Nefopam Containing Transdermal-Matrix Patches Based on Pressure-Sensitive Adhesive Polymers

March 2, 2006
Pharmaceutical Technology Editors

Pharmaceutical Technology, Pharmaceutical Technology-03-02-2006, Volume 30, Issue 3

Transdermal matrix-type patches of Nefopam hydrochloride with a combination of pressure-sensitive adhesives were developed. The polymeric composition provided a controlled and sustained release of the drug from the patches and demonstrated favorable physicochemical characteristics.

Nefopam (3,4,5,6-tetrahydro-5-methyl-1-phenyl-1H-2,5-benzoxazocine) hydrochloride, a nonsteroidal, anti-inflammatory drug used to treat disorders such as acute and constant pain, is typically administered orally or by intramuscular injection. The drug, however, possesses several characteristics that make it a suitable candidate for transdermal drug-delivery systems (TDDSs). Optimizing the selection of pressure-sensitive adhesives used in the TDDS is an important consideration. This study shows that a combination of Duro-Tak 387-2516 and Duro-Tak 87-2852 (National Starch and Chemical Company, Bridgewater, NJ) at a ratio of 4:5 volume per volume is suitable for developing a pressure-sensitive adhesive matrix-type TDDS for administering nefopam.

A TDDS administers a drug directly to the systemic circulation through intact skin to bypass hepatic first-pass metabolism and to provide controlled release of the drug for an extended period of time (1, 2). Nefopam is an example of a drug with characteristics needed for a TDDS. It causes nausea and vomiting, undergoes hepatic first-pass metabolism, and only a fraction of the oral dose is circulated (3, 4).

Nefopam is a weak base with a molecular weight of 253.34 Da. As a hydrochloric salt, a 30–90 mg dose is administered in tablet form three times daily by mouth or in an 20-mg intramuscular injection. It is extensively metabolized orally to the demethylated product, and its elimination half-life is 4 h. Its log P value is 3.519, which contributes to its lipid solubility and hydrophilicity. All these factors favor transdermal permeation. Moreover, the drug often is used as an alternative treatment in patients suffering from severe injury or in postoperative cases. Morphine injection is used in severe situations for immediate pain relief. For sustained treatment management or prolonged therapy to overcome morphine dependence following morphine injection, however, a constant drug-plasma level of nefopam from a TDDS was fabricated in pressure-sensitive adhesives.

This study aimed to develop a transdermal matrix-type patch with an appropriate adhesion property to the skin using a combination of pressure-sensitive adhesives (Duro-Tak 387-2051, Duro-Tak 387-2516, and Duro-Tak 87-2852) and nefopam. Duro-Tak polymers alone do not possess the desired tackiness. This study shows that a blend of some Duro-Tak polymers can be used for achieving the desired consistency and tackiness for a TDDS, without adding substances such as gelling agents. This study shows that nefopam also can be formulated using the Duro-Tak blend for a controlled-release TDDS. The few studies using Duro-Tak polymers for TDDSs reported so far have been carried out with rodent skin (mouse or rat). This study depicts drug permeation after releasing Duro-Tak matrix patches through human cadaver skin. It also evaluates in vitro release and in vitro permeation of the drug at a controlled rate to provide a therapeutically effective drug level for a prolonged period of time and further examines the various physiochemical properties of the patches.

Methodology: solubility study

Solubility studies for each case were carried out by adding an excess amount of drug in phosphate buffer (pH 7.4) and keeping the flasks containing the solutions on a mechanical shaker for 24 h at 25 °C (5). After 24 h, the solutions were transferred into test tubes and centrifuged at 2000 rpm for 30 min at room temperature. The test tubes were placed aside to settle for 30 min. One mL of supernatant liquid from each test tube was placed into 100-mL volumetric flasks and diluted with as much as 100-mL of phosphate buffer (pH 7.4). They were shaken for proper mixing before a 5-mL solution from each volumetric flask was mixed with 5 mL of phosphate buffer (pH 7.4) in each test tube. The mixture was filtered, and the absorbencies were read at 266 nm with a UV–vis spectrophotometer (DU-64 model, Beckman Coulter Inc., Fullerton, CA) and using a phosphate buffer (pH 7.4) as a blank. The amount of drug dissolved was quantified from the standard curve. The average solubility from four such experiments was determined.

