Design and evaluation of adhesive type transdermal patches of Carvedilol

 

Sakhare AD¹, Biyani KR¹, Sudke SG²

¹Anuradha College of Pharmacy, Chikhli 443201, Maharashtra, India.

²GES’s Satara College of Pharmacy, Satara 415004, Maharashtra, India.

 

ABSTRACT:

The transdermal adhesive patches of carvedilol were designed using pressure sensitive acrylic adhesives such as DUROTAK^® 87-235A, DUROTAK^® 87-8301 and DUROTAK^® 87-4287. The patches were evaluated for physicochemical characterization, in-vitro drug permeation across dialysis membrane and ex-vivo drug permeation through the pork ear skin using diffusion cell, stability studies and skin irritability study. The Scanning Electron Microscopy (SEM) of patches does not show any evidence of recrystallization indicating the presence of drug in the molecular form in the adhesive matrix. The physicochemical properties of patches were found to be in acceptable limit. Among the three acrylic adhesives used, DUROTAK^® 87-4287 exhibited maximum flux (8.47 ± 0.18 μg/cm².hr). To enhance the drug permeation, peppermint oil was used as penetration enhancers (2%) in the patches. Out of those, formulation A6 exhibited a flux of 10.04 ± 0.83 μg/cm².hr revealing that formulation A6 was the optimized formulation. The patches of A6 formulation showed excellent in-vitro-ex-vivo correlationship. The stability study was carried out using optimized fresh (A6) formulation for 3 months old patches stored at room (25 ± 2 °C/60 ± 5%RH) and at accelerated condition (40 ± 2 °C/75 ± 5%RH). The investigation reveals that the adhesive type patches of carvedilol were stable and devoid of skin irritation and hypersensitive response. Therefore, may serve as a potential drug delivery system for carvedilol.

 

 

 

INTRODUCTION:

The dosage forms designed for the application onto the skin are broadly classified into two groups namely topical and transdermal. The topical dosage forms deliver the drug for local action of skin without systemic absorption. The transdermal formulations deliver the drug into the systemic circulation to achieve effective concentration and minimizing local effect¹. For the transdermal application, a patch is the best dosage form with respect to efficiency, economy in manufacture and application simplicity². The transdermal patches are widely accepted and a best substitute when oral administration of dosage forms which are difficult such as in case of patient unable to swallow, or may results in erratic absorption (e.g. nausea, vomiting), or in coma³.

 

The transdermal patches are generally categories into four types namely- reservoir, polymer matrix/monolithic or multi-laminate, drug-in-adhesive (DIA) and micro-reservoir type. A DIA matrix patches are made up of a drug, excipient, pressure-sensitive-adhesive (PSA)^{4, 5}, backing film and release liner². The DIA patches has several merits over other patches due to its small size and thickness, better flexibility, uncomplicated production process, straightforward design and patient choice^6–8. Moreover, dose adjustment, for example for patients with impaired hepatic or renal functions, can easily be attained by cutting/dividing the patch⁹. In case of DIA patch system, drug incorporated adhesive layer is in contact with the skin surface after application. Therefore, the selection of a suitable adhesive is important. Commonly used PSA polymers in transdermal DIA patch are polyisobutylenes, silicones and acrylics^10–12.

 

The stratum corneum (SC) is an exterior layer of skin, which permits only lipophilic actives with small molecular weight (< 500 Da) to reach systemic circulation via passive diffusion to achieve desirable plasma concentration¹³. Due to this prime reason, only few transdermal therapeutic systems (TTS) are available commercially. Nowadays, two approaches (chemical and physical) have been utilized to increase the drug permeation through the skin to achieve drug concentration in blood/plasma in the therapeutic level. The chemical approach using penetration enhancers (PEs) has been considered most often for the development of successful DIA patches².

