Utilization of adsorption technique in the development of oral delivery system of lipid based nanoparticles

Colloids and Surfaces B: Biointerfaces 81 (2010) 563–569

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Utilization of adsorption technique in the development of oral delivery system of lipid based nanoparticles Subhashis Chakraborty, Dali Shukla, Parameswara Rao Vuddanda, Brahmeshwar Mishra, Sanjay Singh ∗ Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India

a r t i c l e

i n f o

Article history: Received 29 April 2010 Received in revised form 25 July 2010 Accepted 26 July 2010 Available online 3 August 2010 Keywords: Adsorbed lipid nanoparticles Solid lipid nanoparticles Neusilin Flow Stability Stearic acid Carvedilol phosphate

a b s t r a c t The objective of the present study was to employ suitable adsorbent with free flowing characteristics for improving the stability and physical properties of solid lipid nanoparticles (SLN) for oral administration. Stearic acid based nanoparticles of carvedilol phosphate were fabricated by solvent emulsification evaporation technique in sodium taurocholate solution prepared in pH 7.2 buffers (I—KH2 PO4 /NaOH or II—NaH2 PO4 /Na2 HPO4 ) with 1% polyvinyl alcohol. Nanoparticles were then adsorbed by passing the nanodispersion through a Neusilin US2 (adsorbent) column. Interestingly, scanning electron microscopy revealed round deformed and even collapsed nanoparticles in Buffer-I and discrete spherical to ellipsoidal nanoparticles in Buffer-II which indicates the inability of nanoemulsion to crystallize and form SLN in Buffer-I. The successful formation of SLN in Buffer-II was confirmed by differential scanning calorimetry and X-ray diffraction. The retention of SLN from the nanodispersion by adsorption on the adsorbent imparted good flow property and resulted in a marked stability improvement of the formulation in terms of drug retention efficiency and release profile as compared to the simple nanosuspension. In conclusion, the adsorbent technology would be instrumental in imparting additional features to the existing conventional colloidal system for pharmaceutical application which would ease the process of capsule filling at industrial scale, simplify the handling of formulations by patients and can significantly improve the shelf life of the product for a longer period of time as compared to liquid formulations. © 2010 Elsevier B.V. All rights reserved.

1. Introduction Solid lipid based colloidal carriers of drugs have attracted considerable attention in the last two decades [1–4]. As they are derived from physiologically compatible lipids, solid lipid nanoparticles (SLN) represent a safe and effective alternative which include additional advantages and are devoid of the potential toxicities of conventional polymeric nanoparticles [5–7]. SLN for oral drug administration have specifically been employed for improving bioavailability by targeting the uptake of the drug by lymphatic system which prevents its hepatic first pass metabolism [8–11]. Despite the perceived therapeutic advantages of SLN, the technology available so far for the fabrication of SLN is restricted to the development of nanodispersion which has not had been so encouraging. In an aqueous nanodispersion, the SLN have a tendency to undergo particle aggregation under accelerated storage conditions due to the gelation phenomenon (an irreversible conversion of low viscosity lipid based nanoparticles dispersion into a viscous gel) due to which the dispersion is usually lyophilized into a dry powder to

∗ Corresponding author. Tel.: +91 542 6702712; fax: +91 542 2368428. E-mail addresses: chakraborty [email protected] (S. Chakraborty), [email protected], [email protected] (S. Singh). 0927-7765/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.colsurfb.2010.07.058

improve stability. However, the coexistence of high concentration of stabilizing agents (surfactants) along with the lipid nanoparticles (LNs) in the final product is not desirable because of their toxic effects on the mucosal lining of the GIT. Moreover, the process of lyophilization is critical as rate of freezing governs the structure and properties of the lipid crystals which finally determines its drug retention capacity during storage. Alternatively, filtration of the nanoparticles as a whole is a costly and exhaustive process due to the requirement of sophisticated equipments for retaining particles in nanosize range. Apart from the above, surfactants essentially employed in the production of SLN increase solubility of the poorly soluble/insoluble drug in the external phase. This matter is of serious concern during production and upon long term storage as it results in progressive leaching of drug from the particles to external phase which results in reduced drug loading efficiency. The above issues have been discussed in detail in literature [12]. The above discussion indicates that there is a necessity to develop a method which can separate the nanoparticles from the dispersion and immobilize them in order to retain their individual morphological identity upon storage. Harvesting the SLN from the nanodispersion by surface adsorption or retention on a submicron size inert pharmaceutical excipient with good flowability, compressibility and adsorption capacity may be an excellent approach to overcome the above mentioned issues. The prepared “Adsorbed

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Table 1 Quantities of ingredients used in the preparation of SLN. Batch no.

