Dried Formulations of Nanoparticle-Coated Capsules

Abstract

A method of producing a dried formulation for an active substance such as a drug compound is described. The method involves dispersing a discontinuous phase (e.g. an oil-based or lipidic medium) comprising the active substance into a continuous phase (e.g. water) so as to form a two-phase liquid system comprising droplets of said discontinuous phase, allowing nanoparticles to congregate at the phase interface at the surface of the droplets such that at least one layer of nanoparticles coat the droplets and thereby provide sufficient structural integrity to the droplets to enable the subsequent removal of the continuous phase, and thereafter removing the continuous phase from the nanoparticle-coated droplets to produce a dried formulation.

Description

FIELD OF THE INVENTION[0001]The present invention relates to the encapsulation by nanoparticles of a liquid droplet or a lipid vesicle to form a stable capsule.BACKGROUND OF THE INVENTION[0002]The development of new forms of active substances such as drug compounds and pesticides, as well as a desire to increase the efficacy of existing substances, has created a need to develop new and effective ways of delivering substances to their appropriate targets. It is likely that many potentially useful active substances have not been commercialised because of inadequate formulation. In many cases, the inability to formulate the active substance into a deliverable form could simply be due to solubility problems.[0003]Although useful as vehicles for the delivery of active substances, most emulsions and liposomes are limited by the fact they are thermodynamically unstable and, generally, over time, will coalesce and may eventually separate into two distinct liquid phases (emulsions) or will d...

AI Technical Summary

Benefits of technology

[0030]In a further variation, the discontinuous phase may, optionally, be cross-linked or otherwise comprise a gelling material so as to form a matrix. While re-dispersed capsules from dried formulations produced in accordance with the present invention are permeable (i.e. the nanoparticle coating will be porous), and thereby typically show controlled release of the active substance at rates dependent upon the degree of permeability (e.g. a capsule with a lower degree of permeability (i.e. a “semi-permeable” capsule), will show sustained release of the active substance), the inclusion of a cross-linked or gelled matrix within the discontinuous phase can be used to provide further control to the release of the active substance from the capsules, particularly sustained release.

[0043]The present invention provides a method for producing dried formulations of nanoparticle-coated capsules comprising a drug compound. An advantage of such formulations is that the dried capsules (e.g. in the form of a dry powder), have a long shelf life and do not exhibit substantial leaching of the drug compound over times that drug formulations are commonly stored (e.g. 1 to 9 months). In addition, the capsules have a low propensity to coalescence. The dried capsules can be readily re-dispersed into a liquid to re-form a stable emulsion, thereby providing a useful drug formulation for the pharmaceutical industry. The capsules can be readily stored and / or transported dry.

[0045]The ability to protect the active substances from the degradative effects of acidity, makes the dried formulation of the present invention particularly useful in the oral administration of labile drug compounds (i.e. where it is desirable that the drug compound be protected from the high acidity of the stomach before reaching the small intestine where the drug compound may be adsorbed into the bloodstream).

[0048]In one preferred embodiment of the formulation of the further aspect, the capsules are provided with a polymer layer around the periphery to modify the interfacial properties of the capsule. In this way, the capsules may be made to be “lipoadhesive”, particularly if the polymer layer has adhesive properties with lipid-like surfaces. One significant aspect of this is that the capsules can be then be engineered to adhere to particular sites in vivo (e.g. mucoadhesive polymer layers facilitate adhesion to mucous membranes), thereby ensuring long contact times and effective transport of the active substance. This can be particularly useful for the delivery of poorly soluble drug compounds to various parts of the gastrointestinal tract (i.e. to improve bioavailability). It may also be used to facilitate delivery of an active substance to the mouth.

Problems solved by technology

It is likely that many potentially useful active substances have not been commercialised because of inadequate formulation.

In many cases, the inability to formulate the active substance into a deliverable form could simply be due to solubility problems.

Although useful as vehicles for the delivery of active substances, most emulsions and liposomes are limited by the fact they are thermodynamically unstable and, generally, over time, will coalesce and may eventually separate into two distinct liquid phases (emulsions) or will degrade and release the fluid-filled core into the surrounding media (liposomes).

This instability is exacerbated in veterinary and pharmacological applications since the vehicles are used under circumstances (e.g. increased salt (electrolyte) or variations in pH) which put a severe strain on the vehicle structure.

The degradation of vehicles containing active substances is undesirable since considerable time and effort is spent in formulating the delivery system.

In the veterinary, pharmaceutical and nutriceutical industries in particular, if vehicle stability is compromised, the bioavailability of the active substance may be affected.

Particle stabilised emulsions are known, however, the stability of the resulting capsules remains poor over a period of time.

This means that it is difficult to transport the capsules over long distances and it is difficult to store the capsules for a delayed time of use.

Leaching or uncontrolled release of active substances can pose a serious problem in the delivery of certain drugs in the body, since one intent of the encapsulation process is to shield healthy cells from the drug's toxicity and prevent the drug from concentrating in vulnerable tissues (e.g. the kidneys and liver).

These liquid formulations usually have a low active substance content to liquid ratio and, in addition, during storage or transport, there is a risk of microbial growth in the liquid which can cause serious infections or spoilage.

A further problem is coalescence of the capsules to form capsules with an increased diameter.

Larger capsules are less stable over time, and larger capsules cannot be delivered to some areas where the diameter of the capsule will not be permitted (e.g. capillaries in the body).

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