 

Carvedilol is a new, multiple-action cardiovascular drug that is approved in many countries for the effective treatment of hypertension. The reduction in blood pressure is caused by carvedilol due to beta-adrenoceptor blockade and vasodilation. The vasodilation is resulting from alpha 1-adrenoceptor blockade. The several other carvedilol actions with reference to cardioprotection in animal models are occurs to a degree that is greater than that observed with other drugs. Due to these multiple actions of carvedilol is rationale drug of choice in the treatment of coronary artery disease and congestive heart failure¹⁴. It is well absorbed from the gastrointestinal tract but is subjected to substantial presystemic metabolism in the liver; its absolute bioavailability is only about 25%. It has a biological half-life of 2.2 ± 0.3 hr; longer half-lives of about 6 hr have been measured at lower concentrations^{15, 16}.

 

The recrystallization of drug may have effect on the adhesive properties of the patch. It was observed from the previous studies that the adsorption of drug such as ethyl estradiol and levonorgestrel onto the insoluble carrier cross-povidone (CPVP) prevented the drug re-crystallization^10,17. The quality control tests or investigation of pharmaceutical product must be carried out as per international standards to define shelf life of a drug.  It can also provide information about various aspects of stability in term of chemical, physical and microbiological^{18, 19}.

 

Carvedilol was chosen as a model drug for the present study since it possess majority of ideal characteristics that a drug must have to design a transdermal drug delivery system. The aim of the study was to design and evaluate adhesive type transdermal patches of carvedilol so as to prevent its first-pass metabolism and achieve controlled release.

 

MATERIAL AND METHODS:

Carvedilol was a kind gift from Dr. Reddy’s Laboratories Ltd., India. DUROTAK^® 87-9301, 87-9301 and 87-4287 were purchased from Henkel Ltd., United Kingdom. Scotchpack^TM 1022 was a kind gift sample from # M Pharmaceuticals St. Paul, MN, USA. All other chemicals and dialysis membrane were purchased from Sigma Aldrich, India.

Preparation of adhesive type transdermal patches:

The transdermal patches of carvedilol were designed using the acrylic type adhesives viz. DUROTAK^® 87-9301, 87-9301 and 87-4287 with and without peppermint oil as a penetration enhancer by employing solvent evaporation technique. The weighed amount of drug and/or peppermint oil were dissolved in the solvent ether [Table 1]. The adhesives were added to above solution and stirred for 20 min using cyclone mixer [Remi Instruments, India] at room temperature. The mixture was degassed by placing over ultrasonic bath [Remi Instruments, India]. The mixture was cast over polyster film, Scotchpack^TM 1022 (release liner) of 400 µm thickness with adjustable micrometer adjustable film applicator [Culture Instruments, India]. The patches were kept for evaporation of residual solvent and laminated with polyster film laminate (Scotch Pak™ 1012) backing layer and cut into cut into suitable sizes (figure was made supplementary), packed into aluminium foil, and stored at room temperature until further study. The final dry thickness of the DIA matrix was fixed at 100 μm. Also the effect of penetration enhancer was observed²⁰.

 

Table 1: Formulation of adhesive type patch of carvedilol

Where, ^† and ‡ indicates the quantity was taken in % w/w and % v/w respectively.

 

Evaluation of Adhesive type transdermal patches:

Physical appearance:

The patches were examined for color, clearness, elasticity, smoothness and uniformity.

 

Surface morphology:

The surface morphology of the patches before and after in-vitro drug release study was analyzed by Scanning Electron Microscopy (JEOL-JSM-6360, Jeol Datum Ltd., Japan). The samples were cut into small pieces and sticked onto stubs using one side of a double side adhesive dried carbon tape (NEM Tape, Nisshin Em. Co. Ltd., Japan). These samples were mounted on the SEM instrument and scanning was performed. The SEM photographs were taken at the required magnification at room temperature. The working distance of 39 mm was maintained and acceleration voltage used was 17 kV at a chamber pressure of 79.99 Pa with the secondary electron image (SEI) as a detector²¹.

 

Uniformity of weight:

It was determined by weighing randomly selected six patches using a digital single pan balance (Citizen, CX-220, India). The average weight and standard deviation of patches were reported²².

Uniformity of thickness:

The thickness of the drug-containing polymer matrix was determined by measuring the thickness using micrometer screw gauge (Sterling Manufacturing Company, India)[23]. The average thickness of the drug containing polymer matrix was determined by Eq (1).

