Formulation and Evaluation of Quetiapine Loaded Pressure Sensitive Adhesive Patch for Transdermal Drug Delivery

 

Milan B. Agrawal, Mayur M. Patel*

Department of Pharmaceutics, Institute of Pharmacy, Nirma University, SG Highway,

Chharodi, Ahmedabad: 382 481, Gujarat, India.

 

ABSTRACT:

The present research work was intended to develop and characterize the transdermal adhesive patch of quetiapine using different types of acrylate, polyisobutylene and silicon adhesives. Various permeation enhancers such as 1, 8 – cineole, D-limonene, Azone, IPM and Oleic acid were also evaluated to achieve desired permeation rate and hence to attain the improved bioavailability of quetiapine as compared to oral formulation. Formulations prepared were evaluated for physicochemical characterization, permeability enhancement potential by ex vivo, and stability studies. The results of the optimized formulation showed peel strength of 423 ± 4.13 cN/cm, flux of 54.92 ± 0.79 (µg/h/cm²) and % drug content of 98.16 ± 0.43% which was stable up to six months in accelerated condition. The results of the study revealed that the developed transdermal patch of quetiapine can be a promising alternative which provides effective management of schizophrenia in terms of improved patient compliance and reduced dosage frequency.

 

 

 

INTRODUCTION:

Schizophrenia is characterized by disintegration of thought processes and of emotional responsiveness. It is a severe form of mental illness affecting about 21 million people worldwide^1,2. Quetiapine is an atypical antipsychotic agent categorized as serotonin antagonist which binds to 5-HT 2A/2C receptors. It has strong affinity to several dopaminergic receptors but exerts weak antagonism for D₂ receptor which is responsible for modulating the neuroleptic activity³.

 

Quetiapine tablets are taken twice daily, orally where it undergoes the extensive hepatic first pass metabolism resulting in very less oral bioavailability of quetiapine which is reported to be less than <9%⁴. Quetiapine is majorly metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive⁵.

 

Hence, the delivery of quetiapine is a difficult task for the successful treatment of schizophrenia, where prolonged drug delivery is mandatory for the patients who may need assistance to receive medication by other routes.

 

The topical drug delivery provides various benefits as compared to traditional dosage forms viz. improved compliance of patients on long-lasting therapy⁶, maintaining a prolonged and constant plasma level of drug (thereby diminishing the side effects associated with the oral route), bypassing biotransformation⁷, reducing inter and intra-patient variability and making it possible to put an end to drug therapy whenever needed⁸.

 

Therefore, the main purpose of this study was to evolve transdermal drug delivery system (TDDS) of quetiapine to diminish the risk of significant oral side effects along with to provide better patient acceptability. Additionally, transdermal adhesive patch provides constant drug delivery for an extended period of time and thereby reduces the dosing frequency and thus facilitates caregiver by dropping such obstacles associated with oral delivery.

 

Hence, taking into consideration above mentioned facts, quetiapine loaded transdermal drug delivery system consisting of various types of pressure sensitive adhesives (PSAs) along with different categories and concentration of the penetration enhancers at different drug loading level will be evaluated.

 

MATERIALS AND METHODS:

Materials

Drug sample of quetiapine provided by Piramal pharmaceuticals, India. Various types of pressure-sensitive adhesives (PSA), backing membranes and release liners were procured from Henkel Corporation and 3M Healthcare. 1, 8-Cineole received from Mentha & Allied Products Pvt. Ltd., New Delhi, India while d-limonene, oleic acid, and isopropyl myristate (IPM) received through Loba Chemie, Mumbai, India.

 

Preparation of adhesive patches:

Quetiapine adhesive patches were manufactured by dissolving the drug in a concentration of 15%w/w along with pressure-sensitive adhesive (DT-387-2516) in a solvent system of methanol. In addition to this IPM was put together with prepared mixture at a concentration of 7.5% w/w. The mixture was stirred for half an hour and was poured on a release liner (Scotchpack 1022, 3M, USA). After that, the film was kept at room temperature for 10-15 minutes and after that kept into the oven for 5 min at 45°C. The PSA film was laminated with the backing membrane (Scothpack 9723, 3M, USA) (9)(10).

