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Research Paper Development and Characterization of Aspirin-Phospholipid Complex for Improved Drug Delivery
A. Semalty*, M. Semalty, D. Singh and M.S.M. Rawat
H.N.B. Garhwal University, Srinagar, India.
Aspirin (acetylsalicylic acid) is one of the most widely used analgesic. Aspirin is poorly soluble in water and causes gastrointestinal (GI) irritation. To improve the solubility (and hence the bioavailability) and minimize the GI irritation, its complexes with soya-phospholipid-80 % (in 1: 1 molar ratio) were prepared in an organic solvent and evaluated for solubility, drug content, scanning electron microscopy (SEM), FT-IR spectra, X ray diffraction, differential scanning calorimetry (DSC) and in vitro dissolution study. Aspirin-phospholipid complex were found to be disc shaped with rough surface in SEM. Drug content in the complex was found to be 95.6 %. DSC thermograms, XRD and FTIR confirmed the formation of phospholipid complex. Solubility of the prepared complex was found to be improved. Aspirin complex and aspirin showed 90.93 % and 69.42 % of drug release at the end of 10 h in dissolution study in pH 1.2 acid buffer. It was concluded that the phospholipid complex of aspirin may be of potential use for improving the solubility of aspirin and hence its bioavailability. The complexes may also reduce GI toxicity of the drug.
KEYWORDS: Pharmacosomes; Phospholipids complex; Aspirin; NSAIDs Introduction
Aspirin (acetylsalicylic acid, ASA) is one of the most widely used therapeutic substances due to its analgesic, antipyretic and anti-inflammatory properties. Despite the proliferation in development of new non-steroidal antiinflammatory drugs (NSAIDs), ASA remains one of the most effective ‘over-the-counter’ drugs in the treatment of rheumatic diseases. Furthermore, due to its anti-thrombotic properties, ASA is now prescribed at low doses in the prevention and treatment of cardiovascular diseases, strokes and disorders associated with platelet aggregability (Van and Botting, 1992). ASA use is commonly associated with gastrointestinal (GI) side-effects ranging from dyspeptic symptoms and ulceration to life-threatening episodes of bleeding (Hollander, 1994). ASA is poorly soluble in the acidic conditions of the stomach, which can delay absorption of high doses for 8 to 24 hours. Modifying the water solubility of aspirin may prove to be beneficial for improving its absorption. The rate of release of a drug is a function of its intrinsic solubility and influenced by particle size, crystallinity, drug derivatization and formation of more-soluble complexes
* For correspondence: A. Semalty, E-mail: firstname.lastname@example.org
(Leuner and Dressmann, 2002; Rabinow, 2004 ; Patravale et al.. 2004; Kesisoglon et al. 2007; Nijlen 2003; Various approaches have been Nokhodchi, 2005). investigated to improve the absorption and permeation of biologically active constituents of synthetic and natural origin. These include, development of more soluble prodrug, solid dispersions, preparing complexes with complexing agents like metals, cyclodextrin and phospholipids. Apart from other methods used for modifying the solubility, the complexation with phospholipids have been found to show improvement in both, absorption as well as permeation of the active constituents (Semalty et al., 2009a; Semalty et al., 2009b). Phospholipids (like phosphatidylcholine) play a major role in drug delivery due to its amphiphilic nature, that can modify the rate of drug release for the enhancement of drug absorption across biological barriers. Developing of amphiphilic drug-lipid complexes or pharmacosomes may prove to be a potential approach for improving therapeutic efficacy of the drugs by improving the bioavailability (through improvement in solubility in GI fluid and permeation across the biomembranes). Any drug possessing an active hydrogen atom (-COOH, -OH, -NH2, etc.) can be esterified to the lipid, with or without spacer chain. Synthesis of such compound may be guided in such