 

TMavg = TTPavg - TBMavg                                            (1)

 

where, TM_avg = average thickness of the drug containing polymer matrix, TTP_avg = average thickness of the whole patch and TBM_avg = average thickness of the backing membrane.

 

Drug content:

To determine the drug content of a transdermal patch, the drug, carvedilol was extracted by dipping a patch of 1 cm × 1 cm in the 10 ml of solvent mixture solvent ether and acetonitrile in the ratio (60:40) for 24 hr. The mixture was further ultrasonicated for 15 min and filtered using 0.22 µ membrane filters. The drug content in the filtrate was determined using UV-visible spectrophotometer²².

 

Surface pH:

The transdermal patches were kept in contact with 1 ml of double distilled water for 1 hr in glass tube and were allowed to swell. The combined glass electrodes were put on the surface of patch and the pH value was recorded by allowing the contact of electrode for a min²¹.

 

Tensile strength:

Tensile strength is the highest stress applied to a particular point to break a transdermal patch. The determination of tensile strength of patch was determined using tensiometer. A rectangular patch strip of 25.4 mm × 50 mm was fixed between the jaws of the tensiometer. The weight on the each patch was regularly enhanced to a highest at a velocity of 50 mm/min and the alteration in the length of the patches that occurred with increasing stress was measured²³.

 

Tensile strength = break force / a × b (1 + ΔL/L)        (2)

 

where, a = patch width, b = patch thickness, L = patch length, ΔL = patch elongation at breakage point, and break force = weight (gm) required for patch breakage.

 

Percent elongation:

The ability of a transdermal patch to deform earlier to breakdown is called as elongation. The % elongation of the patch was estimated using tensiometer [24]. The load on the film was gradually increased to a maximum at a speed of 50 mm/min. The percent elongation was calculated using Eq (3)

 

Elongation (%) = [(L₁- L₂)/L₂] ×100                              (3)

where, L₁ = final length of transdermal film and L₂ – initial length of transdermal film.

Folding endurance:

The folding endurance was determined by cutting a strip of patch of uniform size (2 × 2 cm) and repeatedly folded at the same place till the patch breaks. The numbers of folds upto which a patch remain unbreakable called as folding endurance²⁵.

 

Flatness:

A transdermal patch was cut into three longitudinal strips from right side, left side and the center. The length of each strip was measured²⁶. The flatness of patch was determined using Eq (4):

Constriction (%) = (L1 – L2) × 100                                 (4)

where, L1 = strip initial length and L2 = strip final length.

 

Thumb tack test:

Tackiness is the ability of pressure sensitive adhesives to bind under conditions of light contact pressure and in a short contact time. The pressure sensitive adhesives adhere to the skin surface with no more force then applied finger pressure, have a strong holding force, and are tacky in nature. The adhesive properties of the patches were expressed by the following value range: no adhesion (−), poor adhesion (+), medium adhesion (++) and good/excellent adhesion (+++)²⁷.

 

Peel adhesion test: 

The peel adhesion is the force required to pull the tape to make sure that the adhesive does not damage the skin and that no residues are left on the skin²⁸.

 

Moisture content:

The transdermal patch was weighed accurately and kept in a desiccators containing anhydrous calcium chloride for 24 hr at room temperature. The patch was weighed repeatedly until weight of patch remains constant. The percent moisture content was determined²⁹ using Eq (5).

 

                                      Final weight-Initial weight

Moisture content (%)= –––––––––––––––––––––––×100                 (5)

                                                Initial weight

 

Moisture uptake:

The weighed patch was kept in a dessicator at room temperature and exposed to relative humidity of 79.5% using a 100 ml of saturated solution of aluminum chloride in a dessicator. The patch was weighed until it showed a constant weight³⁰. Percent moisture uptake was determined using Eq (6).

 

                                          Final weight-Initial weight

Percent moisture uptake = ––––––––––––––––––––––×100             (6)

                                                Initial weight

 

Moisture loss:

The patch was weighed and placed in desiccator containing anhydrous calcium chloride and maintained at 40ºC. After 24 hr, the patches were reweighed and moisture loss was calculated³¹.