CP (mg)

SA (mg)

PVA (%, w/v)

STC (mM)

Buffer type

I II III IV V VI VII

20 20 20 20 20 20 20

100 100 100 100 100 100 100

– – – – 1 1 1

10 15 25 35 10 10 –

I I I I I II II

Volume of STC solution: 75 ml.

Lipid Nanoparticles” (ALN) would not only maintain the integrity of each adsorbed nanoparticle but also ease its filling into capsules or compression into tablet. To our knowledge, such a unique approach in the development of SLN delivery system has not been reported so far. However, limited studies involving the use of adsorbents to obtain lipid based granules for oral drug delivery have been reported wherein adsorbents were found to enhance the bioavailability of the drug and impart significant flow and compressibility to the final blend [13–15]. The drug employed here is carvedilol phosphate, a non-selective ␤-blocker. The drug exhibits poor aqueous solubility and high lipophilicity (log P) which makes it an excellent candidate for SLN encapsulation [16,17]. A study conducted previously in our laboratory using different types and concentration of surfactants at different pH has shown that sodium taurocholate (STC) has both minimum molar solubilization capacity and binding constant for carvedilol phosphate at pH 7.2 [18]. Therefore, the objective of the present work was to develop SLN of carvedilol phosphate using STC as a stabilizing agent and pH 7.2 phosphate buffer as dispersion medium, and improve the physicochemical properties of the nanoparticles by adsorbing them onto Neusilin (magnesium aluminometasilicate), an inert pharmaceutical excipient used as adsorbent. 2. Materials and methods 2.1. Materials Carvedilol phosphate was a kind gift of Lupin Ltd. (Pune, India). Stearic acid (SA), Neusilin US2 (NUS) and sodium taurocholate (STC), were gifts of Witco Chemicals (Newark, NJ, USA), Fuji Chemical Industry Co., Ltd. (Toyama, Japan) and New Zealand Pharmaceuticals (New Zealand), respectively. Polyvinyl alcohol (PVA) (cold water soluble, mol. wt. 140,000) was purchased from Himedia Labs Pvt. Ltd. (Mumbai, India). Other chemicals of analytical grade were purchased locally and used as received. 2.2. Preparation of solid lipid nanoparticle suspension The nanodispersion was prepared by solvent emulsification evaporation technique. Carvedilol phosphate and SA were dissolved in 3 ml mixture of dichloromethane and methanol (2:1). The organic phase was emulsified in the dispersion medium (STC solution maintained at 75 ◦ C) using ultraturrax (IKA, Germany), operated at 15,000 rpm for 10 min. The emulsion was then sonicated for 5 min at a frequency of 0.5 cycles and 60% amplitude using an ultrasonicator (Heilscher, Germany). One percent (w/v) PVA (presoaked in water) of dispersion was added and dissolved in the emulsion by shaking. The nanoemulsion (o/w) was then gradually allowed to cool to room temperature. The compositions of the prepared nano dispersions are presented in Table 1. Two different types of pH 7.2 phosphate buffers were used as dispersion medium which are as follows: Buffer-I: KH2 PO4 /NaOH

(prepared as per US Pharmacopoeial method) and Buffer-II: NaH2 PO4 /Na2 HPO4 [19]. 2.3. Preparation of adsorbed lipid nanoparticles A 2 ml glass syringe (plunger removed) was fixed to a burette holder and 50 mg of Neusilin US2 was packed into it by gentle tapping. The nanodispersion was then allowed to drop gently on the top surface of the column and the eluent was collected. The process was continued till the adsorbent was saturated as indicated by the turbidity in the eluent. The adsorbent was then replaced with fresh one and the process was repeated. The total amount of adsorbent used for each batch of nanodispersion was pooled and dried at room temperature for 24 h to obtain ALN. 2.4. Physical characterization of SLN and ALN 2.4.1. Determination of drug loading efficiency The nanodispersion was passed through a silica gel (60–120 mesh) column prepared in-house. The eluent was collected, further filtered through 0.20 ␮m syringe filter, diluted appropriately using distilled water and free drug content (FDC) was estimated spectrophotometrically at 240.2 nm (max ) using Shimadzu UV-1205 UV–vis spectrophotometer (Japan). The standard curves prepared for the determination of drug concentration in samples were linear with R2 > 0.999. Drug loading efficiency (DLE) was calculated using Eq. (1) [20]. DLE =

 theoretical drug content − FDC  theoretical drug content

× 100

(1)

