Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-11-14
2003-07-08
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S450000, C424S451000, C424S489000, C424S490000, C424S497000
Reexamination Certificate
active
06589548
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the sustained controlled release system constructed by the conjugation of drug molecules with biodegradable polyester polymer, which may be formulated into microspheres, nanoparticles or films, and method for conjugation thereof. According to the system of this invention, the drug release rate can be regulated to be proportional to the chemical degradation rate of the biodegradable polyester polymer, resulting in near zero order kinetic profile of release without showing a burst effect. Moreover, it is possible to achieve the high loading efficiency of hydrophilic drugs in the formulation into microspheres, nanoparticles, or films.
DESCRIPTION OF THE PRIOR ART
It is difficult to maintain constant drug concentration in blood through the established injection or oral routes of administration. Therefore, in order to maintain constant drug concentration in blood, methods in which a polymer carrier is slowly degraded have been studied for the release of drug in biodegradable polymer carrier at a constant rate [Langer, R.,
Chem. Eng. Commun
., 6, 1-48 (1980); Langer, R. S. and Peppas, N. A.,
Biomaterials
, 2, 201-214 (1981); Heller, J. CRC Crit.,
Rev. Ther. Drug Carrier Syst
., 1(1) 39-90 (1984); Holland, S. J. Tighe, B. J. and Gould, P. L.,
J. Controlled Release
, 155-180 (1986)]. Such a biodegradable polymer carrier system has an advantage that, since the polymer carrier is degraded into low molecular weight molecules, the additional elimination process of the carrier is not needed.
Many kinds of biodegradable polymers have been used as carriers. In general, aliphatic polyester polymers have been frequently used, such as poly(lactic acid), poly(glycolic acid), poly(D-lactic-co-glycolic acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid), poly(caprolactone), poly (valerolactone), poly(hydroxybutyrate) and poly (hydrovalerate), etc. [Peppas, L. B.
International journal of pharmaceutics
, 116, 1-9 (1995)]. In particular, poly(D-lactic-co-glycolic-acid), poly(L-lactic-co-glycolic acid), poly(D,L-lactic-co-glycolic acid) (hereinafter, generically refered to as poly(D/L-lactic-co-glycolic acid) have been widely used. It was ascribed that biodegradable polymers with various life spans of degradation could be produced and drug release could be regulated for weeks or years, by controlling the molar composition ratio of monomer comprised of lactic acid and glycolic acid or controlling the molecular weight of the polymer.
However, formulations comprising drugs and aliphatic polyester polymers as carriers have had some difficulties in controlling the rate of drug release over a desired period due to an initial burst effect. This resulted from the fact that drug release is not dependent on the polymer erosion process but on the diffusion of drug. Particularly, this problem is serious for hydrophilic drugs such as peptides or proteins. For example, microspheres or films consisting of gentamycin sulfate and polyester polymer carrier were observed to show the initial burst effect. Also, it was reported that hydrophilic gentamycin compound had initial burst effects over 50% [Mauduit, J., Bukh, N., and Vert. M.,
J. Controlled release
, 23, 209-220 (1993); Mauduit, J., Bukh, N., and Vert. M.,
J. Controlled release
, 23, 221-230 (1993); Mauduit, J., Bukh, N., and Vert. M.,
J. Controlled release
, 25, 43-49 (1993)] and neurotensin analog over 20% [Yamakawa I., Tsushima, Y., Machida, R., and Watanable, S.,
J. Pharma. Sci
., 81, 808-811 (1992)]. To solve such a problem, there have been efforts to develop new methods for manufacturing various microspheres, nanoparticles and films [Peppas, L. B.
International journal of pharmaceutics
, 116, 1-9 (1995)].
