Design and Evaluation of Transdermal Patches Containing Risperidone

Ismail Hussain¹, Ravikumar²*, Narayanaswamy VB³, Injamamul Haque¹, Mohibul Hoque⁴

¹M.Pharm (Pharmaceutics), Research Scholar, Karavali College of Pharmacy, Mangalore

²Department of Pharmaceutics, Karavali College of Pharmacy, Mangalore

³Department of Pharmacognosy, Karavali College of Pharmacy, Mangalore

⁴Department of Pharmacology, Karavali College of Pharmacy, Mangalore

*Corresponding Author E-mail: ravikumar300@gmail.com

ABSTRACT:

Transdermal drug delivery systems are also known as patches, containing dispersed or dissolved drug with plasticizers, polymers, etc. are intended to deliver a therapeutically effective amount of drug across the skin. In the present work, Transdermal drug delivery of Risperidone were formulated in different concentration (10%, 20% and 30% ) of glycerine and polyethylene glycol 400 as plasticizer and a blend of two in different concentrations of polymers (PVPK30,HPMC,PVA and Eudragit RS 100) were formulated by solvent casting method. Drug polymer interaction study was carried out using FTIR and DSC studies. In this study the results indicates, as increase in the concentration of glycerine and Polyethylene glycol increases the diffusion rate of Risperidone patches. The physico-chemical parameters like weight variation, thickness, folding endurance. Percentage Flatness and Water vapour transmission of the Risperidone patches were evaluated. All the physico chemical parameters were found to be satisfactory. Risperidone patches formulated by using 30% glycerine 30% PEG400shows enhanced rate of diffusion than the patches prepared with 10% and 20% glycerine10% and 20% PEG400 respectively. Risperidone patches formulated with 20% glycerine 20% PEG400 had enhanced rate than the patches prepared with 10%glycerine/10% PEG400 respectively. Among polymers, combination of HPMC and Eudragit had enhanced diffusion rate than the combination of HPMC and PVPK30 in all formulations formulated by using glycerine as plasticizer. The polymers, combination of PVPK30 and Eudragit had enhanced diffusion rate than the combination of PVPK30 and PVA in all formulations formulated by using PEG400 as plasticizer. The Risperidone transdermal patches shows greater diffusion rate when formulated with higher concentration of plasticizer hence the30% of glycerine and PEG 400 had shown a values higher than 20 and 10 % glycerine and PEG 400. The kinetic study and mechanism for the diffusion of Risperidone transdermal patches obeys higuchi, peppas model. The correlation coefficient (R2) values were greater, indicating from the analysis of diffusion data as per above models. The T50 and T80 values for Risperidone patches formulated with glycerine andPEG400 are exhibited good results. The SEM films indicating uniform distribution of the drug with polymers and plasticizers.

KEYWORDS: Transdermal Drug delivery, Diffusion rate, Eudragit, Risperidone, Plasticizer, HPMC.

INTRODUCTION:

Transdermal delivery of drugs through the skin to the systemic circulation provides a convenient route of administration for a variety of clinical indications. 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 incontinence¹. Transdermal route offers many advantages over the conventional dosage forms or controlled release oral systems. Transdermal routes provide constant blood levels, avoids first pass metabolism, increased patient compliance, and avoids dose dumping. The choice of drugs delivered transdermally, clinical needs, and drug pharmacokinetics are some of the important consideration in the development of transdermal drug delivery system. The application of transdermal delivery to a wider range of drugs is limited due to the significant barrier to penetration across the skin which is allied primarily with the outermost stratum corneum layer of the epidermis². Polymers are used in transdermal delivery systems in various ways, including as matrix formers (such as cross linked polyethylene glycol, acrylic acid matrices, ethyl cellulose and polyvinyl pyrrolidone, hydroxypropyl methylcellulose, organogels), rate controlling membranes (such as silicon rubber, polyurethane, polyisobutylene, polyacrylates, silicones), pressure sensitive adhesives (ethylene vinyl acetate copolymers, paraffin waxes, polyamides, styrene butadiene copolymers), backing layer (polyethylene, polyvinyl chloride, ethylene vinyl acetate, polypropylene, polyurethane, polyethylene terephthalate), release liner³.

