Enhancement of dissolution and in vivo evaluation of lornoxicam ternary system with Gelucire 50/13 and polysorbate 80

 

Mohamed A. Amin¹, Shalam Mohamed Hussain^2*

¹Department of Pharmaceutics, Faculty of Pharmacy, Al-Azhar University, Egypt

¹Department of Pharmaceutics, College of Pharmacy, Qassim University, Kingdom of Saudi Arabia.

² Department of Pharmacology, College of Pharmacy, Qassim University, Kingdom of Saudi Arabia

 

ABSTRACT:

Background: Lornoxicam is an important non-steroidal anti-inflammatory agent. It is practically insoluble in water leading to difficulty in formulation and adversely affecting its pharmacokinetic and pharmacodynamic properties. For drugs like lornoxicam, the rate of absorption is often controlled by the rate of dissolution. Thus the enhancement of the dissolution rate and in turn solubility of poorly soluble drugs is important. Aims: The purpose of this present study was to prepare binary and ternary systems with lornoxicam, carrier and surfactant. Materials and Methods: Binary solid dispersions of lornoxicam with Gelucire 50/13were prepared at different drug to carrier ratios(1:1), (1:3), and (1:5). Polysorbate 80, a nonionic surfactant, was incorporated as a third component to obtain the ternary solid dispersion system. The solubilizing and absorption enhancer properties of this ternary solid dispersion system was then investigated. Solid systems were prepared by mixing or co precipitation and were characterized by different scanning calorimetery, X- ray diffractometery followed by tests for dissolution behavior. Results: The results thus obtained showed a remarkably improved dissolution of drug from the ternary solid dispersion systems when compared with the binary solid dispersion systems. In order to verify the improved dissolution therapeutically, a paw edema test for the formulation was carried in rats where in the ternary system exhibited a potent local anti-inflammatory activity against carrageenan induced paw edema when compared to pure drug. Thus vindicating the solubilizing and dissolution enhancing effect due to the addition of third additive to the binary system of lornoxicam. ­­­­­­­­­Conclusions: The drug loaded lornoxicam binary solid dispersion with GL50/13 exhibited faster dissolution rate than drug alone. The significant high drug-dissolution rate was obtained in a ternary solid dispersion system using tween 80 as a third component. The fastest drug dissolution obtained was in the ratio of 1:5:1 w/w/w (LOR /GL50/13/ tween 80). The in vivo experimental results corroborated the in vitro outcomes of lornoxicam.

 

 

1. INTRODUCTION:

Lornoxicam (LOR), (2-[2-[2-(2,6dihydrophyl) amino phenyl]acetyl]oxyacetic acid),is an important non-steroidal anti-inflammatory agent used for the management of rheumatoid arthritis, post-traumatic pain, musculo-skeletal and joint disorders. LOR is practically insoluble in water causing a major problem with formulation development and adversely affecting its pharmacokinetic and pharmacodynamic properties. For poorly soluble orally administered drugs, the rate of absorption is often controlled by the rate of dissolution [1]. Thus the enhancement of the dissolution rate and in turn solubility of poorly soluble drugs can be achieved with the use of auxiliary substances or by application of various technological possibilities [2].

 

Solid dispersions of drugs in water-soluble carriers have attracted a considerable interest as a means of improving the dissolution rate for a number of hydrophobic drugs and thus possibly improving the bioavailability of such drugs [3]. In solid dispersion systems, drug undergoes reduction in particle size and the consequent increase in the surface area results in the improved dissolution, breaking up the crystal lattice and increase in drug wettability by surrounding hydrophilic carriers [4, 5].

