Role Of Novel Penetration Enhancer in The Transdermal Patch of Naproxen Sodium for Dysmenorrhea Management

Dysmenorrhea, commonly referred to as painful menstruation, is a prevalent gynaecological condition that significantly impacts women of reproductive age, often leading to reduced quality of life. It is characterized by severe cramping and pain in the lower abdomen, typically occurring just before or during menstruation. Dysmenorrhea can be classified into two categories: primary and secondary. Primary dysmenorrhea refers to menstrual pain without an underlying gynaecological issue, while secondary dysmenorrhea is associated with conditions such as endometriosis, pelvic inflammatory disease, or uterine fibroids. Among the available treatment options, nonsteroidal anti-inflammatory drugs (NSAIDs) such as Naproxen Sodium have proven effective in managing the symptoms of primary dysmenorrhea by inhibiting prostaglandin synthesis, which plays a key role in the occurrence of uterine contractions and pain.

Naproxen Sodium is a widely used NSAID due to its potent anti-inflammatory, analgesic, and antipyretic properties, making it a standard treatment for dysmenorrhea. However, the conventional oral administration of Naproxen Sodium is associated with several limitations, particularly gastrointestinal (GI) side effects. Long-term oral use of NSAIDs can lead to adverse outcomes such as gastric irritation, ulcers, and even renal toxicity, which are major concerns for patient compliance. In addition, oral administration requires systemic absorption, resulting in delayed onset of action and the need for frequent dosing to maintain therapeutic levels. For dysmenorrhea management, an ideal treatment would provide rapid pain relief while minimizing systemic side effects and improving patient adherence to the therapeutic regimen.

In recent years, transdermal drug delivery systems (TDDS) have emerged as a promising alternative to oral administration for various medications, including NSAIDs like Naproxen Sodium. Transdermal patches offer a non-invasive route of drug administration that bypasses the GI tract, reducing the risk of GI-related side effects. By delivering the drug directly through the skin into the systemic circulation, transdermal patches enable controlled and sustained drug release, which can improve therapeutic outcomes and patient adherence. Additionally, transdermal delivery allows for the administration of lower doses of the drug, as it avoids first-pass metabolism in the liver, which is often a significant contributor to drug degradation in oral routes. However, one of the major challenges in the development of effective transdermal patches is the ability of the drug to penetrate the skin's protective barrier, known as the stratum corneum. The stratum corneum acts as a formidable barrier to most drugs due to its lipophilic nature and tightly packed structure of corneocytes embedded in a lipid matrix. As a result, the permeation of hydrophilic or larger molecular weight drugs through the skin is often limited, necessitating the use of penetration enhancers to improve drug delivery. Penetration enhancers, also known as permeation enhancers, are substances that temporarily modify the skin barrier to facilitate the movement of active pharmaceutical ingredients (APIs) through the stratum corneum and into the deeper layers of the skin. They achieve this by interacting with the lipid matrix or proteins in the skin, increasing skin permeability without causing damage or irritation. Traditionally used penetration enhancers include substances such as ethanol, propylene glycol, and oleic acid, which have shown varying degrees of success in enhancing transdermal drug delivery. However, these conventional enhancers often come with drawbacks such as skin irritation, hypersensitivity reactions, and limited effectiveness, which have driven the search for novel and safer penetration enhancers.

The focus of this study is to evaluate the role of a novel penetration enhancer in the formulation of a transdermal patch for Naproxen Sodium, specifically aimed at improving the management of dysmenorrhea. The incorporation of an effective penetration enhancer into the transdermal patch formulation is expected to enhance the permeability of Naproxen Sodium through the skin, thereby increasing its bioavailability and ensuring rapid pain relief. In addition to enhancing permeability, the ideal penetration enhancer should be non-toxic, non-irritating, and compatible with the other components of the patch, including the drug and the polymeric matrix. The transdermal patch system used in this study is designed to deliver Naproxen Sodium in a controlled manner over an extended period, providing sustained relief from dysmenorrhea-related pain. The patch matrix consists of polymers such as Hydroxy Propyl Methyl Cellulose (HPMC) and Ethyl Cellulose, which play crucial roles in providing structural integrity, ensuring mucoadhesion, and controlling the release of the drug. The use of a novel penetration enhancer in combination with these polymers could potentially overcome the limitations of conventional transdermal delivery systems, resulting in a more efficient and patient-friendly treatment option.