Risperidone is a potent antipsychotic drug which is mainly used to treat schizophrenia (including adolescent schizophrenia), schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism. Risperidone, a benzisoxazole derivative, is an atypical antipsychotic drug with high affinity for 5-hydrotryptamine (5-HT) and dopamine D₂ receptors. It is used primarily in the management of schizophrenia, inappropriate behaviour in severe dementia and manic episodes associated with bipolar I disorder. Risperidone is effective for treating the positive and negative symptoms of schizophrenia owing to its affinity for its “loose” binding affinity for dopamine D₂ receptors and additional 5-HT antagonism compared to first generation antipsychotics, which are strong, non-specific dopamine D₂ receptor antagonists. In the present study an attempt has been made to design and evaluate transdermal patches containing Risperidone using suitable polymers and permeation enhancers.

MATERIALS AND METHODS:

Materials:

Risperidone acetate was obtained as gift sample from Torrent Pharmaceuticals, Baddi, India. All other materials, excipients, solvents and reagents were either analytical or Pharmacopoeial grade and they were procured from S. D. fine Chemicals Mumbai.

Drug- Polymer Interaction Studies:

This study has been done to check whether there is any compatibility related problems are associated with drug and excipients used for the formulation of tablet.

Fourier Transform Infra-Red (FT-IR) Spectral Analysis:

Fourier–Transform Infrared (FT–IR) spectrums of pure Risperidone and combination of drug and excipients were obtained by a Fourier-Transform Infrared spectrophotometer, (FTIR 8300, Shimadzu, Japan) using the KBr disk method (2 mg sample in 200 mg KBr). The scanning range was 400 to 4000 cm-1 and the resolution was 1cm-1. This spectral analysis was employed to check the compatibility of drugs with the excipients used.

Differential Scanning Calorimetry (DSC) analysis:

Differential Scanning Calorimetry (DSC) curves of pure Risperidone and combination of drug and excipients were obtained by a differential scanning calorimeter (DSC-60, Shimadzu, Japan) at a heating rate of 10°C/min from 40°-300°C in nitrogen atmosphere (20 ml/min) with a sample weight of 3mg.

PREPARATION OF TRANSDERMAL PATCHES:

The weight quantity of Risperidone was dissolved in required volume of methanol in a beaker. The selected concentrations of polymers are added to the above beaker containing Risperidone in methanol and make up the volume up to 10 ml by adding distilled water. Keep the beaker on thermostatically controlled magnetic stirrer which is maintained at room temperature, initially stirring at low rpm and later at higher speed. The required quantity of plastizer is added drop wise to the beaker while stirring is continued until the drug is dispersed with polymer. The solution was poured into an umbra Petridis; an inverted funnel was placed over the mould to prevent fast evaporation of the solvent and dried at 40-50°C in an air circulation dryer for 12 hrs. Patches of 2.0 cm diameter were prepared by cutting with borer and packed in an aluminium foil and stored in desiccators for further use (table 1-2).

Evaluation of transdermal patch:^4-6

Physical appearance:

All the prepared patches were visually inspected for colour, clarity, flexibility and smoothness.

Thickness of the film:

The thickness of the formulated film was measured at 3 different points using a digital calliper and average thickness of three readings was calculated.

Weight uniformity:

The films of different batches were dried at 60^oC for 4 hours before testing. Three patches from each batch were accurately weighed in a digital balance. The average weight and the standard deviation values were calculated from the individual weights.

Table 1: Composition of different batches of Risperidone transdermal patches containing different concentration of glycerine as plasticizer

INGREDENTS	FORMULATIONS
INGREDENTS	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12
Risperidone	20	20	20	20	20	20	20	20	20	20	20	20
PVP K30	3%	7%	--	--	3%	7%	--	--	3%	7%	--	--
HPMC	7%	3%	4%	5%	7%	3%	4%	5%	7%	3%	4%	5%
Eudragit (RS-100)	--	--	9%	9%	--	--	9%	9%	--	--	9%	9%
Glycerine	5%	5%	5%	5%	10%	10%	10%	10%	15%	15%	15%	15%
Methanol	4	4	4	4	4	4	4	4	4	4	4	4
Methylene chloride	6	6	6	6	6	6	6	6	6	6	6	6

Table 2: Composition of different batches of risperidone transdermal patches containing different concentration of PEG-400 as plasticizer