2.4.2. Determination of total drug content Two milliliters of nanodispersion or 50 mg of the ALN was dispersed thoroughly in 3 ml mixture of dichloromethane and methanol (2:1), diluted with distilled water in a 100 ml of volumetric flask and heated for 15 min at 75 ◦ C. The solution was cooled to room temperature and volume of water was adjusted to 100 ml. The total drug content (TDC) of the solution filtered through 0.2 ␮m syringe filter was estimated at 240.2 nm using similarly treated placebo formulation as blank. 2.4.3. Determination of adsorption efficiency The adsorption efficiency of the adsorbent (AE) was calculated using Eq. (2). AE =



TDC Theoretical drug content



× 100

(2)

2.4.4. Viscosity measurement The viscosity of samples was measured using glass capillary viscometer (2425 Cannon Fenske, USA). 2.4.5. Particles size and zeta potential analysis The mean particle size, polydispersity index (PDI) and zeta potential of the formulations were determined using zeta potential

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Table 2 Characterization results of the prepared batches (n = 3). Batch no.

Drug loading efficiency (%) Particle size (nm) Polydispersity index Zeta potential Stability (15 days)

I

II

III

IV

V

VI

VII

98.16 ± 1.88 – – – Unstable

83.28 ± 2.04 – – – Unstable

63.87 ± 1.93 – – – Unstable

29.83 ± 2.38 – – – Unstable

96.38 ± 2.01 344.6 ± 11.1 0.454 ± 0.011 −9.78 ± 0.33 Stable

93.89 ± 2.63 295.3 ± 5.2 0.221 ± 0.013 −10.4 ± 0.49 Stable

73.84 ± 1.26 321.8 ± 6.9 0.245 ± 0.019 −11.5 ± 0.41 Stable

The results are expressed as mean ± SD.

and particle size analyzer, A53878A Delsa Nano C (Beckman Coulter, USA) based on dynamic light scattering technique. In case of ALN, the sample was re-dispersed in 1% PVA solution, centrifuged at 5000 rpm for 15 min (Remi, India) and the supernatant was subjected to particle size analysis. For each sample, the mean diameter ± standard deviations of three determinations were calculated. PDI is a dimensionless number indicating the width of the size distribution, having a value between 0 and 1 (0 being for monodispersed particles). 2.4.6. Morphological evaluation The morphologies of the samples were observed using scanning electron microscope (SEM) (QUANTA 200 FEI). The samples were placed on an aluminum pan and the excess water was left to dry at room temperature (25 ◦ C). Dry samples were attached to specimen stubs using double sided tape and imaged using a 5 kV accelerating voltage. 2.4.7. Solid state characterization The thermal behavior of the samples was determined by using DSC model-Q 1000 of TA Instruments, Delaware (USA) equipped with an intracooler and a refrigerated cooling system. Each sample placed in an aluminum pan was hermetically sealed with an aluminum cover. All measurements were performed over 25–105 ◦ C at a heating rate of 10 ◦ C/min. Nitrogen was purged at 50 ml/min through cooling unit. The physical state of the formulations were characterized using X-ray diffractometer (Rigaku DMAX3, Japan) with CuK␣ radiation at a scanning speed of 2◦ /min. 2.5. In vitro drug release study The drug release study was performed in two different media (0.1 N HCl and pH 6.8 sodium phosphate buffer) using the dialysis bag method. The dialysis membranes (thickness 0.025 mm, mol. wt. cutoff 6000–8000 Da) (Sigma–Aldrich) were kept overnight in the dissolution medium before dialysis to ensure thorough wetting of the membrane. Two milliliters of nanodispersion or ALN containing 2 mg equivalent of carvedilol phosphate along with 2 ml of the media was placed into the bag with the two ends tied and fixed by clamps. The bag was inserted into a beaker containing 250 ml of dissolution medium (37 ◦ C and stirring at 100 rpm) to maintain sink condition [18]. Samples of 2 ml were withdrawn at fixed time intervals with immediate replacement with equal volumes of the same medium. The samples were filtered through 0.2 ␮m syringe filters and the drug content was determined. All the operations were carried out in triplicate. 2.6. Study of flow characteristics The flow characteristic of ALN was evaluated by measurement of angle of repose using funnel method. Accurately weighed powder was taken in a funnel maintained at 4 in. from the surface. The powder was allowed to flow through the funnel freely onto the sur-