 

The use of solid dispersions is reported widely in the pharmaceutical literature although only few marketed products rely on the solid dispersion strategy for their formulation. The main reason for this discrepancy is the possible physical instability of these structures that can be metastable [6, 7].Phase separation, crystal growth or conversion from the amorphous (metastable) to the crystalline state during storage, inevitably results in decreased solubility and dissolution rate. The use of a carrier is often adequate to prevent recrystallization in these systems [8,9]. However, in recent years the use of surface-active and self-emulsifying carriers for the solid dispersion of poorly water soluble drugs has increased [10,11]. Furthermore, it was reported that a solid dispersion in mixture of polyethylene glycol and Polysorbate 80 could improve the dissolution rate and enhance the bioavailability of LAB687, a poorly water soluble drug [12]. The bioavailability in such solid dispersions was increased 10-fold when compared to the drug blend of micronized drug with microcrystalline cellulose. In addition to this, the solid dispersion system was physically and chemically stable for at about 16 months at 25 C˚/60% RH. In order to improve the dissolution properties of LOR, a new combination, consisting of Lornoxicam, a new hydrophilic carrier GL 50/13 and a surfactant was investigated.

 

Gelucire (GL) is a family of vehicles derived from the mixtures of mono-, di- and triglycerides with polyethylene glycol (PEG) esters of fatty acids. These Gelucires are available with a range of properties depending on their hydrophilic-lipophilic balance (HLB) and melting point range (33–65 C) [13,14]. They have a wide variety of applications in pharmaceutical formulations as in the preparation of fast release and sustained release formulations [15,16].

 

The selection of carriers and the surfactants is based on the fact that one most dissolves the drug in the solid state, leading to a stable system without phase separation, while the other one must increase the stability and dissolution rate of the drug. In the present study Gelucire 50/13 was selected as a hydrophilic carrier because it was able to molecularly disperse lornoxicam in the solid state [17-19]. Polysorbate 80 was selected as a surfactant because of its solubilizing action on several drugs [20]. The compatibility between the carrier and drug seems to be a stabilizing factor for the solid dispersion. However, little is reported on the ternary system.

 

The purpose of the present study was therefore to investigate the solid state properties of both binary and ternary system to contribute to our understanding how materials behave in a ternary system. Also the anti-inflammatory activities of ternary system solid dispersion was compared with binary system using paw edema method.

 

2. MATERIALS AND METHODS:

Drugs and chemicals

Lornoxicam was obtained as a gift sample from Chema Pharm, Egypt., Polysorbate 80 (Tween) [(polyoxethylene (20) sorbiton monooleate (POE)] (BDH chemical ltd. Co., Poole England), Gelucire 50/13, having a melting point of 50⁰C and HLB value of 13, was provided by Gattefosse (Cedex, France). Other materials and solvents used were of analytical grade and they were used without further purification.

 

Equipment

Shaking water path, thermostatically controlled BF21 (SBS Instruments, Germany), Spectrophotometer UV.1601 (Shimadzu Co., Japan), Sieve shaker, Rx-86-1 (Cole-Parmer Instrument Co., USA), Dissolution test apparatus, SR11 6flask (Hanson Co., USA), pH meter, Ama digital (Ama CO., Germany), X-ray diffractometer (Philips Co., Netherlands), T.A. 501 Differential scanning calorimeter, DSC (Shimadzu Co., Japan).

 

Methods

Preparation of lornoxicam physical mixture

The physical mixtures of binary system of lornoxicam with GL50/13at a ratio (1:1, 1:3 and 1:5 %w/w drug: carrier) were prepared by gentle and smooth blending of the desired amounts of the drug and the carrier using a mortar and a pestle. Samples were pulverized and sieved to obtain a particle size range of 125-250µm.The obtained samples were stored in a desiccators over calcium chloride.

 

Preparation of lornoxicam solid dispersion

LOR solid dispersion of both binary and ternary systems was prepared by conventional solvent method using GL50/13 as a carrier. In the binary system, the solid dispersion of 1:1, 1:3, and 1:5 %w/w of drug to carrier were prepared. The mixture of drug (100mg) and carrier was dissolved in acetone (10mg). In the ternary system, the surfactant was added into the solution of drug and carrier to obtain the final weight ratio of drug /carrier/surfactant 1:5:1 %w/w/w. the solvent was evaporated under reduced pressure at 40 C˚ till constant weight is obtained. The co-evaporates were pulverized and sieved to obtain a particle size range of 125-250 µm and then stored in desiccator over calcium chloride.