 

                                          Initial weight- Final weight

Percent moisture loss = ––––––––––––––––––––––×100                 (7)

                                                Initial weight

 

Water vapor transmission rate:

The three clean and dried glass vials of same diameter were selected. The patch was attached over brim of glass vial containing 1 gm anhydrous calcium chloride. Each vial was exactly weighed and placed in a desiccator containing potassium chloride’s saturated solution for maintaining 84% relative humidity. The cells were taken out after 48 hr and reweighed³².¹⁸ The WVTR can be calculated using Eq. (8).

 

                                                      Final weight-Initial weight

Water vapour transmission rate = ––––––––––––––––––––––×100   (8)

                                                          Time × Area

 

In-vitro permeability study:

In-vitro drug permeability from transdermal patches was carried out using Franz diffusion cell and dialysis membrane (Sigma Aldrich, Mumbai). The dialysis membrane was soaked in phosphate buffer pH 7.4 prior study. The diffusion study was performed using phosphate buffer (pH 7.4) as receptor fluid maintained at 32 ± 0.5°C. The samples were withdrawn at predetermined interval and analyzed using UV spectrometer at 242 nm³³.

 

Calculation of targeted release rate (in- vivo release) to attain steady state plasma concentration of drug:

Cumulative amount of drug permeated in μg/cm² was plotted against time. The drug flux (μg/cm².hr) at steady state was calculated by dividing the slope of the linear fraction of the curve through the skin (3.14 cm²). The permeability coefficient was calculated by means of dividing the flux with initial drug load. The target flux was estimated with the following Eq (9). It also concluded that the lag time necessary for penetration³⁴.

 

                      Css Clt BW

J_Target = ––––––––––––––––                                                             (9)

                            A

 

where, J_Target = Target flux, A = the transdermal system’s surface area (i.e., 3.14 cm²), BW = body weight of adult human of 70 kg, Css = steady state concentration of drug (0.534 µg/ml) and Clt = the total body clearance 0.52 L/hr/kg (8.5 ml/min/kg).  The estimated target flux value for carvedilol was 10.11 μg/cm²hr.

 

Ex-vivo permeability study:

The fresh hairless skin of pork ears were collected from a slaughter house. The fatty tissues of ears and blood stains were removed from ears by using double distilled water and forceps. The ear skin sample was cut into required size and placed into the deep freezer (−20 °C) until its use. It is appropriate for the permeation studies and providing results comparable to human skin [35]. The skin sample was used within a week for the permeability study. The stored skin samples were hydrated for 60 min using the receptor medium and then placed on receptor compartment in such a way that the stratum cornea faced toward donor compartment³⁶. The ex-vivo permeation study of transdermal patch was carried out using six-station vertical diffusion cell (Kshitij International, Ambala, India) with 3.14 cm² exposed surface area and 20 ml receptor compartment capacity. The phosphate buffer of pH 7.4 prepared from double distilled water was used as the receptor medium. The receptor compartment and skin surface temperature were maintained at 32±1°C. The samples of 0.5 ml were withdrawn at predetermined time interval from the receptor medium through the sampling port and replacing with equal volume fresh receptor fluid. The concentration of carvedilol in the sample was analyzed using UV spectrophotometer at 242 nm. The sink condition of carvedilol in receptor medium was maintained. The saturation solubility (Cs) of carvedilol in above medium was 70.28 ± 0.87 µg/ml at 37 °C. The sink condition was maintained, when the highest concentration of drug in receptor medium is less than 1/10th of its Cs value in the same medium (C < Cs × 0.1). Therefore, final concentration of carvedilol i.e., after the complete release of carvedilol in phosphate buffer of pH 7.4 and acetonitrile (70:30 ratio) maintained below 702 µg/ml. The steady state flux (Jss, µg/cm²/hr), permeability coefficient (Kp, cm/hr), and enhancement ratio were calculated by utilizing the data obtained from in vitro permeation study. Measurement of Jss was carried out from the slope of the linear portion of the cumulative amount permeated per unit area versus time plot³⁷.