INGREDENTS	FORMULATIONS
INGREDENTS	F13	F14	F15	F16	F17	F18	F19	F20	F21	F22	F23	F24
Risperidone	20	20	20	20	20	20	20	20	20	20	20	20
PVA	3%	7%	--	--	3%	7%	--	--	3%	7%	--	--
PVP K300	7%	3%	4%	5%	7%	3%	4%	5%	7%	3%	4%	5%
Eudragit ( RS-100)	--	--	9%	9%	--	--	9%	9%	--	--	9%	9%
PEG400	5%	5%	5%	5%	10%	10%	10%	10%	15%	15%	15%	15%
Methanol	4	4	4	4	4	4	4	4	4	4	4	4
Methylene chloride	6	6	6	6	6	6	6	6	6	6	6	6

Folding endurance:

The folding endurance was measured manually for the prepared films. A strip of film (5 x 5 cm) was cut and repeatedly folded at the same place till it broke. The number of times the film could be folded at the same place without breaking/cracking gave the value of folding endurance.

Percentage moisture absorption:

The physicochemical studies like moisture content and moisture uptake provide the information regarding the stability of the formulation. The films were weighed accurately and placed in the desiccators containing 100 mL of saturated solution of potassium chloride, which maintains 80-90% RH. After 3 days, the films were taken out and weighed. The study was performed at room temperature. The percentage moisture absorption was calculated using the formula:

Final Weight - Initial weight

% Moisture absorption=---------------------------------------- X 100

Initial weight

Percentage moisture loss:

The films were weighed accurately and kept in a desiccators containing anhydrous calcium chloride at room temperature for 24 hours. After 3 days, the films were taken out and weighed. The percentage moisture content was calculated using the formula:

Initial weight- Final Weight

% Moisture Loss =---------------------------------------- X 100

Initial weight

Moisture content:

The prepared films were marked, then weighed individually and kept in desiccators containing activated silica at room temperature for 24h. The films were weighed again, until constant weight is achieved. The % moisture content was calculated as a difference between initial and final weight with respect to final weight.

Initial weight- Final Weight

% Moisture Content (MC) =---------------------------------------- X 100

Initial weight

Water vapour transmission rate:

Glass vials of 5 ml capacity were washed thoroughly and dried to a constant weight in an oven. About 3 g of fused calcium chloride was taken in the vials and the polymer films of 2.25 cm2 were fixed over the brim with the help of an adhesive tape. Then the vials were weighed and stored in a humidity chamber of 80-90% RH condition for a period of 24 h. The vials were removed and weighed at 24 h time intervals to note down the weight again.

Final Weight - Initial weight

% Transmission Rate =---------------------------------------- X 100

Time X Area

Tensile strength:

Tensile strength of the film was determined with Universal strength testing machine. The sensitivity of the machine was 1 g. It consisted of two load cell grips. The lower one was fixed and upper one was movable. The test film of size (4 ×1 cm2) was fixed between these cell grips and force was gradually applied till the film broke. The tensile strength of the film was taken directly from the dial reading in kg. Tensile strength is expressed as follows:

Tensile load at break

Tensile strength =---------------------------------------- X 100

Cross section area

Flatness:

Longitudinal strips were cut out from the prepared medicated patches, the length of each strip was measured, and then the variation in the lengths due to the non-uniformity in flatness was measured. Flatness was calculated by measuring constriction of strips and a zero percent constriction was considered to be equal to a hundred percent flatness.

Constriction (%) = (L1 – L2)/L2 x 100

Where,

L1 is initial length of each strip;

L2 is final length.

Drug content Uniformity of Films:

The patches (1cm²) were cut and added to a beaker containing 100 ml of phosphate buffer of pH 7.4. The medium was stirred with magnetic bead. The contents were filtered using Whatmann filter paper and the filtrate was examined for the drug content against the reference solution consisting of placebo films (contains no drug) at 322 nm spectrophotometrically. The experiment was repeated to validate the result.

Microbial Studies:

The potential of transdermal patch for promoting growth of micro-organisms was evaluated by bacteriological cultures. The film strips of different formulations were cut into small pieces of 1cm2 and aseptically transferred into each petri plate containing 25 ml of nutrient agar media. These agar plates were incubated at 37±0.5⁰C for 48 h. After incubation, sample was observed under microscope.

Skin Irritation Test:

Selection of Animals:

Rats of Wistar strain and mice of albino strain of either sex were selected for the studies. They were kept with husk bedding and were fed with standard rodent pellet diet and water. Light & dark cycles with 12 hours light and 12 hours dark were maintained. The temperature and relative humidity conditions were 28±2⁰C and60±15% respectively. The protocols for all animal studies were approved by Institutional Ethical Committee (Approval No: KCP/IAEC/Ph.Ceutics/19/2015-2016).

