Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1995-09-29
1998-08-04
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424489, 424405, 424406, 424409, 47 485, A61K 916, A61K 950
Patent
active
057889910
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/00881 filed Mar. 21, 1994 .
The present invention relates to agglomerates of coated biologically active microparticles, a process for preparing such agglomerates and a method of using these agglomerates in sustained-release formulations.
Encapsulation techniques are known and described, for example, in U.S. Pat. No. 4,938,797. The processes known to coat solid particulate active substances suffer from a number of disadvantages: due to the irregular geometry of particulate matter, coating is usually incomplete and the user risks skin-contact with the active substance. Furthermore, the problems of non-linear and/or incomplete release include environmental damage due to residual active substance, and unpredictable efficacy rates.
Microencapsulated agricultural chemicals are described in published PCT application WO 91/04661. Microencapsulation by curing of a prepolymer may be accomplished in a single stage or in repeated stages. The polymer layers form a homogeneous coating which is a mono-coating since the repeated stages are carried out in the same reaction mixture by adding fresh hardener and/or prepolymer. The rate of release is rapid to begin with, but falls after an initial burst.
In EP patent application 0 079668 A1 granules are described comprising the pesticide in a solid core, such core then being coated with at least one layer of a particular membrane selected from the group of dienes and an unsatturated fatty acid radical. The application of plural layers is also described each layer increasing the thickness of the coating, but no discrete phase boundary being formed between each layer.
Minute encapsulated clusters of capsules are described in U.S. Pat. No. 3,041,289. A coacervation process is used to prepare the encapsulated clusters in which coating layers are deposited under changing pH conditions. A multiple component system is present in which micro-emulsions are used.
It is further known that the coating of microparticles using low-speed stirring results in the formation of agglomerates where the microparticles adhere together through the polymer coating. These agglomerates show undesirable release properties because a complete coating cannot be achieved.
There is a need for a more efficient and predictable sustained-release delivery system for biologically active substances. A particular need is found in agriculture where the release characteristics of granular pesticide delivery systems tend to comprise a strong initial burst, followed by an ever-diminishing rate of release of the active substance. A constant rate of release can be illustrated graphically by a linear relationship between time and the amount of active substance released.
Surprisingly it has now been found that much-improved sustained release rates of active substance can be achieved with agglomerates of microparticulate biologically active substances, the microparticles being coated by a polymeric material and the agglomerate being formed of a cluster of coated particles which is itself coated by the same polymeric material. There exist discrete phase boundaries between the particles and their coating layers, between the individual coating layers, and between the outer envelope layer(s) around the cluster and the particle coatings. It has been found that in this way, high initial release rates observed in the prior art can be suppressed. This is especially useful when the active substance is a pesticide. Moreover handling safety is improved, and a reduced amount of coating material is achieved while effecting complete coating.
One object of the invention, therefore, is to provide encapsulated biologically active solid microparticle agglomerates, each agglomerate comprising either
I coated partially or completely by at least one discrete layer of a polymer, and envelops the coated microparticles to form an agglomerate of closely associated microparticles, or
II microparticle being coated partially or completely by at least one layer of a polymer, the microparticles adhering together thro
REFERENCES:
patent: 3041289 (1962-06-01), Katchen et al.
patent: 4891172 (1990-01-01), Matsushita et al.
patent: 4938797 (1990-07-01), Hasslin et al.
patent: 5335449 (1994-08-01), Beatty
Chemical Abst. 107:213619y, Dietrich et al., p. 224, (1987).
Leonhardt Andreas
Nastke Rudolf
Neuenschwander Ernst
Benston, Jr. William E.
Mathias Marla J.
Novartis Corporation
Page Thurman K.
Teoli, Jr. William A.
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