000. Solubility To determine the change in solubility due to complexation. rotary vacuum evaporator (Perfit Modle No. The study deals with its characterization for drug content. SEM of complex was performed at UGC-DAE consortium Indore (India) by Scanning Electron Microscope (JEOL JSM 5600). USA) in the transmission mode with the wave number region 4.Semalty et al. or hexagonal aggregates. The thermal behavior was studied by heating 2. The dried residues were collected and placed in vacuum desiccators overnight and then subjected to characterization. increased entrapment efficiency. complex equivalent to 100mg were weighed and added in 100mL of pH 1. are stable and more bioavailable with low interfacial tension between the system and the GI fluid. easy removal of unentraped drug from the formulation. 50 mg of aspirin (and 50 mg equivalent in case of complex) was taken in a 100 mL conical flask. 3). Materials and Methods Materials Aspirin was purchased from E-Merck Mumbai. 2. this study aims to develop the amphiphilic lipid complexes or pharmacosomes of aspirin to improve solubility and hence its dissolution. phase transition behaviour (DSC) and in vitro dissolution study. Pharmacosomes are defined as colloidal dispersions of drugs covalently bound to lipids. The salient features of pharmacosomes are. The solvent was evaporated off under vacuum at 40 oC in a . 5600 Buchi type). These amphiphilic drug-lipid complexes. micellar. Methods Preparation of Aspirin. no loss of drug due to leakage. Drug content To determine the drug content in Aspirin-PC complex.2 HCl buffer and n-octanol by shake flask method. developing the drugs as lipid complexes (pharmacosomes) may prove to be a potential approaches to improve solubility and to minimize the GI toxicity of NSAIDs. 1995).2 mg of each individual sample in a covered sample pan under nitrogen gas flow (Fig.3nm. Infrared Spectroscopic Analysis FTIR spectra for the various powders were obtained on a Perkin Elmer FTIR spectrometer (Perkin Elmer Life and Analytical Sciences. no problem of drug incorporation and no influence of encaptured volume and drug-bilayer interaction on entrapment efficiency (Semalty et al. 2006). The equimolar concentration of PC (in 1: 1 molar ratio) and aspirin were placed in a 100 mL round bottom flask and dissolved in dichloromethane. and may exist as ultrafine vesicular. The suspension was then transferred to 250mL separating funnel with 50mL of n-octanol and was shaken well. crystallinity (XRD). All other chemicals were of analytical grade. Concentration of the drug was determined from the aqueous layer spectrophotometrically at 228. tissue. The investigations were carried out over the temperature range 25-250º with a heating rate of 10ºC/min. The volumetric flask was stirred continuously for 24hr on a magnetic stirrer. Soya phosphatidylcholine (LIPOID S-80) was obtained as a gift sample from LIPOID Gmbh Germany.. : Development and Characterization of Aspirin-Phospholipid Complex for Improved Drug Delivery 941 a way that strongly results in an amphiphilic compound. Moreover. Differential Scanning Calorimetry (DSC) Thermograms of Aspirin. Separating funnel was allowed to stand for about 30 minutes.2 hydrogen chloride buffers. MA. The results were shown in Fig. which will facilitate membrane. in the organism.4E.0±0. or cell wall transfer. solubility of aspirin and aspirin-PC complex was determined in pH 1. and aspirin-PC complex were recorded using a 2910 Modulated differential scanning calorimeter V4. Dilutions were made suitably and measured for the drug content at 228. tissue. depending on the chemical structure of the drug lipid complex. in the organism.. 50mL of pH 1. KBr pellets were prepared by gently mixing 1 mg sample powder with 100mg KBr. thereby facilitating membrane. Therefore. 2009a. the incorporation of NSAIDs with phospholipids has been also suggested to improve GI safety of these drugs. It has been reported that the diffusion of NSAIDs across lipid membranes and into target cells is accelerated when it is present as a complex with phosphatidylcholine (PC) (Lichtenberger et al. or cell wall transfer.3nm UV spectrophotometrically by Lambda25 Perkin Elmer UV/Visible Spectrophotometer. chemical interaction (FTIR). Therefore.2 HCl buffer was added and then stirred for 15 minutes.. Biju et al.500 cm-1. phosphatidylcholine (80%). Scanning electron microscopy (SEM) To detect the surface morphology of the pharmacosomes.PC Complex Aspirin-PC complex was prepared by associating aspirin with an equimolar concentration of PC (80 % purity grade of soya-phospholipids). solubility.