The rationale behind the use of a novel penetration enhancer is grounded in the need to strike a balance between efficacy and safety. While improving drug permeation is essential for enhancing therapeutic outcomes, it is equally important to ensure that the enhancer does not compromise the integrity of the skin or cause adverse effects. Previous research has demonstrated the potential of various natural and synthetic compounds to act as effective penetration enhancers. For example, quercetin, a flavonoid derived from plant sources, has shown promise as a natural penetration enhancer due to its ability to interact with skin lipids and disrupt the stratum corneum, thereby improving drug absorption. In this study, quercetin will be investigated as the primary novel penetration enhancer in the transdermal patch formulation.

The choice of quercetin as a penetration enhancer is supported by its favorable pharmacological profile, which includes antioxidant, anti-inflammatory, and analgesic properties. These additional therapeutic benefits make quercetin an attractive candidate for inclusion in a transdermal system designed for dysmenorrhea management. Furthermore, quercetin’s natural origin reduces the risk of adverse effects commonly associated with synthetic penetration enhancers, making it a safer alternative for long-term use.

This study aims to optimize the formulation of the Naproxen Sodium transdermal patch by incorporating quercetin as a novel penetration enhancer, evaluating its impact on skin permeability, drug release profiles, and overall therapeutic efficacy. The ultimate goal is to provide an improved, non-invasive treatment option for dysmenorrhea that combines the advantages of transdermal drug delivery with the enhanced permeability afforded by a novel enhancer. By minimizing side effects and improving patient compliance, this approach could offer a significant improvement over existing treatment modalities for managing menstrual pain.

In conclusion, this research seeks to address the challenges associated with the transdermal delivery of Naproxen Sodium for dysmenorrhea management by incorporating a novel penetration enhancer into the patch formulation. Through the systematic evaluation of quercetin’s role as a permeability enhancer, the study aims to demonstrate its potential to enhance drug delivery, provide sustained pain relief, and improve the overall therapeutic experience for patients suffering from dysmenorrhea. The findings from this study could contribute to the development of safer, more effective transdermal systems for the treatment of various conditions requiring NSAID therapy, with broader implications for transdermal drug delivery technology.

MATERIALS AND METHODS:

MATERIALS:

The materials utilized in this study were obtained from various manufacturers, each serving a specific role in the formulation. Naproxen Sodium, which acts as the Active Pharmaceutical Ingredient (API), was procured from Tokyo Chemical Industry India Pvt. Ltd., Hyderabad. Quercetin, sourced from the same manufacturer, was employed as a penetration enhancer. For the formulation's structural integrity, Hydroxy Propyl Methyl Cellulose (HPMC), a sustained release polymer, was acquired from Dipa Chemical Industries. Ethyl Cellulose, which provides mucoadhesive properties to the formulation, was also obtained from Dipa Chemical Industries. To ensure flexibility and durability of the formulation, Dibutyl phthalate was used as a plasticizer. Methanol and Chloroform, both serving as solvents in the preparation process, were additionally sourced from Dipa Chemical Industries. These materials were used in their specified quantities to achieve the desired characteristics in the formulation.

METHODS:

Characterization of Drug ^1,2

 Melting behavior

Melting point of Naproxen Sodium was determined using automated melting point apparatus OptiMelt (SRS).

 UV spectroscopy

A UV spectrum of Naproxen Sodium was recorded in Methanol (MeOH) using ‘Spectrum Measurement’ function of UV-Visible Spectrophotometer (Lasany)

 Vibrational spectroscopic study

After starting the instrument, ‘Background Measurement’ was performed without placing the drug on panel. For ‘Sample Measurement’, pure Naproxen Sodium was placed on cleaned panel of FT-IR Spectrometer (Bruker). The placed Naproxen Sodium was sandwiched between panel and upper arm. This sample was scanned over a wave number range of 4000 to 400 cm^-1.³

Construction of calibration curve for Naproxen Sodium

To prepare drug solutions, a suitable amount of Naproxen Sodium was accurately weighed on aluminium foil using a pre-calibrated analytical balance. The weighed sample was transferred to a volumetric flask and dissolved in analytical grade Methanol (MeOH). Before UV analysis, the cuvettes were thoroughly washed twice with distilled water and rinsed twice with Methanol to ensure cleanliness. For the UV analysis, the cuvettes were filled with Methanol, and the instrument was calibrated using the 'Auto Zero' function. Subsequent UV absorbance measurements were then recorded.⁴