Method:

Skin irritation studies and histopathological studies were carried out according to modified Draize test on Wistar rats for selected formulations (F24). Wistar rats were used to study any hypersensitivity reaction on the skin. Rats were divided into 5groups, each containing 6 animals. The hairs of the dorsal portion were removed physically with the help of sharp surgical scissors and the skin was washed properly one day prior to use. The animals of group I was served as normal, without any treatment. One group of animals (group II, control) were applied with marketed adhesive tape (official adhesive tape in USP). Transdermal patches (blank and drug loaded) were applied on to nude skin of animals of III and IV groups respectively. A 0.8%v/v aqueous solution of formalin was applied as standard irritant (group V).The experiment was carried out for 7 days and the application sites were graded according to a visual scoring scale. The scores of erythema and edema were as follows: 0 for none, 1 for slight, 2 for well defined, 3 for moderate and 4 for scar formation and severe erythema and edema. After evaluation of skin irritation, skin samples were processed for histological examination.

In Vitro Drug Permeation Study:

In vitro skin permeation studies were performed by using a modified Franz diffusion cell with a receptor compartment capacity of 20 ml. The cellophane membrane was mounted between the donor and receptor compartment of the diffusion cell. The formulated patches were cut into size of 1cm2 and placed over the drug release membrane and the receptor compartment of the diffusion cell was filled with phosphate buffer pH 7.4. The whole assembly was fixed on a magnetic stirrer, and the solution in the receptor compartment was constantly and continuously stirred using magnetic beads at 50 rpm; the temperature was maintained at 37 ±0.5⁰C. The samples of 1 mL were withdrawn at time interval of 0.5,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hr analyzed for drug content spectrophotometrically at 322 nm against blank. The receptor phase was replenished with an equal volume of phosphate buffer at each time of sample withdrawal. The cumulative amounts of drug permeated per square centimeter of patches were plotted against time.

Scanning Electron Microscopy:

Film morphology of optimized formulation (F24) was characterized by scanning electron microscopy. Sample was mounted on round brass stubs (12mm diameter) using double-backed adhesive tape and then sputter coated for 8 min at 1.1 LV under argon atmosphere with gold palladium before examination under the scanning electron microscope (JEOL, JSM-6100, Japan). The images were captured on an Ilford PANF50 black and white 35mm film. The samples include film before permeation study and after permeation study.

Drug release kinetic study:

To examine the drug release kinetics and mechanism, the cumulative data of optimized batch (F24) was fitted to models representing zero-order, first order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas models. The criterion for selecting the most appropriate model was chosen on the basis of the goodness-or fit test.

Stability studies:

The purpose of stability study is to provide evidence on 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. Optimized batch (F24) was selected for stability studies on the basis of physiochemical characteristics, in vitro drug release of the formulations. The formulation was subjected to accelerated stability studies as per ICH (The International Conference of Harmonization) guidelines. The most satisfactory formulation was sealed in an aluminium foil and stored at 30±2 ºC, 65 ± 5% RH and at 40 ± 2ºC, 75 ±5% RH for 2 month. Patches were periodically removed and evaluated for physical parameters, drug content and in vitro permeation study.

In Vivo Pharmaco Dynamic Studies:

Risperidone usually cause a state of sedation and motor in-coordination. Rota rod and grip tests were used to assess muscular strength or neuromuscular function in rodents which can be influenced by sedative drugs and muscle relaxant compounds. Swiss mice were divided into 3 groups, each containing four animals. First group served as control i.e. without drug, second group was administered with oral dose (1mg/kg for Risperidone) of marketed formulation (RISPID® tablet by Panacea Biotec) in 0.5% carboxy methyl cellulose (CMC) and third group was treated with Selected transdermal formulation (F24) containing equivalent dose as that of oral formulation. For rota rod test, animals were placed on an aluminium rod; revolving at 10 rpm and the time taken to fall of animal from the rod was noted. The test was terminated at 270s. For grip test, the animals were exposed to a horizontal thin metallic wire suspended about 30 cm in air which they immediately grasp with the 4 paws. The mice were released to hang on with its four limbs. Control animals were able to hold the wire with hind limbs and to climb up within 5 s. After oral or transdermal administration, the animals were not able to hold the wire with the hind limbs within 5 s or fall off from the wire and they were considered to be impaired. The test was continued for 6 hand repeated after every hour. The general behaviors were observed from selected batches in cages and observations noted. Only if their behavior and their motility in the cages seem to be normal, the disturbance of grasping reflex is considered as caused by central relaxation.