Duro-Tak 387–2516 is a yellow-colored liquid polymer used as a pressure-sensitive adhesive with a petrol-like odor and is insoluble in water. It is, however, soluble in a mixture of ethylacetate 63%, ethanol 27%, n-heptane 8%, and methanol 2%. Its boiling point is 60 °C, solid content is 41.5%, viscosity is 4350 cP, glass-transition temperature is -36 °C, flash point is -4 °C, relative density is 0.87, and volatiles are 57–60%. Duro-Tak 87-2852 is a colorless liquid polymer with a hydrocarbon-like odor and is insoluble in water. It is soluble in a mixture of ethylacetate 65%, isopropanol 19%, hexane 12%, toluene 3%, and 2, 4-pentanedione <1%. Its boiling point is 65.5 °C, solid content is 33.5%, viscosity is 2550 cP, glass-transition temperature is -26 °C, and flash point is less than -6.67 °C. In addition, its relative density is 0.98 and volatiles are 66.4%.

Preparation of the patch

Preparation of the backing membrane. The backing membrane was prepared with an aqueous solution of a 6 % w/v poly(vinyl alcohol) (S.D. Fine Chemicals, Boisar, India). A weighed amount of poly(vinyl alcohol) was added to a requisite volume of warm, glass-distilled water and a homogeneous solution was made by constant stirring and intermittent heating at 60 °C for a few seconds. Care was taken during stirring to prevent the formation of any bubbles during the preparation of this solution. The homogeneous solution (3 mL each) was then poured into glass molds (2.55-cm inner diameter) made by wrapping aluminum foil around one of the open-ends of an 4-cm tall, hollow-glass cylindrical mold. The molds were kept at 60 °C for 24 h, forming a smooth, uniform, transparent backing membrane.

Casting of drug matrix over the backing membrane. Suitable transdermal-matrix-type patches of nefopam hydrochloride with varied ratios of the polymers Duro-Tak 387-2051, Duro-Tak 387-2516, and Duro-Tak 87-2852 were developed. The aim was to establish the best polymeric combination to formulate transdermal patches having the desired skin-adhesion properties, physicochemical properties, and skin-permeation capabilities. Thumb tack tests were performed for all formulations. Most of the formulations were very sticky or less sticky with respect to skin adhesion. The formulation prepared from Duro-Tak 387-2516 and Duro-Tak 87-2852 in a ratio of 4:5 (v/v) was the best formulation in terms of skin adhesion.

The polymers Duro-Tak 387-2516 and Duro-Tak 87-2852 were measured in the requisite ratio (4:5) and dissolved in a mixture of ethyl acetate–isopropyl alcohol– toluene–n-hexane (12:6:1:1). A homogeneous solution was made using a magnetic stirrer and a small magnetic bead. Nefopam hydrochloride (30 mg per patch) was added to the mixture and stirred further for 20 min until a homogeneous suspension was generated. The uniform dispersion (3 mL each) was then casted on the prepared backing membrane and dried at room temperature for 24 h, resulting in the formation of a uniform, flat medicated matrix patch of nefopam hydrochloride.

Patch evaluation and characterization

Evaluation of adhesion (thumb tack test). One week after the preparation of the TDDSs, a thumb tack test was performed by lightly pressing a thumb on a patch for ~5 s and then quickly removing it (6). By varying the pressure and time of contact, and considering the difficulty of pulling the thumb from the adhesive, it was possible to guess how easily, quickly, and strongly the adhesive formed a bond with the skin. The test was performed blindly on various types of formulations to determine the proper formulation for further studies. The patches were applied on the forearm of 10 volunteers. After 24 h, the patches were removed to study the skin-adhesion capability and compatibilities of the formulations with the skin. Ultimate scoring of acceptability was based on result of a thumb tack test as well as skin adhesion, removal capacities, and the formulations' compatibilities with the skin.

Drug–excipients interaction. Nefopam hydrochloride was mixed with infrared-grade potassium bromide. The well-ground and mixed-powder sample was compacted into pellets by applying 5.5 metric tons of pressure in a hydraulic press. Two thin patches of two polymers were prepared, with and without the drug. One thin patch comprised a mixture of the drug with the two polymers Duro-Tak 387-2516 and Duro-Tak 87-2852 in a ratio = 4:5. The other comprised a mixture of the two polymers Duro-Tak 387-2516 and Duro-Tak 87-2852 in a ratio = 4:5. The two patches were placed between disks of sodium chloride windows and scanned over a wave number range of 4000–400 cm-1 in a Fourier transform infrared (FTIR) instrument ("Magna IR 750 series II," Nicolet, Madison, WI).