 

Evaluation of transdermal patches

Uniformity of weight

The formulated films having 25 mg (4.41 cm²) dose were checked for uniformity of weight using an electronic balance (Scientech, Boulder, USA).

 

Thickness of patch:

Thickness of the patch was evaluated by a digital caliper (Mitutoyo, Japan) at random points (11).

 

Peel strength:

Peel strength was determined by loyd universal testing machine (LRX+) (Testometric, Rochdale, United Kingdom) (12)(13).

 

Drug content:

Drug content was quantified by dissolving the patch of size 4.41 cm2 in 100 mL of methanol, which was then analyzed spectrophotometrically at a wavelength of 259 nm (4) (14).

 

Ex vivo Permeation Study:

Franz diffusion cell filled with phosphate buffer pH 7.4 was utilized (15) with rat skin to carry out this study (Approval no. ROFEL/IAEC/2018/3). Withdrawn aliquots were assessed spectrophotometrically (16). The permeation of the drug was estimated as per the following formula (17).

 

Where C_n is the receiver solution concentration of the drug, C_i is the i_th sample drug concentration, V₀ and V_i are the receptor medium volume and aliquot volume, respectively, while S is the effective area of diffusion (18) (19).

 

Stability Study

It was performed in accelerated conditions at temperatures of 40 ± 2ºC and 75±5% RH for 0,1,3 and 6 months (20). Films were assessed for drug content, peel strength, and permeation rate and results were compared with freshly prepared patches (21).

 

RESULTS AND DISCUSSION:

Selection of Pressure Sensitive Adhesives

Based on the type and different physicochemical properties polyisobutylene, silicon and acrylate adhesives are selected for the study. Acrylate adhesives used for the study were based on functional groups, crosslinkers, vinyl acetate and viscosity of PSA (Table1).

Table 1. Selection of PSA based on their physicochemical properties.

PSA	Type of PSA	Contains Vinyl Acetate	Functional Group	Cross-linkers	Viscosity mPa.s
DT-87-6908	Polyisobutylene	No	None	n/a	6000
Bio-PSA 7-4302	Silicone	No	None	n/a	9250
DT-87-9301	Acrylate	No	None	n/a	9500
DT-87-4098	Acrylate	Yes	None	n/a	6500
DT-387-2287	Acrylate	Yes	-OH	No	18000
DT-387-2516	Acrylate	Yes	-OH	Yes	4350
DT-387-2510	Acrylate	No	-OH	No	4250
DT-387-2353	Acrylate	No	-COOH	No	8000
DT-387-2852	Acrylate	No	-COOH	Yes	2500
DT-387-2052	Acrylate	Yes	-COOH	Yes	2750

 

Calculation of the required flux of drug ²²

J = (Cp * Cl * W)/A (2)

Here: J corresponds to flux (µg/h/cm²), Cp corresponds to concentration of plasma (50 µg/L), A is the area of patch (4.41 cm²), W corresponds to patient’s body weight (considered as 60 Kg) while Cl is the rate of clearance (0.068 L/h/kg)²³. The target flux was required 46.26 µg/h/cm² (~50 µg/h/cm²) which is necessary for achieving the adequate drug plasma concentrations. Initially, for the screening of PSA, batches were prepared with 10% drug loading.

