Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
1999-02-24
2002-07-16
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
C424S489000, C424S464000, C424S465000, C424S497000, C424S486000
Reexamination Certificate
active
06419957
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to cross-linked high amylose starch and in particular, cross-linked high amylose starch having functional groups. Such cross-linked high amylose starch imparts sustained release to a pharmaceutical agent when compressed in a tablet form.
BACKGROUND OF THE INVENTION
The controlled release of bioactive molecules, e.g., pharmaceutical agents, has been the subject of extensive research over the last half of the twentieth century. The controlled release of pharmaceutical agents is of high importance for biopharmaceutical applications. Long acting doses of a variety of drugs are now available, allowing once or twice-a-day dosage regimens where immediate release forms called for multiple and sometimes impractical administrations. Effective slow-release dosage regimens have demonstrated superior patient compliance and hence improved efficacy over multiple immediate release forms.
There are several types of polymers that have been used as a matrix for the slow-release of drugs. Thus, polymeric materials such as polyvinyl chloride, polyethylene polyamides, ethylcellulose, silicone, poly (hydroxyethyl methacrylate), other acrylic co-polymers, polyvinylacetate-polyvinyl chloride copolymers and other polymers have been described as an adequate matrix for tablet preparation (see for example U.S. Pat. Nos. 3,087,860; 2,987,445; and
Pharm. Acta Helv.,
(1980), 55:174-182, Salomon et al.).
Polysaccharides have been used widely in pharmaceutical, chemical, and biochemical drug delivery. This family of natural polymers has been applied to the are of controlled release coatings, matrices, macromolecular carriers and biodegradable carriers. One of the most frequent problems associated with the use of polysaccharides, such as starch, as drug delivery agents is its susceptibility to degradation by intestinal polysaccharidases such as &agr;-amylase. The use of polysaccharides in colonic drug delivery has been reviewed (Critical Reviews™ in Therapeutic Drug Carrier Systems, 13 (3 & 4):185-223 (1996).
Starch is, however, one of the most attractive biopolymers for use as a drug delivery agent since it can be mass produced with a high purity at a very economical price. Recently, in order to apply amylose to the controlled release field, a chemically modified amylose was prepared by cross-linking amylose in the gelatinized state as described in U.S. Pat. No. 5,456,921.
Amylose is a natural substance obtained from starch. It is essentially a linear, non-branched, polymer of glucopyranose units with &agr;-D-(1-4) linkages. In starch, amylose is usually accompanied by amylopectin, which is a branched polyglucose polymer with a significant frequency of branching points based on &agr;-(1-6)-glucosidic bonds.
Cross-linked amylose (CLAm) is an excipient for the controlled release of drugs in solid drug dosage forms. CLAm is produced by the reaction of amylose with a suitable cross-linking agent in an alkaline medium. Different degrees of cross-linking (CLAx) can be obtained by varying the ratio of cross-linking agent, such as epichlorohydrin, to amylose in the reaction vessel where x indicates the amount (g) of cross-linking agent used for cross-linking 100 g of amylose (i.e., CLAx with x=0, 6, 11, 15 or 30).
CLAm tablets are prepared by direct compression, and are highly resistant to mechanical stress in the dry state. When placed in contact with aqueous fluids, water diffuses into the CLAm matrix, with subsequent formation of a gel layer. Progressive water sorption leads to significant swelling of the matrix. With degrees of cross-linking below 11, the swollen polymeric matrix does not undergo any erosion during in vitro experiments performed in the absence of amylase. Amylase found in the human duodenum catalyzes the hydrolysis of amylose, drastically reducing its sustained-release properties.
Accordingly, it would be desirable to provide a slow-release system having greater resistance to amylase-induced degradation, with overall improved sustained release properties.
Another feature of cross-linked amylose is its ability to release drugs at a constant rate, following zero-order kinetics, such as described in S.T.P.
Pharma
(1986), 2:38-46 (Peppas et al.). The approach called “swelling-controlled” systems consists of glassy polymers into which a water front penetrates at a constant rate. Behind this front, the polymer is in a rubbery state. Provided the drug diffusion coefficient in the rubbery polymer is much higher than in the glassy polymer, a zero order release can be achieved to a certain degree. However, the delivery rate is constant only for a limited fraction of the release, usually around 60% of the total amount of contained drug, and requires a low initial drug concentration.
X-ray diffraction studies show different morphologic forms for amylose in correlation with its origin, preparation mode or hydration state (French D. - “Organization of starch granules”—in Starch: Chemistry and Technology [Whistler R., L., BeMiller J., N. and Paschall E. F., Eds.], Acad. Press, 1984). The structures of A and B-type amylose are based on double helices parallel stranded and antiparallel packed, the individual strands being in a right-handed sixfold helical conformation (Wu H. C. and Sarko A.,
Carbohydr. Res.,
61:7-25, 1978). Amylose A contains 8 molecules of H
2
O and Amylose B (hydrated) contains 36 molecules of H
2
O per elementary cell unit. V-Amylose is made from single helix chains and exists as complexes with small organic molecules, water or iodine. Even though the inside of the helix channel of V-amyloses is primarily hydrophobic, intrahelical water has been found in anhydrous (Va), as well as in the hydrated (Vh) forms. Some intermolecular hydrogen bonds are formed through interstitial water molecules. It has been suggested that the presence of a substantial amount of complexing agent (e.g., ethanol) can mainly stabilize single helices of amylose, whereas a predominance of water can induce conformational changes leading to the formation of double helices (Buleon A., Duprat F., Booy F. P. and Chanzy H., Carbohydr.
Polymer,
4:61-173, 1984). All forms of amylose become B-type in gel phase (Wu H. C. and Sarko A.,
Carbohydr. Res.,
61:27-40, 1978); the interchange of morphological structures tends to reach the more stable double helix form with the corresponding molecules of water.
Accordingly, it would be desirable to provide a slow release system following a zero-order kinetics, and allowing a controlled release of a drug at a constant rate until all the drug is released, whatever the concentration of the drug in the system.
Citation or identification of any reference in Section 2 of this application shall not be construed as an admission that such reference is available as prior art to the present invention.
SUMMARY OF THE INVENTION
In accordance with the present invention there is now provided a solid slow release oral pharmaceutical dosage unit which comprises a solid dosage unit made up of an admixture of a therapeutic dosage of an orally effective pharmaceutical agent and covalent cross-linked polymer of high amylose starch made by reacting high amylose starch with a suitable cross-linking agent, wherein the covalent cross-linking of the polymer has been carried out with from about 0.1 to about 40 g of cross-linking agent per 100 g of amylose.
In a preferred embodiment of the invention, the cross-linked polymer is modified with a functional group.
In a further aspect of the invention, there is provided a solid slow release oral pharmaceutical dosage unit made up of an admixture of a therapeutic dosage of an orally effective pharmaceutical agent, an optional polysaccharide or polyol and a cross-linked polymer of high amylose starch made by reacting high amylose starch with a suitable cross-linking agent.
In another aspect of the invention, the pharmaceutical agent is present in the tablet in an amount of from 0.01 to 80% w/w.
In a further aspect of the invention, a method is described to obtain a matrix resistant to all types
Chouinard Francois
Ispas-Szabo Pompilia
Lenaerts Vincent
Mateescu Mircea Alexandru
Labopharm Inc.
Page Thurman K.
Pennie & Edmonds LLP
Pulliam Amy E
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