Scanning electron microscopy (SEM). The external morphology of the transdermal patches before and after administration on the skin and on the dorsal side of the skin 50 h after the in vitro skin permeation experiments had begun, were analyzed with a scanning electron microscope ("JSM 6100 JEOL," JEOL Ltd., Tokyo, Japan). The same procedure was done to the patches 100 h after the dissolution studies. The section of the experimental samples were cut and mounted onto stubs and coated with gold. The sections then were then examined by SEM.

Thickness measurement. Thicknesses of the backing membranes (before casting the drug matrix) and of whole patches (adhesive matrix with the drug plus the backing membrane) were measured at four points using digital calipers (Digmatic Massschieber, model CD-6 CS, Mitutoyo Corp., Japan). The average thicknesses of the backing membrane and of the drug matrix with the backing membrane were determined.

The thickness of the drug-containing polymer matrix was determined by measuring the thickness of the whole patch (adhesive matrix with the drug plus the backing membrane) and subtracting the thickness of the backing membrane. The average thickness of the drug-containing polymer matrix was determined.

Area of the patches. The diameter, D, of each patch was measured using a millimeter scale, and the area (π[D/2]2 ) of each patch was calculated.

Moisture content. The moisture content, which affects the rate of drug release from the patch, was determined (7). A small amount of moisture in patch-type formulations helps maintain stability and prevents the formation of a dried and brittle film. A greater amount, however, can lead to microbial contamination during storage. The moisture content is determined by variations in the water content of the dried film and undried film. Percent moisture content is determined as follows:

Moisture uptake. This study can predict the moisture-absorbing capacity of a particular type of patch at various humidity levels. Little moisture uptake indicates the stability of the formulation. A good amount of moisture uptake indicates bulkiness of the formulation and the chance of microbial growth. Moisture uptake is determined as follows:

Flatness. An ideal transdermal patch should possess a smooth surface and should not constrict over time after application on skin (8). The patches for this flatness study were prepared using (3.4 X 3.4 cm) square glass molds, and strips were cut out and measured. One hundred-percent flatness means that there is no constriction. Percent flatness is determined as follows:

in which, l1 and l2 are the initial length and final lengths of each strip, respectively.

In vitro release: dissolution study

Conducting a drug-release study of the patch is essential to ensure the drug concentration at the surface of the stratumcorneum is greater than the drug concentration in the body to achieve a constant rate of permeation through diffusion (8).

The dissolution study was conducted using a USP basket-type dissolution apparatus. The patches were placed in the basket with their drug matrix exposed to a phosphate buffer (pH 7.4). All dissolution studies were carried out at 37 ± 0.5 °C and 100 ± 5 rpm, with each dissolution jar carrying 900 mL of the phosphate buffer. A 5-mL sample was withdrawn at various time intervals and replaced with 5 mL of the phosphate buffer. Samples were analyzed with a UV spectrophotometer at 266 nm against the phosphate buffer as a blank. The quantity of drug dissolved was calculated at a particular time interval from the calibration curve (9).

The study was conducted in two dissolution apparatuses simultaneously, with one containing patches with the drug (the test) and the other containing patches without the drug (the control). The difference between the test and control reading was the absorbance caused by the drug. In each case, the mean cumulative percentage of drug released per square centimeter of patch was plotted against time.

In vitro human cadaver skin permeation study

The in vitro skin permeation study was conducted using a modified Keshary-Chien 100-mL diffusion cell. Human cadaver skin (Calcutta National Medical College, Kolkata, India) was stored in a fixative solution of 4% buffered formaldehyde. The adhering fat was removed, and the epidermis was separated from the full-thickness tissue after immersion in normal saline solution for 1 h. The stripped skin was stored in the fixative solution until use. Two sections of skin were cut and kept in phosphate buffer (pH 7.4) for 2 h before use.