 

It was described from the results (Table 2) that flux for DT-387-2516 acrylate adhesives with –OH (hydroxyl) functional group was found to be 29.38±1.32 µg/h/cm² while in case of DT-387-2353 and DT-387-2052 acrylate adhesives with –COOH (Carboxyl acid) functional group the flux was found to be 13.65±0.98 µg/h/cm² and 17.15±1.06 µg/h/cm² respectively (figure 1). Here, the flux was found highest with –OH functional group which could be due to its characteristic of reducing the drug-tissue binding by occupying hydrogen bonding sites ²⁴ and giving the solvating effect of alpha-keratinin within corneocytes which leads to the marginal increase in lipid fluidity and hence the drug permeability²⁵. So, it improves the solubility of the drug within stratum corneum and resulting in increased drug partition into the skin. According to literature peel strength, less than 300 cN cm^-1 leads to poor adhesion, as shown in results peel strength was found greater than the mentioned criteria for all the adhesives. So, based on the result and discussion DT-387-2516 was selected for further studies.

 

Table 1. Physico-chemical characterization of quetiapine transdermal patch (mean ± SD, n=3).

PSA	Weight (mg)	Thickness (mm)	% Drug Content	Peel Strength (cN/cm)	Flux (µg/h/cm2)
DT-387-2516	251.4±1.02	0.10±0.02	97.29±1.14	702±6.23	29.38±1.32
DT-387-2353	248.9±1.23	0.10±0.01	98.01±1.19	745±6.89	13.65±0.98
DT-387-2052	252.7±1.19	0.12±0.02	97.26±1.26	681±5.39	17.15±1.06

 

Table 2. Characterization of quetiapine transdermal patch with different drug loading (mean ± SD, n=3).

Formulation	Drug loading (%)	Flux (µg/h/cm2)	Weight (mg)	Thickness (mm)	Peel Strength cN/cm
A1	5	19.16±0.77	502.7±2.36	0.13±0.02	869±5.49
A2	10	29.38±1.32	251.4±1.02	0.10±0.02	702±6.23
A3	15	35.39±1.47	167.1±1.27	0.09±0.02	527±4.17
A4	20	34.02±1.21	124.9±0.87	0.08±0.01	457±4.38

 

Figure 1. Effect of different PSA on ex vivo skin permeation.

 

Optimization of drug loading:

To optimize the concentration of quetiapine, batches A1 to A4 were prepared with drug loading in a range of 5% - 20% to check its impact on skin permeation. It was considered on the basis of results (Table 3) as the amount of drug climbs from 5% to 15% skin permeation increases from 19.16±0.77 µg/h/cm² to 35.39±1.47 µg/h/cm². This was due to the higher concentration gradient of the drug which creates reservoirs in the skin and from where permeate the drug²⁶. Flux was comparable for batches A3 and A4 (Figure 2) which was due to the saturation of the skin beyond the threshold concentration of the drug. Hence, 15% of drug loading was found to be optimum. As shown in the results it can also be inferred that as the drug concentration increases PSA concentration decreases and hence the peel strength of the patch also decreases.

 

Figure 2 Ex vivo skin permeation at different drug loading.

 

Table 3. Details of different Permeation enhancers used for the study (mean ± SD, n=3).

Formulation	Penetration Enhancers	Conc. Used (%)	Flux (µg/h/cm2)	Enhancement Ratio	Peel Strength cN/cm
B1	1,8-cineole	5	36.69±1.13	1.04	512±4.21
B2	D-limonene	5	38.39±0.87	1.08	503±4.03
B3	Azone	5	39.78±1.28	1.12	491±4.45
B4	Isopropyl Myristate	5	47.81±1.06	1.35	497±4.67
B5	Oleic acid	5	43.57±1.43	1.05	482±3.98

 

Table 4. Impact of concentration of IPM (mean ± SD, n=3).

