Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-07-18
2003-11-18
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S501000
Reexamination Certificate
active
06649192
ABSTRACT:
DESCRIPTION
Application of nanoparticles based on hydrophilic polymers as pharmaceutical forms for the administration of bioactive molecules.
The major constituents of these nanoparticles are two hydrophilic polymers: chitosan, which has a positive charge, and poly(oxyethylene), which has a non-ionic character. The active ingredient, which may be also a major constituent of these nanoparticles, is an antigenic or therapeutic macromolecule (peptide, protein, oligonucleotide, RNA, DNA . . . ). The electrical charge of these colloidal particles can vary, depending on the ratio of the two hydrophilic polymers, from a highly positive value to a near zero value. The size of the nanoparticles can be modulated as well, from few nanometers to a few microns, by adequately selecting the preparation conditions.
Chitosan is a natural cationic polymer produced by deacetylation of the polysaccharide chitin which is obtained from crustacean shells. Chitosan is available in the market in a variety of forms (with different molecular weights and degrees of deacetylation and, also, in the form of chitosan base or chitosan salt: e.g., hydrochlorhydrate, glutamate, lactate).
Poly(oxyethylene) or poly(ethylene oxide) (PEO) is a synthetic non-ionic polymer. PEO and its block copolymers with poly(propylene oxide) (PPO) are available in the market with different molecular weights and various ratios of ethylene oxide to propylene oxide groups. These block copolymers, especially the one containing 80% ethylene oxide, have been extensively used in the preparation of parenteral colloidal drug carriers because of their lack of toxicity.
Bioactive macromolecules can be associated with these nanoparticles by different extents depending on the composition of the nanoparticles (on the ratio of the two main hydrophilic polymers and on the physicochemical characteristics of the macromolecule which is associated).
The incorporation of bioactive macromolecules within the nanoparticles can be achieved by a very simple and mild procedure which is particularly effective for preserving the stability of the macromolecules.
The formation of the nanoparticles occurs spontaneously due to the simultaneous precipitation of chitosan and the bioactive macromolecule caused by the incorporation of a molecule with a basic character, i.e., sodium tripolyphosphate (counter anion). This process can be also considered as a process of ionic gelation or ionic crosslinking of chitosan with the counter anion. In this method, the utilization of organic solvents, extreme pH conditions or auxiliary substances of toxic nature are avoided.
The association of bioactive macromolecules with the nanoparticles occurs by a combined mechanism which may involve ionic and non-ionic interactions between the bioactive macromolecule and chitosan and a physical entrapment process. The ionic interaction between chitosan and negatively charged polymers has been previously described as the main mechanism involved in the formation of microcapsules by complex coacervation (T. Takahashi, K. Takayama, Y. Machida and N. Nagai, Chitosan-Alginate complex coacervate capsules: effects of calcium chloride, plasticizers and polyelectrolites on mechanical stability, Biotechnology Progress, 4, 76-81, 1988) and of polyion complexes (M. M. Daly and D. Knoor. Characteristics of polyion complexes of chitosan with sodium alginate and sodium polyacrylate, Int. J. Pharm. 61, 35-41, 1990). However, the association of bioactive macromolecules to nanoparticles made of chitosan or chitosan-PEO, according to an ionic interaction mechanism, has not yet been described. In addition, the originality here relies in the fact that the incorporation of the bioactive macromolecule into the nanoparticles occurs upon the incorporation of an ionic crosslinking agent such as sodium tripolyphosphate.
The current interest of hydrophilic nanoparticles is clearly illustrated by the growing amount of literature in this field. In this respect, it is worthwhile to mention several papers describing various methods of preparation of nanoparticles made of natural hydrophilic polymers and macromolecules (W. Lin, A. G. A. Coombes, M. C. Garnett, M. C. Davies, E. Stacht, S. S. Davis and L. Illum., Preparation of sterically stabilized human serum albumin nanospheres using a novel dextrano-MPEG crosslinking agent, Pharm. Res., 11, 1588-1592, 1994). (H. J. Watzke and C. Dieschbourg, Novel silica-biopolymer nanocomposites: the silica sol-gel process in biopolymer organogels, Adv. Colloid. Interface Sci. 50, 1-14, 1994), (M. Rajaonarivony, C. Vauthier, G. Courrage, F. Puisiex and P. Couvreur, Development of a new drug carrier from alginate, J. Pharm. Sci., 82, 912-917, 1993). However, the application of these nanoparticles for the association and delivery of high molecular weight active compounds such as peptides, proteins, antigens and oligonucleotides has not been described thus far. This could be partially due to the fact that most of the procedures described until now for the preparation of nanoparticles involve the use of organic solvents and/or covalent crosslinking agents as well as drastic conditions such as high temperatures or emulsification processes, which are extremely harmful for bioactive macromolecules. On the other hand, it has recently also been proposed the use of amphiphilic synthetic nanoparticles made of copolymers of lactic acid and PEO, for the delivery of macromolecules (P. Quellec, R. Gref, P. Calvo, M. J. Alonso and E. Dellacherie, Encapsulation of a model protein and a hydrophobic drug into long-circulating biodegradable nanospheres, Proceed. Intern. Symp. Control. Rel. Bioact. Mater., 23, 815-816 1996). Once again, however, the main limitation of these nanoparticles is the necessity of using organic solvents and emulsification processes for their preparation.
Despite the important efforts which have been dedicated over the last years to the formulation of macromolecules, nothing has been reported so far dealing with the application of chitosan or chitosan-PEO nanoparticles for the association and delivery of bioactive macromolecules with therapeutic or immunological interest. The preparation of chitosan nanoparticles without using harmful crosslinking agents such as aldehydes has not been yet reported either.
The new pharmaceutical composition described in this patent, based on the association of bioactive macromolecules to hydrophilic nanoparticles, overcomes problems previously encountered in the formulation of macromolecules. As indicated before, the main ingredients of the nanoparticles are two hydrophilic polymers: chitosan or chitosan salts and PEO or the block copolymers of poly(oxyethylene)-poly(oxypropylene) (PEO-PPO). The presence of PEO or PEO-PPO is not a requisite for the formation of the nanoparticles; however, the incorporation of these polymers in the system makes it more versatile since they affect the physicochemical properties of the nanoparticles such as the particles's size and zeta potential, as well as their release behavior and increase their biocompatibility. The chitosan: PEO ratio can vary enormously, reaching a value of 1:50. The association efficiency of the bioactive macromolecules to the nanoparticles can reach values as high as 100%.
The nanoparticles covered in this invention, which are intended for the association and delivery of bioactive macromolecules, offer numerous advantages over other types of nanoparticles previously described in the literature. These advantages rely not only in their preparation conditions but also from the point of view of their application for the administration of macromolecules by various routes. The most important benefits include: (1) the procedure for the incorporation of the bioactive macromolecule to the nanoparticles is instantaneous and does not require the use of ingredients which could be toxic for humans such as organic solvents, oils and aldehydic crosslinking agents; (2) the physicochemical properties of the nanoparticles, more specifically, their size, hydrophilic surface and surface charge, can be modu
Alonso Fernandez Maria Jose
Calvo Salve Pilar
Remunan Lopez Carmen
Vila Jato Jose Luis
Universidade de Santiago de Compostela
Webman Edward J.
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