enhancer were added and again set aside for about 2hrs after subjecting to ultra sonication. The resulting solution was poured in a petridish lubricated with liquid paraffin. The solvent was allowed to evaporate at ambient conditions of room temperature and humidity for 24 hours to obtain medicated polymer matrix. The patches were stored in desiccators for further evaluation.^{10 - 13}

 

Table: 1 formulation of Tramadol HCl transdermal patches.

Formulation Code	F 1	F2	F3	F4	F5	F6	F7	F8	F9	F10
Tramadol HCl(mg/2X2cm2)	100	100	100	100	100	100	100	100	100	100
HPMC (mg)	200	300	400	500	600	200	300	400	500	600
ERL100 (mg)	100	100	100	100	100	-	-	-	-	-
EC (mg)	-	-	-	-	-	100	100	100	100	100
PEG 4000(%)	15	15	15	15	15	15	15	15	15	15
Tween 80(%)	8	8	8	8	8	8	8	8	8	8

 

 

Evaluation tests:

All the prepared formulations were subjected for preformulation studies like determining the solubility, melting point, and partition coefficient and drug excipients compatibility studies. Weight variation is studied by individually weighing randomly selected patches and calculating the average weight. The individual weight should not deviate significantly from the average weight.^{14, 17}

 

The thickness of transdermal film is determined by screw gauge at 5 different points of the film. The average of the five observations was calculated.¹⁵

 

The content uniformity was determined by dissolving 100mg of drug in 100 ml of suitable solvent in which drug is soluble and then the solution is shaken continuously for 24 h in shaker incubator. Then the whole solution is sonicated. After sonication and subsequent filtration, drug in solution is estimated spectrophotometrically by appropriate dilution.⁹

 

For the determination of WVT (water vapour transmission studies), weighed one gram of calcium chloride and placed it in previously dried empty vials having equal diameter. The polymer films were pasted over the brim with the help of adhesive like silicon adhesive grease and the adhesive was allowed to set for 5 minutes. Then, the vials were accurately weighed and placed in humidity chamber maintained at 68 % RH. The vials were again weighed at the end of every 1^st hr, 2^nd hr, 3^rdhr up to a period of 24 hrs and an increase in weight was considered as a quantitative measure of moisture transmitted through the patch¹⁰.

 

WVT = W/ ST

Where W is the increase in weight in 24 h, S is area of film exposed (cm²) ,T is exposure time.

 

Evaluation of folding endurance involves determining the folding capacity of the films subjected to frequent extreme conditions of folding. Folding endurance is determined by repeatedly folding the film at the same place until it break. The number of times the films could be folded at the same place without breaking is folding endurance value. This is important to check the ability of sample to withstand folding. This also gives an indication of brittleness.^{16, 18}

 

Permeation studies are performed by placing the fabricated transdermal patch with rat skin or synthetic membrane in between receptor and donor compartment in a vertical diffusion cell such as Franz diffusion cell or keshary-chien diffusion cell. The transdermal system is applied to the hydrophilic side of the membrane and then mounted in the diffusion cell with lipophillic side in contact with receptor fluid i.e., buffer. The whole assembly is kept on magnetic stirrer and solution in the receiver compartment is constantly and continuously stirred throughout the experiment using magnetic beads. The pH of the dissolution medium ideally should be adjusted to pH 5 to 6, reflecting physiological skin conditions. For the same reason, the test temperature is typically set at 32°C (even though the temperature may be higher when skin is covered). Ph Eur considers 100 rpm a typical agitation rate and also allows for testing an aliquot patch section. The agitation speed and temperature are kept constant. The samples are withdrawn at predetermined time intervals and equal amount of fresh receptor fluid is replaced each time. The samples are diluted appropriately and absorbance is determined spectrophotometrically.^{19- 21}

 

RESULTS:

 

Table 2 preformulation studies

Melting point	179-180
pH	3.82
Solubility	42.98 µg/ml
Partition coefficient	1.8

 

 

 

Figure 1: FTIR spectra of pure drug Tramadol HCl

 

 

Figure 2: FTIR spectra of pure Tramadol HCl and HPMC 6 cps mixture

 

 

Figure 3: FTIR spectra of pure Tramadol HCl and ethyl cellulose.