 

Kp = Jss/C                                                                           (10)

 

 

             Flux with peppermint oil

ER = ––––––––––––––––––––––––                                      (11)

         Flux without peppermint oil

 

Kinetics of drug release:

To recognize the drug release mechanisms form the patches the various kinetic models like zero-order (% release v/s time), first order (Log % retained v/s time), Higuchi model and Korsmeyer Peppas equation were applied. The regression coefficient (r) values were used to define the mechanism. The value of ‘n’ of Korsmeyer Peppas equation is used as marker of the drug release mechanism³⁸.

 

Stability studies:

The stability study is regularly carried out to establish the stability potential of the medicament available in the optimized formulation. The stability study at room and accelerated conditions for the optimized drug in adhesive type patch was carried out for 6 months, according to the ICH guidelines under the following conditions: 40 ± 2°C temperatures and 75 ± 5% relative humidity (RH) and 25 ± 2 °C temperatures and 60 ± 5% relative humidity (RH) using a stability chamber³⁹.

 

Skin irritation study:

The patches were tested for their possible to cause i.e., skin irritation in healthy White Albino Rats. The rats were divided in 4 groups. The placebo patches, drug patch, 0.8% formalin solution and drug solution were applied respectively to the rats of each group. The skin was shaved and cleaned with spirit before application. On 8^th day the skin rats was observed for any sign of redness, itching, erythema and edema⁴⁰. Before study the protocol was sanctioned from Institutional Animal Ethics Committee was obtained for conduction of experiment (Ref: IAEC/ACPC/07/2019).

 

RESULTS AND DISCUSSION:

Evaluation of adhesive type carvedilol TDDS:

Physical appearance:

All the transdermal patches were found to be clear, translucent, flexible, smooth with uniform in size and shape.

 

Surface morphology:

The scanning electron microscopy studies were carried out to ensure the uniform drug distribution in the transdermal patch. Fig. 1 consist of SEM images of dummy patch, drug loaded patch and dried patch. The SEM of the transdermal patches shows homogeneous distribution of carvedilol throughout the patch. The SEM of transdermal patches was devoid of bubbles and were rigid in nature [Fig.1].

 

Fig. 1: SEM of dummy patch, drug loaded patch and dried patch

 

Uniformity of weight:

The mean weight of the patches was ranges between 24.22±0.017 to 28.32±0.007 mg. As the concentration of peppermint oil in formulation increases the average weight of patches was also increases [Table 2]. The low standard deviation value of weight indicates the capability of method to produce reproducible results.    

 

Uniformity of thickness:

The average thickness of the patches ranges between 0.17±0.005 to 0.19±0.003 mm [Table 2]. The lower standard deviation value indicates the reproducibility of the technique.

 

Drug content:

The drug content was found in range from 96.73±1.57‒100.02±0.09% [Table 2]. The low standard deviation of drug content revealed that the present method was suitable preparing patches.

 

Surface pH:

The surface pH of patches was range from 6.83 ± 0.058 to 7.2 ± 0.100. The surface pH of the patches was found near to skin pH indicates safety for skin application [Table 2].

 

Tensile strength:

The tensile strength of transdermal patches was range from 25.86 ±0.165 N/ 25.4 mm to 30.19±0.042 N/ 25.4 mm [Table 2]. The tensile strength of the transdermal patches differs based on type of adhesive and use of permeation enhancer in the transdermal patch.

 

Percent elongation:

The % elongation of patches was found between 268.53±6.37 to 286.50±2.65% [Table 2]. It was observed to be a function of type of adhesive and more or less the penetration enhancer present in the patch. This confirms the adhesives plays important role in providing elastic properties to the patches.

 

Folding endurance:

Folding endurance of the patches was estimated to be between 151‒190 which were within satisfactory limits [Table 2]. As folding endurance values were greater than 151 in all the patches indicates that the patches have capability to withstand mechanical stress with better flexibility property. The patches would not break or loss their integrity while skin folding takes place during application.

 

Flatness:

An ideal formulation should have smooth surface and avoid contraction with time. The value of % contraction was range from 0.333±5.77 to 1.667±5.77%. The low value of % contraction meant that solvent evaporation method was a reproducible technique [Table 2].