 Preparation of Stock Solution

10 mg of Naproxen Sodium was exactly weighed using pre-calibrated analytical balance, transferred in 10 mL volumetric flask and dissolved in sufficient Methanol using sonication. It produced a solution of 1mg/mL strength (Stock-1). From the Stock -1 take out 1 ml and dilute up to 10 ml with methanol to give 100µg/mL (Stock-2) solution which was used for the determination of maximum analytical wavelength. The Stock-1 containing flask was covered with foil and sealed with paraffin film to avoid degradation and loss due to evaporation.

Determination of Analytical Wavelength (?_max)

Sufficient volume of Stock-2 was scanned under UV region of 400-200 nm using Methanol as blank. The wavelength, at which there was maximum absorption, was selected as wavelength for analysis.⁵

 Preparation of Standard curve

A six point standard curve of Naproxen Sodium was prepared using different concentrations. The concentration range selected was from 4 µg/mL to 25 µg/mL. Concentrations of 4 µg/mL, 8 µg/mL, 12 µg/mL, 16 µg/mL, 20 µg/mL, and 25 µg/mL were prepared by appropriate dilutions of Stock-1.

Preparation of Preliminary Batches of Transdermal Patches

The preliminary batches of transdermal patch were tried on the basis of previous reports. These batches were prepared and evaluated for optimizing the formulation components like amount and ratio of polymers, plasticizer amount and concentration of penetration enhancer.

Formulation development ^3,4

Following critical formulation parameters were identified

• Polymer ratio (Hydroxy Propyl Methyl Cellulose: Ethyl Cellulose) (HPMC : EC)
• Solvent ratio (Chloroform: Methanol) (CHL : MeOH)
• Plasticizer (Dibutyl phthalate) amount (DBP)
• Amount of penetration enhancer (QCT)

Naproxen Sodium-loaded transdermal patches were prepared using the solvent casting method. Matrix-type patches were made from varying ratios of HPMC, EC, dibutyl phthalate (DBP), and quercetin (QCT), cast on a glass slab with glass rings (5.3 cm diameter). Chloroform and Methanol were used as solvents, and DBP acted as a plasticizer. The process began by accurately weighing the drug and polymers. The solvent mixture of Chloroform and Methanol was prepared, followed by dissolving the polymers in the solvent with continuous stirring to form a homogeneous mass. The drug and penetration enhancer were dissolved in Methanol and added to the polymeric mixture, ensuring even distribution. The plasticizer was then added, and the resulting viscous solution was poured into glass rings for uniform casting. Patches were dried at room temperature for 24 hours, allowing solvent evaporation. Once dried, the patches were removed, cut into squares, and stored in polythene bags with butter paper separators in desiccators until use.

Evaluation of Transdermal Patches ^5-8

Transdermal patches have been developed to improve clinical efficacy of the drug and to enhance patient compliance by delivering smaller amount of drug at a predetermined rate. Hence this makes evaluation studies more important in order to ensure their desired performance and reproducibility under the specified environmental conditions. These studies are predictive of performance of transdermal patch and can be classified into following types:

1. Physicochemical evaluation
2. In-vitro evaluation

 Physicochemical evaluation

1. Physical Appearance

The appearance of the prepared transdermal patch of Naproxen Sodium with penetration enhancer was observed physically.⁹

2. Thickness

The thickness of transdermal patch was determined using screw gauge. The thickness of patch was measured at five different points of patch (4 at corners and 1at centre). The average of these five readings was calculated and reported as thickness ± SD in millimetres.¹⁰

3. Uniformity of weight

The prepared patches were studied for weight variation by individually weighing 10 randomly selected patches and calculating the average weight. The individual weight should not deviate significantly from the average weight. Lesser the deviation more is the uniformity.^11-12

4. Drug content determination

A 50 mg portion of patch was weighed accurately and dissolved in 3mL of Methanol in a 10 mL beaker. It was shaken slowly to ensure complete immersion of patch portion into the solvent. This was sonicated for 2 minutes. After sonication, an accurate volume of resultant solution (1mL) was taken out by micropipette and transferred to 5mL volumetric flask. The volume was made up to 5mL using Methanol. The amount of drug was then estimated by UV spectrophotometer method at 331 nm and % drug content was reported.^13-15