Formulation	Penetration Enhancers	Conc. Used (%)	Flux (µg/h/cm2)	Enhancement Ratio	Peel Strength cN/cm
D1	IPM	5	47.81±1.06	1.35	497±4.67
D2	IPM	10	57.64±1.32	1.63	421±3.12
D3	IPM	15	60.07±1.47	1.70	352±2.78

 

Figure 3. Ex vivo skin permeation with various permeation enhancers

 

Effect of permeation enhancer type:

Batches B1 to B5 were formulated with different PEs with the amount of 5% w/w (Table 4). The flux values of quetiapine (µg/h/cm²) in the presence of the enhancers evaluated and found to be highest for IPM viz. 47.81±1.06 µg/h/cm² (batch B4) and lowest for 1,8-cineole viz. 36.69±1.13 µg/h/cm² (batch B1). Permeation profiles are shown in Figure 3.

 

Penetration was achieved to be lowest for 1, 8 Cineole and highest for IPM could be due to the PEs lipophilicity difference^27,28. log p for IPM and OA is comparable viz. 7.17 for the former and 7.7 for the latter ¹⁰ and hence almost similar flux was achieved. IPM alters lipid fluidization and enhances the flux²². Azone (log p ~6.2) gets partitioned in lipid⁹. 1,8-cineole also works on the same mechanism as of Azone viz. lipid layer disruption²⁹ and d-limonene promotes extraction of lipid³⁰. For 1,8- cineole log P is 2.82 ± 0.25³¹. So, according to the above observation IPM was chosen as the most appropriate enhancer³².

 

Effect of permeation enhancer concentration

Batches D1, D2 and D3 were prepared with IPM at concentration of 5%, 10% and 15% respectively based dry polymer weight. The penetration rate of quetiapine (µg/h/cm2) for batches D1 to D3 was achieved 47.81±1.06 µg/h/cm², 57.64±1.32 µg/h/cm² and 60.07±1.47 µg/h/cm² respectively (Table 5). As the amount of IPM increased the flux also increased, reaching highest at 15% (Figure 4). Almost similar flux obtained with 10% and 15%³³.

 

Figure 4. Ex vivo skin permeation at various concentration of permeation enhancers.

 

Stability study:

During the stability study, the appearance of the patch was not changed. The results of drug content³⁷, peel strength, and permeation rate were obtained 98.16 ± 0.43%, 423 ± 4.13 cN/cm, and 54.92 ± 0.79 µg/h/cm² respectively. Results obtained were comparable with the initial (Table 6). The results of % assay and permeation rate confirmed the absence of the crystallization of quetiapine which divulges the formation of the steady patch³⁸.

 

Table 5. Results of Stability Study (mean ± SD, n=3).

Time Point	Drug Content (%)	Peel Strength (cN/cm)	Flux (µg/h/cm2)
Initial	98.66 ± 0.28	421 ± 3.12	57.64 ± 1.32
1 Month	98.82 ± 0.35	439 ± 4.52	55.81 ± 0.83
3 Month	98.31 ± 0.21	428 ± 4.69	56.04 ± 0.71
6 Month	98.16 ± 0.43	423 ± 4.13	54.92 ± 0.79

 

CONCLUSION:

Quetiapine transdermal patch was formulated using pressure sensitive adhesives along with permeation enhancers to provide the sustained release of the drug with better permeation rate and hence the bioavailability as compared to the marketed formulation. Hence, the developed quetiapine PSA patch proves to be a better alternative to conventional dosage forms and can be utilized in schizophrenics with improved patient compliance with reduced dosage frequency.

 

ACKNOWLEDGEMENT:

We acknowledge that the funding of this research came from the self-financing of the authors and the authors are grateful to Amneal Pharmaceutical Pvt. Ltd., Ahmedabad for rendering generous support to carry out the research work. The authors are thankful to the Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India for providing the necessary facilities to generate the manuscript that is a part of Doctor of Philosophy (Ph.D.) research work of Mr. Milan Agrawal to be submitted to Nirma University, Ahmedabad, India.

 

DECLARATION OF INTEREST:

The authors report no conflicts of interest.

 

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Received on 29.03.2020           Modified on 10.05.2020

Accepted on 30.06.2020         © RJPT All right reserved