face. The height and diameter of the powder cone was measured and angle of repose was calculated using Eq. (3): q = tan−1

h r

(3)

where q is the angle of repose, h is height in cm of the powder cone and r the radius in cm of the powder cone. 2.7. Stability study Preliminary screening of batches was carried on the basis of visual observation. The prepared batches of nanodispersion were assessed for their ability to withstand phase separation on standing for a period of 15 days at room temperature. Thus the batches were selected and subjected to further analysis. The nanodispersion of Batch VI and its ALN were subjected to stability study at room temperature in a dessicator (25 ◦ C/60% RH) for a period of 3 months. The stability samples were analyzed for their total drug content, in vitro drug release study and particle size analysis, and only free drug content and pH was checked for the nanodispersion. 3. Results and discussion 3.1. Effect of process parameters on drug loading efficiency and physical stability of SLN The nanoparticles were fabricated using different concentrations of STC (10–35 mM) as a stabilizer. The characterization results of the prepared batches are presented in Table 2. It was observed that the DLE was maximum (98.2%) at 10 mM STC concentration (Batch I), and it decreased drastically with increase in STC concentration. The high DLE achieved was in agreement with the ability of STC to significantly retard solubility of the drug particularly at 10 mM concentration in pH 7.2 (with respect to other surfactant concentrations and the buffer alone), as observed in our earlier study [18]. However, none of the batches with only STC (Batches I–V) as stabilizer were found to be stable as phase separation occurred within 15 days of storage at room temperature (Fig. 1A). In order to achieve a homogenous dispersion, PVA, a polymeric excipient was added to the nanoemulsion. Addition of 1% (w/v) PVA (Batch VI) significantly improved the stability of the nanodispersion, as shown in Fig. 1B. The increased viscosity (from 1.08 cps (Batch I) to 4.3 cps (Batch VI)), by almost four folds, of the nanoemulsion upon addition of PVA may be the factor responsible to prevent the agglomeration by reducing the mobility of the nanoparticles in the dispersion medium. Moreover, PVA being a hydrophilic polymer acts as a coat to shield the particle surface charge responsible to cause their agglomeration [21]. It is probably due to this reason that the nanoparticles were found to be stable despite its low zeta potential. Preparation of a stable nanodispersion in presence of PVA alone (Batch VII) indicates its ability to immobilize nanoparticles by the viscosity imparted by the polymeric solution. However, the DLE of the batch was significantly

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Fig. 1. Observation of phase separation in (A) Batch V and (B) Batch VI.

low (73.84%) due to absence of the solubility retarding effect of STC. Therefore, it can be concluded from the above study that PVA as an emulsion stabilizer and STC as a solubility retardant, together contributed in the development of a stable nanodispersion with high drug loading efficiency. 3.2. Morphological evaluation of lipid nanoparticles An interesting phenomenon was observed during the scanning electron microscopic (SEM) analysis of Batch V. The micrograph indicated the absence of nanoparticles in the pure solidified state as the particles which appeared to be round and shiny were deformed and even collapsed (Fig. 2A). This implies that the proper crystallization on cooling, required for maintaining the structural integrity of a lipid particle, did not take place and, therefore, SLN were not formed. Furthermore, it is perhaps for the same reason that although the nanoemulsion did not undergo phase separation, the particles had a tendency of agglomeration as pointed by arrows in the same figure. In order to overcome the above issue, it was decided to alter the buffer composition (without change in pH) and check its effect on the crystallization behavior of stearic acid. Surprisingly, on changing the buffer composition to Buffer-II (Batch VI), discrete spherical to ellipsoidal nanoparticles were observed in the SEM photograph, indicating successfully formed SLN (Fig. 2B). 3.3. Solid state properties of lipid nanoparticles Apart from the morphological interpretation, the physical state of lipid in both the batches was further evaluated by DSC and XRD studies. The DSC thermogram of the Batches V and VI along with

Fig. 3. Differential scanning calorimetric thermographs of (A) Batch V, (B) Batch VI and (C) pure lipid.