 

Table 3: Data obtained from physico-chemical evaluation

FC	Weight uniformity (mg)	Thickness uniformity (mm)	Drug content uniformity (%)	WVT (gcm/cm2.24h)	Folding Endurance
F1	122±1.79	0.17±0.0020	97.86±4.2	5.91±0.059	270±4.32
F2	135.6±1.75	0.20±0.0035	97.91±1.7	6.70±0.052	261±3.00
F3	140.2±2.35	0.25±0.0060	97.1±2.5	6.65±0.030	250±5.21
F4	148.5±2.51	0.20±0.0025	98.95±4.1	6.45±0.026	249±3.87
F5	150±1.31	0.40±0.0024	98.4±3.4	6.25±0.029	246±4.60
F6	100±1.91	0.20±0.0041	96.85±3.5	5.99±0.038	316±4.15
F7	125±2.39	0.17±0.0032	97.5±4.9	5.93±0.023	309±3.89
F8	131.5±2.15	0.22±0.0023	98.65±2.5	5.57±0.049	297±5.10
F9	136.8±1.85	0.10±0.0042	98.79±1.7	5.19±0.035	293±5.15
F10	137.2±1.20	0.31±0.0035	98.65±2.6	4.90±0.05	290±4.72

 

Table 4: Cumulative % drug release of all the formulations

Time in hours	FORMULATION CODE
	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10
0	0	0	0	0	0	0	0	0	0	0
1	9.25	0	6.8	2.53	1.73	9.15	9.23	5.63	3.45	11.52
2	24.19	5.29	17.5	5.78	4.98	36.45	21.45	13.70	7.23	27.8
4	33.56	19.68	24.93	12.30	7.25	40.93	32.32	27.82	15.57	40.1
6	45.30	30.19	39.20	15.6	11.23	50.85	45.8	38.5	43.24	45.26
8	51.93	45.99	45.79	19.23	13.76	60.87	55.10	49.26	50.10	55.93
10	63.5	56.90	68.23	25.63	25.3	70.37	68.57	59.50	55.23	63.89
12	89.43	65.20	79.46	71.45	51.59	83.29	78.52	69.71	61.7	94.19

 

 

 

 

 

 

 

 

Table 5: Kinetic data of optimized formulation (F10)

Formulation code	Zero order (R2)	First order (R2)	Higuchi (R2)	Korsemeyer-Peppas(R2)
F10	0.9409	0.0112	0.9686	0.8629

 

Table 6: Stability study data(F10) - % Drug content

Formulation	Time Period
	Initial	1 month	2 months	3 months
F10	98.52%	98.41%	98.37%	97.31%

 

Table 7: Stability study data (F10) - % CDR

Formulation	Time Period
	Initial	1 month	2 months	3 months
F10	94.19%	94.10%	93.92%	93.85%

 

DISCUSSION:

From the table 2 The solubility of the drug in a given vehicle determines the active concentration at which the drug could be presented on to the surface of skin.Tramadol HCl is soluble in phosphate buffer pH 7.4 (be 42.98 µg/ml) and 0.1 N NaOH, Chloroform, Dichloromethane and Methanol.Melting point of Tramadol HCl found to be 179-180°C. This value is same as that of the literature citation. Partition coefficient indicates that Tramadol HCl is an ideal candidate for Transdermal drug delivery system.

 

The FTIR spectra (Figure 2, 3, 4) of pure Tramadol HCl, physical mixture of drug-polymer were studied. The characteristic absorption peaks of Tramadol HCl obtained and the peaks obtained in the spectrum of each physical mixture of the drug and polymers. By correlating peaks of pure drug spectrum with physical mixtures of the drug and polymer it was found that the drug is compatible with the formulation components.

 

The polymers HPMC 6 cps, ERL 100, EC used for the preparation of transdermal films (Table 1)showed good film forming properties. Eudragit, EC & HPMC both have good film forming capacity. The sticky nature of polymeric solutions of some formulations may be attributed to HPMC. The liquid paraffin used as lubricant for casting the films on petri plate was found satisfactory. Films were easily removed from the Petri plate due to lubrication. Solvent evaporation technique was simple and satisfactory. Solvents were completely evaporated. Air entrapment can be overcome by constant and slow stirring while mixing of polymers. Ultrasonication of polymeric solutions can remove the air bubbles to a large extent and also results in homogenous polymeric solutions.