was 95.20 15.6% (w/w). Content of aspirin in phospholipid complex. phosphatidylcholine (80%). to maintain sink conditions.D8 Discover Powder X-ray diffractometer (Germany).3nm.942 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 • Issue 2 • July-September 2010 Fig. Samples (three ml each) of dissolution fluid were withdrawn at different intervals and replaced with the equal volume of fresh media. Diffraction patterns were obtained on a Bruker Axs.05 was considered statistically significant. Complexation is giving a good percent loading of the drug that makes the delivery of drug clinically feasible.2 HCl buffer.86 Dissolution Study In vitro dissolution studies for aspirin complex as well as plain aspirin were performed in triplicate in a USP XXIII six station dissolution test apparatus (Veego Model No.6DR) at 100 rpm and at 37 oC. 1 provides the solubility data.4 o/min). Solubility of the aspirin complex was found to be much higher (in water and n octanol) than the aspirin.44 ± 1.45 ± 1. In all tests. using the Ka lines of copper as the radiation source. n=3 . as estimated by UV spectrophotometry. which is peculiar to them. Results and Discussion In the present experiment aspirin–phospholipid complex (pharmacosomes) were prepared by a simple and reproducible method.54 ± 2. The increase in solubility of aspirin in the complex can be explained by the solubilization resulted from the formation of micelle in the medium and by the amorphous characteristics of the complex.98 Solubility in nOctanol layer (in µg/ mL) * 24. and aspirin-PC phosphatidylcholine complex were analyzed with X-ray diffractions. a probability value of P<0. The X-ray generator was operated at 40 KV tube voltages and 40 mA of tube current.98 ± 1. Table 1 Solubility study of aspirin and its complex. Aspirin. The scanning angle ranged from 1 to 60o of 2θ in step scan mode (step width 0. phospholipids could increase the solubility of the drug by the action of wetting and dispersion. Drug Aspirin Statistical analysis Results are expressed as mean values and standard deviations (± SD) and the significance of the difference observed was analyzed by the Student’s t test.46 31. Table. Aspirin-PC complex * Data expressed as mean values and standard deviations (± SD). The results were shown in Fig.45 mm membrane filter) and diluted suitably and then analyzed spectrophotometrically at 228. the complex showed an amphiphilic nature. 1 SEM of phospholipid complex of aspirin (a) 750 X magnification (b) 85 X magnification. which in turn may prove to be responsible for improved bioavailability of the drug. As an amphiphilic surfactant. X-ray Powder Diffraction Analysis The crystalline state of aspirin in the different samples was evaluated with X-ray powder diffraction. Withdrawn samples were filtered (through a 0. An accurately weighed amount of the complex equivalent to 100 mg of aspirin was put into 900 ml pH 1. 4. Pharmacosomes showed a high percentage of drug loading. Solubility in aqueous layer (in µg/ mL)* 8. Unlike non-polar nature of aspirin.
1.24 773.54 876.01 598.01.70 1697.12 2648.81 2622.49 803.0 0. Aspirin showed the characteristic IR (KBr) peaks of O-CO.0 0. The formation of the complex can be confirmed by the IR spectroscopy comparing the spectrum of the complex with the spectra of the individual components and their mechanical mixtures (Semalty et al. The differential scanning calorimetry is a tool used to measure the temperature and energy variation involved in the phase transitions. –OH (out of plane) bending at 916.00 896.0 26 24 32 30 28 26 22 20 18 24 22 %T 20 18 16 %T 14 12 16 14 12 10 8 1254. As the phospholipids are natural component their different purity grades may have different effects in shape and surface morphology.86 1548. phospholipid complex of Aspirin (APC 80) and their Physical mixture. FT-IR spectra for various powders were obtained on a Perkin Elmer FTIR spectrometer in the transmission mode with the wave number region 4.04 1960.71 3000 2000 cm-1 1500 4000.25 1371. On the other hand the surface of the complexes prepared with the high purity grades of phospholipids (80 %) show rough.39 647. Thus the FTIR spectra indicate the interaction of PC with the aspirin’s – COOH group.10 1093.20 542.83 1744.18 1605.21 757.000-500 cm-1. Scanning Electron Micrographs of the complex are shown in Fig.74 593. The peak size and shape of the DSC curves are useful in determining the crystallinity of the drug and the carrier.04 1472.0 4000. PC-80.65 843.16 1582.stretching at 1756. The OCO.4 34 (b) PC-80 27. non-sticky and free flowing nature as in the present study (Semalty et al.78 1181.75 1306.75 cm-1 in aspirin has been shifted to higher wave number side in the complex with medium absorption band.74 1012. FT-IR spectra of complex were significantly different from that of components and that of physical mixtures (Fig.61 452.55 2596.0 (a) Aspirin 36.75.09 916.85 3267.84 1457.54 1417.34 1454.03 20 619.19 720.0 65 60 55 50 45 550 500 522.47 2850.87 1220.0 0.08 4 1740.10 10 8 6 6 4 2 4000.71 cm-1.46 665.44 %T 450 400 350 300 250 200 150 100 3397.0 3000 2000 cm-1 1500 1000 500 400.98 691.33 2918.74 748.0 3000 2000 cm-1 1500 1000 500 400.61 30 25 1314.34 2740. 