Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-01-19
2004-06-01
Wax, Robert A. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S025000, C424S489000, C424S493000, C424S494000
Reexamination Certificate
active
06743775
ABSTRACT:
INTRODUCTION
The invention relates to slow release formulations.
One of the most important parameters defining the effect of a drug applied to the organism is its physicochemical characteristics. Properties underlying the application of the drug may be acquired during its synthesis or else in the particular dosage form only.
Aside from topically applied drugs, most drugs are delivered through what may be called a “water path” within the organism. Most organic drugs, on the other hand, are also soluble in hydrophobic media such as lipids. A related characterisitic is the distribution coefficient defined as the ratio of solubility in non-polar (lipids) and polar (water) media. It's value affects not only the delivery rate of the drug to the target site in the organism, but also the duration of it's effect.
The best known and simplest method of affecting both the delivery rate and the duration of effect of an active substance in the organism is the creation of it's salt using a suitable salt-forming ion. So called Hosmeister lyotropic ion series have been established to classify the ions according to the size of their hydration/solvation envelopes which determines the solubility of the salts in a particular environment.
The most important indifferent cation and anion, not contributing to the physiological properties of a drug, are Na
+
and CI ions. Interesting salt-forming, though physiologically not fully indifferent anions are carboxylate anions such as those derived from citric, lactic, tartaric, glycolic, gluconic, or glucuronic acids.
Drug salts containing these anions are generally less soluble than chlorides or sulphates and therefore tend to display a prolonged or protracted effect of the drug.
Prolongation of the effect of the active substance of a drug can be attained through the use of a similar salt of the substance having a limited solubility.
Prolongation can also be achieved by fixing the active substance to ionogenic functional groups of a suitable type of polymer.
This invention is directed towards providing a polymer system to achieve slow release of an active drug in the organism.
The invention in particular involves the use of polyanhydroglucuronic acids and salts thereof. The term polyanhydroglucuronic acid and salts there of as used herein also includes copolymers thereof, especially with anhydroglucose. This is hereinafter referred to as PAGA.
Co-pending patent application PCT IE98/00004 describes particular polyanhydroglucuronic acids and salts thereof and a method of preparing such compounds. In particular therefore, the term polyanhydroglucuronic acids and salts thereof includes the acids and salts referred to in this co-pending application.
STATEMENTS OF INVENTION
We have now found that fixation of suitable types of drugs to microdispersed or microfibrillar PAGA, and salts, complex salts, or intermolecular polymer complexes thereof, preferably as prepared according to the method disclosed in PCT IE/98/00004, can be used as a means for preparing drug dosage forms with a significantly protracted effect and a reduced toxicity.
A prolongation of the effect of a drug fixed to this type of polymer chain makes it possible to reduce the amounts dosed and the frequency of dosing and thereby makes the therapy more comfortable for the patient and reduces potential systemic toxicity of the drug, the latter issue being especially of concern with, for instance, certain types of antibiotics or cytostatics.
When the polymer matrix is biodegradable. The matrix, insoluble at the origin, can then be degraded by hydrolysis or an enzyme-assisted hydrolysis in the organism whereby it slowly releases the active substance fixed to the ionogenic groups of the structural units of the biopolymer and makes it free to permeate through biological membranes.
We have found that microdispersed and microfibrillar PAGA, containing uronic carboxyl groups in the polysaccharidic polymer chain, owing to it's small particle size, high porosity and high specific surface area, and a fully open inner surface, appears to be an ideal biopolymer suitable for physicochemical fixation of a number of biologically active substances.
The open inner surface makes it possible for the molecules of the active substance to uniformly penetrate into the polymer matrix and to get uniformly fixed thereto by way of formation of either a simply salt of an acetate type or a complex salt. This uniformity, in turn, provides for a uniform release of the active substance and for the uniformity of it's effect in the organism.
Though an appropriate selection of the amount of the active substance, selection of further cations fixed to the polysaccharidic polymer chain, and possibly introduction of a certain density of cross links within the chain, it is possible to influence and vary the rate of the release from the polymer matrix. A pronounced prolongation of the drug effect and reduction of systemic toxicity with, for example, cytostatic drugs can be achieved, and the release of the active substance from the matrix can be well controlled.
Last but not least, a concomittant contribution to the reduction of drug toxicity can be attained owning to the release of glucuronic acid, which is a detoxication agent of a mammalian organism, simultaneously occurring during the biodegradation of the polymer matrix.
According to the invention there is provided a slow release formulation including a biocompatible anionic polysaccharide material containing glucuronic acid in the polymer chain.
Preferably at least 5% of the basic structural units are glucuronic acid.
Preferably the polysaccharide material is polyanhydroglucuronic acid, biocompatible salts thereof, copolymers thereof, or a biocompatible intermolecular complex thereof.
In a preferred embodiment of the invention the biocompatible intermolecular polymer complex is a complex of:
an anionic component comprising a linear or branched polysaccharide chain containing glucuronic acid; and
a non protein cationic component comprising a linear or branched natural, semi-synthetic or synthetic oligomer or polymer.
Preferably at least 5% of the basic structural units of the anionic component are glucuronic acid.
The cationic component preferably contains nitrogen that either carries a positive charge or wherein the positive charge is induced by contact with the polysaccharidic anionic component.
The cationic component may be selected from derivatives of acrylamide, methacrylamide and copolymers thereof. In this case the cationic component is selected from polyacrylamide, copolymer of hydroxyethylmethacrylate and hydroxypropylmetacrylamide, copolymers of acrylamide, butylacrylate, maleinanhydride and/or methylmetacrylate.
In one embodiment the cationic component is a cationised natural polysaccharide.
Preferably the polysaccharide is a starch, cellulose or gum.
The gum is preferably guargumhydroxypropyltriammonium chloride.
Alternatively the cationic component is a synthetic or semi-synthetic polyamino acid. In this case preferably the cationic component is polylysin, polyarginin, or &agr;,&bgr;-poly-[N-(2-hydroxyethyl)-DL-aspartamide].
In another embodiment the cationic component is a synthetic anti-fibrinolytic.
In this case preferably the anti-fibrinolytic is a hexadimethrindibromide (polybren).
Alternatively the cationic component is a natural or semi-synthetic peptide.
In this case preferably the peptide is a protamine, gelatine, fibrinopeptide, or derivatives thereof.
In another embodiment the cationic component is an aminoglucane or derivatives thereof.
In this case preferably the aminoglucane is fractionated chitin or its de-acetylated derivative chitosan. The aminoglucane may be of microbial origin or is isolated from the shells of arthropods such as crabs.
In an especially prepared embodiment of the invention the anionic component is polyanhydroglucuronic acid and/or bicompatible salts and/or copolymers thereof.
Most preferably the polyanhydroglucuronic acid and salts thereof contain in their polymeric chain from 8 to 30 percent by weig
Briestensky Jiri
Kiss Frantisek
Santar Ivan
Alpenstock Holdings Limited
Desai Anand
Jacobson & Holman PLLC
Wax Robert A.
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