In the recent years, fixation of physiologically active molecules, such as pharmaceutical molecule, enzyme molecule and the like, on a polymeric support is extensively studied.
Cross-linked poly(allylamine) polymers have found many therapeutic applications as substrate-binding polymers:    a) in hyperphosphatemia, phosphate-binding polymers are provided for removing phosphate from the gastrointestinal tract by oral administration;    b) in hypercholesterolemia, bile acid-binding polymers are used as effective treatment for removing bile salts from a subject and thereby reducing the subject's cholesterol level. Because the sole biological precursor to bile salts is cholesterol, the metabolism of cholesterol to make bile salts is accompanied by a simultaneous reduction in the cholesterol in the subject.
Hyperphosphatemia is one of the major complications of hemodialysis subjects and plays a key role in the pathogenesis of cardiovascular calcification and secondary hyperparathyroidism. Hyperphosphatemia, especially if present over extended periods of time, leads to severe abnormalities in calcium and phosphorus metabolism, often manifested by aberrant calcification in joints, lungs, and eyes. Therapeutic efforts to reduce serum phosphate include dialysis, reduction in dietary phosphate, and oral administration of insoluble phosphate binders to reduce gastrointestinal absorption. Dialysis and reduced dietary phosphate are usually insufficient to adequately reverse hyperphosphatemia, so the use of phosphate binders is routinely required to treat these subjects. Phosphate binders include calcium or aluminium salts, or organic polymers that act as ion exchange resins.
Calcium salts have been widely used to bind intestinal phosphate and prevent absorption. Different types of calcium salts have been utilized for phosphate binding. The major problem with all of these therapeutics is the hypercalcemia that causes serious side effects such as cardiac arrhythmias, renal failure, and skin and visceral calcification. Frequent monitoring of serum calcium levels is required during therapy with calcium-based phosphate binders.
Aluminium-based phosphate binders have also been used for treating hyperphosphatemia, but prolonged use of aluminium gels leads to accumulations of aluminium, and often to aluminium toxicity, accompanied by such symptoms as encephalopathy, osteomalacia, and myopathy.
Among the most widely used phosphate binders, Sevelamer hydrochloride, an organic polymer that acts as ion-exchange resin, shows the best characteristics of low toxicity and binding efficiency.
Sevelamer hydrochloride is a compound of Formula (III),
a poly(allylamine) cross-linked with epichlorohydrin, which is disclosed in EP 716 606 B1 (whose United States equivalent is U.S. Pat. No. 4,255,431) and marketed under the trade name RENAGEL®. Sevelamer hydrochloride is a polycation polymer and binds phosphorus in the gastrointestinal tract to facilitate phosphorus excretion in faeces, thereby inhibiting phosphorus absorption from the gut, and thereby lowering the plasma phosphorus concentration.
Hyperphosphatemia and metabolic acidosis frequently accompanies diseases associated with inadequate renal function. Current treatments for hyperphosphatemia do not address the issue of metabolic acidosis; its consequences can be serious. The human body is constantly gaining H+ ions from the metabolism of sugars, fats, protein and lactic acid (produced under anaerobic metabolism). To maintain a constant pH the body must excrete H+ ions. Decreased excretion of H+ ions occurs in patients suffering from renal disease or renal failure, which results in metabolic acidosis and, hence, a low blood pH due to excess H+ ions. To treat metabolic acidosis, Sevelamer carbonate represents a good alternative. Sevelamer carbonate is a poly(allylamine) polymer cross-linked with epichlorohydrin, disclosed in EP 716 606 B1 (whose United States equivalent is U.S. Pat. No. 4,255,431), and marketed under the trade name RENVELA®.
The patent application WO 2007035313 discloses a powder formulation comprising a pharmaceutically acceptable anionic stabilizer and cross-linked poly(allylamine) polymers or a pharmaceutically acceptable salt thereof, such as Sevelamer carbonate, mixed with the anionic stabilizer. The powder formulation contains less than 5 wt % of particles having a particle size more than 300 μm and less than 5 wt % of particles having a particle size less than 10 μm.
Reabsorption of bile acids from the intestine conserves lipoprotein cholesterol in the bloodstream. Conversely, blood cholesterol levels can be diminished by reducing reabsorption of bile acids. One method of reducing the amount of bile acids that are reabsorbed and, thus, reducing serum cholesterol is the oral administration of compounds that sequester the bile acids and cannot themselves be absorbed. The sequestered bile acids consequently either decompose by bacterial action or are excreted. Compounds which have been suggested for bile acids sequestration include various ion exchange polymers. One such polymer is Colesevelam hydrochloride, a poly(allylamine) hydrochloride cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethylammonium bromide, disclosed in EP 764.174 B1 (whose United States equivalents are U.S. Pat. Nos. 5,693,675 and 5,679,717), and marketed under the trade name WELCHOL®. Colesevelam hydrochloride is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, impeding their reabsorption.
As said above, phosphate-binding polymers, such as Sevelamer hydrochloride, Sevelamer carbonate, and bile acid-binding polymers, such as Colesevelam hydrochloride, are cross-linked polymers characterized by allylamine as repeating unit, “poly(allylamine) polymers”, or a salt thereof. Several methods have been used to prepare cross-linked poly(allylamine) polymers.
The methods disclosed in EP 716.606 B1 (whose United States equivalent is U.S. Pat. No. 4,255,431), to obtain cross-linked poly(allylamine) polymers, such as Sevelamer hydrochloride, involves a two step process consisting of:    a) preparing poly(allylamine) hydrochloride from allylamine;    b) neutralizing with NaOH and cross-linking poly(allylamine) with epichlorohydrin by an alkylation reaction.
U.S. Pat. No. 6,362,266 discloses a process for producing a cross-linked poly(allylamine) polymer having reduced cohesiveness from an aqueous solution of a washed cross-linked poly(allylamine) polymer treated with a surfactant.
U.S. Pat. No. 4,605,701 discloses a process for producing a small-globular cross-linked polymer of monoallylamine through a post-polymerization reaction of a crosslinking agent with the monoallylamine homopolymer in an inverse emulsion.
All these methods involve a non economical two steps process and usually the poly(allylamine) polymers obtained are a gel like substances.
When a gel like substance is obtained, mechanical or chemical processes (e.g. grinding, slurring, lyophilisation, . . . ) are further needed to transform a gel like substance in a solid state.
The cross-linking agent of choice in the prior art is epichlorohydrin, a harmful and suspect carcinogenic substance. Further, the cross-linking of poly(allylamine) with epichlorohydrin or with any other suitable difunctional molecule may lead to a poor compositional homogeneity of the final cross-linked polymer. This is particularly true if the difunctional cross-linking molecule is not soluble in the aqueous solvent that is the solvent of choice for the polymerisation of allylamine, and if the two functional groups of said molecule have different reactivity. Furthermore, purification of the cross-linked product from any unreacted cross-linking agent is a costly and possibly poorly efficient procedure.
Therefore, a novel process for preparing cross-linked poly(allylamine) polymers, a method applicable to producing a variety of hyperbranched polymers by means of a single step consisting of free radical polymerization in batch, semi-continuous or, even more preferably, a continuous reactor would be highly desirable.
An object of the present invention is to provide a novel, efficient, economic and commercially useful, one step process for preparing cross-linked poly(allylamine) polymers or salts thereof, that avoid the above-mentioned disadvantages.
USPTO Backgrounds
USPTO Backgrounds