- *Corresponding Author:
- P. Zakeri-Milani
Liver and Gastrointestinal Diseases Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
E-mail: [email protected]
|Date of Submission||18 August 2012|
|Date of Revision||10 February 2013|
|Date of Acceptance||12 February 2013|
|Indian J Pharm Sci, 2013;75(2):143-148|
The aim of this work was to develop the best formulations for naproxen suppositories. The effects of different bases and surfactants on the physicochemical characteristics of the suppositories were determined by several tests such as weight variation, melting point, assay, hardness, and release rate. All formulations met the standard criteria for tested physicochemical parameters; weight variation (97-112%), content uniformity (97-105%), melting point (4.66-8.7 min) and hardness tests (>5400 g). Based on release rate studies, hydrophilic, and lipophilic bases without surfactants were not suitable bases for naproxen suppository. Amongst the formulations containing surfactants only Witepsol H15 with 0.5% w/w of Tween 80 and Witepsol W35 with 0.5% of cetylpyridinium chloride were suitable and released nearly complete drug during 30 and 60 min, respectively. This study demonstrates the effects of incorporation of known agents on the in vitro release characteristics of naproxen suppository.
Naproxen, polyethylene glycols, suppository, surfactant, Witepsol
Naproxen (NPX), 6-methoxy-α-methyl-2-naphthal ene acetic acid, belongs to an important group of medicines called nonsteroidal antiinflammatory drugs with antiinflammatory, analgesic and antipyretic properties and is widely used in the treatment of rheumatic and other inflammatory diseases and for the relief of mild to moderate pain. Antiinflammatory effects of NPX are generally thought to be related to its inhibition of cyclooxygenase and consequent decrease in prostaglandin concentrations in various fluids and tissues and often preferred to acetylsalicylic acid (aspirin) because of its better absorption following oral administration and fewer adverse effects [1-3]. Oral administration is the route choice for drug administration. However, oral drug delivery becomes impossible in certain cases such as nausea, vomiting or convulsion. In such situations, the rectal route may provide a practical alternative. Melting or liquification of the fatty or hydrophilic base suppository leads to the release of the active drug. The latter process is dependent on rectal environment, drug substance, and suppository base [2,4-10]. Although rectal dosage forms are not common because of cultural and psychological biases, there are several advantages for administration by the rectal route. For example, the absorption site is near the administration site, hence there is a rapid absorption with a rapid increase in plasma drug levels with reduced sideeffects, specifically gastrointestinal irritation and the first pass effect is avoided [11-13]. However, the rectal route also has some potential disadvantages. For instance many drugs are poorly absorbed from rectal mucosa. Moreover a limiting absorbing surface area, dissolution problems due to the small fluid content of the rectum and drug metabolism in microorganisms and rectal mucosa can make it unfavorable route for drug administration. On the other hand, physicochemical and pharmaceutical factors such as solubility, particle size, partition coefficient, pKa, concentration of active substances, composition of the base, melting temperature range, viscosity, spreading in situ of suppository bases affect the rate and extent of drug absorption from suppositories [14-18]. To modulate drug release and absorption from suppositories, several studies have examined the use of surfactants, absorption enhancers, mixed micelles, fatty acid derivatives, and polymers [5,11,19-24]. In general, rectal bioavailability tend to be lower than the corresponding oral values; however, previous studies have demonstrated that the bioavailability of rectal NPX could be similar to its oral form while its side-effects are lower . Therefore to ensure the rapid release of drug from suppositories, in the present study three types of surfactants were incorporated in the formulations and in vitro release characteristics of NPX from hydrophilic and hydrophobic suppository bases were evaluated.
Materials and Methods
NPX was a gift from Pars Daru Pharmaceutical Company, Tehran, Iran. Sodium hydroxide, sodium lauryl sulphate, cetylpyridinium chloride, tween 80, polyethylene glycol 400, 2000, and 6000 were purchased from Merck, Darmstadt, Germany. Witepsol H15 (WH15) and Witepsol W35 (WW35) were procured from Daruphakhsh Pharmaceutical Company, Tehran, Iran. KH2PO4 was obtained from Riedel-de Haen, Hanover, Germany.