RESULTS AND DISCUSSION:

Identification of Pure Drug:

IR spectral analysis of pure drug sample showed characteristic peaks as shown in figure 1. Risperidone exhibited characteristic peaks at 2968 and 2931cm-1(aliphatic CH stretching); 1590 and 1551 cm-1(C=N stretching, 1462 and 1431 cm-1(aromatic C=C stretching); 820 cm-1(C-C l stretching). The IR spectra of pure drug complied with the reference standard IR spectrum of Risperidone which revealed identity to drug sample. Observed frequencies of functional groups present in Risperidone were matching with standard theoretical frequencies of functional groups, which confirm identity of Risperidone.

Drug-excipient compatibility studies:

Fourier Transform Infrared (FTIR) Spectroscopy

Physical mixture of Risperidone and formulative ingredients were subjected for IR spectroscopic analysis to ascertain whether there was any interaction between drug and excipients used. The IR spectra showed similar characteristic peaks at their respective wavelengths with minor differences. The similarity in the peaks indicated the compatibility of drug with formulation excipients. IR spectra of the physical mixture of drug with formulative ingredients were depicted in figure 2-5.

EVALUATION PARAMETERS:

EVALUATION OF RISPERIDONE TRANS DERMAL PATCH:

Physical Appearance:

All the prepared patches were visually inspected for colour, clarity, flexibility and smoothness. All the formulated transdermal patches were most elegant, uniform, thin, flexible, smooth and transparent.

Thickness Uniformity:

The thickness of the formulated film was measured at 3 different points using a digital calliper and average thickness of three reading was calculated. The thicknesses of formulated transdermal patches were ranged from 0.51±0.06 to 0.67±0.02 mm among the various batches; the uniformity in thickness indicates that the polymeric solution of the drug is well dispersed in the patches. Low standard deviation values in the film thickness measurements ensured uniformity of the patches prepared by solvent evaporation.

Weight uniformity:

Weight variation test was performed by weighing three patches and average value was taken as the weight of the film. All the formulations exhibited uniform weight with low standard deviation values indicating the uniformity of the films prepared by solvent casting method. The weight of the films varied between 168 to 178 mg, which indicates that different batches were relatively similar in weights. The probable reason for slight weight variation may due to viscosity variation of polymeric solution used in the polymeric films.

Folding endurance:

The folding endurance of transdermal patches was measured manually. The folding endurance measures the ability of patch to withstand rupture. Folding endurance test results indicated that the patches would not break and would maintain their integrity with general skin folding when applied. Folding endurance values of matrix films found more than 150 indicating good strength and elasticity, which is explained by the linear nature of the cellulose structure.

Tensile strength:

The tensile strength of film indicates the strength of film, elasticity of the film and the risk of film cracking it also measures the ability of a patch to withstand rupture. But no sign of cracking in prepared transdermal films and it was observed that all the batches of transdermal patches were strong and flexible, which might be attributed to the addition of the plasticizer, poly ethylene glycol and glycerol. Tensile strength of formulated patches was ranges from 0.361±0.01 to 0.480±0.01 kg/mm2. The patches prepared from PVA and eudragit show more tensile strength than the patches prepared from HPMC and eudragit. As the concentration of polymers increased in the formulation was increased there was increase in tensile strength.

Flatness Study of film:

The flatness study showed that all the formulations had the same strip length before and after their longitudinal cuts, indicating 100% flatness. Thus no constriction was observed indicating all patches had a smooth and flat surface.

Drug Content Uniformity of Films:

Uniformity of drug content among the batches was observed with all formulations and ranged from 94 to 99 %. The results indicate that the process employed to prepare transdermal patches in this study was capable of producing formulations with uniform drug content and minimal patch variability.

