Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-08-17
2001-10-16
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S490000, C424S496000, C424S497000
Reexamination Certificate
active
06303148
ABSTRACT:
The present invention relates to a process for the preparation of a system having good controlled release behaviour, and to microspheres with a good controlled release behaviour.
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 parasital 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 parentally, i.e. by injection. The pharmacokinetical 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 have been proposed in the art, while synthetic biodegradable, rather well-defined polymers are used 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 polymers. 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 with 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 and 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.
Hydrogels have also been used in the preparation of delivery systems for protein drugs. One of these systems comprises crosslinked dextrans obtained by radical polymerization of glycidyl methacrylate derivatized dextran (dex-GMA). In this respect, reference is made to Van Dijk-Wolthuis et al. in Macromolecules 28, (1995), 6317-6322 and to De Smedt et al. in Macromolecules 28, (1995) 5082-5088.
It appeared that the release of the 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).
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. This is especially the case, when the drug is a macromolecular compound. Unless the pore size of the hydrogel or the microspheres 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. 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 behaviour has an undesirable effect on the release of the proteinaceous material from the beads.
To additionally illustrate the undesired release behaviour, it is noted that the profiles shown in the article are—from a pharmacological point of view—entirely unsuitable to be used in controlled release systems. Moreover, the gel beads are too large (cylinders with a diameter of 1.5 mm) to be suitably used for administration in the human or animal body.
In EP-A-0 213 303 a method for producing spherical polymer particles from systems containing two liquid aqueous phases is described. One of the two phases is dispersed in the form of droplets in the other phase to form an emulsion. Subsequently, the droplets are caused to solidify. In the phase to be dispersed, a macromolecular substance may be dissolved. Further, low molecular substances such as medicaments, vaccines and insecticides can be chemically bonded to the particle forming substance in the dispersed phase. Nothing is being said about the release behaviour of the dissolved substance, nor over the application of the spherical polymer particles formed or the size thereof.
The principle of affinity partitioning in PEG-containing two-phase systems is also known from Göte Johansson, Affinity Partitioning in PEG-containing Two-phase
Franssen Okke
Hennink Wilhelmus Everhardus
Morrison & Foerster
Octoplus B.V.
Page Thurman K.
Tran S.
LandOfFree
Process for the preparation of a controlled release system does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of a controlled release system, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of a controlled release system will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2585908