The skins, stratum corneum side facing upward, were tied with an adhesive tape on the holder of the diffusion cells. The patches with the drug (the test) and without the drug (the control) were placed on the stratum corneum side of the skin in the donor compartments facing the drug-matrix side toward the skin. The holders containing the sections of skin and the formulations were placed on the reservoir compartments of two diffusion cells containing phosphate buffer (10) maintained at 38 ± 0.5 °C using a circulating water jacket to get 34 °C at the skin surface (10). The enire assembly was kept on a thermostatic magnetic stirrer. The solution in the receiver compartment was continuously stirred with a magnetic bead during the experiment.

The samples were withdrawn 1 mL at a time at various time intervals, and an equal amount of phosphate buffer was replaced. The samples were diluted appropriately and filtered. Absorbances of the samples were measured spectrophotometrically at 266 nm taking phosphate buffer (pH 7.4) as the blank. Drug absorbances were determined by calculating the differences of the individual sets of readings of the absorbances of the test and control samples to eliminate the interferences of any materials leaching from the skin. The amount of drug permeated per square centimeter at each time interval was calculated from the calibration curve. The mean cumulative percentage of the drug permeation per square centimeter of skin was plotted against time.

Results

Solubility study. The solubility study was conducted to determine whether the media phosphate buffer could maintain sink conditions in dissolution as well as in permeation studies. The mean concentration of the drug dissolved in the phosphate buffer was 34.071 ± 0.75 mg/mL (mean ± standard deviation, n = 4). Results showed that the phosphate buffer (pH 7.4) could be chosen as the dissolution and permeation medium because a sufficient amount of drug dissolves in it, which is necessary to maintain the sink condition (11).

Thumb tack tests. Thumb tack tests of all types of formulations were conducted (see Table I). The formulations using the polymers Duro-Tak 387-2516 and Duro-Tak 87-2852 in a 4:5 v/v ratio showed optimum tackiness with the thumb and good adherence capacity with human skin. After testing on 10 human subjects for 24 h, this combination resulted in proper skin adhesion, easy removal, and compatibility with the skin. Thus, this polymeric composition was selected for use in further evaluations.

Table I: Degree of tackiness of the experimental patches.

Drug–excipients interaction study. A transdermal matrix patch of nefopam hydrochloride was formulated with the polymers Duro-Tak 387-2516 and Duro-Tak 87-2852 in a 4:5 v/v ratio. FTIR spectroscopy was used to study the drug–excipients interaction. Figure 1 and Figure 2 show the IR spectra of a mixture of the polymers Duro-Tak 387-2516 and Duro-Tak 87-2852 in a 4:5 v/v ratio and a mixture of the drug with these polymers, respectively. Between the 2600 cm-1 and the 1800 cm-1 wave numbers, some drug–polymer interactions were observed. Alkenyl (C = C) (2260 cm-1 – 2100 cm-1 ), nitryl (C = N) (2260 cm-1 – 2220 cm-1 ), cyanide (C–N) (2300 cm-1 – 2100 cm-1), alkyne (C–C) (2300 cm-1 – 2100 cm-1 ), carbonyl (C = O) (1900 cm-1 – 1600 cm-1 ) stretches are mainly responsible functional groups stretches for this region. Some weak bonding (e.g., hydrogen bonding) may take place between the nitrogen atoms and the methyl groups of the drug and between the olefin and carbonyl groups of the polymers in the region.

Figure 1

Results of determining the average thickness, moisture content, moisture uptake, and flatness of the patches were as follows: mean patch thickness was 1.14 ± 0.13 mm (mean ± SD, n = 25). The mean thicknesses of the backing membranes was 0.18 ± 0.018 mm (mean ± SD, n = 25). The mean thickness of the drug–polymer matrix layers was 0.92 ± 0.14 mm (mean ± SD, n = 25). These results show that very thin patches have been developed (thereby helping to increase patient compliance). The patches were circular with an average diameter of 2.4 ± 0.063 cm (mean ± SD) and an average area of 4.70 ± 0.24 cm2 (mean ± SD) for 25 patches. The average percent moisture content was 2.008 ± 0.36 (mean ± SD, n = 6). A low average moisture content is one of the desirable physicochemical characteristics in the development of transdermal patches (12). The percent moisture uptake was 1.73 ± 0.37 (mean ± SD, n = 6). Moisture uptake of the formulations indicates that in a high-humid environment, the patches may absorb a small amount of moisture, boosting the moisture content ~2%, but not too much. This result favors the stability and compatibility of the formulations in a high-humid environment. The average length of the strips was 3.4 ± 0.077 cm (mean ± SD, n = 10). No predominant constriction was observed in any of the formulations, indicating that they will not constrict upon application.