the pure lipid is presented in Fig. 3(A–C). The thermogram of Batch V is of prime interest as the melting transition seen in Fig. 3A is very broad and blunt with low melting enthalpy value as compared to a much sharper endothermic peak of Batch VI and extremely sharp peak of the pure bulk lipid. This indicates considerable defects in the lattice arrangement or less ordered crystal lattice of the lipid of Batch V which shows incomplete lipid solidification or the coexistence of its amorphous state. The thermogram of lipid particles of Batches V and VI showed shifted peaks with relatively low heat of enthalpy than that of the pure lipid. This may be due to the presence of drug as a foreign body in the pure lipid and drastic reduction in particle size of lipid which together result in imperfections in the crystal lattice and, therefore, decrease in melting enthalpy. As the quantity of heat required to melt the impure lipid is reduced, a shift in the melting point of the lipid in the nanoparticles is observed. The X-ray diffraction patterns of Batches V and VI along with the pure lipid and drug are presented in Fig. 4(A–D). The XRD results obtained are in good agreement with the results established by DSC measurements. Although, crystalline reflections are visible for SLN of Batch V, the figures demonstrate that the scattering profile

Fig. 2. Micrographs of nanoparticles by scanning electron microscopy (A: Batch V, B: Batch VI).

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Fig. 4. X-ray diffraction pattern of (A) stearic acid, (B) carvedilol phosphate, (C) Batch V and (D) Batch VI.

exhibited by nanoparticles of Batch VI were of much higher intensity which is again an indication of the existence of lower ordered crystalline state and/or amorphous state of the latter. It can be also observed that after the addition of drug, scattering profile of the lipid remains unchanged, indicating that the lattice order inside the hydrocarbon chains is still conserved. The disappearance of the drug peaks in the formulation shows that the lipid has arrested the re-crystallization of the drug particles from the solvent system upon its evaporation. The investigations related to morphology and solid state characteristics confirm that the crystal structure of the lipid in Batch V has several imperfections and, therefore, exists in a solid liquid transition state or a semisolid state. The inability of the lipid emulsion to recrystallize in presence of Buffer-I may be attributed to partial neutralization of stearic acid in the presence of metallic hydroxide due to which the lipid forms a creamy base and, therefore, fails to regain its solid state in the aqueous medium [22]. However, the drug retention ability of the Batches V and VI was independent of the crystal arrangement as no significant difference in their DLE was observed which indicates that the lipid crystals have sufficient space to accommodate the added quantity of drug. The PDI values of Batches VI and VII reveal sufficiently uniform particle size distribution. The comparatively larger PDI of Batch V may be attributed to its physical state, as discussed above, due to which the particles have a tendency of agglomeration and is even visible clearly in the micrographs. 3.4. Evaluation of adsorbed lipid nanoparticles Batch VI which showed the presence of lipid nanoparticles in the solidified state with sufficiently high DLE was further processed

to prepare ALN. Approximately, 7–8 ml of the nanodispersion was found to saturate 50 mg of the adsorbent used in each process of each batch. The physiochemical properties of the ALN were evaluated and are presented in Table 3. The drug loading efficiency of the adsorbent was estimated to be 79.8 ± 2.3%. Apart from free drug, the loss during the separation process can also be related to particle size and PDI of the nanoparticles. The improvement in the PDI and relative increase in the average particle size of the re-dispersed nanoparticles relative to that of the nanodispersion indicates that a part of nanoparticles of lower size range were screened and not adsorbed on the adsorbents. This may be due to the fact that the pores of the adsorbents were filled with the nanodispersion and after saturation of these pores; the adsorbent was able to retain nanoparticles of only higher size range trapped in the inter-particulate void space. The above fact was determined by the analysis of the pooled eluent which revealed nano dispersion with 84.5 ± 9.3 nm particle size (PDI = 0.09 ± 0.01). Further drug content analysis on re-dispersion of nanoparticles in aqueous solution containing 1.0% PVA indicated that the re-dispersed amount corresponds to the amount of nanoparticles adsorbed. The photo micrograph of the ALN (Fig. 5) reveals Neusilin particles randomly

Table 3 Physical parameters of ALN (n = 3). Sl no.

Parameters

Results

1 2 3 4

Adsorption efficiency (%) Particle size (nm) Polydispersity index Angle of repose

71.8 309.4 0.164 37.8

The results are expressed as mean ± SD.

± ± ± ±

1.42 7.5 0.08 2.31

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Fig. 7. Dissolution profiles of Batches V and VI in 0.1 N HCl and pH 6.8 phosphate buffer. Fig. 5. Micrographs of adsorbed lipid nanoparticles. Table 4 Stability study after 3 months of storage at room temperature.

surrounded by polymeric flakes which play a significant role in the adherence of the nanoparticles on the adsorbent. The angle of repose of the ALN projects that the product has a good flow property (Fig. 6) which is an essential parameter required for efficient capsule filling process.

