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Introduction of Nano Capsules

By: Pharma Tips | Views: 3536 | Date: 12-Jul-2011

Nanocapsules were synthesized in O/W microemulsion by complex coacervation with natural polymer of arabic gum and gelatin.

Abstract:
              Nanocapsules were synthesized in O/W microemulsion by complex coacervation with natural polymer of arabic gum and gelatin. The synthesis conditions of polymeric nanocapsules were analyzed. Transmission electron microscopy (TEM) and photon correlation spectroscopy (PCS) show that sizes of nanocapsules are 30~100 nm with a narrow distribution. The effects of the composition of microemulsion, the concentration of polymer and the condition of complex coacervation on the characteristics of nanocapsules were investigated. The entrapment efficiency of cypermethrin in the nanocapsules manufactured was above 60%. This method is a novel approach to produce polymeric nanocapsules in mild condition.

Poly(ethylcyanoacrylate) (PECA) nanocapsules suitable for use as drug delivery systems were prepared by in situ polymerization, adding the monomer to an organic phase and subsequent mixing of the latter to an aqueous phase containing a nonionic surfactant. Different preparation conditions have been able to influence the final PECA nanocapsule colloidal suspension. In particular, the kind of organic solvent caused the formation of either simple PECA nanocapsule suspensions (aprotic fully water-miscible solvents) or PECA nanoparticle colloidal suspensions consisting of nanospheres and nanocapsules (protic water-miscible solvent). Both mechanisms, the interfacial precipitation of a pre-formed polymer and the interfacial polymerization, could play a significant role in nanocapsule formation. Also other variables, such as the kind of the nonionic surfactant and the monomer concentration, affected in different ways the nanocapsule formation process.
 

Why nanocapsules?
 
Before asking ourselves about the need for nanocapsules we should start with the keynote of drug delivery and drug targeting. The fundamental idea traces back to Paul Ehrlich´s vision of a “magic bullet” which transports the drug directly to the targeted organism bypassing healthy tissue. Although this exceptionally gifted scientist died ninety years ago, his idea is up-to-date. When we combine Ehrlich´s vision with the ideals of our age, the age of nanotechnology, we end up with nano-scaled carriers. Nano-scaled drug delivery systems, or as a synonym, colloidal drug carriers, are only defined by their submicron size. They are made from different materials and include a variety of structures.

A lot of research has been going on during the last two decades to develop adequate drug delivery systems for challenging drug candidates which belong to the classes II and IV of the biopharmaceutical classification system (BCS) [2-4]. There is a need for nano-sized carriers because often the therapeutic goal can not be achieved with micro-sized or even larger drug delivery systems. Regarding i.v. application, poor water solubility of injection candidates and active drug targeting are some of the tasks which can only be solved by colloidal carriers. Especially for the parenteral way of application, nanoparticles are superior to microparticles because they can be administered without any risk of embolia. Furthermore high food dependency or insufficient bioavailability after peroral application can only be circumvented by carriers in the nano-scale.

While intensive research lead to marketed products for microemulsions [5-13] (Sandimmun Optoral™, Neoral™), nanoemulsions [14-21] (Diazepam Lipuro™), mixed micelles [22-24] (Konakion MM™), nanosuspensions [25-30] (Rapamune™), liposomes [31-39] (AmBisome™) and liquid crystalline structures [40-42] (Elyzol™), solid lipid nanoparticles (SLN) [43-46], nanostructured lipid carriers (NLC) [46,47], nanospheres [48,49] and nanocapsules are still in the research state. Nanocapsules are submicroscopic colloidal drug carriers which can morphologically be ranged between nanoemulsions and nanospheres (Figure 1.1). Compared to nanoemulsions, nanocapsules hold a solid shell around the oily core. The core can also be aqueous as it is in the so-called polymersomes which are generated by
vesicular self-assembly of polymers [50,51]. Nanospheres can be distinguished from nanocapsules by their completely solid character.
 
In nanospheres the drug is dispersed within the polymer throughout the particle, in nanoemulsions and nanocapsules the drug is located in the oily moiety which is in the case of nanocapsules surrounded by a polymeric shell.