Preparation of suppositories
Different types of Witepsols are often used in commercial formula as main fatty bases and various grades of polyethylene glycols (PEG) are used as the main water soluble bases [7,25-27]. Lipophilic and hydrophilic base suppositories were prepared using WH15, WW35, and different combination of PEG 400, 2000 and 6000, respectively. Suppository formulations were produced manually on a small scale by homogenizing NPX (500 mg/suppository) into the melted suppository bases. Accurately weighed quantities of the respective suppository bases, after mixing with PEG 400, 2000 and 6000 (in the case of hydrophilic suppository according to Table 1) were melted on a water bath at an appropriate temperature for each base. Finally NPX powder (500 mg) and/ or additive were incorporated using the displacement values calculations into the melted base along with continuous stirring. The melted mass was poured into the appropriate suppository mould (3 g capacity, Erweka-type 126 ALC, Germany) and allowed to cool at room temperature. Excess base was scraped off after solidification. Before molding of some hydrophilic suppositories (B, C and D combinations), it was necessary to lubricate the moulds with liquid paraffin. Displacement value was calculated based on the following equation: f=(100×(E−G))/(G×x)+1. Where f is the displacement value, E is the weight of the suppository without active substances (the calibration value of the mould for the certain base), G is the weight of the suppository with active substances and x is the active substance content in percentage .
|Formulation code||Base composition (%)|
|PEG A||PEG 6000|
|PEG B||PEG 6000 (75)+PEG 2000 (25)|
|PEG C||PEG 6000 (25)+PEG 2000 (75)|
|PEG D||PEG 6000 (50)+PEG 2000 (50)|
|PEG E||PEG 6000 (75)+PEG 400 (25)|
Table 1: Composition of Different Formulations Of Hydrophilic Bases
Physicochemical analysis of suppositories
The weight of five separate suppositories was checked and means weight value was calculated. Melting point was measured by the collodion tube method for three suppositories (Erweka SSP, German). Hardness was measured by the resistance to crushing using hardness tester (Erweka SBT, German). The uniformity of drug content for each base (20 suppositories) was determined by dissolving PEG base suppositories in phosphate buffer at pH 7.2 in 37°, after 30 min stirring, the absorbance was measured by spectrophotometry (Shimadzu 120A, Japan) at a wavelength of 230.2 nm after dilution. The procedure was repeated to determine the uniformity of drug content of lipophilic base suppositories using repeated extraction with phosphate buffer (pH 7.2). To ensure complete extraction of the drug from the bases, blank suppositories without the drug were prepared and subjected to the same analytical procedure to serve as the blank for spectrophotometric determination.
Dissolution rate studies
A number of in vitro dissolution techniques for determination of the dissolution rate of drug substances from suppositories such as dialysis method and through a flow cell method were described in the literature [4,7,8,10,12,15,26,29-33]. In this study, the in vitro dissolution rate of NPX from the suppositories was examined using the basket method (Apparatus I, Erweka-Type DT6R, Germany). The temperature was maintained at 37° and the stirring rate was kept constant at 50 rpm. One thousand millilitre phosphate buffer (pH 7.2), was used as a dissolution medium, and samples of 5 ml test solution were collected manually at specified time intervals for up to 3 h and 4 h for lipophilic and hydrophilic bases, respectively. The withdrawn volume of the sample was replaced with the equal volume of fresh dissolution medium contained at the same temperature. The samples were analyzed for NPX concentration after appropriate dilutions. The US Pharmacopeia describes a UV spectrophotometric method for the assay of NPX tablets and for a dissolution study. In this study, the amount of dissolved NPX was detected at 230.2 nm on a UV spectrophotometer. Calibration curve data were generated using phosphate buffer (pH 7.2), in the concentration range of 0.3125-5 μg/ml (r2=0.999). For investigation of the effect of nonionic, anionic and cationic surfactants on the release rate of NPX, Tween 80, sodium lauryl sulphate, and cetylpyridinium chloride with concentrations of 0.5 and 1% w/w were used in formulations.
Results and Discussion
Variations in weight for the suppositories without surfactant and for the suppositories containing surfactant were in the range of 97-112%, which met the standard criteria (85.0-115.0%). Standard deviations were less than 0.031. The mean content of each suppository preparation was in the range of 97-104% and 97-105% of the labeled value for the suppositories without and containing surfactant, respectively (SD≤14.86), which is in the acceptable range (95-105%) . Mean liquification time for suppositories without surfactant was between 7.7 and 8.7 min (SD≤1.57). The respected range in the presence of surfactants was 4.66-8.66 min (SD≤1.15). Hardness test results showed that hardness of all formulations were more than 5400 g (proper hardness).
