Comminution of ibuprofen to produce nano-particles for rapid dissolution
Lena Nanoceutics Ltd., Institute of Pharmaceutical Innovation, Bradford BD7 1DP, UK. International Journal of Pharmaceutics
(Impact Factor: 3.65).
06/2011; 415(1-2):307-14. DOI: 10.1016/j.ijpharm.2011.06.002
A critical problem associated with poorly soluble drugs is low and variable bioavailability derived from slow dissolution and erratic absorption. The preparation of nano-formulations has been identified as an approach to enhance the rate and extent of drug absorption for compounds demonstrating limited aqueous solubility. A new technology for the production of nano-particles using high speed, high efficiency processes that can rapidly generate nano-particles with rapid dissolution rate has been developed. Size reduction of a low melting ductile model compound was achieved in periods less than 1h. Particle size reduction of ibuprofen using this methodology resulted in production of crystalline particles with average diameter of approximately 270nm. Physical stability studies showed that the nano-suspension remained homogeneous with slight increases in mean particle size, when stored at room temperature and under refrigerated storage conditions 2-8°C for up to 2 days. Powder containing crystalline drug was prepared by spray-drying ibuprofen nano-suspensions with mannitol dissolved in the aqueous phase. Dissolution studies showed similar release rates for the nano-suspension and powder which were markedly improved compared to a commercially available drug product. Ibuprofen nano-particles could be produced rapidly with smaller sizes achieved at higher suspension concentrations. Particles produced in water with stabilisers demonstrated greatest physical stability, whilst rapid dissolution was observed for the nano-particles isolated in powder form.
Available from: Maria Malamatari
- "slurry viscosity, size of milling beads and milling speed are involved, influencing particle size distribution as a function of time (size reduction rate) but not the steady state particle size of the NPs obtained. The later mainly depends on the intrinsic physicomechanical properties of the drug crystals as brittleness, yield stress, plasticity and elasticity (Lee, 2003; Plakkot et al., 2011). Furthermore, the inability of Pluronic 1 L64 to stabilise the indomethacin nanosuspensions seems to be interesting, especially when compared with the high success rate of Pluronic 1 F68 in stabilising nanosuspensions of indomethacin (Fig. 2) and of other poorly water-soluble drugs (Illum et al., 1987; Karmwar et al., 2012). "
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ABSTRACT: Nanoparticles (NPs) were prepared and assembled to microsized agglomerates with and without matrix formers (mannitol and L- leucine) by coupling wet milling and spray-drying to harmonise the advantages of NPs with handling and aerodynamics of microparticles without induction of amorphisation. Indomethacin was selected as poorly water-soluble drug and poloxamers with different ratios of hydrophilic to hydrophobic domains were evaluated as stabilisers comparatively to D-α- Tocopherol polyethylene-glycol succinate (TPGS). Particle size of nanosuspensions and morphology, size, crystal form, drug loading, redispersibility, in vitro dissolution, and in vitro aerosolisation of NP-agglomerates were determined. Molecular weight of stabilisers affected the rate but not the limit of NP size reduction and the length of hydrophilic segment in poloxamers was found important for the nanosuspension stabilisation. SEM revealed the structure of agglomerates consisting of nanocrystal assemblies. XRPD with DSC proved that NP agglomerates retained their crystallinity. NP-agglomerates exhibited enhanced dissolution compared to physical mixtures of drug and stabilisers while incorporation of matrix formers enabled redispersibility upon hydration and further increased the drug dissolution. Also, matrix formers resulted in significantly improved aerosolisation with higher fine particle fractions (49-62%) and smaller mass median aerodynamic diameters (<3.5μm), compared to cases without matrix formers (34-43% and <4.5μm).
Available from: Stefano Giovagnoli
- "dissolution rate of poorly water-soluble drugs  . Particle size remains one of the key parameters that affects the degradation rate of the PLGA polymer matrix and thereby drug release rates . "
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ABSTRACT: Theaimof this study was to prepare injectable depot formulations ofOlanzapine using four poly(D,L-lactide-co-glycolide) (PLGA)
polymers of varying molecular weight and copolymer composition, and evaluate in vivo performance in rats. In vivo release
profiles from the formulations were governed chiefly by polymer molecular weight and to a lesser extent, copolymer composition.
Formulations A and B, manufactured using low molecular weight PLGA and administered at 10mg/kg dose, released drug within
15 days. Formulation C, prepared from intermediate molecular weight PLGA and administered at 20mg/kg dose, released drug in
30 days, while Formulation D, manufactured using a high molecular weight polymer and administered at 20mg/kg dose, released
drug in 45 days. A simulation of multiple dosing at 7- and 10-day intervals for Formulations A and B revealed that steady state was
achieved within 7–21 days and 10–30 days, respectively. Similarly, simulations at 15-day intervals for Formulations C and D indicated
that steady state levels were reached during days 15–45. Overall, steady state levels for 7-, 10-, or 15-day dosing ranged between 45
and 65 ng/mL for all the formulations, implying that Olanzapine PLGA microspheres can be tailored to treat patients with varying
Available from: Christopher JH Porter
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ABSTRACT: The LFCS Consortium was established to develop standardized in vitro tests for lipid-based formulations (LBFs) and to examine the utility of these tests to probe the fundamental mechanisms that underlie LBF performance. In this publication, the impact of bile salt (sodium taurodeoxycholate, NaTDC) concentration and drug loading on the ability of a range of representative LBFs to generate and sustain drug solubilization and supersaturation during in vitro digestion testing has been explored and a common driver of the potential for drug precipitation identified. Danazol was used as a model poorly water-soluble drug throughout. In general, increasing NaTDC concentrations increased the digestion of the most lipophilic LBFs and promoted lipid (and drug) trafficking from poorly dispersed oil phases to the aqueous colloidal phase (AP(DIGEST)). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations ≥3 mM, NaTDC effects on either digestion or drug solubilization were modest. In contrast, increasing drug load had a marked impact on drug solubilization. For LBFs containing long-chain lipids, drug precipitation was limited even at drug loads approaching saturation in the formulation and concentrations of solubilized drug in AP(DIGEST) increased with increased drug load. For LBFs containing medium-chain lipids, however, significant precipitation was evident, especially at higher drug loads. Across all formulations a remarkably consistent trend emerged such that the likelihood of precipitation was almost entirely dependent on the maximum supersaturation ratio (SR(M)) attained on initiation of digestion. SR(M) defines the supersaturation "pressure" in the system and is calculated from the maximum attainable concentration in the AP(DIGEST) (assuming zero precipitation), divided by the solubility of the drug in the colloidal phases formed post digestion. For LBFs where phase separation of oil phases did not occur, a threshold value for SR(M) was evident, regardless of formulation composition and drug solubilization reduced markedly above SR(M) > 2.5. The threshold SR(M) may prove to be an effective tool in discriminating between LBFs based on performance.
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