 

In vitro evaluation studies

Differential scanning calorimetery (DSC)

Samples about 5mg were placed in aluminum pans. DSC thermo grams were measured by heating the samples from 30-250 C˚ at a rate of 10 C˚min^-1 under nitrogen flow of 40ml/min.

 

X-ray diffraction studies

The X-ray diffractograms for different samples with particle size range of 250-125 µm were determined using Philips 1710 automated diffractometer. The relation was provided by Cuka radiation operating at 40Kv and current of 30mA, Ka^- =1.5418.The system was calibrated using standard polycrystalline silicon. The differential patterns were achieved using continuous scan mode with 2θ ranging from 4˚ to 60˚. The obtained output data were represented by 2 θ, dA intensities and determined via the microprocessor of the PW/1710.

 

Determination of the drug content of the prepared solid dispersions

An accurately weighed sample of the prepared solid dispersion system ( binary or ternary) equivalent to 250mg of the drug was added to 100mg volumetric flask, then dissolved in minimum amount of alcohol and complete the volume to100ml by phosphate buffer (pH=7.4) after suitable dilution, LOR content was determined spectrophotometrically at λmax 376 nm. Only the samples containing 100±5% of the claimed amounts of lornoxicam were considered for further studies.

 

Dissolution studies

Dissolution experiments were carried out in triplicate with USP apparatus II dissolution using paddle at a rotation speed of 100 pm. Powdered samples of each preparation equivalent to 25 mg of lornoxicam were added to the dissolution medium (900 ml) of phosphate buffer, (pH= 7.4) kept at 37±0.5 C˚. At time intervals, 5ml of the solution was withdrawn using cotton plug from the dissolution medium and replaced with an equal volume of the fresh dissolution medium equilibrated at 37 C˚. The samples were assayed spectrophotometrically at λ max 376 nm. It was found that none of additives used interfered with the spectrophotometrically assay of the drug in the dilution range used. The mean of three determinations was considered.

 

In vivo evaluation studies

Anti-inflammatory activity: carrageenan induced rat paw edema

Rats were procured from animal facility, college of pharmacy, Qassim University. Animal studies were performed after obtaining necessary permission from Institutional Animal Ethics Committee. The rats were divided into five groups of six animals. The first group was challenged with a subcutaneous injection of 0.1 mL of 1% w/v solution of carrageenan (10 mg of carrageenan was dissolved in 1 mL of 0.9% saline) into the plantar side of the left footpad of the rats to induce edema. In the other four groups, 30 min before the carrageenan injection, the animals were treated orally with different formulation of lornoxicam (4%) at dose of 2 mg/kg [21]. The photos of feet from a lateral view were taken immediately after injection (0 h) and then after 4 h of carrageenan injection (as maximum edema formation reached its peak after 4 h of carrageenan injection) [22, 23]. Photos were taken using a digital camera; foot thickness was measured from the photos as described by Maruyama et al. [24]. The edema was calculated by the difference of thickness between 0 and 4 h. The control rat received 0.1 mL of saline solution. We used a non-treated right foot of the same animal as a reference. Data was then converted to percentage change of paw thickness using the following equation,

 

% Change of paw thickness = (100 × (THICKpost-THICKpre)/ THICKpre)

 

Where, THICKpost and THICKpre are the paw thickness after and before carrageenan injection, respectively.

 

3. STATISTICAL ANALYSIS:

Data comparisons were performed using one-way ANOVA followed by Dunnett's post hoc test for multiple comparisons. p<0.05 was considered to be statistically significant. The results are presented as mean ± SEM.