Percentage Moisture Loss and Percent Moisture Absorption:

The % moisture loss was found to be between 0.65 ±0.20 to 11.42±2.26 and % moisture absorption was found to be 1.71 ±0.45 to 7.50 ±0.88. The result revealed that the moisture absorption and loss was found to increase with increasing concentration of polymers. The moisture content varied to a small extent in all the trials. The moisture content of the prepared transdermal film was low, which could help the formulations remain stable and from being a completely dried and reduce brittleness during storage. The moisture uptake of the transdermal formulations was also low, which helps the film to remain stable, brittle and free from complete drying. Again low moisture absorption could protect the formulations from microbial contamination and also reduce bulkiness of films. PVP K30, Eudragit RS 100 and HPMC combination patches showed minimum water uptake capacity as compared to PVP K30, Eudragit RS 100 and PVA patches. Among these, PVP-Eudragit RS 100combination exhibited highest moisture uptake capacity.

Water vapour transmission studies (WVT):

Water vapour transmission indicates the degree of occlusion of the patch. Occlusion of the patch is an important parameter it may hinder hydration of stratum conium, skin temperature and blood flow can also increase the percutaneous absorption of certain drug substances depending on the site of application and nature of drug vehicle. Various skin parameters such as pH and bacterial flora are also influenced by an occlusive patch resulting in an increased risk of infection and skin irritation. Degree of occlusion is an important feature for delivery systems that are supposed to be worn on the skin for prolonged period of time. According to British Pharmacopoeia (B.P.) a material can be considered permeable to water vapour when WVT exceeds 0.05 gm/cm2/24h. All the values of WVT showed permeability above the limit set in B.P. and therefore they can be considered as non-occlusive. The enhancement of water vapour transmission increases as concentration of mucilage increases due to effect of plasticizers. PVP- Eudragit patches showed better water vapour transmission as compared to other series. PVP- HPMC combination showed minimum water vapour transmission capacity. Increase in concentration of hydrophilic polymers such as PVP has found to increase water vapour transmission capacity. It is also evident from the literature that, WVT increases with increase in moisture content of the patch from the above facts it is necessary that, critical moisture uptake, moisture content and WVT will decide good physicochemical character of the TDDS.

Percentage moisture content:

The results of moisture content indicated that, all the patches were having specific moisture content in them. Percentage moisture content ranged from 2.15 ±0.30 - 28.92±2.28%. HPMC patches were containing minimum amount of moisture while PVP- Eudragit RS 100 patches were having maximum moisture content. Significant changes in physical properties such as increased porosity and increased pore size in case of hydrophilic polymer containing polymer matrix due to water uptake have been reported, this in turn significantly alter the drug permeation rate ( table 3-4).

In vitro drug release studies:

Release studies are required for predicting the reproducibility of rate and duration of drug release. The importance of polymer dissolution on drug release from matrices has been known for ensuring the sustained release performance. The result indicated that the release of drug from patches increases with increasing concentration of polymers. The cumulative percent of drug release in 12 h was found to be the highest (98.188± 0.198) from formulation F24 carrying PVPK30 and Eudragit RS 100 combinations and minimum (72.831± 0.168) from formulation F1carrying PVPK30and Eudragit RS 100 combinations. The drug release was found to increase on increasing the concentration of hydrophilic polymer in the polymer matrix. This is due to the fact that dissolution of aqueous soluble fraction of the polymer matrix leads to the formation of gelaneous pores. The formation of such pores leads to decrease the mean diffusion path length of drug molecules to release into the diffusion medium and hence, to cause higher release rate. Risperidone patches formulated by using 30% glycerine /30% PEG400 shows enhanced rate of drug release than the patches prepared with 10% and 20% glycerine / 10% and 20% PEG400 respectively. The rate of drug release patches have an impact of plasticizer concentration in the formulations, the 30% concentration showing enhanced diffusion rate then the 20%and 10% concentration. (30% > 20% > 10%). Among polymers, combination of HPMC and Eudragit had enhanced diffusion rate than the combination of HPMC and PVPK30 in all formulations formulated by using glycerine as plasticizer. The polymers, combination of PVPK30 and Eudragit had enhanced diffusion rate than the combination of PVPK30 and PVA in all formulations formulated by usingPEG400 as plasticizer. Formulation F24 containing PVPK30 and Eudragit RS 100combinations showed cumulative % drug release of 98.188± 0.198 in 24 h, emerging as a best formulation by fulfilling the requirement of better and sustained release which was not possible with HPMC and PVA alone or in combination.

Microbial studies on formulated transdermal films:

Formulated transdermal patches were subjected to Microbial studies and it confirmed no microbial growth in transdermal formulations.