Biodegradable, biocompatible matrices for drug delivery including microspheres, nanoparticles, and films have been widely used for an injectable depot formulation of various small molecular weight drugs, peptides, and proteins which required multiple administrations. It has been known that drug release kinetic rate from the microspheres, nanoparticles, and films is determined by diffusion and/or polymer erosion process [D. D. Lewis, et al, in Biodegradable Polymers as Drug Delivery System, in M. Chasin and R. Langer (Eds.), Marcel Dekker, New York (1990) pp. 1-41]. For small diameter microspheres and nanoparticles as an injectable dosage form, it has been difficult to predictably control the drug release kinetic rate over a desired period due to an initial burst effect combined with the process of relatively faster diffusion of the drug than the erosion of the matrices. This problem is particularly acute for hydrophilic drugs that are believed to exist in pre-formed microporous aqueous channels within the microspheres [S. Cohen, et al.,
Pharm. Res
. 8 (1991) 713-720].
The most common method of preparing microspheres and nanoparticles for hydrophilic drugs is a double emulsion solvent evaporation technique which adopts a two phase emulsion system composed of polymer dissolved organic phase containing primary aqueous emulsion droplets as a dispersed phase and a continuous phase of water [Y. Ogawa, et al.,
Chem. Pharm. Bull
. 36 (1988) 2576-2588]. This method inevitably generates porous morphology in the microspheres and nanoparticles matrices, leading to burst and very fast release kinetics of the hydrophilic drugs through pre-existing macro- and micro-pores. For hydrophobic drugs, a single oil-in-water emulsion system has been employed to prepare drug loaded microspheres and nanoparticles. In this case, drug release kinetic rate was mainly controlled initially by diffusion through existing pores and later by polymer erosion process, resulting in a triphasic release profile. Most of previous studies for controlled release of hydrophilic drug from biodegradable polyester microspheres and nanoparticles, however, could not achieve a zero order release profile over an extended period because of complicated nature of drug release mechanism, that is, a diffusion coupled polymer erosion process (H. T. Wang, et al.,
J. Controlled. Release
17 (1991) 23-32].
On the other hand, a new drug delivery system has been developed through conjugating a synthetic polymer to a drug via a covalent bond or by modifying the biodegradable polymer. For example, the system developed by conjugating drug with polyethylene glycol(hereinafter, refered to as PEG) approved by FDA, which is hydrophilic, linear, and non-immunologic polymer, was reported to increase circulation time of the drug in blood stream [Zhu, K. J., XiangZhou, L. and Shilin, Y.
J. Appl. Polym. Sci
. 39, 1-9 (1990; Davis, F. F., Kazo, G. M., Nucci, M. L., and Abuchwski, A., In Lee, V. H. L.(Ed.), Peptide and Protein Drug Delivery, Dekker, New York, 831-864 (1991)]. PEG has been applied to many drugs. At least six classes of PEG-enzyme comlexes, including PEG-adenosine amylase, PEG-antigen, PEG-asparaginase, and PEG-uricase, are under the clinical trials or approved by FDA.
Recently, anti-cancer drugs have been chemically conjugated to various polymers for the purpose of their efficient passive targeting to solid tumors [R. Duncan, et al.,
Anti
-
cancer Drugs
, 3:175-210 (1992), H. Maeda, et al.,
J. Med. Chem
, 28: 455-461 (1985), T. Minko, et al.,
J. Control Release
, 54: 223-233 (1998)]. The “enhanced permeation and retention (EPR)” effect on the site of tumor capillaries plays a critical role in accumulating the polymer conjugates in the solid tumors, while minimizing the glomerular excretion rate [H. Maeda., et al.,
CRC Crit. Rev. Ther. Drug Carrier Sys
., 6: 193-210 (1989), L. W. Seymour, et al.,
CRC Crit. Rev. Ther. Drug Carrier Sys
., 9: 132-187 (1992)]. Water soluble polymer conjugates based on poly(N-(2-hydroxypropyl)methacrylamide) have been extensively studied and are now under clinical trials [V. Omelyanenko, et al.,
J. Control Release
, 53: 25-37 (1998)]. Another promising approach is to
Lee Keon Hyoung
Nam Yoon Sung
Oh Jong Eun
Park Tae Gwan
Mogam Biotechnology Research Institute
Muserlian, Lucas & Mercanti, LLP
Tran S.
LandOfFree
Controlled drug delivery system using the conjugation of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Controlled drug delivery system using the conjugation of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Controlled drug delivery system using the conjugation of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3073798