Effective assessment and management of wound pain can facilitate both improvements in healing rates and overall quality of life. From a pharmacological perspective, topical application of nonsteroidal anti-inflammatory drugs in the form of film wound dressings may be a good choice. Thus, the aim of this work was to develop novel layered film wound dressings containing ibuprofen based on partially substituted fibrous sodium carboxymethylcellulose (nonwoven textile Hcel NaT). To this end, an innovative solvent casting method using a sequential coating technique has been applied. The concentration of ibuprofen which was incorporated as an acetone solution or as a suspension in a sodium carboxymethylcellulose dispersion was 0.5 mg/cm2 and 1.0 mg/cm2 of film. Results showed that developed films had adequate mechanical and swelling properties and an advantageous acidic surface pH for wound application. An
The European Wound Management Association (EWMA) Position Document acknowledges that pain is a major issue for patients with acute and chronic wounds [
Wound-related pain can be temporary (acute) or persistent (chronic) [
Wound pain management includes nonpharmacological and pharmacological measures. Multiple pharmacological agents may be used to combat pain. Guidelines for pharmacological wound pain management based on the recommendations by the World Health Organization recommend the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for patients with mild to moderate pain [
Topical NSAIDs are formulated for direct application to the painful site and for producing a local pain-relieving effect while avoiding body-wide distribution of the drug at physiologically active levels [
Different polymers may be used to prepare the film. Polyurethane is currently the most used material for such purposes [
For our experiment, carboxymethylcellulose (CMC), more specifically its sodium salt (sodium carboxymethylcellulose: NaCMC), was chosen because it ranks among the materials with excellent film-forming properties [
The aim of the presented research was to prepare novel layered films with microfibrous NaCMC and ibuprofen and evaluate their physicochemical properties as well as the influence of the method of ibuprofen incorporation on
The partially substituted (DS 0.35) sodium carboxymethylcellulose in the form of nonwoven textile (Hcel NaT) was supplied by Holzbecher, spol. s r. o., Bleaching & Dyeing Plant in Zlíč (Czech Republic), ibuprofen, macrogol 300, and acetone (all Ph. Eur. grade) were purchased from Fagron (Czech Republic), and the Sanatyl 20 medical grade polyester mesh was purchased from Tylex Letovice, a. s. (Czech Republic). All other chemicals and reagents used in the study were of analytical grade.
The polymer dispersion was composed of 1% w/w NaCMC and 2% w/w macrogol 300 in purified water. Nonwoven sodium carboxymethylcellulose textile (Hcel NaT) was cut into small pieces and poured over with a solution of macrogol in hot water (80°C). This mixture was then heated to maintain a temperature of 80°C for 3 hours and then left to cool at an ambient temperature for 24 hours. The resulting dispersion was homogenized for 3 min using an ULTRA-TURRAX T 25 dispersing device (IKA Werke Staufen, Germany) at 16,000 rpm. Polymer dispersion with ibuprofen was prepared in the following way. Thoroughly grinded ibuprofen (82.5 mg or 165 mg for one film) was added to the NaCMC dispersion after 24 hours of swelling, and the mixture was homogenized for 8 min using an ULTRA-TURRAX T 25 dispersing device at 16,000 rpm.
Layered films with or without ibuprofen were prepared with an innovative solvent casting method using a sequential coating technique. This technique involved forming one film and pouring the next layer directly onto the previous one after predrying. The polymer dispersion was casted on an 11 × 15 cm (165 cm2) stainless steel plate. Four types of layered films, differing in both concentration and incorporation method of ibuprofen, were prepared (Table
Preparation of layered films.
Film | 1st step | 2nd step | 3rd step | 4th step |
---|---|---|---|---|
0.5-Ibu-1 | NaCMC → Sanatyl → pre-drying | 1% Ibu sol. → evaporation | NaCMC | pre-drying and drying |
0.5-Ibu-2 | NaCMC → Sanatyl → pre-drying | NaCMC with Ibu | — | pre-drying and drying |
1.0-Ibu-1 | NaCMC → Sanatyl → pre-drying | 2% Ibu sol. → evaporation | NaCMC | pre-drying and drying |
1.0-Ibu-2 | NaCMC → Sanatyl → pre-drying | NaCMC with Ibu | — | pre-drying and drying |
|
||||
1-blank | NaCMC → Sanatyl → pre-drying | acetone → evaporation | NaCMC | pre-drying and drying |
2-blank | NaCMC → Sanatyl → pre-drying | NaCMC | — | pre-drying and drying |
3-blank | NaCMC → pre-drying | acetone → evaporation | NaCMC | pre-drying and drying |
4-blank | NaCMC → pre-drying | NaCMC | — | pre-drying and drying |
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0.5-Ibu-1 without Sanatyl | NaCMC → pre-drying | 1% Ibu sol. → evaporation | NaCMC | pre-drying and drying |
0.5-Ibu-2 without Sanatyl | NaCMC → pre-drying | NaCMC with Ibu | — | pre-drying and drying |
Microscopic properties of the prepared films were evaluated using an optical microscope (STM-902 ZOOM, Opting, Czech Republic) and a color digital camera (DFW X700, Sony, Japan). The appearance of the films was observed at a magnification factor of 7.5, 20, and 50. Illustrative digital images were taken at the same time.
