Technical Notes On Nano Suspension - (Pharmacy Minor Project Report) Part 3
Bio pharmaceutical aspects:The ability of lipids and/or food to enhance the bio availability of poorly water‐soluble drugs has been comprehensively reviewed andthe interested reader is directed to these references for further details. Although incompletely understood, the currently accepted view is that lipids may enhance bio availability via a number of potential mechanisms, including.
a.Alterations (reduction) in gastric transit
Thereby slow delivery to the absorption site and increasing the time available for dissolution.
b.Increase in effective luminal drug solubility
The presenceof lipids in the GI tract stimulates an increase in the secretion of bile salts (BS) and endogenous biliary lipids including phospholipid (PL) and cholesterol (CH), leading to the formation of BS/PL/CH intestinal mixed micelles and an increase in the solubilization capacity of the GI tract. However,inter calation of administered (exogenous) lipids into these BS structures either directly (if sufficiently polar), or secondary to digestion, leads to swelling of the micellar structures and a further increase in solubilization capacity.
c.Stimulation of intestinal lymphatic transport
For high lylipophilic drugs, lipids may enhance the extent of lymphatic transport and
increase bio availability directly or indirectly via reduction in first‐pass metabolism.
d. Changes in the biochemical barrier function of the GI tract
It is clear that certain lipids and surfactants may attenuate the activity of intestinal efflux transporters, as indicated by the pglycoproteinefflux pump, and may also reduce the extent Of enterocyte‐based metabolism.
e.Changes in the physical barrier function of the GI tract
Various combinations of lipids, lipid digestion products and surfactants have been shown
to have permeability enhancing properties. For the most part, however, passive
in test inalpermeability is not thought to be a major barrier to the bio availability of the
poorly water‐soluble, and In particular, lipophilic drugs.
f. Effect of oils on the absorption
Such formulations form afine oil‐in‐water emulsion with gentile agitation, which may be provided by gastrointestinal motility. A SES also improves the reproducibility of the plasma level–time profile. Various physiological mechanisms have been proposed to explain thee effect of oils on the absorption of water‐insoluble compounds,including altered gastrointestinal motility, increased bile flowand drug solubilization, increased mucosal permeability,enhanced mesenteric lymph flow, and increased lymphaticabsorption of water insoluble drugs and bio availability also increased of hydrophobic compound.
Characterization of Self-Emulsifying:-
Drug Delivery Systems
The efficiency of self-emulsification could beestimated by visual assessment, turbiditymeasurements, droplet-size distribution andrate of emulsification,
Visual assessment
This may offer vital information regarding the self-emulsifying and microemulsifyingproperty of the mixture and the resulting Zeta potential measurement Dispersion.
Turbidity measurement
This may recognize a capable self emulsificationby establishing whether the dispersion
reaches equilibrium rapidly and ina reproducible time.
Droplet size
This is a critical factor in self-emulsification process, since it determines the rate and extent
of drug release as well as the stability of the emulsion. Photon correlation spectroscopy,microscopic techniques or a Coulter Nano sizerare mainly used for the determination of the emuls
ion droplet size. The reduction in droplet size to the values below 50μm leads to the formation of SMEDDSs, which are stable,isotropic and clear o/w dispersion This is used to identify the charge of the droplets. In conventional SEDDSs, the charge on an oil droplet is negative due to the presence of free fatty acids.
Determination of emulsification time
Self-emulsification time, dispersibility,appearance and flow ability were observed and scored according to techniques describe din H. Shen et al. Used for the grading of formulations.
Cryo- Transmission Electron Microscopy (TEM) studies:
For these studies, samples were prepared in a controlled environment confirmation system.
In this study we have to get thin liquid film on the grid, by placing small amount of sample
on a carbon paper, which is supported by a filter paper. Thereafter this grid is quenched in
liquid ethane at - 180oc and transferred to liquid nitrogen at -196oC. Then the samples were characterized with a TEM microscope. studies in the absence of agitation to replicated GI conditions. In this study one dosage form for example tablet is enclosed in a transparent
polyethylene film and tied to the bulb of a thermo meter with a thread. And then which placed in a round bottom flask containing 250ml of simulated gastric fluid without pepsin
maintained at 37 ± 180oC.The time taken for
Electron microscopic studies
Freeze-fracture electron microscopy has been used to study surface characteristics of such
dispersed systems. Particle size analysis and low-frequency dielectric spectroscopy have
been used to examine the self-emulsifying properties of a mixture of mono- and diglycerides of capric and caprylic acids, and Tween 80 systems.