 

Thumb tack test:

The formulations, A1, A2 and A3 were devoid of penetration enhancers were with medium tackiness (++) and A4, A5 and A6 with Penetration enhancer with highest degree of tackiness (+++).

 

Peel adhesion test:

The force required to peel out the transdermal drug delivery system which was mounted on human cadaver skin was determined and recorded in [Table 3]. The peel adhesion force (PAF) required for each formulation was depend upon the type of adhesive material, the use of penetration enhancer and storage conditions. The use of penetration enhancer in the transdermal patch slightly decreases the peel adhesion force and increased storage temperature as well as humidity decreases the value of peel adhesion force.  

 

Table 2: Evaluation of carvedilol transdermal patches

Where, ^a and ^b indicates the values as mean ± SD when sample size used were (n=6) and (n=3) respectively.

 

 

Table 3: Moisture content, moisture uptake, moisture loss and WVTR of patches

Where, ^a indicates the values as mean ± SD when sample size used were (n=3).

 

 

Moisture content:

The moisture content is very significant factor in maintaining physical, chemical stability and flexibility of the patches. The moisture content of patches was found within the range of 0.58 ±0.011 to 0.71 ±0.019 % [Table 3]. This reveals the formulations were form flexible and non-sticky films since the moisture content was in the significant limit.

 

Moisture uptake:

The moisture uptake is an important property needed for drug diffusion through skin. The extent of moisture uptake by the patch from the skin and atmosphere at the time of application is very important. It is also very crucial factor for patch to maintain its mechanical integrity. The % moisture uptake by the patches containing adhesives and with /without penetration enhancers were in the range of 1.113±0.008 to 1.229±0.007%. The presence of peppermint oil in the patch increases the moisture holding capacity [Table 3].

 

Moisture loss:

The % moisture loss was found to be 0.01 ±0.002 to 0.05 ±0.003%. The values were increased as the use of penetration enhancer in the formulations [Table 3]. Higher the moisture loss leads to loss in the elastic nature as well as increase the drug release from formulation.

 

Water vapor transmission rate:

The WVTR values were found to be in the range of 1.38±0.01and 3.02±0.02 mg/cm²sec. The water vapor transmission of the transdermal patch was depends upon the nature of adhesive and permeation enhancer used in transdermal patch [Table 3]. The transdermal patch with permeation enhancers shows slightly higher water vapour permeability.

 

In-vitro permeability study:

In-vitro permeability study is a prime means that predicts in advance how the drug permeation takes place in-vivo. The lowest drug release was observed from A1 patch because contains DURO-TAK 87-9301 which is a comparatively higher viscosity grade (9500 cP) adhesive and low solid content. Formulation A2 comparatively showed higher release than A1 that may be because of presence of n-hexane and ethyl acetate residue and lower viscosity (8000 cP) of DURO-TAK 87-235A.  Whereas, DUROTAK 87-4287 showed highest drug release due to higher solid content i.e. 39% than former (36%) and lower viscosity than DURO-TAK 87-9301 that is 8000 cP. The drug release was higher from the patches containing penetration enhancers as compared to the patches without penetration enhancer. When 2% of peppermint oil was used in the patches, the permeation of drug through dialysis membrane was also increased. The drug permeation from patches was highly affected by type of polymer used and the permeation enhancer employed [Fig.2].

 

Fig. 2 In-vitro drug permeation study

 

Kinetic analysis of data:

The in-vitro drug release data was fitted using various kinetic models. The release from all patches fits into zero order kinetics. The Korsmeyer- Peppas model ‘n’ values for the formulations were between 0.5 to 1 indicates drug release mechanism by non-Fickian diffusion. As permeation enhancer used was mainly responsible for diffusion of drug from the formulations [Table 3].                 

 

Table 3:  Kinetic analysis of data                     

Where ^a indicates the best fitted kinetic model for the formulation.