 

The transdermal films of all formulations were thin, transparent, flexible, smooth and uniform. Incorporation of PEG 4000 yielded smooth and flexible patches. The transparent nature of films may be more prominently attributed to ERL than EC. The flexibility can be due to HPMC. The weights of all transdermal films were found to be uniform as observed from their low SD values. Low SD values in the film thickness measurements ensured uniformity of thickness in each formulation. Homogeneous uniform drug distribution is one of the important characteristic of a transdermal film that ensures the uniform reproducible sustained release of the drug from the patch. Estimation of drug content indicated that the drug is uniformly distributed throughout the patches, evidenced by the low values of the SD. The consequence of water uptake could be the formation of empty spaces within the film that could make its structure less resistant to mechanical stresses. (Table 3)

 

HPMC film showed good water vapour permeation than that of ERL. Though Eudragit is immiscible with water films are freely permeable to water. All the formulations were permeable to water vapour.(Table 3)

 

The rate of WVT of films was affected by the polymer concentration and crosslink density. There was a decrease in WVT with increasing film thickness and crosslink density, which may be due to the increased path length for diffusion and increased film rigidity at higher crosslink densities. The folding endurance measures the ability of film to withstand rupture. It was found to be satisfactory. The results indicated that the films would not break and would maintain their integrity with general skin folding when used.(Table 3)

 

The drug permeability depends on the polymer concentration and the crosslink density of patches. Release of the drug from transdermal films is controlled by the chemical properties of the drug and delivery form, as well as physicochemical properties of the dialysis membrane.The release of the drug from its transdermal film formulations can be ranked in the following descending order:

 

F10 > F1 > F6 > F3 > F7 > F4 > F8 > F2 > F9 > F5

 

The highest % release from F10 formulation may be due to the presence of EC and HPMC. The cumulative percent drug permeation was higher in case of HPMC containing polymer matrix because of its high permeability. The reason for release from HPMC polymer could be explained by the hydrophilic nature of this polymer and the existence of the quaternary ammonium groups which could affect the release from the films because of the hydration and swelling of the films. The addition of EC in the drug polymer matrix was also driven by the fact that HPMC produce crystallization free polymeric patches leading to higher permeation. Tween80 might have improved the permeation due to its ability to improve the solubility of drug.(Table 4)

The coefficient of correlation of each of the kinetics was calculated and compared. The in- vitro permeation profiles of all the different formulations of transdermal films did not fit to zero order behaviour truly as the films were of matrix type. The optimized formulation may be best fit to Higuchi model because a linear relationship was observed with cumulative drug release vs. square root time as observed from comparatively higher regression coefficient value (0.9686). This observation thus supports that the patches released the drug by diffusion dominated mechanism.The data was further treated as per Korsmeyer's equation. The slope (n) values obtained by this equation indicated that the drug released by Fickian diffusion predominated with all formulations. (Table 5)

 

The accelerated stability studies has shown that there were no visible physical changes in the films like colour, transparency, flexibility, smoothness and clarity. (Table 6) There were no physical changes in appearance, flexibility and colour. The percentage of degradation with respect to drug content and percentage drug release was observed negligible. Hence, the formulations can be considered stable. (Table 7)

 

CONCLUSION:

The transdermal patches of Tramadol HCl were successfully prepared by using solvent evaporation method and all the evaluation parameters has shown that we are in front of a patient friendly flexible delivery system which allows obtaining versatile properties and performances by just simple, yet of high significance, modifications. Therefore, although already proved, this study can assure that the use of polymeric systems appears to be an attractive way enabling the designing of the intended formula. Also formulating a transdermal formula seems to improve patient compliance of the drug from which many complain during oral administration due to its bitter taste and gastrointestinal side effects. A patch seems to be new look among Tramadol pharmaceutical dosage forms providing additional privileges in parallel with the obvious well known advantages of transdermal delivery.

 

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