Small-angle neutron scattering
Small-angle neutron scattering can be used to obtain information on the size and shape of
the droplets. This study uses the interference effect of wavelengths scattered from different
materials in a sample (different scattering length densities).
Small-angle X-ray scattering
This small-angle scattering technique gives the information about shape and size of macromolecules, characteristic distances of partially ordered materials, pore sizes and other data. By this technique we get structural information of macromolecules between 5 and 25 nm, of repeat distances in partially ordered systems of up to 150 nm.In addition to these techniqques, others – such as nuclear magnetic resonance and differential scanning colorimetry – have also been exploited to characterize these self-emulsifying systems for a enhanced approaching.
EVALUATION
Thermodynamic stability studies
The physical stability of a lipid basedformulation is furthermore essential to itsperformance, which can be inauspiciouslyaffected by precipitation of the drug in theexcipient matrix. In addition, the formulationhaving poor physical stability can affects theformulation performance, and visualappearance is not satisfactory, and it also leadto phase separation of the excipient.
Heating cooling cycle
There are six cycles between the temperatures40C and 450C. In between these temperatures
the formulation to be stored and storage ateach temperature is not less than 48 h isstudied. The formulations, which are stablehere, are then subjected to centrifugation test.
Centrifugation
Those formulations are stable above arecentrifuged thaw cycles between 210C and +250C.
And the storage time at eachtemperature is not less than 48 h, and iscarryout at 3500rpm for 30 min. Ifformulations that are stable here, that means they does not show any phase separati
on, thenthey are transferred for the freeze thaw stresstest.
Freeze thaw test
Three freeze for the formulations. Thoseformulations passed this test showed good
stabilitywith no phase separation, creaming, orcracking.
Dispersibility test
The effectiveness of self-emulsification of oralnano or micro emulsion is assessed by using a
standard USP XXII dissolution apparatus 2.One milliliter of each formulation was addedto 500 mL of water at 37+/- 0.5o c, at 50rpm.The in vitro performances of the formulations
are visually assessed by using the followinggrading system:
Grade A: Rapidly forming (within 1 min)nanoemulsion, having a clear or bluish
Appearance.
Grade B: Rapidly forming, slightly less clearemulsion, having a bluish white appearance.
Grade C: Fine milky emulsions that wereformed within 2 min.
Grade D: Dull, grayish white emulsion havingslightly oily appearance that is slow toemulsify (longer than 2min).
Grade E: Formulation, exhibiting either pooror minimal emulsification with large oil
globules present on the surface.
Turbidimetric Evaluation
Nepheloturbidimetric evaluation is made to observe the growth of emulsification. Fixed
amount of Self emulsifying system is added t suitable medium (0.1N hydrochloric acid) under continuous stirring (50 rpm) onmagnetic plate at ambient temperature, and the increase in turbidity is measured using a turbidimeter. However, since the time required for complete emulsification is too short, it is not possible to monitor the rate of change of turbidity (rate of emulsification)15.
Viscosity Determination
The SEDD system is generally administered insoft gelatin or hard gelatin capsules. So, it can
be easily pourable into capsules and suchsystem should not too thick to create a
problem. The rheological properties of themicro emulsion are evaluated by Brookfield
viscometer. This viscosities determinationconform whether the system is w/o or o/w. If
system has low viscosity then it is o/w type ofthe system and if high viscosities then it are
w/o type of the system.
Droplet Size Analysis Particle Size Measurements
The photon correlation spectroscopy techniquewas used to measure the droplet size of the
emulsions. In which the light scattering wasmonitored at 25o c at a 90o angle, after external
standardization with spherical polystyrenebeads. It analyses the fluctuations in light
scattering due to Brownian motion of theparticles.This was done by using a Zetasizerwhich measures the sizes between range of 10and 5000 nm.
Refractive Index and Percent Transmittance
Refractive index and percent tranmittanceproved the transparency of formulation. The
refractive index of the system is measured byrefractometer by placing drop of solution on
slide and it compare with water. The percenttransmittance of the system is measured at
particular wavelength using UVspectrophotometerkeeping distilled water asblank. If refractive index of system issimilar to the refractive index of water(1.333)and formulation have percent transmittance >99 percent, then formulation have transparentnature.
Approaches of Self-Emulsifying DrugDelivery System
Super saturable self-emulsifying drug delivery system
Mainly the Supersaturable SEDDS (S-SEDDS)formulations have been designed and
developed to reduce the surfactant effects, SES into free-flowing powder materials which
has adsorption capacity and mixes themuniformly using a blender. This mixture is solidified to powder forms using three kinds of adsorbents: microporous calcium silicate(Florite™ RE), magnesium aluminum silicate(Neusilin™ US2) and silicon dioxide(Sylysia™ 320). After then this powder mixture is filled into capsule or added to more ingredients before compression into tablets.