Skin irritation studies:

The skin irritation studies were performed on the optimized transdermal patch (F24) to observe any visual skin irritation after the application of the patch to the rats. The results indicated that neither the blank patch nor the drug incorporated patch caused any noticeable irritation, no signs of erythema, oedema or ulceration on the rat skin throughout the study. The absence of edema indicates that the polymeric patches are compatible with the skin and hence can be used for transdermal application. Histopathological studies also revealed that Risperidone TDDS is free from skin irritation and compatible with skin. The Visual and histopathological evaluation after skin irritation studies are shown which confirms that the formulation is free from skin irritation.

Figure 14: Photo graph of skin irritation test of optimized Transdermal patch (F24)

SEM studies:

Scanning electron microscopic was used to visualize what actually happens when the drug diffuses through the skin and how it diffuses from the patch formulation (F24). SEM images showed homogenous and particulate drug distribution in matrix patches of Risperidone. Though the drug, polymers and plasticizer are completely soluble in methanol-methylene chloride solvent system, the distribution of the drug in the polymer matrix was in a particulate distribution. These results confirm that the drug remains in cluster form when it reaches the surface. After permeation experiment the film showed that the presence of pores/channels indicating the drug permeation is diffusion controlled.

Figure 15: SEM photograph of (a) Risperidone loaded film before permeation study;(b) Risperidone loaded film after permeation study.

Drug release kinetics study:

To know the mechanism of drug release, the release data from the optimized batch were fitted to models representing zero-order, first-order Higuchi and Korsmeyer-Peppas. Drug release efficiency of the matrix depends largely on the concentration of drug and polymer. The kinetic parameters for dissolution, rate constants and r2values indicate that the dissolution as well as resistance offered due to tortuosity of the matrix contributed to the release of the drug. The data revealed that the release pattern of formulations are best fitted for Higuchi kinetics equation as the formulation coefficient of correlation values predominates over zero order and first order release kinetics. This complies with Higuchi's equation for drug release from a matrix; a slow and controlled release was observed, indicating that the drug release mechanism was by diffusion, as proposed by Higuchi. Based on Korsmeyer-Peppas semi-empirical model, the best fitting was obtained with n≤0.5, indicating a fickian release mechanism. In swellable systems, factor affecting the release kinetics are liquid diffusion rate and polymeric chain relaxation rate. When the liquid diffusion rate is slower than the relaxation rate of the polymeric chains, the diffusion is Fickian: whereas when the relaxation process is very slow as compared to the diffusion, the case II transport occurs on the basis of these consideration it is clear that patches released the drug by diffusion-dominated mechanism. T50 (time taken for 50% diffusion), T80 and k1 cm-1 values were recorded from the diffusion data profile, the diffusion parameters for Risperidone transdermal patches formulated with different concentrations of glycerine and PEG400 were shown. The T50 values for Risperidone patches formulated with glycerine and PEG400 are exhibited in between 6.48hrs to8.10hrs and 5.30hrs to 8.06hrs respectively. The T80 values for valsartan patches formulated with glycerine and PEG400 are exhibited in between 10.24hrs to11.54hrs and 8.39hrs to 11.30hrs respectively.

Figure 16: Zero order plot for F24 Risperidone transdermal patch

Stability study:

The stability studies were carried out on the most satisfactory formulations F24 at 30±2°C/65±5% RH and 40 ±2°C/75 ±5% RH for two months to assess their long term stability as per ICH guidelines. At fixed time intervals of 30 days and 60 days, the formulation was evaluated for the physicochemical properties, in vitro drug permeation study. There was no significant difference in the physic chemical parameters, in vitro drug permeation profiles were found to be super impossible with the initial readings at zero day results. It indicates that the formulated patches were withstanding with all standard requirement for their stability.

Table 6: Stability studies data for optimized Risperidone transdermal patch

(F24)

*+ = Good, Translucent, - = Hard; * All values are the mean of three readings ± SD

Table 7: Stability Study Diffusion Rate data profile of optimized Transdermal patch (F24) containing Risperidone

Figure 20: Comparison of in vitro diffusion profile of optimized Risperidone transdermal patch (F24) during stability study

CONCLUSION:

From the study conducted and from the observations and the results obtained thereof, following conclusions were drawn:

· FT-IR spectra and DSC thermo grams indicated that drug is compatible with polymers and also there were no chemical interactions between polymers.