5. Tensile strength determination

In this test, the prepared patch was cut in the shape of rectangle. The two ends of it were tied separately to corked linear iron plates. One end of this was kept fixed by tying it the firm base, and other end was connected to a freely movable thread over a pulley. The weights were added to pan in gradually increasing manner. This pan was attached with the hanging end of the thread over that pulley. A pointer on the thread was observed to measure and note the elongation of the film. The weight just sufficient to break the patch was noted. The tensile strength can be calculated using the following equation:

Tensile strength = Fa×b × (1+Ll)

Where F = force required to break the patch (N/cm²)

            a = width of patch used (cm)

            b = thickness of patch used (cm)

            L = length of patch used (cm)

            l = elongation of patch at break point (cm)

6. Folding endurance

The folding endurance of the patch is the number of times that patch could be folded at the same place without breaking it. Folding capacity of the patch was determined in this test. In this test, the selected portion of patch was folded repeatedly at the same place until it breaks. The number of folds required to break the patch, was reported as its folding endurance.^16-17

7. Flatness

To determine the flatness of a patch, a strip was cut from the centre and two from each side of patch. The length of each strip was measured and variation in length was noted. This data was used to determine percent constriction and results were shown in the form of % flatness. 0 % constriction indicates 100 % flatness.

It is calculated from following formula:

% constriction = L1- L2L1 × 100

            Where L₁= Initial length of strip (cm)

                        L₂= Final length of strip (cm)

8. Percentage of moisture content

For this test, one patch from each batch was selected and weighed accurately (W₁ mg). These weighed patches were kept in a desiccator containing Calcium chloride at room temperature for 24 hours. After the specified interval, patches were weighed again until a constant weight was obtained (W₂ mg). The percent moisture content was calculated using following formula:

% Moisture content = W1- W2W1 × 100

1. Percentage of moisture uptake

Patches were selected from each batch and weighed accurately (W1 mg). These patches were kept in dessicator at room temperature for 24 hours. Then patches were taken out and exposed to 84% relative humidity using a saturate solution of Potassium chloride in another dessicator. Exposure was continued until a constant weight (W2 mg) was obtained. The percent moisture uptake was calculated using following formula:

% Moisture uptake=W2- W1W2 × 100

In vitro evaluation

In vitro dissolution studies

In vitro drug dissolution studies of the transdermal patch were conducted using a six station USP XXII type I apparatus.  The apparatus was first equilibrated at 37 ± 0.5 ºC and 50 rpm. The dissolution studies were carried out in 900 ml of pH7.4 phosphate buffer under sink condition. The accurately weighed portion of patch (equivalent to 50mg of patch) was used for study. An aliquot of 5mL was withdrawn the dissolution medium at specified intervals of 5, 10, 15, 30, 45, 60, 120, 240, 360, 480, 600, 720, 840 and 960 minutes. After removal of sample after each interval, it was replaced by fresh medium to maintain the constant volume. The samples were filtered and analysed by UV spectrophotometric method at 331nm. The % cumulative drug release was reported.^18-20

In vitro skin permeation studies

In vitro skin permeation studies were conducted using a Franz diffusion cell with a 10 mL receiver compartment. Prior to the experiment, chicken skin was equilibrated in a 0.01M phosphate buffer (pH 7.4) for 2 hours. The full-thickness skin was mounted in the diffusion cell with the stratum corneum facing the donor compartment, and the receptor medium was introduced. The mixture was continuously stirred at a constant speed, and the receptor chamber temperature was maintained at 37 °C using a water bath. A 1 mL blank sample was withdrawn from the receptor compartment to check for residual absorbance at 331 nm. After adhering the patch to the skin, the stopwatch was started, and 1 mL samples were withdrawn at intervals of 1, 2, 4, 6, 8, 10, 12, and 24 hours, with fresh buffer replacing the withdrawn volume. The samples were diluted and analyzed UV spectrophotometrically at 331 nm, and the amount of drug permeated per square centimeter was calculated for each time interval.^21-23

Stability study of Transdermal Patch

The Stability study of Transdermal Patch was stored in amber coloured glass bottles at 3 different temperatures 4^oC, Room temperature and 40±0.5 ^oC for a period of 3 months. The samples were withdrawn after 60, 120 and 180 days and analysed for physical appearance, drug content, folding endurance.^24-25

Results and Discussion

Characterization of Drug

Melting Behavior

The melting range of Naproxen Sodium was found to be 152 to 155 °C by OptiMelt.