At the measurement of film thickness, a rectangular sample of the film was vertically secured in a holder, the microscope was focused on the edge of the film, and sample thickness was measured at 5 different places of the film at the points with and without Sanatyl fiber. This was repeated 3 times with each film sample.
Surface pH of the prepared films was evaluated using a WTW pH 3210 SET 2 pH-meter (WTW, Germany) with a flat glass electrode. A moistened pH meter electrode was enclosed in the surface of the film and the value was recorded after stabilization (approximately 30 s). All measurements were taken in triplicate on both sides of the film.
Alterations of the surface pH in the conditions simulating the wound environment were assessed using an artificial wound model (Petri dish, sponge soaked with a physiological buffer solution of pH 7.2). Four cm2 (2 × 2 cm) samples of the film were cut and put on the surface of the wound model. The Petri dish was covered with a lid to prevent water evaporation, and surface pH was measured at determined time intervals in triplicate on both sides of the film.
Swelling properties of the prepared films were measured in a physiological buffer solution of pH 7.2. For these purposes, an artificial wound model was used (Petri dish, sponge soaked with a test liquid). Four cm2 (2 × 2 cm) samples of the film were cut and weighed (
A modified method according to Shidhaye et al. was used to evaluate the mechanical properties of the prepared films [
The drug content uniformity test was performed to ensure the uniform distribution of the drug throughout the films. Standard solutions of 0.005, 0.01, 0.015, 0.02, and 0.025% ibuprofen (w/w) were prepared using a physiological buffer solution of pH 7.2 (PBS, pH 7.2). The absorbance values of the standard solutions at 264 nm were measured using a UV spectrophotometer (Lambda 25, Perkin Elmer Instruments, USA), and calibration curves were constructed. Samples (2 × 2 cm) were precisely cut from ten random sites in each film (
Data were first analyzed with descriptive statistics and statistical tests (QC Expert, v. 3.2, Trilobyte software) and subsequently with multiple linear regression (MLR) using multiway ANOVA (analysis of variance) with the Unscrambler X program (v. 1.3, Camo software). The design was set for a full factorial with two concentrations of ibuprofen (0.5-Ibu, 1.0-Ibu) and two methods of ibuprofen incorporation (Ibu-1, Ibu-2). Experiments were carried out a minimum of three times, depending on the measured properties. The resulting MLR models were used to identify the influence of process-formulation variables or the effects of their interactions on the measured properties. Film thickness was evaluated by Scheffe’s test of pair comparisons in R software, R package: agricolae (v. 1.2-1, Felipe de Mendiburu, 2014).
An ideal film dressing must be supple and possess homogenous and smooth surfaces [
In the case of medicated film, an active substance may be dissolved, suspended, or emulsified. Since ibuprofen is poorly water soluble, it is very difficult to achieve its solubility in the film formulation. Thu et al. [
The ibuprofen concentration in the films was expressed as mg/cm2 of film. This expression facilitates dosage since wound dressings are applied to a certain surface area. Moreover, it is independent of the weight of the film which may vary considerably, as NaCMC films are hydrophilic with fluctuating moisture content. The same 0.5 mg/cm2 concentration of ibuprofen was chosen as in the foam dressing Biatain Ibu [
Visual examination did not show differences between prepared films—all of them were homogenous and translucent with smooth surface independently of the method of ibuprofen incorporation. Therefore, microscopic evaluation which is capable of imaging inner structure was necessary. Observation of microscopic appearance of prepared films confirmed that partially substituted CMC maintained fibrous nature—digital images showed well-marked microfibrous structures (Figure
Microscopic appearance of NaCMC film without ibuprofen and Sanatyl: (a) magnification 20x, bar 500
Microscopic appearance of the film with suspended ibuprofen (0.5-Ibu-2 without Sanatyl): (a) magnification 7.5x, bar 1000
Microscopic appearance of the film with ibuprofen crystallized from acetone solution (0.5-Ibu-1 without Sanatyl): (a) magnification 7.5x, bar 1000
Microscopic appearance of the films with Sanatyl and the same concentration of ibuprofen (magnified 7.5x, bar 1000
Film thickness is an important parameter from the technological point of view. Uniform thickness means correct method of preparation and good assumption to drug content uniformity as well as to regular process of drug release. The thickness of all films with ibuprofen and Sanatyl did not differ significantly and ranged from
Values of surface pH of all prepared films were below 6 (Table
Surface pH of the films.