Spray drying
In this technique, the formulation (which contains oil, surfactant, drug, solid carrier,etc.,) is sprayed into a drying chamber through a nozzle. The volatile vehicles are evaporated and leaving the small solid particles. These particles are then filled into capsules or compressed
into tablets.
Melt extrusion
This formulation technique depends on the property of the plastic mass material which can be easily extruded with pressure. Here, the powder agglomeration is achieved through the addition of a binder that melts at low temperature. It is a one-step process, there is no need for addition of liquid form of excipient but a constant temperature and pressure needs to be maintained12
Dosage Forms From Self-Emulsifying System:
Self-emulsifying capsule
It is a capsule containing liquid or semi solid form of SES. In the GIT, the capsules get disprrs
ed to SES uniformly in the fluid to micron size, enhancing the bio availability.Second type
of self-emulsifying capsule is solid SES filled into capsule.
Self-emulsifying beads
SES can be formulated as a solid dosage form by using less solidifying excipient. Patil and
Paradkar discovered that deposition of SESinto micro porous polystyrene beads was done
by solvent evaporation. Porous poly styrenebeads (PPB) with complex internal void structure
s were typically produced by copolymerizing styrene and divinyl benzene.It is inertand
It is inert and stable over a wide range of pH,temperature and humidity. Geometrical features
such as bead size and porearchitecture of PPB, were found to preside over the loading efficiency and in vitro drugrelease from SES loaded PPB24.
Self-emulsifying implants
SE implants have very much improved efficacy under application of SSEDDS, since they
have short half-life. As an example, 1,3-bis(2 chloroethyl)-1-nitrosourea (carmustine,BCNU) is a chemotherapeutic agent used to treat malignant brain tumors. In order to enhance its stability compared with that released from poly (d,l-lactide-coglycolide)(PLGA) wafer implants, SES was formulated with tributyrin, Cremophor RH 40(polyoxyl40 hydrogenated castor oil) and Labrafil 1944 (polyglycolyzed glyceride). There fore SES increased in vitro half-life ofBCNU up to 130 min compared with 45 min of intact BCNU. Invitro release of BCNU from SEPLGA wafers were extended up to 7days.Such wafers had higher in vitro antitumoractivity and were less prone to hydrolysis than those wafers without of SES38
Self-emulsifying sustained/controlled releasepellets
Serratoni et al. prepared SE controlled-releasepellets by incorporating drugs into SES,
thereby improved their rate of release, andthen by coating pellets with a water-insoluble
polymer that reduces the rate of drug release.To formulate and prepare SEDDS, there were
some basic guidelines are considered: safety,compatibility, drug solubility, efficient
self emulsification efficiency and droplet size, etc.Pellets are multiple unit dosage forms, they
may provide many advantages than conventional solid dosage forms, due to some factors like flexibility of manufacture, reducing intra subject and inter subject variability of plasma
profiles and minimizing GI irritation without lowering drug bio availability. Thus, it
is very interesting to combine the advantages of pellets with those of SEDDS by SE pellets.
They were prepared by extrusion/spheronization and contained two water-insoluble model drugs (methyl and propyl parabens); SES contained monodiglycerides and Polysorbate.
Selfemulsifying sustained releasemicrospheres
Zedoary turmeric oil (ZTO; a traditionalChinese medicine) shows effectivepharmacological actions like tumorsuppressive, antibacterial, and antithromboticactivity. You et al. prepared solid SE sustainedrelease microspheres using the quasiemulsion-Solvent diffusion method of thespherical crystallization technique, in thistechnique ZTO used as oil phase. ZTO releaseactivities might be controlled by the ratio ofhydroxyl propyl methylcellulose acetatesuccinate to Aerosil 200 in the formulation.After oral administration of such microspheres
to rabbits, the plasma concentrations wereachieved with increased bioavailability of135.6% with respect to the conventional liquidSEDDS28.
Self emulsifying suppositories
Some investigators proved that solid-SEDDscould not only increase the GI absorption but
also increase the rectal/vaginal adsorption.Glycyrrhizin, hardly achieves therapeuticplasma concentrations by oral route, but canachieve acceptable therapeutic levels forchronic hepatic diseases by either vaginal orrectal SE suppositories. The formulationincluded glycyrrhizin and a mixture of a C6–C18 fatty acid glycerol ester and a C6–C18fatty acid macrogol ester.
-Reference Taken From Wikipedia.