Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1998-08-21
2002-05-21
Lovering, Richard D. (Department: 1712)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S469000, C424S497000, C424S501000, C427S213360, C514S965000
Reexamination Certificate
active
06391338
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to the art of administering bio-affecting agents to bio-systems, and, in particular, for rendering agents, which are substantially non-dissoluble in an aqueous environment, available for interaction with a host bio-system, e.g., a human or animal.
Bio-systems, such as humans, plants, insects, fish, birds, and mammals, are primarily aqueous systems. In order to effectively administer an bio-affecting agent to such bio-systems, it is necessary to make the agent available for interaction with physiological activity in the bio-system. This is referred to herein as “bio-availability.” In the case of bio-affecting agents which are non-dissoluble in an aqueous environment, as well as in the case of those which are only poorly water-soluble, effective administration of the bio-affecting agent can be difficult due to inadequate bio-availability of the agent and consequent low pharmacological activity. These solubility problems affect many parameters of administration, such as the method of administration, the rate of administration, the concentration of administration, etc.
It is known that rate of dissolution of drug particulates can be increased by increasing the surface area of the solid, i.e., decreasing the particle size. Consequently, methods of making finely divided drugs have been studied and efforts have been made to control the size and size range of drug particles in pharmaceutical compositions. For example, dry milling techniques have been used to reduce particle size and thereby influence drug absorption. However, in conventional dry milling, as discussed by Lachman et al.,
The Theory and Practice of Industrial Pharmacy,
Chapter 2, “Milling”, p. 45 (1986), the limit of fineness is reached in the region of about 100 &mgr;m (=100,000 nm), where the milled material begins to cake onto the surfaces of the milling chamber. Lachman et al. note that wet grinding is beneficial in further reducing particle size, but that flocculation restricts the lower particle size limit to approximately 10 &mgr;m (=10,000 nm). There tends to be a bias in the pharmaceutical art against wet milling due to concerns associated with contamination. Commercial airjet milling techniques have provided particles ranging in average particle size from as low as about 1 &mgr;m to 50 &mgr;m (=1,000 nm to 50,000 nm).
Other techniques for preparing pharmaceutical compositions with enhanced aqueous solubility properties include loading drugs into liposomes or polymers, e.g., during emulsion polymerization. However, such techniques have problems and limitations. For example, a lipid-soluble drug is often required in preparing suitable liposomes. Further, unacceptably large amounts of the liposome or polymer are often required to prepare unit drug doses. Further still, techniques for preparing such pharmaceutical compositions tend to be complex. A principal technical difficulty encountered with emulsion polymerization is the removal of contaminants, such as unreacted monomer or initiator (which can be toxic) at the end of the manufacturing process.
U.S. Pat. No. 4,540,602 (Motoyama et al.) discloses a solid drug pulverized in an aqueous solution of a water-soluble high molecular weight substance using a wet grinding machine. However, Motoyama et al. teach that, as a result of such wet grinding, the drug is formed into finely divided particles ranging from 0.5 &mgr;m (500 nm) to less than 5 &mgr;m (5,000 nm) in diameter.
EPO 275,796 describes the production of colloidally dispersible systems comprising a substance in the form of spherical particles smaller than 500 nm. However, the method involves a precipitation effected by mixing a solution of the substance and a miscible non-solvent for the substance, and results in the formation of non-crystalline nanoparticles. Furthermore, precipitation techniques for preparing particles tend to provide particles contaminated with solvents. Such solvents are often toxic and can be very difficult, if not impossible, to adequately remove to pharmaceutically acceptable levels. Accordingly precipitation methods are usually impractical.
U.S. Pat. No. 4,107,288 describes particles in the size range from 10 to 1,000 nm containing a biologically or pharmacodynamically active material. However, the particles comprise a crosslinked matrix of macromolecules having the active material supported on or incorporated into the matrix.
U.S. Pat. No. 5,145,684 describes a method for providing drug particles having an effective average particle size of less than about 400 nm. The method includes wet milling the drug in the presence of a grinding medium in conjunction with a surface modifier. As in previous methods, the '684 protocol requires grinding or milling to produce size reduction. The method further requires the use of an additive in the form of a surface modifier.
Moreover, drugs prepared by milling, even wet milling such as that described in the '684 disclosure, are subject to degradation resulting from heat as well as physical and chemical trauma associated with fracture. Grinding also creates “hot spots,” i.e., volumes of localized higher temperatures which can exceed the melting point or degradation of the drug. The process is also lengthy, requiring attrition exposure over several days. This type of process effectively exposes the drug to a long “heat history”, wherein exposure to elevated temperatures has been significant, and the purity and potency of the drug is diminished to a significant extent. Furthermore, particles reduced by milling are often contaminated by the residue of the grinding operations, especially when ball milling is used and the grinding balls are worn down by abrasion.
It has also been known in the art of drug delivery to improve bio-availability by aggregating substantially non-dissoluble active ingredients on the surface of soluble substrates, such as water-soluble beads. The active ingredient can be deposited on such substrates by spraying a solution of the active ingredient over a fluidized bed while “flashing off” the solvent used for the active ingredient. This method is highly inefficient in that it requires several hours to deposit a sufficient amount of active ingredient to prepare a useable delivery system. Furthermore, an additional ingredient which is unnecessary to the system must be used, i.e., the solvent required to dissolve the active ingredient. As previously mentioned, the solvent must be flashed off during aggregation. Thus, this system is a long and cumbersome process and does not provide efficiency of dosage delivery.
Solubilization techniques for drugs which have low aqueous solubility require the use of organic solvents for processing in a solution state. This requires the use of expensive recovery systems for solvent handling capability. When general melt processing techniques are used to form dispersions, bulk melting and mixing steps often expose the drug to a prolonged heat history.
It is desirable to provide stable dispersible drug particles in the sub-micrometer size range which can be readily prepared in the absence of size reduction by grinding or milling. Moreover, it would be highly desirable to provide pharmaceutical compositions having enhanced bio-availability.
It is, therefore, an object of the present invention to overcome the disadvantages associated with methods for preparing delivery systems for bio-affecting ingredients, especially those which are substantially non-dissoluble. As a consequence of overcoming the drawbacks known in the art, it has been found that other and further objects which enhance the art of delivery systems have been realized as a result of the present invention.
SUMMARY OF THE INVENTION
The invention is a composition for delivery of a bio-affecting agent to a bio-system, and a methods of making and using a delivery system which includes a bio-affecting agent. The composition and method include the use of:
a solid dispersion of the bio-affecting agent in an increased-energy state in a water-soluble (or wate
Blake Andrea S.
Frisbee Steven E.
Fuisz Richard C.
Myers Garry L.
Yang Robert K.
Biovail Technologies Ltd.
Lovering Richard D.
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