Film | pH of the surface intended for contact with wound | pH of the outside |
---|---|---|
0.5-Ibu-1 | 5.17 ± 0.17 | 5.25 ± 0.26 |
0.5-Ibu-2 | 5.18 ± 0.27 | 5.07 ± 0.26 |
1.0-Ibu-1 | 5.12 ± 0.1 | 5.22 ± 0.19 |
1.0-Ibu-2 | 5.27 ± 0.23 | 4.95 ± 0.23 |
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1-blank | 5.42 ± 0.02 | 5.47 ± 0.09 |
2-blank | 5.62 ± 0.06 | 5.49 ± 0.08 |
3-blank | 5.67 ± 0.11 | 5.61 ± 0.08 |
4-blank | 5.61 ± 0.09 | 5.51 ± 0.06 |
Alterations to the surface pH of the films with ibuprofen during 8 hours in the conditions simulating a wound environment are shown in Figure
Surface pH of the films with ibuprofen in the conditions simulating a wound environment.
Figure
The swelling behavior of the films is an important property for their practical application. Liquid uptake of the film creates conditions for moist wound healing. It may be affected by several factors such as pH or the presence and character of ions. A physiological buffer solution of pH 7.2 is similar to wound fluid with regard to ion content as well as pH value, and thus determined swelling values of prepared films could adequately reflect those in a real wound.
Films exhibited a mild degree of swelling, indicating moderate holding capacity for the exudate while still maintaining their structural integrity for a reasonable time period. It has been reported that exudate levels in wounds of various etiology differ significantly, as they do in leg ulcers at a range of 0 to 1.2 g/cm2/day [
Degree of swelling (Sw) was time-dependent and it was in the ascending order 0.5-Ibu-2 < 1.0-Ibu-2 < 0.5-Ibu-1 < 1.0-Ibu-1 < 1-blank < 2-blank < 3-blank < 4-blank (Figure
Swelling behavior of prepared films.
The mechanical properties of the prepared films are shown in Table
Mechanical properties of films.
Formulation | Tensile strength
|
Deformation/elongation
|
Work
|
---|---|---|---|
0.5-Ibu-1 | 13.35 ± 1.62 | 3.79 ± 0.71 | 119.36 ± 20.65 |
0.5-Ibu-2 | 22.24 ± 1.62 | 7.34 ± 1.33 | 151.47 ± 20.5 |
1.0-Ibu-1 | 11.0 ± 0.97 | 3.72 ± 0.57 | 110.95 ± 20.04 |
1.0-Ibu-2 | 12.89 ± 1.87 | 4.08 ± 0.61 | 140.97 ± 21.69 |
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1-blank | 17.19 ± 2.36 | 5.36 ± 0.68 | 119.11 ± 31.97 |
2-blank | 15.4 ± 1.24 | 5.32 ± 0.51 | 112.11 ± 8.02 |
3-blank | 15.87 ± 0.78 | 6.28 ± 0.48 | 68.15 ± 5.27 |
4-blank | 17.61 ± 1.39 | 6.76 ± 0.45 | 83.8 ± 12.8 |
Mechanical properties of the films without ibuprofen were evaluated by Scheffe’s test of pair comparisons which confirm a significant effect (
Mechanical properties of films: work done during the process of measurement and deformation/elongation of film at the moment of tearing.
The influence of process-formulation variables on the mechanical properties of films with ibuprofen was evaluated with MLR regression using ANOVA. The obtained regression models had the following goodness of fit characteristics:
The drug content uniformity (
Drug content uniformity in films with ibuprofen.