Vibrational spectroscopic study

The spectrum of Naproxen Sodium was recorded & is shown in Figure 1. Structural assignments for the characteristics absorption bands in the spectrum.

       
           
       
Figure 1: FTIR Spectrum of Naproxen Sodium

Initially, the drug was characterized by its melting behavior and FT-IR spectroscopic studies. The melting range of Naproxen Sodium matched with that of standard range, indicating the drug was in its pure form and was not degraded. FT-IR spectrum of Naproxen Sodium showed the prominent peaks at the wavelengths (cm^-1) 1048.34, 1357.18, 1674.87, 3296.23. These peaks appeared for the C-H (Phenyl ring substitution); C-O stretching vibrations; C-O stretching vibrations (Acids); C-H bending vibrations; C=C stretching vibrations (Aromatic ring); -C=O stretch vibrations (Carboxylic acids) and O-H stretching vibrations respectively. These functional groups matched with the groups in the structure of Naproxen Sodium, hence confirming the functional groups in the structure.

       
           
       
Figure 2: FTIR Spectrum of Naproxen Sodium with HPMC

Maximum Wavelength for Naproxen Sodium was found to be 331 nm. The standard calibration curve of Naproxen Sodium was obtained by plotting the absorbance of the standard solution against its concentration at 331 nm. The standard solution of Naproxen Sodium showed the linear curve with correlation coefficient of 0.9993. Their equations of lines was y = 0.0448x + 0.0769 at selected ?_max. Following table shows absorbance of respective standard solution. The standard curve for Naproxen Sodium at 331 nm is shown in Figure 4.

       
           
       
Table 5: Calibration range for Naproxen Sodium

       
           
       
Figure 4: Standard curve for Naproxen Sodium

Although a pre-validated UV method was used for the analysis, ?_max for Naproxen Sodium was confirmed by scanning standard solution of Naproxen Sodium. ?_max was found to be 331 nm. The calibration curve was developed in the concentration range of 5-30 µg/mL. The solvent used for the calibration curve development was MeOH. The method was found to be linear (R² =0.9993). R² near 1 gave the confidence that standard solutions of Naproxen Sodium follow the Beer-Lambert Law.

Evaluation of Transdermal patch for Naproxen Sodium with Quercetin

Physicochemical evaluation

1. Physical appearance

All prepared ocular Inserts films have good appearance with smooth surface. Films prepared were semi-transparent. Surface texture was smooth and uniform.

       
           
       
Figure 5: Transdermal patches of Naproxen Sodium casted on glass slab

2. Thickness evaluation of transdermal patch

The average thickness of transdermal patches is shown in following table 6.

       
           
       
Table 6: Average thickness of transdermal patches

3. Uniformity of weight

A good weight uniformity of all formulation indicates an even distribution of drug and the polymers in the matrix film prepared by solvent evaporation technique. It was also accounted that weight and thickness of films were increasing with increasing polymer concentration. The average weight of prepared ocular inserts film is shown in following table 7.

       
           
       
Table 7: Uniformity of weight of Transdermal Patch

      * All values are mean±SD (n=3)

4. Drug content determination

The prepared 6 batches were tested for their drug content. From results, it was found that the calculated drug loading obtained from the drug content test yielded a satisfactory result ranging from 88.70 ±0.4 % to 97.12 ±0.5 % of the theoretical drug distribution. The % drug content of prepared patches is shown in following table 8.

       
           
       
Table 8: Percent Drug content of transdermal patch for Naproxen Sodium

     * All values are mean±SD (n=3)

E. Tensile strength determination

Sufficient tensile strength is required for patch to remain intact in case stretching conditions. Plasticizer amount plays the important role here. The tensile strength for transdermal patch ranged from 2.21 ±0.3 to 4.46 ±0.1 kg/cm². Batch B3 showed highest tensile strength and batch B4 showed lowest tensile strength. The tensile strength was found to be increased with increase in amount of plasticizer and HPMC in the formulation. Tensile strength data of ocular inserts film was obtained as shown in table below.