Figure 2

In vitro dissolution study. A dissolution study is essential for ensuring a sustained drug release and the reproducibility of the rate and the duration of drug release. Dissolution studies of the formulations were carried out in a USP basket-type dissolution apparatus using phosphate buffer as dissolution media at 37 ± 0.5 °C (13). True absorbance of the drug was measured by deducing the absorbance of the control sample from the absorbance of the test sample (see Figure 3).

Figure 3

In vitro skin-permeation study. In vitro skin-permeation study is predictive of the in vivo skin-permeation performance of a drug (14). A permeation study was carried out across abdominal human cadaver skin using phosphate buffer as an in vitro study fluid in the receptor compartments of modified diffusion cells at 38 ± 0.5 °C. True absorbance of the drug was measured by deducing the absorbance of the control sample from the absorbance of the test sample (see Figures 4 and 5).

Figure 4

SEM. The surface morphology of the patches before and after release of the drug from the patch and the dorsal surfaces of the skin 50 h after in vitro skin-permeation study were scanned with a scanning electron microscope. Figure 6 shows that the drug clusters were uniformly distributed in the polymer matrix as small particles (mean size 2 μm). Figure 7 shows how the polymer matrix behaves after the drug molecules released and how the patch surface is maintained even after 50 h of application.

Figure 5

Discussion

Pressure-sensitive adhesives adhere to the skin surface with no more force than applied finger-pressure, have a strong holding force (15), and are tacky in nature. Tackiness is taken into consideration when these adhesives are used for the drug matrix or other transdermal patches to adhere onto the skin surface. With a little pressure, a liquid-like flow in the adhesive wets the skin surface and forms a strong bond to the skin. Upon removal of pressure, the adhesive layer remains adhered to the skin because of its visco-elastic characteristics (16). A good transdermal pressure-sensitive adhesive should be removed from the skin surface without leaving a residue (15). Tackiness is the ability of a polymer to adhere to the substance with low contact pressure. This measurement is used to quantify or realize the sticky feel of the material. In this study, thumb tack tests of various formulations were performed and the degree of tackiness was determined. The Duro-Tak varieties used in the studies are liquid, and the desired consistency and tackiness were achieved using their blends without the addition of any further excipients. The blend seemed to provide high cohesion because of its high internal strength. A shear test showed a holding power ~2.4 psi for 24 h at 25 °C, which is good enough to adhere to the skin surface and without causing problems during patch removal.

Figure 6

The Duro-Tak polymeric matrices and the matrices prepared by the combination of the Duro-Tak variations had noticeable levels of tackiness. Out of the 12 types of polymeric matrices tested, seven were very sticky in nature and two had insufficient tackiness to apply onto the skin. Only three of the formulations: Duro-Tak 387-2516 and Duro-Tak 87-2852 in a ratio of 1:1 v/v; Duro-Tak 387-2516 and Duro-Tak 87-2852 in a ratio of 4:5 v/v; and Duro-Tak 387-2516 and Duro-Tak 87-2852 in a ratio of 2:3 v/v had acceptable tackiness. The patches from these formulations were easily removable, did not leave residue on the skin's surface, and did not inflict pain during removal. Out of these three varieties, Duro-Tak 387-2516 and Duro-Tak 87-2852 in a ratio of 4:5 v/v had the greatest degree of acceptability with regard to the adherence capacity and ease of removal. This composition was selected for further studies.

Figure 7

For in vitro skin permeation studies, various media such as phosphate buffer (pH 7.4), normal saline, and 20% polyethylene glycol 400 in normal saline were used (5, 7, 8, 17, 18). Solubility of nefopam hydrochloride was studied in phosphate buffer and 34 mg of the drug was dissolved per milliliter of the buffer solution. This indicates that the phosphate buffer is a suitable medium to maintain the sink condition of the drug in dissolution as well as in skin permeation studies. Phosphate buffer was chosen as the media for dissolution as well as in vitro skin permeation studies.