Formulation | Ibuprofen content (mg/cm2) | Number of samples within interval ±10% | Number of samples out of interval ±15% | Number of samples out of interval ±25% |
---|---|---|---|---|
0.5-Ibu-1 | 0.498 ± 0.091 | 6 | 2 | 2 |
0.5-Ibu-2 | 0.542 ± 0.042 | 9 | 1 | — |
1.0-Ibu-1 | 0.872 ± 0.102 | 8 | 2 | — |
1.0-Ibu-2 | 0.839 ± 0.056 | 10 | — | — |
Box diagrams for the drug content uniformity: box encloses 50% of the data and the median as the center of the cross; the whiskers indicate the maximum or minimum value.
Generally, ibuprofen release was dependent on the method of its incorporation. When the drug was suspended in an NaCMC dispersion (Ibu-2), about 70% and 50% of ibuprofen were released in the case of 0.5-Ibu-2 and 1.0-Ibu-2, respectively. Incorporation of ibuprofen as an acetone solution retarded drug release, as only about 35% and 40% in the case of 0.5-Ibu-1 and 1.0-Ibu-1 of the drug had been released from the films by the end of 8-hour testing period (Figure
Release of ibuprofen from prepared films.
The reason why a larger amount of the released drug in Ibu-2 films was achieved could be that the films with ibuprofen suspended in an NaCMC dispersion (Ibu-2) had smaller particles in comparison with Ibu-1 films, and ibuprofen was released from them more easily. Tang et al. [
All prepared films were found intact after the 8-hour dissolution study and exhibited biphasic drug release (Figure
Kinetic models for the time interval 0–150 min.
Model | Zero order | First order | Higuchi | Hixson-Crowell | Korsmeyer-Peppas | Baker-Lonsdale | |
---|---|---|---|---|---|---|---|
Sample |
|
|
|
|
|
|
|
0.5-Ibu-1 | 0.828 | 0.764 | 0.924 | 0.828 | 0.962 | 0.285 | 0.883 |
0.5-Ibu-2 | 0.905 | 0.792 | 0.972 | 0.905 | 0.975 | 0.530 | 0.968 |
1.0-Ibu-1 | 0.887 | 0.799 | 0.962 | 0.887 | 0.978 | 0.437 | 0.944 |
1.0-Ibu-2 | 0.913 | 0.809 | 0.974 | 0.913 | 0.980 | 0.600 | 0.966 |
Kinetic models for the time interval 150–480 min.
Model | Zero order | First order | Higuchi | Hixson-Crowell | Korsmeyer-Peppas | Baker-Lonsdale | |
---|---|---|---|---|---|---|---|
Sample |
|
|
|
|
|
|
|
0.5-Ibu-1 | 0.846 | 0.858 | 0.812 | 0.846 | 0.787 | 0.083 | 0.832 |
0.5-Ibu-2 | 0.989 | 0.989 | 0.979 | 0.989 | 0.978 | 0.335 | 0.981 |
1.0-Ibu-1 | 0.821 | 0.829 | 0.770 | 0.821 | 0.722 | 0.066 | 0.813 |
1.0-Ibu-2 | 0.931 | 0.940 | 0.893 | 0.931 | 0.858 | 0.116 | 0.922 |
Korsmeyer-Peppas, Higuchi, and Baker-Lonsdale models properly described the release of ibuprofen from all films during the first 150 min. In this period, all the films predominantly acted as an insoluble matrix, and the drug was released in two ways, mainly based on Fickian diffusion—by extraction from the matrix into the medium and by leaching through the media which entered into the matrix through the pores. In this stage, the films contained sodium salt of ibuprofen and an acidic form of CMC.
The first order model best described the drug release from all the films in the interval 150–480 min, and Fickian diffusion remained the main mechanism of drug release. Because the drug release was also well described by Hixson-Crowell and zero order models, CMC in the films was probably gradually dissolved due to the gradual formation of soluble sodium or potassium salts of CMC which arose from the acidic form of CMC after contact with PBS containing monovalent ions.
The diffusion process was the main drug release mechanism during both stages of the dissolution study. This finding is supported by Perioli et al.’s statistical evaluation of
New film wound dressings with ibuprofen were successfully prepared using an innovative solvent casting method with a sequential coating technique. The films had adequate mechanical and swelling properties and advantageous acidic surface pH for wound application. An
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was supported by finances from the Technology Agency of the Czech Republic ALFA Program (Research Project no. TA04010065) and IGA VFU Brno, Czech Republic (Research Project no. 53/2014/FaF).