Parameters

Nanodispersion

ALN

Drug content Drug loading efficiency Particle size pH

97.21 ± 2.08% 59.72 ± 1.21% 292.8 ± 9.33 nm 7.11 ± 0.03

96.87 ± 1.48% – 314.7 ± 5.51 nm –

Initial pH was 7.18 ± 0.03, the results are expressed as mean ± SD, n = 3.

3.5. In vitro drug release study The dissolution profiles of Batch VI and ALN prepared from the same batch were studied in 0.1 N HCl and pH 6.8 phosphate buffer and are presented in Figs. 7 and 8. The rate of drug release of both the formulations in 0.1 N HCl was found to be very high while in pH 6.8 medium the drug release was retarded by almost 6 h which may be attributed to the solubility of the drug in the respective media [18]. Based on the above observation, it may be suggested to target the release of the formulation in the alkaline environment of the intestine to utilize maximum benefit of the lipid vehicle during the drug’s absorption process [11]. Thus, the present formulation may not only improve the bioavailability of the drug due to coadministration of lipid but would also reduce fluctuations in plasma drug concentration due to controlled drug release for a prolonged period of time. The above qualities would be instrumental in reducing the dosage requirement and also minimize its common side effects. The initial retarded release of the ALN in 0.1 N HCl may be

Fig. 6. Photograph showing flowability of adsorbed lipid nanoparticles.

due to its dry physical state and trace amount of surfactant available relative to that of the dispersion. 3.6. Stability study The results of the stability study are presented in Table 4 and Figs. 7 and 8. No significant changes were observed in the drug content, particle size and dissolution profile of the ALN as well as the pH of the nanodispersion. However, among all parameters, a significant decrease in drug loading efficiency (from initially 94% to 62% after 3 months) of the nanodispersion was observed. This indicates that during storage, the drug from the particles has leached into the external medium to attain its saturation level. It was due to the presence of this free drug that an increase in initial drug release was

Fig. 8. Dissolution profiles of stability batches (Batches V and VI) in 0.1 N HCl and pH 6.8 phosphate buffer.

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distinctly observed in the drug dissolution profile in pH 6.8 buffer. Thus, the development of ALN helped to improve the stability of the product in terms of its drug loading efficiency and drug release profile. No significant change in the dissolution behavior was observed in case of other batches. 4. Conclusion SLN with high DLE were successfully fabricated using STC and PVA as a solubility retarding agent and stabilizer, respectively, in pH 7.2 mixed sodium phosphate buffer as dispersion medium. This study indicates that the type and concentration of surfactant and viscosity of the external medium together play a significant role in obtaining stable nanodispersion with high DLE. In addition, buffer composition was also found to play a significant role in determining the physical state of the nanoparticles. The observations made during the study emphasize the need of adequate solid state characterization and morphological evaluation to ensure the physical state of the nanoparticles based on which they may be termed either as ‘nanoemulsion’ or ‘nanosuspension’. The use of adsorbent for the retention of the nanoparticles helped to impart good flow characteristics and improved stability to the formulation both in terms of drug retention efficiency and drug release profile. 5. Future perspective The present study is a unique technological blend involving the development of colloidal dispersion of lipid and the adsorption of colloidal particles on an adsorbent which together helps to impart additional features to the existing conventional colloidal system. This is an attempt to fabricate a suitable delivery system of solid lipid nanoparticles using a pharmaceutically acceptable and free flowing excipient for oral use which can be easily manufactured and administered, and can remain stable for longer period of time. The relatively high stability of the product upon storage has already been demonstrated in the study. In addition, the free flowing characteristic of the powder can help in its easy filling into capsules which can be handy to patients for oral administration as compared to liquid formulations. At the same time the patients would be able to utilize the benefit of solid lipid nanoparticles devoid of surfactants which is otherwise an essential part of the nanodispersion and may disturb the integrity of the gastrointestinal mucosa. This technology of obtaining a dry nanoparticulate drug product would be cost effective and productive as compared to the exist-

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ing technique of lyophilization. Though the free flowing powder can also be compressed into tablets along with other necessary directly compressible excipients, the integrity of the ALN after compression needs to be considered. Although the data presented in this work is applicable to carvedilol phosphate we hope that the present investigation will assist pharmaceutical researchers to select suitable stabilizers and adsorbents to develop oral formulations of ALN of other drugs as well. Acknowledgment The first author gratefully acknowledges the financial assistance provided by Indian Council of Medical Research, New Delhi, India, in the form of Senior Research Fellowship to support this research work. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19]

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