Title:  Cross-linked high amylose starch resistant to amylase as a matrix for the slow release of biologically active compounds

United States Patent:  6,284,273

Appl. No.:   028385

The present invention is concerned with a solid slow release oral pharmaceutical dosage unit resistant to amylase which comprises a solid dosage unit made up of an admixture of a therapeutic dosage of an orally effective pharmaceutical product, an optional polysaccharide or polyol, and cross-linked high amylose starch, wherein the cross-linking of the high amylose starch has been carried out with a covalent or non-covalent cross-linking agent with from about 0.1 g to about 30 g of cross-linking agent per 100 g of high amylose starch.

DETAILED DESCRIPTION OF THE INVENTION

The cross-linking of amylose is well known in the literature. For example, the desired cross-linking can be carried out in the manner described in BIOCHMIE 1978, 60, 535-537 (Mateescu) by reacting amylose with epichlorohydrin in an alkaline medium. In the same manner, amylose can also be cross-linked with 2,3-dibromopropanol, sodium trimetaphosphate and other suitable cross-linking agents described herein.

Essentially, the high amylose starch is swollen in water by generally known gelatinization techniques such as alkaline or heat treatment and after homogenization, an appropriate amount of cross-linking agent is added. After substantial homogenization, the reaction medium is transferred onto a water bath and heated for one hour at a temperature of from 40^o to 45^oC. and the temperature is then raised from 60^o to 75^oC. for a further period of from 1 to 2 hours after which time the reaction is complete. The duration of heating can be varied as well as the amount of cross-linking agent used in the reaction.

The resulting cross-linked material is then sieved in wet form and the granules ranging from about 25 to about 700 um are collected for the preparation of the slow-release tablet of the present invention. The granules of 25 to about 300 um representing at least 50% of the granules are selected for use in accordance with the presented invention.

The preferred cross-linked polymers of high amylose starch with covalent cross-linking agents suitable for the purposes of the present invention are those where from about 0.1 to about 30 g of covalent cross-linking agent have been used to cross-link 100 g of high amylose starch. More preferred cross-linked polymers were obtained when from about 0.5 g to about 6.0 g of covalent cross-linking agents over 100 g of high amylose starch were used.

It has been surprisingly found that when a mixture of amylose and amylopectin between about 10-60% amylopectin by weight is cross-linked by a covalent cross-linking agent comprising sodium trimetaphosphate, 2,3-dibromopropanol, epichlorohydrin, and epibromohydrin or mixed with a suitable polysaccharide or polyol are compressed into tablets, those tablets are resistant to amylase degradation provided that the lubricant used for tableting is not magnesium stearate. These tablets can then be used for the controlled release of oral pharmaceutical products. Conversely, when the objects of the invention are dispersed as a powder in an amylase medium, they are readily degraded. Therefore, when placed in a tablet, it was entirely unexpected that the objects of the invention were stable to amylase.

It has also been surprisingly found that when covalently cross-linked high amylose starch of the invention is exposed to water, it predominantly forms a double helix similar to the B-form of amylose. Upon placement of a high amylose cross-linked starch tablet in water, a gel is formed very quickly at the polymer surface. As the progression of the gel front toward the center of the tablet ceases rapidly, water diffuses into the polymer and reaches the center in about 30 min. As water continues to penetrate, the water gradient in the core progressively diminishes and the core expands, mainly radially. This process goes on for several hours, until the core turns into a gel and equilibrium swelling is reached. In the gel state, the cross-linked high amylose starch, which was initially arranged mainly in the amorphous state and in V type single helices, progressively adopts the B-type double helices conformation, forming a three-dimensional physical network over a long distance. Both amylose and PVA can adopt helical confirmations. PVA is an interesting polymer with alternating hydrophilic (CHOH) and hydrophobic (CH₂) groups, and consequently, undergoes lower swelling in water than amylose.

Claim 1 of 34 Claims

We claim:

1. A solid controlled release oral pharmaceutical dosage unit in the form of a tablet comprising a blend of 0.01-80% by weight of the tablet of a dry powder of a pharmaceutical product, and 20-99.99% by weight of the tablet of a dry powder of high amylose starch, wherein said high amylose starch comprises a mixture of from about 10-60% by weight of amylopectin and from about 40-90% amylose, wherein said high amylose starch has been covalently cross-linked with a covalent cross-linking agent wherein the cross-linking has been carried out with from about 0.1 g to about 30 grams of cross-linking agent per 100 g of said high amylose starch, wherein said dosage unit is resistant to degradation by amylase.

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