Zero order release and temperature-controlled microcapsules...

Stock material or miscellaneous articles – Coated or structually defined flake – particle – cell – strand,... – Particulate matter

Reexamination Certificate

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C264S004300, C264S004320, C264S004400, C264S007000, C264S013000, C428S403000

Reexamination Certificate




The present invention relates to micro-encapsulation, and more particularly to the micro-encapsulation of core materials that release the encapsulated core contents into its environment in a controlled manner. The microcapsules of the present invention are useful for example in the pharmaceutical, nutriceutical, food, cosmetics and agricultural industries.
Microcapsules have many applications, such as in the manufacture of pharmaceuticals, herbicides, foods, cosmetics, pesticides, paints, adhesives, and many other chemical products. Microcapsules are especially useful where it is desired to provide a controlled release of the substance being encapsulated.
Various processes for forming microcapsules are described in the references: Vandegaer, “Microencapsulation Processes and Applications”, Plenum Press, New York, 1974, M. Gutcho, “Microcapsules and other Capsules”, Chemical Technology Review, No. 135, Noyles Data Service, Park Ridge, N.J. 1979, and the Kirk-Othmer Encyclopedia of Chemical Technology, 3rd Edition (1981), volume 15. The above-mentioned references describe several liquid-phase methods of encapsulation. These methods include coacervation, thermal coacervation, complex coacervation, interfacial polymerization, and others. In the process of coacervation, the core and shell materials are mixed together in a liquid medium. When the core and shell materials have been agitated for a sufficient period of time, portions of the core material become coated with shell material, thus forming capsules within the liquid medium. The size of these capsules is controlled by the speed and design of the mixing element within the vessel. A further chemical treatment process adjusts the thickness of the shell material.
Microcapsules used in industry must be capable of withstanding large shear forces, or other stressful conditions, when the capsules are added to a host material. Suitable host materials could be paints, plastics, foam products, building materials, paper products and others. Each host material requires varying conditions of heat and stress to produce the final product, and the capsules must have suitable physical properties to enable the capsules to be used during the manufacture of the final product. Capsules used in industry must generally be very small.
There are special problems in the development of sustained release compositions, and particularly zero order release compositions, of environmentally sensitive materials or biologically active macromolecules due to the susceptibility to chemical and structural alteration or reaction upon mixing with excipients, upon processing and upon storage. These problems are understood by those skilled in the art of pharmaceutical formulation and can be categorized as problems of chemical stability. Inadequate chemical stability of compositions resulting from irreversible alteration of the structure of the core and/or interactions with the excipients can result in compositions that are either inactive or do not provide the desired function.
Another category of problems for pharmaceutical formulations is physical stability. One obvious example is attrition of tablets or implants during processing, packaging, or storage. Another example is a physical separation of a cream, paste or gel into component parts, which can lead to a heterogeneous distribution of active ingredient as well as alteration of the consistency. The consequence of such physical deterioration of the formulation can be loss of the desired ease of use characteristics and an unpredictable dosing to the patient. Less obvious physical changes in a pharmaceutical formulation include various alterations to the crystalline or microscopic structure of the excipients. These types of changes can lead to marked alterations in the release of active agents. It should be clear that changes in the physical stability of pharmaceutical dosage forms whether they are for oral or parenteral administration would be most problematic for sustained release preparations. It is the sine qua non of commercially viable sustained release pharmaceutical dosage forms that they have maintained release characteristics across production lots and after relatively long periods of time in storage. Physical stability of the pharmaceutical dosage form is intended to describe both constancy of the handling characteristics such as hardness, flowability, or viscosity, and constancy of pharmacological performance.
The present invention provides a specific dual mechanism release profile microcapsule and a method for its preparation.
Microencapsulation technology has long been used for the controlled delivery of pharmaceuticals. As early as 1964 aspirin was encapsulated in ethylcellulose (U.S. Pat. No. 3,155,590) with improvements made to the basic process (U.S. Pat. No. 3,341,416). Microencapsulation has also been used to deliver potassium salts to humans (U.S. Pat. No. 4,259,315).
Other drugs have also been microencapsulated using a variety of methods. For example, U.S. Pat. No. 4,938,967 discloses microcapsules with a higher than usual density by including a weighting agent, such as barium sulphate, to increase the residence time in the stomach. U.S. Pat. No. 4,574,080 discloses a controlled release formulation that contains additional particles of the active substance adhered to the surface of the coating. U.S. Pat. No. 4,606,940 discloses a process for encapsulation by dissolving the compound to be encapsulated in a solvent, mixing the solution with a solution of encapsulating material and electrolyte, and gelling the encapsulating material.
One of the primary reasons for encapsulating a drug is to slow the release of the drug into the body. Thus, a controlled release microencapsulated formula may be substituted for several non-microencapsulated doses. The release rate of the drug is typically controlled primarily through the thickness of the coating. Typically the release pattern is first order in which the rate decreases exponentially with time until the drug is exhausted (Kirk-Othmer, Encyclopedia of Chemical Technology, p.485, 1981). This release pattern is due to the concentration difference between that inside and that outside the capsule which difference decreases continuously during dissolution.
Exemplary sustained release microcapsules include those described in the following patents:
U.S. Pat. No. 4,837,381 discloses a microsphere composition of fat or wax or mixture thereof and a biologically active protein, peptide or polypeptide suitable for parenteral administration. The patent discloses the utility of the compositions for slow release of a protein, peptide or polypeptde in a parenteral administration, and discloses methods for increasing and maintaining increased levels of growth hormone in the blood of treated animals for extended periods of time and thereby increasing weight gains in animals and increasing milk production of lactating animals by the administration of compositions of the invention.
U.S. Pat. No. 5,213,810 discloses water insoluble fat or wax microspheres containing biologically active protein, peptides or polypeptides wherein the fat or wax shell includes an oil, semi-soft fat or fatty acid derivative disclosed as stabilizing the microsphere by accelerating the formation of the beta crystal form of the fat or wax subsequent to spray atomization of the mixture.
However, often a zero order, constant-release rate is preferred in which case the microcapsules deliver a fixed amount of drug per unit time over the period of their effectiveness. Zero-order release core delivery systems provide for the core to be released at a uniform rate independent of the core concentration (in the dosage form) during the period of release. Such an ideal core delivery system can produce uniform core concentration levels for a prolonged period of time. In a pharmaceutical system, the zero-order delivery system is capable of providing maximum therapeutic value while minimizing the side effects. It can also reduce the dosing


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