Preparative separation of nanocapsules from nanoemulsions and nanospheres can be carried out by centrifugation in a density gradient, whereas the density of nanocapsules was found to be intermediate between that of nanospheres and nanoemulsions.

In theory nanocapsules are superior to nanoemulsions because the shell prevents direct contact of the encapsulated drug with the environment. Therefore fast interactions between drug and physiological contents should be minimized and the drug may be better protected from degradation. Also irritation at the side of administration might be reduced. Furthermore the polymeric shell is responsible for the long term stability of the particles (storage). The advantage over nanospheres is a much higher degree of drug load. In physically loaded nanocapsules, the drug to polymer ratio can be as high as 5:1, when the core consists of pure drug, while this ratio is usually around 1:10 for nanospheres [53]. Another advantage is their low polymer content compared to nanospheres. It is also beneficial that a burst effect may be avoided by incorporating the drug in a cavity.

Besides nanoemulsions, nanocapsules compete with lipid-based nanocarriers like SLN and NLC (oil-loaded SLN). Though for both systems nearly 100% incorporation rate, controlled release and protection from the outer environment had been claimed [43,54-57], former [58-60] and recent studies [46] showed fundamental problems within these formulations. For both systems missing protection from the outer environment and low incorporation capacities as well as poor long-term stability (gelation, particle growth) were found. These refuting findings are in accordance with physical laws, e.g. crystalline solid lipids do not tend to incorporate large amounts of foreign molecules or controlled release cannot be achieved when diffusion paths are in the nanometer range. Therefore SLN and NLC are not really competitors to nanocapsules. Concerning peroral application, the incorporation rates are too low and particle growth and platelet shape are a risk for the intravenous route.

When regarding the oral administration of nanocapsules, they can be classified after Pouton [61] as lipid delivery systems, which generally consist of a drug dissolved in a blend of two or more excipients, which may be triglyceride oils, partial glycerides, lipophilic or hydrophilic surfactants or co-surfactants [61]. Lipid formulations are pharmaceutically attractive due to their ability to keep hydrophobic drugs in a dissolved state throughout their transit through the gastrointestinal (GI) tract. Thereby a slow dissolution step is avoided. By presenting the drug as a solubilisate within a colloidal dispersion the availability of the drug for absorption can be enhanced further leading to improved bioavailability. The group of Pouton [62] developed a simple classification system for lipid formulations for oral administration of drugs based on the polarity of the excipients used.

Formulations which comprise drug dissolved in triglyerides and/or mixed glycerides are classified as type I, the so-called non-emulsifying drug delivery systems. Type II systems contain an additional lipophilic surfactant (HLB<12) which promotes emulsification and improves solvent capacity of formulations. These systems are known as self-emulsifying drug delivery systems (SEDDS). In addition to the already mentioned excipients, type III systems include water-soluble components (hydrophilic surfactants with a HLB>11 and/or water-soluble co-solvents as propylene glycol, poly(ethylene glycol) or ethanol. Type IIIb can be distinguished from type IIIa by its very hydrophilic properties. Due to very small particle sizes of the resulting dispersions type III systems are named “self-microemulsifying drug delivery systems”, with Neoral™ being a prominent representative. Depending on the different types of lipid formulations, aqueous dilution and digestion have significant influence on the bioavailability of incorporated drugs. In general the highly lipophilic formulations are dependent on digestibility whereas the highly hydrophilic “lipid” formulations are sensitive to dilution.

From the viewpoint of composition, nanocapsules, which comprise an oily core composed of triglycerides, can be classified as a type I lipid system. Taking fat digestion into consideration, the polymer shell of nanocapsules might partly protect the oily core before digestion. This might lead to an uptake of entire nanocapsules from the GI tract. Although this happens to a certain extent, the availability of the majority of encapsulated drug will depend on digestion, which again follows type I in the lipid classification system. On the other hand nanocapsule dispersions have mean particle sizes of approximately 200 nm which are typical for type II or III. Therefore nanocapsules can not clearly be classified by Pouton´s system.