The effect of different suppository bases on the in vitro release of drugs has been described in several investigations [15,35]. In general, drug release from a number of suppository bases depends on the drug solubility in the base, the chemical composition of the base and drug particle size. Numerous studies have shown that drug release from suppository bases is influenced by the presence of other additives in the formulation and may result in an increase or decrease in the rate of release depending on not only the nature of the base but also the additive and its concentration considering the safety, efficacy, and compatibility with other ingredients of the formulation [35,36]. Results of dissolution tests in the present study showed that drug release profiles from both lipophilic bases were approximately the same (fig. 1a) and 100% of drug released after 180 min. Furthermore dissolution rates of five tested hydrophilic bases did not show considerable difference (fig. 1b) and in all formulations the total amount of drug released in 240 min. NPX is a lipophilic drug and it has low solubility in hydrophilic bases like PEGs. Therefore, it is expected to have a tendency to diffuse out the hydrophilic bases into the dissolution medium. However, the findings of this study revealed slow release of NPX from both fatty bases and PEGs. In a study about the crystallization behavior and microstructural evolution of solid dispersions prepared by co-melting method, it was found that for the fast crystallizing drugs like NPX, the interaction between the drug and the PEG matrix slowed down the crystallization rate of NPX and made larger drug domains . It was also found that, drugs with strong interaction in PEG (e.g., NPX/ PEG) favored the inter-lamellar incorporation of NPX in PEG matrix before crystallization of NPX . Moreover, formation of hydrogen bonds between NPX and PEG was also reported . All these interactions change physicochemical behavior of NPX resulting in slower dissolution rate. However, it is obvious that because of long time required for drug release, none of the investigated bases is ideal for NPX suppository formulation per se. Obtained results of release kinetic investigation showed that the release rates of all above formulations were best described with Peppas model (R2>0.96, 0.5<n<1) indicating diffusion and erosion as drug release mechanisms (Table 2). In Peppas model (ln F=ln kp+nlnt), the value of n characterizes the release mechanism of drug. n≤0.50 corresponds to a diffusion mechanism, while 0.50<n<1 communicate to combined mechanism of diffusion and polymer erosion. Fig. 2, illustrates the effect of addition of three types of surfactants into WH15 base. Results showed that tween 80, which has a hydrophilic-lipophilic balance of 14.9, had maximum effect on drug release rate enhancement and 100% of the drug was released in 30 min. The rationale for using tween at concentrations of 0.5 and 1% was to ensure its safety following rectal administration to humans. The mechanism of dissolution enhancement effect of surfactants is complex and not fully understood. The main possible mechanisms could be as a result of their moistening effects which increase the surface area of the suppository mass, and also shortening disintegration times of lipophilic suppositories, which is caused by changing their lipophilic characteristics to a lipohydrophilic nature. However, the enhancement effect was seen to a lesser extent by adding sodium lauryl sulphate. Moreover, addition of cetylpyridinium chloride into suppository base had almost no effect on drug release and couldn’t be considered as suitable additive. Both sodium lauryl sulphate and cetylpyridinium chloride changed drug release kinetic model from Peppas to first order model (R2>0.94) which indicates that the release mechanism alters from diffusion to erosion (Table 2). Fig. 3 depicts the effect of mixing of surfactants into the WW35 base on drug release. It is evident that only cetylpyridinium chloride could enhance dissolution rate of NPX from WW35. In formulations containing sodium lauryl sulphate and tween 80 no significant amount of NPX was released and therefore they are not suitable enhancers for this base. It is known that WW35 is a fatty base with higher hydroxyl value compared to WH15 (40-50 vs. 5-15), having higher monoglyceride contents. The different level of interaction between monoglcerides and polar group of dissolution medium may be added to surfactant addition effect leading to a different drug release rates from the investigated fatty base suppositories [39,40]. On the other hand, it is possible that sodium lauryl sulphate and Tween 80 cause interactions between NPX and WW35 base, which could result in decreased drug release. Fig. 4 compares the release profiles of hydrophilic bases and effect of addition of tween 80 and sodium lauryl sulphate into these bases. Release profiles showed that addition of these surfactants had no significant effect on drug release rate. This result could be a consequence of the presence of surfactants in concentrations around the critical micelle concentration, which prolong drug release because of micellar entrapment of drug . In summary, it can be concluded that hydrophilic bases are not suitable bases for NPX suppository formulation. Results indicated that formulations consisted of WH15 with 0.5% w/w of tween 80 and WW35 with 0.5% of cetylpyridinium chloride were most suitable bases for NPX rectal dosage form. This conclusion is more confirmed by the fact that fatty bases are better from a patient comfort perspective, since, the PEG bases are known to cause rectal mucosa irritation, due to their osmotic effects. However to optimize NPX release from different bases, further investigations using more enhancers and more characterizing techniques like differential scanning calorimeter, infrared spectroscopy are necessary.
|Formulation code||First order||Peppas|
|PEG A+tween 1%||0.995||0.925||0.921|
|PEG D+tween 1%||0.992||0.815||0.954|
|PEG A+SLS 1%||0.971||0.765||0.921|
WH15=Witepsol H15, WW35=Witepsol W35, PEG=polyethylene glycols, SLS=sodium lauryl sulphate, CPC=cetylpyridinium chloride, RSQ=R squared
Table 2: Kinetic Parameters For Analysis Of Formulations Release Data
The authors would like to thank the authorities of Faculty of Pharmacy, Tabriz University of Medical Sciences For their support.
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