 

4. RESULTS AND DISCUSSION:

Differential scanning calorimetery

Thermal analysis by DSC, a powerful tool in evaluating drug-carrier interaction [25]. Interactions in the samples are derived from DSC by changes in the thermal behaviors such as elimination of an endothermic or exothermic peak or appearance a new peak [26]. The thermal behavior of pure components and some selected drug-GL50/30, physical and dispersed mixtures are depicted in (Fig.1).DSC thermogram of pure LOR exhibited a small endothermic peak at 230.5 °C with simultaneously sharp exothermic peak at 235.2 °C which was probably due to the decomposition of LOR with melting.GL50/13 showed an endothermic peak at 41.55 C due to its melting point [27].The thermal behavior of LOR-GL system demonstrated the absence of interactions between LOR and GL 50/13. In fact, the fusion endothermic of lornoxicam reduced in intensity in ratios LOR: GL50/30 1:1 and 1:3 including physical mixture and coevaporates mixtures, as well, until fully disappearing in a ratio of 1:5 coevaporate, revealing total drug amorphization. Tween 80 was liquid at room temperature, therefore, it was not possible to record a DSC trace under the experimental conditions used. The thermal behavior of lornoxicam in ternary system was similar to that of binary systems. These results indicated that tween 80 did not play role in the thermal behavior of lornoxicam. Similar findings were found by Okongi S., et al., [28] who studied the thermal behavior of binary and ternary solid dispersions system of ofloxacin.

 

Fig.1 DSC curves of lornoxicam and various systems with Gelucire 50/13

A-lornoxicam alone, B-Gelucire 50/13, C-Physical mixture (1:1), D-Binary mixture (1:5), E-Ternary mixture (1:5:1)

 

X-ray diffraction pattern

X-ray diffractometry patterns of lornoxicam and its various ratios withGL 50/13 are shown in (Fig. 2). The diffraction spectrum of pure LOR showed that the drug was crystalline in nature as demonstrated by numerous distinct peaks. The predominant peaks of the drug were observed at 2θ of 6.09˚, 11.43˚, 15.53˚, 16.82˚, 22.92˚, 27.72˚, 30.31˚, 33.27˚, and 35.66˚ etc. (Fig.2 trace A). GL50/13 shows no characteristic peaks indicating its amorphous nature. (Fig.2, trace B).  Physical mixture of the drug with GL at ratio (1:5 w/w drug: carrier) still show the characteristic peaks of the drug. The XRD pattern of lornoxicam binary solid dispersions with PVP at 1:5 ratios showed the absence of crystalline diffraction peak of lornoxicam . The XRD patterns of lornoxicam ternary solid dispersions were similar to those of binary system. Incorporation of tween 80 had no effect on XRD pattern of lornoxicam in the solid dispersion. It was considered that tween 80 might exist in the amorphous region of both LOR and GL50/13.These results were corroborate the findings obtained by DSC studies.

 

Fig. 2 XRD spectraoflornoxicam and various systems with Gelucire 50/13

A-lornoxicam alone, B-Gelucire 50/13, C-Physical mixture (1:1), D-Binary mixture (1:5), E-Ternary mixture (1:5:1)

 

 

In vitro dissolution studies

The dissolution of lornoxicam from lornoxicam binary and ternary solid dispersions with Gelucire 50/13 in comparison with the intact drug was examined by plotting the percentage of drug released against time as shown in (Fig. 3). It is clear that the rate of dissolution of pure lornoxicamwas very low, less than 4% of the drug being dissolved within 2 hours. In all cases, solid dispersions exhibited faster dissolution rate than the intact drug. This was supposed to be due to the effect of molecular dispersion of the drug in GL50/13 and the effect of tween 80 in the ternary system.