Parenteral application of nanocapsules aims at the active targeting to specific cells within the vasculature. In the future this goal might be achieved by tailored modification of the polymer shell.

Most of the literature concerning nanocapsules deals with oil-containing nanocapsules but nanocapsules with aqueous cores are published as well [63]. The first oil-containing nanocapsules, prepared in 1986, were proposed as a new type of vesicular colloidal polymeric drug carrier [64]. They were prepared by interfacial polymerisation of alkylcyanoacrylate [65]. The disadvantage of this method is the probable presence of residual, potentially toxic monomers or oligomers.

Two years later, in 1988, Fessi et al. [66,67] presented a novel procedure for the preparation of biodegradable and excretible nanocapsules by interfacial deposition of a preformed polymer following solvent displacement.

Due to its simplicity and robustness this method has been applied by several groups for the encapsulation of lipophilic substances [68-70] making use of biodegradable polymers such as poly(D,L-lactide) [67,70], poly(D,L-lactide-co-glycolide) [71,72], poly(-caprolactone) [73,74] and poly(ethyleneglycol) surface-modified poly(D,L-lactide) [75]. In 1998 Quintanar-Guerrero et al. [52] presented a new process for the preparation of nanocapsules based on an emulsification-diffusion technique.
 
Another approach is the inversion-based process for the preparation of lipid nanocarriers [76-79] though it is the question if lecithin stabilized oil droplets should be termed nanocapsule or nanoemulsion. A new type of designer capsule prepared via layer-by-layer self-assembly of oppositely charged polyelectrolytes [80-82] was introduced by Möhwald’s group and will be discussed in detail in chapter 3.

Approaches to tune the permeability of polymer shells to achieve controlled release have not been successful for nanocapsules produced by polymer deposition so far. Moreover it is claimed that the rate of diffusion of the drug through the thin polymeric barrier does not seem to be a limiting factor, nor does the nature of the polymeric wall [83]. Benoit and his group [77] have shown sustained release properties for amiodarone from lipid nanocapsules produced by the inversion-based process. Antipov [84] summarized how permeability of polyelectrolyte multilayer capsules can be tuned leading to controlled release. Though it is out of the question that release from 18-layered capsules within 10 minutes can be called delayed release. Xing et al. [85] recently published sustained release of capsaicin from polyelectrolyte nanocapsules prepared by complex coazervation of gelatine, acacia and tannin.

Research    also    focused    on    stimuli-responsive    capsules.Thermosensitive nanocapsules based on poly(N-isopropyl acrylamide) have been described recently [86]. Möhwald´s group [80] and Sauer et al. [87] published pH-sensitive nanocapsules based on polyelectrolytes.

After systemic administration, conventional nanoparticles are rapidly opsonized and cleared by macrophages of the mononuclear phagocytes system (MPS) leading to higher concentrations of the encapsulated drug in liver, spleen and lung [88,89].

To overcome the recognition of nanocapsules by the mononuclear phagocyte system (MPS) Barratt´s group [75] developed “Stealth” nanocapsules which are “invisible” to macrophages. This was achieved with surface-modified  anocapsules
from poly(D,L-lactide-)-poly(ethylene glycol) diblock copolymers which provide a “cloud” of hydrophilic chains at the particle surface and thereby prevent opsonization and recognition by macrophages.

Mosqueira et al.showed that covalently attached PEG chains can substantially reduce nanocapsule clearance from the blood compartment after i.v. administration and alter their biodistribution in mice.Active targeting [90], where ligand decoration of nanocarriers allows targeting to specific cells within the vasculature, has not yet been successfully established for nanocapsules. Though for nanospheres it was shown that folate-conjugation of the carriers led to selective targeting towards cancer cells which overexpress folate receptors on their surface [91,92]. The idea of functionalized nanocapsule surfaces is patented by Weber et al. [93]. Integrins as ligands for gastrointestinal, renal, biliary and pulmonary targeting are suggested.
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srivithya  |  06-Mar-2012 18:16:23 IST
where can i get the references mentioned in above paragraphs? CAN ANY ONE PROVIDE ME IF U GET?
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