Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-02-15
2002-05-28
Page, Thurman K. (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S400000, C424S417000, C424S490000, C424S497000, C264S004100, C264S004300, C427S213360
Reexamination Certificate
active
06395302
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of a system having good controlled release behavior, and to microspheres with a good controlled release behavior. More in particular the invention relates to a method for the preparation of microencapsulated colloidal systems, i.e., microspheres which comprise colloidal systems, such as liposomes. These microencapsulated colloidal systems can be used as controlled release systems for the delivery of active ingredients in in vivo and in vitro applications.
BACKGROUND OF THE INVENTION
The fast developments in the biotechnological field lead to a large number of pharmaceutically interesting products, esp. proteins, peptides and genes. Such products can suitably be used in the treatment of life-threatening diseases, e.g. cancer, and several types of viral, bacterial and parasitic diseases.
Due to their nature, proteins and proteinaceous products, e.g. peptides, which group of products will be referred to as protein drugs herein-below, cannot efficiently be administered orally. They have to be brought in the system parenterally, i.e. by injection. The pharmacokinetic profile of these products is such that injection of the product per se requires a frequent administration. In other words, since protein drugs are chemically and physically unstable in the gastro intestinal tract and generally have a short active residence time in the human or animal body, multiple injections in a short time are required to attain a therapeutic effect. It will be evident that this is inconvenient for patients requiring these protein drugs.
For this reason, there is a need for delivery systems which have the capacity for sustained release. A number of options for such systems have been proposed in the art, such as the use of synthetic biodegradable, rather well-defined polymers to control the release of encapsulated drugs.
One of the options described in the prior art is the use of microspheres and nanospheres made of polymeric materials. These microspheres or nanospheres are spherical particles, spherical capsules, nanocapsules or nanoparticles having a particle diameter between about 0.1 &mgr;m and about 100 &mgr;m. In this description and the claims, the reference to microspheres also encompasses microparticles, microcapsules, nanospheres, nanoparticles and nanocapsules. Widely used polymers to prepare these microspheres are poly lactic acid and copolymers of lactic acid and glycolic acid. The polymers should preferably be biodegradable to avoid removal of the polymer carrier after use.
The hitherto known preparation methods for drug containing controlled or sustained release systems generally involve the use of organic solvents. Organic solvents may lead to structural changes in protein structure, esp. in the secondary and tertiary structure. Such changes may lead to a denaturation of the protein drug. Since these structural changes normally lead to a loss in pharmacological activity and the occurrence of undesired side-effects, such changes are undesirable, as will be apparent. Moreover, the use of organic solvents is not desirable from an environmental point of view, either.
Further, it is hardly possible to avoid that traces of organic solvents will remain in or on the microspheres produced. Especially, when toxic solvents are used, such as the widely applied solvents chloroform and dichloromethane, this is a problem.
Another problem is that it is difficult to encapsulate proteins in polymeric matrices in a reproducible way. It is of the utmost importance that predictable and reproducible amounts of proteins or other encapsulated products to be used as drugs are released.
Polymeric hydrogels, i.e., polymeric networks that contain a considerable amount of water, are also widely studied as controlled release systems. Although polymeric hydrogels can be applied successfully as controlled release systems, there remains a need to further modify the release profiles obtained. In particular the lag time, i.e., the time after which the onset of release occurs, and the duration of the pulse in case of pulsed release are parameters that determine the success of the application of a controlled release system to a large extent.
One of the hydrogel systems that has been used in the preparation of delivery systems for protein drugs comprises crosslinked dextrans obtained by radical polymerization of methacrylate derivatized dextran (dex-MA). In this respect, reference is made to van Dijk-Wolthuis et al. in Macromolecules 28, (1995), 6317-6322 and to Van Dijk-Wolthuis et al. in Macromolecules 30, (1997), 3411-3413.
It appeared that the release of proteins from these hydrogels depends on and can be controlled by the degree of crosslinking and the initial water content of the gel (Hennink et al., J. of. Contr. Rel. 39 (1996), 47-57, the contents thereof being incorporated herein by reference).
Encompassed drugs are released from these hydrogels or polymeric microspheres during biodegradation of the polymeric material and/or by diffusion.
Drugs are usually loaded into hydrogels or microspheres derived hereof either by equilibration in a drug-containing solution followed by drying (see e.g. Kim et al. in Pharm. Res. 9(3) (1992) 283-290) or by incorporation of the drug during the preparation of the hydrogel or microspheres (see e.g. Heller et al. in Biomaterials 4 (1983) 262-266). Both techniques have a number of disadvantages other than those arising from any organic solvents used.
Loading by equilibration normally leads to a rather low drug content in the delivery system due to entropic exclusion: larger molecules enter the hydrogel with more difficulty than smaller ones. This is especially the case, when the drug is a macromolecular compound. Unless the pore size of the hydrogel or the microsphere is rather large, the macromolecules will only adsorb onto the outer surface, which may, after application, lead to a burst release in the human or animal system or in vitro. Further, the solvent phase containing the drug, which phase is contacted with the delivery system to load the delivery system, has to be removed from the hydrogel or the microspheres. This can produce the migration of the drug to the surface of the delivery system, and, hence, to a non-homogeneous drug distribution. This tends to result in a significant burst release of the drug, as well, which generally is not desired.
A suitable loading process for incorporating macromolecular drugs is aimed at.
In an article in Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 22 (1995), 145-146, Gehrke et al. have described a technique wherein loading levels higher than obtainable by solution sorption, hence, higher than about 0.1 wt. %, can be achieved in purified, pre-formed hydrogels. The loading technique is based on the fact that certain polymer mixtures split into separate phases when dissolved in water. Proteins dissolved in such a system distribute unevenly between the phases. This principle also holds when one of the polymer phases is a crosslinked gel.
In particular, Gehrke et al. describe a crosslinked dextran gel/poly(ethylene glycol) system, and a crosslinked hydroxypropylcellulose gel/poly(vinyl alcohol) system. Proteins present in an aqueous solution containing beads of the gel are, after the addition of the non-crosslinked second polymer, adsorbed on the beads and partly absorbed through meshes or pores in the bead surfaces.
A disadvantage of this technique is that the proteinaceous material is to a major extent only adsorbed to the beads, which means that if the phase containing the second polymer is replaced by another aqueous system a fast removal of the proteins from the beads is observed. Only when large amounts of pores having a diameter larger than the size of the proteinaceous material to be loaded are present in the bead surfaces, some absorption may occur. This adsorption and limited absorption behavior has an undesirable effect on the release of the proteinaceous material from the beads.
To additionally illustrate the undesired release behavior, i
Franssen Okke
Hennink Wilhelmus Everhardus
Morrison & Foerster / LLP
Octoplus B.V.
Page Thurman K.
Tran S.
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