 

Fig. 3 Ex-vivo permeability study

 

Ex-vivo permeability study:

From Eq. (9) the calculated target flux value for carvedilol from optimized formulation should be 10.11 μg/cm²hr. The Fig. 3 reveals that the formulation A6 has similar drug permeability and flux value up to 24 hr. The similarity factor (f₂) and difference factor (f₁) values when the in-vitro release profile from patch was compared with ex-vivo permeation profile of A6 formulation were 78.6 and 6.2 respectively [38]. This confirms excellent in-vitro-ex-vivo co-relationship for the A6 formulation.

 

In-vitro– ex-vivo correlationship:

The in-vitro permeation study data was correlated with ex-vivo permeability study data for A6 transdermal patch formulation by plotting the graph between in-vitro cumulative drug permeated on Y-axis and ex-vivo cumulative drug permeated on X-axis. Formulation A6 shows good correlation between ex-vivo absorption– in-vitro release data. It shows coefficient of correlation about 0.999 indicates excellent in-vitro-ex-vivo co- relationship [Fig. 4].

 

Fig. 4 in-vitro ex-vivo permeability co-relationship

 

Primary skin irritation study:

The skin irritation for optimized patch was also performed by applying the patch on the shaved back portion of rat but on other side of placebo. The patches were not producing any type of symptoms of visual irritation. After 6 days no significant symptoms of oedema or erythema were observed to the rat applied with drug solution, drug patch and placebo patch. Whereas well defined erythema was observed with formalin (0.8%) solution [Table 4].

 

Table 4 : Skin irritation test

Where, ‘0’ indicates no erythema and ‘2’, well defined erythema

 

 

Stress stability study:

The optimized formulation A6 was stored for short term stability according to ICH guideline. The formulations were evaluated for their physicochemical characteristics as showed in Table 2 to 4]. The formulation stored for stability study was found to be clear, transparent, flexible and smooth. It shows all the physical and chemical characteristics of optimized transdermal patch were in significant limits and in-vitro drug release was shown in [Fig. 5]. The in-vitro release from the A6 formulation on the day of preparation was compared with stored at 25°C and 60% relative humidity condition (A6S1) as per ICH guideline shows similarity factor and difference factor values 93.14 and 2.86 respectively indicates that no significant change in the in-vitro permeation rate from optimized formulation after storing for short term stability study i.e., 3 months. Similarly the in-vitro permeability from the A6 formulation on the day of preparation was compared with (A6S2) formulation stored at 40°C and 75% relative humidity condition (as per ICH guideline shows similarity factor and difference factor values 87.03 and 3.23 respectively indicates that no significant alteration in the in-vitro release profile as well as drug content after 3 months. As the % drug content for A6S1 and A6S2 were 97.83±0.13 and 97.66±0.11%, which were found in significant limit. This indicates the stability of optimized preparation as per short term stability study.

  

Fig. 5: In-vitro permeability study of stability batches.

 

CONCLUSIONS:

Pressure sensitive adhesive type transdermal patches of carvedilol were prepared successfully and effects of type of adhesive and penetration enhancers, peppermint oil on the permeation of carvedilol were studied. The adhesion properties of the patches were very satisfactory. Also, the prepared patches showed good uniformity with regard to drug content. In-vitro and ex-vivo permeation studies of formulations were performed by using Franz diffusion cells through dialysis membrane and pork ear skin respectively. Formulation containing 88% DUROTAK 87-4287 solution and 2% peppermint oil as permeation enhancer showed best in-vitro permeation through dialysis membrane as compared to all other formulations. The results drug release was found to be by zero order kinetics. The study was concluded that the presented data confirms the feasibility of designing pressure sensitive drug in adhesive type transdermal patches of carvedilol. Further study in respect to in vivo performance after transdermal administration is required to establish the therapeutic utility of this system.

 

ACKNOWLEDGEMENTS:

The authors are grateful to the management of Anuradha College of Pharmacy, Chikhali for providing necessary facilities to carry out the above research. Authors also thank to Dr. Reddy’s Laboratories Ltd., India and # M Pharmaceuticals St. Paul, MN, USA for providing kind gift samples of Carvedilol and Scotch pack^TM 1022 respectively.

 

CONFLICT OF INTEREST:

The authors declare that there is no conflict of interest.

 

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Received on 03.03.2020          Modified on 25.04.2020

Accepted on 12.06.2020         © RJPT All right reserved