Drug–excipient interaction is one of the most important characteristics that regulate the availability of drug from the formulation, its release pattern, and its stability in the formulation (19). Drug–excipient interaction was studied at the very outset before the beginning of the development of formulations. Various methods such as differential scanning calorimetry, IR spectra, FTIR spectra, and thin-layer chromatography are used frequently to study the drug–excipient interaction (8, 9, 20). The FTIR spectrum can accurately clarify drug–excipient interactions at the various functional groups between the drug and excipient molecules (21). Figure 1 and Figure 2 depict the FTIR spectra of polymer blend Duro-Tak 387-2516 and Duro-Tak 87-2852 in a ratio of 4:5 v/v and drug–polymer mixture, respectively. When these spectra were analyzed, there were some interaction between the drug and the polymers between wave numbers 2600 and 1800 cm-1 . This region is mainly responsible for alkynyl, nitryl, cyanide, alkyne, and carbonyl stretches. Nitrogen atoms of the drug may interact with the olefin by forming weak bondings (e.g., van der Waals forces and a dipole moment). Similarly, between the methyl group of the drug and the oxygen of the carbonyl group, weak hydrogen bonds may have developed.

Results of the dissolution study showed that drug release was very slow and steady. In ~100 h, the cumulative percentage of release was ~57%. The drug–polymer interactions may release the drug at a very slow rate in spite of good solubility in dissolution media (~34 mg/mL phosphate buffer), thereby indicating that the adhesive polymeric blend of Duro-Tak 387-2516 and Duro-Tak 87-2852 in a ratio of 4:5 v/v was capable of holding the drug and releasing the drug molecules in a slow and steady manner (see Figure 3). The interaction between the drug and the polymers seems to provide a prolonged sustained-release pattern of the drug. Drug transport involves drug flexibility and the motion of the polymer backbone as well as specifies molecular interactions between the drug and the polymer matrix.

Many reports suggest that drug–excipient interactions extend drug release (22–24). Barroug et al. reported on the in vitro controlled release of cisplatin caused by the interaction of cisplatin and calcium phosphate in nanoparticles (25). Miyajima et al. also concluded that the interaction between a poly(L-lactic acid) matrix and basic drug provides two-stage diffusion-controlled release of the drug (26). By studying the drug–excipient interaction and drug-release profile, one may conclude that the interaction between the drug molecules and the polymer molecules extended and controlled the release of nefopam from the formulations.

Various physicochemical tests, including the average thickness and the mean area of the patches, their moisture content, moisture-uptake capabilities, and flatness were conducted. The average thickness of the formulation was below 1 mm, and the mean area was ~4.7 cm2 , thereby indicating that the prepared patches were considerably thin and small in size. The moisture-content study showed how much moisture was present in the formulation. A moisture-uptake study depicted the capability of a formulation to hold a maximum content of moisture when the formulation was exposed to a highly humid climate. In this study, the mean percent moisture content was ~2%, which is reasonably good for a transdermal patch to prevent brittleness with 100% dryness (9). The moisture-uptake study showed that the mean percent-moisture uptake was acceptable (~1.7%), thus indicating that the prepared polymeric formulations with Duro-Tak 387-2516 and Duro-Tak 87-2852 in a 4:5 v/v ratio do not absorb a large amount of moisture when exposed to a highly humid climate. Less moisture uptake indicates the stability of the formulation, whereas a greater moisture uptake means the bulkiness of the formulation and a greater chance of microbial growth (12). Thus, this mixture composition also may be chosen for the preparation of pressure-sensitive adhesive matrix patches in countries with high humidity.

The flatness study indicated whether the formulation became constricted after application onto the skin's surface (12). A 100% flatness indicates that the patch has no level of immediate constriction and that it can be suitably placed onto the skin's surface where it will remain as such without constriction for a long period of time (9). Results of the flatness study showed that the prepared formulation had 100% flatness. The prepared formulations, therefore, were easily and suitably on the skin surface without a constriction problem.