· The physico-chemical parameters of the formulated patches like weight variation in between 168 to 178 mg.

· Thickness and folding endurance of the Risperidone patches were in between 0.51±0.06 to 0.67±0.02 mm and in between 220 to 259 respectively. The result indicates the ability of patches to withstand rupture found to be satisfactory.

· Percentage Flatness and Water vapour transmission of the Risperidone patches were in between 99.2% to 100% and 2.54 to 4.93 respectively. Indicating they could maintain a smooth surface when applied to skin. All the formulations were permeable to water vapour (gcm⁻²h⁻¹)10^-4/24hrs). All the physico chemical parameters were found to be satisfactory.

· The drug content for the Risperidone transdermal patches formulated with glycerine and PEG400 indicates in between 94.07% to 97.82% and92.92% to 97.23% respectively. The low co-efficient variation (CV %) values of Risperidone patches in the percentage of drug content indicates the uniformity of drug content in all formulations.

· Risperidone patches formulated by using 30% glycerine /30% PEG400shows enhanced rate of diffusion than the patches prepared with 10% and20% glycerine / 10% and 20% PEG400 respectively.

· The diffusion rate of patches have an impact of plasticizer concentration in the formulations, the 30% concentration showing enhanced diffusion rate then the 20% and 10% concentration. (30% > 20% > 10%)

· Among polymers, combination of HPMC and Eudragit had enhanced diffusion rate than the combination of HPMC and PVPK30 in all formulations formulated by using glycerine as plasticizer.

· The polymers, combination of PVPK30 and Eudragit had enhanced diffusion rate than the combination of PVPK30 and PVA in all formulations formulated by using PEG400 as plasticizer. From the drug release models, it was found that optimized formulation (F24) follow higuchi kinetic with fickian release mechanism.

· The correlation coefficient (R2) values were greater, indicating from the analysis of diffusion data as per above models.

· The T50 values for Risperidone patches formulated with glycerine and PEG400 are exhibited in between 6.48hrs to 8.10hrs and 5.30hrs to 8.06 hrs. respectively.

· The T80 values for Risperidone patches formulated with glycerine and PEG400 are exhibited in between 10.24hrs to 11.54hrs and 8.39hrs to 11.30hrs respectively.

· The SEM films indicating uniform distribution of the drug with polymers and plasticizers.

· Stability study data shows that there is no much change in the values after stability test when compared with before stability studies. It indicates that the formulated patches were withstanding with all standards requires for their stability.

· Thus the results of the study clearly indicates the systemic medication through topical application and release of drug by developing transdermal drug delivery system to obtain a controlled, predictable and reproducible absorption and release, improved bioavailability, painless and simple application are some of the potential need to formulate the Risperidone transdermal drug delivery system.

ACKNOWLEDGEMENTS:

The authors are thankful to Principal and Management of Karavali College of Pharmacy, Mangalore for providing all the facilities and support for this research project. The authors are also thankful to Torrent Pharmaceuticals, Baddi, India for generous gift samples of Risperidone.

REFERENCES:

1. Panchagnula R. Transdermal Delivery of Drugs. Indian Journal of Pharmacology 1997; 29:140 – 156.

2. Adrian C, Brian W. Penetration enhancers. Advanced Drug Delivery Reviews 2004; 56: 603 – 618.

3. Kandavilli S, Nair V, Psnchagnula R. Polymers in transdermal drug delivery systems. Pharmaceutical Technology 2002; 62 – 80.

4. Y.S. Tanwar, C. S. Chauhan, A. Sharma. Development and evaluation of carvedilol transdermal patches. Acta Pharm, 2007, 57,151–159.

5. Biswajit Mukherjeea, Sushmit a Mahapatraa, Ritu Gupta, Balaram Patraa, Amit Tiwarib, Priyanka Arora. A comparison between povidone ethyl cellulose and povidone-eudragit Transdermal dexamethasone matrix patches based on in vitro skin permeation. European Journal of Pharmaceutics and Biopharmaceutics, 2005, 59,475–483.

6. M. Aqil, Asgar Ali. Transdermal therapeutic system of Enalapril Maleate using piperidine as penetration enhancer, Current Drug Delivery, 2008, 5, 148-152.

Received on 04.05.2016 Accepted on 17.08.2016

Asian J. Res. Pharm. Sci. 2016; 6(4): 208-222.

DOI: 10.5958/2231-5659.2016.00030.8