2)..72 1104.40 515. The –CN stretching in the phosphatidylcholine at 1238 cm-1 (strong band) has shifted to 1240 cm-1 (broadband) in the complex.36 755.22 2956.06 969.17 476.1 800 750 700 650 600 69.61 40 %T 35 423. In order to ..13 562.70 and -OH bending at 916 cm-1.23 502.8 1734. 2009b). Complexes were found to be as free flowing particles.52 766. -OH bending at 1454.56 1756.98 1637. 2009a).28 1571.Semalty et al.62 839.90 704.14 50 4000. -COO at 1697.0 1057.95 972.38 1062. The surface was found to be sticky in the complexes prepared with low purity grades (40 %) of phospholipids. 2003).3 3000 2000 cm-1 1500 1000 500 400. Pharmacosomes were found to be of disc shaped with rough surface morphology.18 cm-1 is missing in the complex.0 (c) APC-80 (complex) (d) Physical mixture Fig.84 1292. which reflects the degree of crystallinity and stability of the solid state of pharmaceutical compounds (Sang et al.18 1363. –OH (in plane) bending at 1371.55 554.72 644. : Development and Characterization of Aspirin-Phospholipid Complex for Improved Drug Delivery 943 866.14 824.36 1485. FTIR spectra showed the changes in peaks in complexes and positions from that of aspirin and PC. 2 FTIR spectra of Aspirin..60 3051.0 0.25 2 1000 500 400.21 15 10 5 2832.stretching vibrations at 1697.50 424.62 cm-1 in aspirin has merged with broadband at 1057.61 1093.
and the aspirin-PC complex. The results of the DSC test confirmed the association of aspirin and PC in the complex as both peaks representing aspirin acid and PC changed position (Fig. (c) phospholipid complex of aspirin. (b) PC-80 and. . DSC analysis was performed on aspirin.944 International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 • Issue 2 • July-September 2010 substantiate the association of aspirin with PC. 3). PC. Fig. 3 DSC thermograms of (a) aspirin.
.. puerarin..45o C. Li et al. XRPD analysis was conducted. 2θ. 2006. Unlike liposomes. The value of 2θ means the diffraction angle of ray beams. These results are well supported by our previous studies done with the phospholipid complexes of diclofenac and naringenin (Semalty et al. On the other hand complex showed two unique peaks (at 50.8o C). 4. 25000 20000 15000 10000 5000 0 ASP Pure Intensity(a.. Semalty et al... The DSC thermograms of the phospholipid complexes of some phytoconstituents like silybin. Semalty et al. 2007.8o and at 63. 2006.. the degree of crystallinity could be evaluated using the relative integrated intensity of reflection peaks in the given range of reflecting angle. 2009c).90o C and a small peak at 64. The acemetacin and indomethacin also showed the significant changes in the DSC thermogram when these arylacetic acid derivatives were complexed with the 1. Maiti et al. 4 High resolution X ray powder diffraction (XRPD) study of Aspirin complex (APC-80) and its components. . 2007. 2006. 2008). Shi et al. The disappearance of aspirin crystalline diffraction peaks confirmed the formation of phospholipid complex.. Yoo et al.6o C. which were different from the peaks of the individual components of the complex. In all these studies the thermogram of the complex also exhibited a single peak which was different from the peak of phytoconstituent and phospholipids. 2009b. which is shown in the abscissa of Fig.2-dipalmitoylphosphatidylcholine (Lúcio et al. might have resulted into the significant change of its X-ray diffraction. 2003). insulin and salmon calcitonin also supported the results obtained (Li et al. The XRPD of aspirin complex revealed a broad peak similar to PC indicating that the aspirin was in amorphous form in phospholipid complex. To check whether the changes in the aspirin crystal morphology correspond to a polymorphic transition and to study the solid state of aspirin phospholipid complex.21o C and 107. Cui et al. 2009c). From these patterns. curcumin and naringenin also revealed the similar results (Yanyu et al. 2007...u) 500 10 400 300 200 100 0 160 140 120 100 80 60 40 20 0 10 15 20 25 30 35 40 45 50 55 60 PC80 15 20 25 30 35 40 45 50 55 60 APC80 10 15 20 25 30 35 2θ 40 45 50 55 60 Fig. It is evident that the original peaks of phytoconstituent and phospholipids disappear from the thermogram of complex and the phase transition temperature is lower than that of phospholipids.Semalty et al. : Development and Characterization of Aspirin-Phospholipid Complex for Improved Drug Delivery 945 PC showed two major peaks at 83. The phospholipid complexes of puerarin. while aspirin showed a sharp endothermic peak at 142. bonding between drug and the phospholipids in development of pharmacosomes (drugphospholipid complex)..
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