Drug dissolution from the prepared patches in the phosphate buffer was conducted for as long as 100 h when the cumulative percentage of drug release was ~57% (see Figure 3). The drug release was prolonged and sustained when the mean cumulative percentage of drug release data were plotted against time (see Figure 3). Moreover, the steady release pattern of the drug indicates that the drug molecules have been released from the pressure-sensitive, adhesive-blend matrices in a very controlled manner. Having proven that a controlled-release pattern up to 100 h (57%-cumulative release) was possible, the dissolution study was concluded. It was understood that the drug molecules will be released from the pressure-sensitive adhesive matrices to maintain a continuous drug pool on the skin surface for a much longer time.

In vitro skin permeation of nefopam hydrochloride from the combination of Duro-Tak 387-2516 and Duro-Tak 87-2852 in a ratio of 4:5 v/v polymeric transdermal matrix patches was conducted in a modified Keshary-Chien diffusion cell through human cadaver skin. Phosphate buffer was taken as a receptor media. The average cumulative amount of drug release steadily increased for as long as 4 h. In the fifth hour, the cumulative percentage drug permeation was ~25% (see Figure 4). The permeation of the drug was very controlled, and gradual enhancement of the drug permeation through the skin was noticed. The study was conducted until 50 h, when the cumulative percentage of the drug permeation was ~32% (see Figure 4), which may be attributed to the fact that in the first few hours, drug permeation was more dependent on the drug concentration at the skin surface and the initial bursting effect provided the sink condition. After the fifth hour, the skin permeation of the drug eventually slowed down because of the slow release of drug from the patches to the skin's surface. The rate of dissolution became closer to the rate of skin permeation. The change in the amount of drug-per-unit length of permeation per unit time when plotted against the average (n = 6) percentage cumulative amount of drug permeated per square centimeter of patches per unit time (see Figure 5) also supported the above findings. There was a noticable and slow, but steady, flux of drug during permeation. The apparent permeation coefficient Papp was 0.59/h.

An SEM photograph shows the drug distribution pattern in the polymeric matrices (see Figure 6). The drug was distributed in the form of small and amorphous particles with an average diameter of ~2 μm. There were few larger particles (diameter 4–5μm or larger) in the matrices. The figure shows that the drug particles were almost homogeneously dispersed in the pressure-sensitive adhesive matrices. Figure 7 shows the SEM photograph of a patch 50 h after skin permeation. The pictures indicate that several drug particles, both large and small, remained to be released. Some openings from which the drug had released were seen on the patch surface. The drug particles leached or dissolved from the patches leaving the area open. In case of the smaller holes, the open areas were gradually healed up because of the elasticity of the pressure-sensitive adhesives. A large drug particle was dissolved gradually from the patch surface, leaving a smaller portion in a hole. This result indicates that the drug cluster eventually dissolved and came in a soluble form.

Conclusion

Pressure-sensitive adhesives Duro-Tak 387-2516 and Duro-Tak 87-2852 in a 4:5 v/v ratio were used to develop pressure-sensitive transdermal patches of nefopam hydrochloride. This polymeric composition provided a controlled and sustained release of the drug from the patches. In vitro skin permeation of the drug after release from the patch formulation also provides a controlled and sustained release profile of the drug. Various physicochemical parameters generated from this study, including moisture content, moisture uptake, flatness, and, most important, tackiness, were favorable for the development of the formulation. Some drug–excipient interactions, although present between the methyl groups and nitrogen atoms of the drug and between the olefin and carbonyl groups of the polymers, seem to contribute to the slow and controlled-release pattern of nefopam hydrochloride. Thus, this composition of pressure-sensitive adhesives is suitable for developing transdermal patches with a water-soluble drug such as nefopam hydrochloride to provide controlled and sustained release of the drug. Further in vivo studies are warranted to monitor the drug level in the blood after the application of the patch on the skin.

Acknowledgment

This work was supported by grants from the University Grants Commission (Government of India) and the Dr. V. Ravichandran Endowment Fund. Nefopam hydrochloride was provided by Jian An Pharmaceutical Co. (Shenzhen, China). The Duro-Tak polymers were provided by National Starch and Chemical, B. V. (Zutphen, The Netherlands) and the National Starch and Chemical Co. (Bridgewater, NJ).

Biswajit Mukherjee, PhD,* is a reader, Surajit Das is a research student, Balaram Patra is a senior research fellow, and Buddhadev Layek is a postgraduate student, all at the Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, India, tel. 191 33 24146677, fax 191 33 24146393, biswajit55@yahoo.com

*To whom all correspondence should be addressed.

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