Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2002-01-14
2004-08-03
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S490000, C424S491000, C424S492000, C424S493000
Reexamination Certificate
active
06770299
ABSTRACT:
A means for achieving a controlled drug administration is the use of particulate vehicles with a particle size in the micrometer range or in the nanometer range. The drug is incorporated into the vehicle, examples are O/W emulsions, liposomes, polymer microparticles, polymer nanoparticles, solid lipid nanoparticles, drug microparticles and drug nanoparticles (nanocrystals, nanosuspensions) (R. H. Müller, G. E. Hildebrand, Pharmazeutische Technologie: Moderne Arzneiformen, Wissenschaftliche Verlagsgesellschaft Stuttgart). The main purpose of using particulate vehicle systems is, in addition to the reduction of side effects, the establishment of an optimized drug release profile. As a rule, a sustained or at least a prolonged release is sought. High initial release (so-called burst release) is undesired. A standard example of this are polymer microparticles with LHRH analogues for the therapy of prostate carcinoma with a release period over four weeks (commercial products: Decapeptyl, Enantone).
A serious problem which in many cases cannot be solved is a high initial release occurring upon the incorporation of drugs into these drug vehicles. As a rule, emulsions are not suitable for a prolonged release as the active ingredient dissolved in the emulsion drops redistributes itself upon dilution (e.g. injection into the blood) within milliseconds into the aqueous blood phase (C. Washington, in (R. H. Müller, S. Benita, B. Böhm, Eds.) Emulsions and Nanosuspensions for the Formulation of Poorly Soluble Drugs, medpharm scientific publishers Stuttgart, 101-117, 1998). A prolonged release from liposomes is possible only to a limited extent as identical redistribution processes of the active ingredient and the metabolization of the phospholipids of the liposomes limit the release time. Only with a suitable preparation technique is a sufficiently prolonged release obtained with polymer microparticles (e.g. Decapeptyl), with an unsuitable preparation technique such as ASES (Aerosol Solvent Extraction System) (B. W. Müller et al., U.S. Pat. No. 5,043,280 (1991)), a very high initial release is obtained. The achievement of a prolonged release is even more difficult in the case of nanoparticles, as the diffusion paths are very short due to the smallness of the particles, and the degradation rate is sometimes very rapid. Drug release takes place instantly due to diffusion, something which was observed both with polymer nanoparticles and with solid lipid nanoparticles (zur Mühlen, A. et al. Eur. J. Pharm. Biopharm. 1998, 45, 149-155). In particular from poorly soluble drugs, microparticles can be prepared from pure active ingredient with size reduction processes. Due to the low water solubility of the active ingredients (in general associated with a low dissolution rate) in combination with the relatively low particle surface, a slow release process results. Examples are corticoid microparticle suspensions for intramuscular or intraarticular injection. For some application areas however, a longer release time would be desirable. By means of high-energy milling, poorly soluble drugs can be reduced to nanoparticles (nanocrystals, called nanosuspensions in aqueous dispersion) (Müller, R. H. et al., Pharm. Ind. 1999, 61, 1 74-78). Due to the greatly enlarged surface, however, dissolution is very rapid with nanocrystals. Intravenously injected nanosuspensions behaved pharmacokinetically like a solution (e.g. cyclosporine) (H. Sucker, in Pharmazeutische Technologie: Moderne Arzneiformen (R. H. Müller, G. E. Hildebrandt, Eds.), Wissenschaftliche Verlagsanstalt Stuttgart, 383-391, 1998). However, microparticles with a size in the lower micrometer range and nanoparticles have advantages described in the literature for drug administration. Thus they adhere to the gastro-intestinal membrane after peroral application. As a result, the bioavailability increases, at the same time the variability decreases. Due to the particle fineness, poorly soluble drugs which do not display sufficient bioavailability after oral application can be injected intravenously (R. H. Müller, in Pharmazeutische Technologie: Moderne Arzneiformen (R. H. Müller, G. E. Hildebrand, Eds.) Wissenschaftliche Verlagsanstalt Stuttgart, 393-400, 1998). Thus a sufficiently high bioavailability is achieved even with poorly soluble drugs. Due to these advantages, it would be desirable to be able to prepare fine particles in which the fast release due to active ingredient diffusion is eliminated or at least minimized.
In the present invention, this is achieved by linking the drug to the matrix material of the particles by covalent bonds, electrostatic interactions, dipole moments, dispersion forces, ion interactions, hydrogen bonds and/or hydrophobic interactions.
Only one of these types of bond can be present, according to some versions according to the invention, or else several of these types of bond can also be present, according to other versions of the invention.
There are thus
a) Versions with covalent bonds,
b) Versions with non-covalent bonds and
c) Versions with a proportion of covalent and a proportion of non-covalent bonds
In particular in the case of the versions with non-covalent bonds in the form of electrostatic interactions, dipole moments, dispersion forces, ion interactions, hydrogen bridges and/or hydrophobic interactions, a proportion of covalent bonding can also be present according to c) above.
Lipids are used as matrix material.
Conjugates from drugs or prodrugs with lipids are already described in the literature, the aim in this case being to increase membrane permeability and thus drug absorption by coupling an active ingredient with a lipophilic component. A prerequisite for a good absorption is however, in addition to membrane permeability, also a sufficiently high solubility in water. It is of no use if such a conjugate is very lipophilic but at the same time is not very water soluble. Due to the low water solubility, in this case, too little drug reaches the membrane. Dissolution rate and water solubility then become the rate-determining step of the absorption. To prevent this, the aim in the case of these lipid-prodrug conjugates was to prepare conjugates with as high a water solubility as possible. In the present invention, exactly the opposite is the case, the water solubility is to be as low as possible in order to minimize an initial release. The drug is to be released by degradation of the conjugate instead of by diffusion, i.e. after chemical cleavage of the conjugate (e.g. by enzymes in the gastro-intestinal tract or in other body fluids such as blood).
In the present invention, not only are stable conjugates produced by covalent bonds, but also the conjugates produced by non-covalent bonding are so stable, despite the absence of covalent bonding forces, that particles can be prepared from them.
Polymer-drug conjugates often have the problem that, as non-physiological components in the organism, they cannot, or can only slowly, be cleaved. Cleavage of the drug from the polymer is however a precondition for release and therapeutic effectiveness. To achieve a better degradation capability in vivo, lipids are therefore used as matrix material in the present invention. Toxicologically there is also the advantage that the lipid part can be metabolized after the cleavage of the conjugate. It serves at the same time as a nutrient.
In the case of lipid-prodrugs which still have corresponding water solubility, the degradation of the molecule takes place in solution. In the case of the insoluble particles described in this invention, it was found that the lipid conjugate, despite its solid aggregate state, can be degraded. This takes place by the anchoring of enzyme complexes on the particle surface, a surface degradation takes place in which the drug molecules are released (e.g. adsorption of the lipase/colipase complex in the gastro-intestinal tract). The better degradability of lipid-drug conjugates compared with polymer-drug conjugates can be explained in that e.g. the lipid-catabolizing enzymes in the organism a
Müller Rainer H.
Olbrich Carsten
Manelli Denison & Selter PLLC
Melcher Jeffrey S.
Page Thurman K.
PharmaSol GmbH
Tran S.
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