 

Fig. 3 Dissolution profile of lornoxicam and its co-evaporates witth Gelucire 50/30

Table (1) Dissolution parameters of different lornoxicam formulation

 

 

 

 

The dissolution rate of LOR from all the prepared systems at the same ratios of GL 50/13 decreased in the following order: Ternary system ˃ binary system ˃ physical mixture ˃ drug alone

 

The increased dissolution rate of LOR from its binary system at a ratio of (1:5 w/w LOR: GL) could be attributed to the conversion of drug in an amorphous form as revealed DSC and X-ray diffraction studies. In addition to this, GL50/13 has good water solubility and can improve the wettability of the dispersed compound thus contributing towards dissolution [29,30].

 

In the ternary system, the dissolution results exhibited were faster at the ratio similar to polymer. Upon exposure to the dissolution medium, tween 80 might have oriented itself on the surface of  LOR particles decreasing drug surface tension leading to higher interaction of LOR-tween 80 resulting increased drug wettability (28).It was noticeable that the concentration of tween 80 in the solid dispersion is high enough to make the diffusion layer surrounding solid dispersion surface in the dissolution medium layer higher than its CMC. Therefore, it was considered that the hydrophobic portion of LOR was also solubilized via surfactant micelles. These effects of tween 80 and the desirable polymer of GL 50/13, an addition to the suitable proportional drug/carrier/ surfactant of 1:5:1 w/w/w gave extremely predominant increment dissolution rate of LOR. Dissolution rate constants (k₁) were calculated from the slopes of the first- order linear plots of the dissolution data. Dissolution efficiency (DE₃₀) values based on the dissolution data were calculated as per Khan (31). T_50% (time taken for 50% dissolution) values were recorded from the dissolution profile. The dissolution parameters were summarized in table (1)

 

Anti-inflammatory activity against carrageenan induced paw edema in rats

The amorphous dispersed binary system at a ratio of 1:5 w/w drug to polymer and the ternary system of 1:5:1 drug: Polymer: surfactant were selected for in vivo experiments in rats. The results of paw edema test were presented in fig.4, (Plane A and B). These results demonstrated that the anti-inflammatory activity of lornoxicam was significantly potentiated when the drug was formulated in solid dispersions with GL50/13. Also, the effects of tween 80 at a suitable ratio of drug/carrier/ surfactant of 1:5:1 gave extremely anti-inflammatory activity (50%±0.45) when compared with binary system(60%±0.7) or drug alone (70%±1.11).This obvious enhancement was also considered to be due to the solubilizing effect of tween 80 existing in the solid dispersion system associated with carrier. These results were in agreement with the findings of Mohammed et al [32] who studied the anti- inflammatory activity of  lornoxicam gel  in albino rats by carrageenan induced paw edema method in where Lornoxicam gel was delivered through rat’s skin by passive diffusion and diffusion with chemical enhancers (tween 80, 2%).

 

5. CONCLUSION:

The drug loaded lornoxicam binary solid dispersion with GL50/13 exhibited faster dissolution rate than drug alone. The significant high drug-dissolution rate was obtained in a ternary solid dispersion system using tween 80 as a third component. Tween 80 played an important role in drug dissolution from the ternary system by improving drug molecular dispersion in the polymer matrix as well as drug wettability and solubility. The fastest drug dissolution obtained was in the ratio of 1:5:1 w/w/w (LOR/GL50/13/tween 80). The in vivo experimental results corroborated the in vitro outcomes of lornoxicam.

 

Fig 4. The effect of lornoxicamwith various systems against carrageenan induced paw edema in rats.

 

A. Graphical Comparison of anti-inflammatory activity of lornaxicam  systems with carrageenan

B. images depicting paw edema thickness in different treated  and control groups.

Statistical analysis for A. was done by one-way ANOVA followed by Dunnett’s’t’ test.Values are expressed as mean ± S.E.M (n = 06). ns- statisticallynon significant, *<0.05, **p < 0.01, ***p < 0.001 when compared to carrageenan alone treated.

 

 

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Received on 12.11.2015          Modified on 28.11.2015

Accepted on 05.12.2015        © RJPT All right reserved