       
           
       
Table 9: Tensile strength of transdermal patch

   * All values are mean±SD (n=3)

Folding endurance test for transdermal patch

Folding endurance is parameter to measure the ability of transdermal patch to withstand the conditions of folding when it is applied to skin. If patch withstand these conditions and does not break, then burst release can be avoided.  Folding endurance of transdermal patch was found to be increase with increasing concentration of plasticizer. The number of folds required to break the patch is shown in following table 10, with respective batches.

       
           
       
Table 10: Folding endurance of transdermal patch

* All values are mean±SD (n=3)

Flatness of transdermal patch

The prerequisite for transdermal patch is that it should have smooth surface and it should not constrict with time. Flatness study shows whether the transdermal patch fulfils above expectations or not. The flatness study showed that all the formulations had the same strip length before and after their cuts, indicating 100% flatness. Percent constriction with respective % flatness of film is shown in table 11.

Moisture content of transdermal patch may affect the release of Naproxen Sodium from it. Relatively “dry” film may need more time to release the drug. Hence, these tests were performed to evaluate the ability of film to lose and to gain the moisture. From results it was found that the moisture content and moisture uptake of transdermal patch changes significantly with change in its HPMC (hydrophilic polymer) content. It was found that there is direct relation between moisture content of film and its HPMC content. This is because HPMC already have high moisture content. Moisture content and moisture uptake studies indicated that the increase in the moisture uptake may be attributed to the hygroscopic nature of the polymer and surfactant composite films. The moisture content of the prepared formulations was low, which could help the formulations remain stable and reduce brittleness during long term storage. The moisture uptake of the formulations was also low, which could protect the formulations from microbial contamination and reduce bulkiness. The weight lost by patches due to loss of moisture is shown in table 12.

       
           
       
Table 12: Moisture content of transdermal patch

   * All values are mean±SD (n=3)

Percentage of moisture uptake

The water uptake or absorption behaviour of the transdermal patch plays an important role at the beginning stage of drug release from dosage form Thus, the patch with higher moisture uptake supposed to give higher drug release rate initially. The moisture uptake of the formulations was also low, which could protect the formulations from microbial contamination and reduce bulkiness. The weight gain of patch due to exposure to moisture is shown in following table.

       
           
       
Table 13: Moisture uptake transdermal patch

  * All values are mean±SD (n=3)

Scanning Electron Microscopy

SEM images can reveal details such as surface roughness, texture, and the presence of any irregularities or defects. Smooth surfaces with uniform texture may indicate well-formed patches, while rough or uneven surfaces could suggest issues with patch fabrication or formulation. The polymer ratio directly influences the porosity and pore structure of the patch. Higher concentrations of HPMC typically result in a more porous structure due to the hydrophilic nature of HPMC, which tends to swell in the presence of water. In contrast, higher concentrations of EC may lead to a denser matrix with fewer pores. Adjusting the polymer ratio allows for control over the pore size, distribution, and interconnectivity within the patch, impacting drug release kinetics and permeation properties. Scanning Electron Microscopy revealed that surface of the transdermal patch are smooth indicating the complete miscibility of HPMC with EC.

       
           
       
Figure 6: Scanning Electron Microscopy (SEM) images of Naproxen Sodium transdermal patch

The DSC curve of Naproxen Sodium shows a single endothermic peak corresponding to the melting event of the substance in the range between 259 – 262°C. The DSC curve of Naproxen Sodium was illustrated in Figure 7.

Table 14 shows % drug release for all batches and Figure 8 show the release pattern for each batch.

       
           
       
Figure 8: Percent Drug release for batches B1-B6

In vitro skin permeation studies

Quercetin may act by disrupting the lipid bilayers of the stratum corneum, increasing skin hydration, or modulating the activity of efflux transporters, thereby facilitating the transdermal delivery of naproxen sodium. uercetin has been shown to synergize with other penetration enhancers and formulation excipients, enhancing their permeation-enhancing effects. By acting through complementary mechanisms of action, quercetin can potentiate the permeation-enhancing efficacy of other compounds, leading to improved drug delivery outcomes. The in vitro permeation of Naproxen sodium of formulation B3 through chicken skin is shown in table 15. The flux and permeability coefficient are also shown.

       
           
       
Figure 9: in vitro permeation of Naproxen sodium through Franz diffusion cell