Microcapsules, method of making and their use

Details Microcapsules, method of making and their use Microcapsules, method of making and their use

1995-11-08

2001-12-25

Hartley, Michael G. (Department: 1619)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

Ultrasound contrast agent

Reexamination Certificate

active

06333021

ABSTRACT:

TECHNICAL FIELD
The invention relates to microcapsules with a mean size from a fraction of micrometer to 1000 micrometers having a biodegradable membrane encapsulating air or gas filled core. The microcapsules disclosed may be non-coalescent, dry and instantly dispersible. The invention concerns a method of making the microcapsules and their use for delivery of therapeutically and/or diagnostically active substances. When in suspension in a physiologically acceptable carrier the microcapsules are useful as delivery vehicles for therapeutically active agents and/or as contrast agents for echographic imaging of organs of human or animal body. The invention also concerns a method of making ultrasound contrast agents using the microcapsules.
BACKGROUND ART
Recognition of the advantages obtained by the targeting and/or the controlled release delivery of therapeutic and diagnostic agents has inspired a lot of research and development of a variety of carrier systems. These range from a general purpose controlled or sustained release systems to systems which are specifically designed to suit a particular application. Depending on the type and nature of the active substance involved, numerous systems for the delivery of antibiotics, vitamins, proteins, etc. have been developed. A number of different carrier materials, from alginate or agar beads and phospholipid coatings or liposomes to very sophisticated polymeric materials, are known or currently in use for the encapsulation of active substances. However, many of the known systems are either too specific, i.e. dedicated to a single substance or at most to a single class of substances, and therefore are of little help when different active substances are considered. Being specifically chosen to carry a specific substance, many of the known delivery vehicles do not provide sufficient flexibility in modifying their release characteristics or biodegradability. Any changes of the nature of the carrier and/or the active to inactive ingredient ratio inevitably requires additional experimentation.
Furthermore, systems known so far do not lend themselves to the production of floating microparticles or floating tablets which can carry different active ingredients. They neither provide for convenient coupling of different functions or incorporation of different active substances within the same microcapsule, such as for example incorporation of a therapeutically active ingredient in the outer encapsulating membrane and a diagnostically active ingredient in the core; nor do they provide of-the-shelf biodegradable microcapsules which could be filled at convenience with a suitable medication in a suitable amount.
EP-A-0 458 745 (Sintetica) discloses air- or gas-filled microballoons bound by an interfacially deposited biodegradable membrane. These microballoons are usable as very efficient sound reflectors in the echographic imaging of body cavities and the blood stream. For preparing the microballoons, a filmogenic polymer is dissolved in a mixture of volatile organic solvents and the resulting organic solution mixed with an aqueous carrier phase to produce an oil-in-water emulsion. The emulsion is then treated, for instance by evaporation or insolubilization, such that the polymer precipitates and deposits to form a membrane at the droplet water/solution boundary. The organic solvent in the microballoons is eventually evacuated and, by lyophilising the suspension, the solvent in the microballoons is replaced by air or a gas. In order to increase their hydrophobicity the microballoons made from biodegradable polymers may contain up to 20% of fats, waxes and high molecular weight hydrocarbons.
U.S. Pat. No. 4,684,479 (D'Arrigo) discloses stabilised bubble suspensions, useful for ultrasound echographic measurements for different applications including echocardiography. The suspensions are formed by vigorously shaking in the presence of air (foaming) mixtures of surfactants with water or mineral oil. The mixtures of surfactants include (a) fatty acid monoglycerides, (b) esters of aromatic acids (like benzoic, phenylacetic, phthalic, salicylic acids, etc.) with sterols (like cholesterol, ergosterol, lanosterol, phytosterol, etc.), (c) a component from the group consisting of sterols, terpenes, bile acids and alkali metal salts of bile acids; and, optionally, (d) sterol esters of aliphatic acids, and (e) a member of the group consisting of glycerol and di- and triglycerides (e.g. dilaurin, trilaurin, dipalmitin, tripalmitin, distearin, tristearin, dimyristin, trimyristin, and the like).
WO-A-93/02712 (Danbiosyst) discloses solid microspheres or hollow (gas or vapour filled) amylodextrin microcapsules prepared by forming a shell from a water soluble starch derivative around a solid or liquid core and subsequently removing the core. The core may be a volatile oil such as perfluorohexane. The microcapsules may be made by an oil-water-oil double emulsion followed by chemical or heat hardening. The microcapsules can be used for echocardiography.
SUMMARY OF THE INVENTION
Briefly summarised, the invention relates to a solid microcapsule with a mean size from a fraction of micrometer to 1000 micrometers (1 mm) having a biodegradable lipidic membrane encapsulating air or gas core. The lipidic membrane comprises one or more biodegradable water insoluble, at room temperature solid, lipids or a mixture of biodegradable water insoluble lipids selected from mono-, di- or triglycerides, fatty acids, fatty acid esters, sterols, waxes and mixtures thereof. Mono-, di-, tri-myristin, -palmitin and -stearin are particularly useful, however, tripalmitin and tristearin are preferred. Non-coalescent, dry and instantly dispersible, the microcapsules when in suspension in a physiologically acceptable carrier are useful as delivery vesicles for therapeutically active substances and/or as ultrasound contrast agents. Optionally, the lipidic membrane may contain up to 75% by weight of biodegradable polymers.
Injectable compositions comprising a suspension of an effective amount of microcapsules of the invention in a pharmaceutically acceptable liquid carrier with usual additives and stabilisers useful as therapeutic and/or contrast agents are also disclosed.
The microcapsules of the invention are made by making a oil-in-water emulsion from an organic solution comprising, dissolved, a mono-, di-, tri-glyceride or a mixture thereof and an aqueous solution optionally containing a surfactant; optionally evaporating a part of the solvent, adding a redispersing agent and freezing the mixture obtained. The frozen mixture is then lyophilised to produce quasi-spherical or spherical microcapsules.
A method of making an ultrasound contrast agent by suspending the microcapsules (microballoons) in a physiologically acceptable carrier phase is also disclosed.


REFERENCES:
patent: 5215680 (1993-06-01), D'Arrigo
patent: 5498421 (1996-03-01), Grinstaff et al.
patent: 5542935 (1996-08-01), Unger et al.
patent: 0 458 745 A1 (1991-11-01), None
patent: 0 467 031 A3 (1992-01-01), None
patent: 0 535 387 A1 (1993-04-01), None

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