High-amylose carboxymethyl starch matrices for oral sustained drug-release: in vitro and in vivo evaluation.

High-amylose corn starch, that contains 70% of amylose chains and 30% of amylopectin, has been used to obtain substituted amylose (SA) polymers. Tablets have been prepared by direct compression, i.e. dry mixing of drug and SA, followed by compression, which is the easiest way to manufacture an oral dosage form. Until now, their controlled-release properties have been assessed only by an in vitro dissolution test. Amylose-based polymers are normally subject to biodegradation by alpha-amylase enzymes present in the gastrointestinal tract, but matrix systems show no significant degradation of tablets by alpha-amylase in vitro. High-amylose sodium carboxymethyl starch (HASCA) is an interesting excipient for sustained drug-release in solid oral dosage forms. In addition to the easy manufacture of tablets by direct compression, the results show that in vitro drug-release from an optimized HASCA formulation is not affected by either acidic pH value or acidic medium residence time. In addition, a compressed blend of HASCA with an optimized quantity of sodium chloride provides a pharmaceutical sustained-release tablet with improved integrity for oral administration. In vivo studies demonstrate extended drug absorption, showing that the matrix tablets do not disintegrate immediately. Nevertheless, acetaminophen does not seem to be the most appropriate drug for this type of formulation.

Renal phosphate wasting in fibrous dysplasia of bone is part of a generalized renal tubular dysfunction similar to that seen in tumor-induced osteomalacia.

Fibrous dysplasia (FD) of bone is characterized by focal replacement of normal bone and marrow with abnormal bone and fibrous tissue. It arises from postzygotic activating mutations of the GNAS1 gene. Hypophosphatemia due to renal phosphate wasting has been reported in association with FD as a part of the McCune-Albright Syndrome (MAS), which is characterized by FD, skin hyperpigmentation, and precocious puberty. To date, the prevalence and mechanism of phosphate wasting has not been well studied. We evaluated 42 patients with FD/MAS. Serum and urine samples were tested for indices of mineral metabolism, amino acid handling, and markers of bone metabolism. Twenty (48%) patients had some degree of renal phosphate wasting. Nephrogenous cyclic adenosine monophosphate (cAMP) was normal in FD patients, suggesting that the underlying cause of phosphate wasting is not the presence of activating GNAS1 mutations in the kidney. In addition, there was evidence of a more generalized renal tubulopathy as represented by the presence of abnormal vitamin D metabolism, proteinuria in 36 (86%) patients, and aminoaciduria in 39 (94%) patients. Renal phosphate wasting significantly correlated with the degree of bone involvement, as assessed by serum and urine markers of bone metabolism, suggesting that a circulating factor produced by FD bone and impacting on the kidney may be the mechanism. These data show that phosphaturia as part of a generalized renal tubulopathy represents the most common extraskeletal manifestation of FD and that the observed tubulopathy is similar to that seen in tumor-induced osteomalacia (TIO).

Effect of some physical parameters on the sustained drug-release properties of substituted amylose matrices.

Substituted amylose (SA) matrix drug tablets prepared by direct compression show sustained drug-release properties. The influence of compression force (CF) and tablet weight (TW) on release properties was studied. CF ranging from 0.5 to 5.0 tons/cm(2) has no significant effect on the release properties of SA,G (glycidol) polymers, with a degree of substitution (DS) greater than 1.5. For a low DS, an augmentation of CF increases the release time of acetaminophen, used as a model drug, until a certain limit is reached. On the other hand, TW has a major effect on the release time of acetaminophen. Release time is directly proportional to TW. The effect of the nature of the active material, its solubility and its concentration in the formulation on the release properties of SA, G polymers was also evaluated, demonstrating the versatility of the system.

Substituted amylose as a matrix for sustained-drug release: a biodegradation study.

Substituted amylose polymers are prepared by reacting amylose chains with a suitable substituent such as 1,2-epoxypropanol (glycidol). Substituted amylose polymers are introduced as novel excipients for controlled release of bioactive materials. Since substituted amylose polymers are amylose-based polymers, they are subject to biodegradation by alpha-amylase enzymes present in the gastro-intestinal tract; thus, gamma spectroscopy is used to follow the release of the natural abundant rhenium (VII) oxide used as a drug model, and to test their resistance to alpha-amylase enzymatic degradation. Two substituted amylose solid dosage forms were prepared: (i) matrix system and (ii) dry-coated tablets. Matrix systems and dry-coated tablets maintained their structure, and controlled the release of [186Re] showing no significant degradation of tablets by alpha-amylase.

Substituted amylose matrices for oral drug delivery.

High amylose corn starch was used to obtain substituted amylose (SA) polymers by chemically modifying hydroxyl groups by an etherification process using 1,2-epoxypropanol. Tablets for drug-controlled release were prepared by direct compression and their release properties assessed by an in vitro dissolution test (USP XXIII no 2). The polymer swelling was characterized by measuring gravimetrically the water uptake ability of polymer tablets. SA hydrophilic matrix tablets present sequentially a burst effect, typical of hydrophilic matrices, and a near constant release, typical of reservoir systems. After the burst effect, surface pores disappear progressively by molecular association of amylose chains; this allows the creation of a polymer layer acting as a diffusion barrier and explains the peculiar behaviour of SA polymers. Several formulation parameters such as compression force, drug loading, tablet weight and insoluble diluent concentration were investigated. On the other hand, tablet thickness, scanning electron microscope analysis and mercury intrusion porosimetry showed that the high crushing strength values observed for SA tablets were due to an unusual melting process occurring during tabletting although the tablet external layer went only through densification, deformation and partial melting. In contrast, HPMC tablets did not show any traces of a melting process.

Substituted amylose as a matrix for sustained drug release.

PURPOSE: Amylose derivatives form an important group of polymers, and many of them can be used as drug sustained-release systems. METHODS: Substituted amylose can be prepared in a 1-step reaction with substituent(s) in a basic medium. The substituents can be represented as (A-R), where (A) serves an epoxy, halide or suitable organic or inorganic function reacting with hydroxyl groups located on the amylose chain, and (R) is an organic radical. RESULTS: The present work shows the synthesis of different polymers and the effect of different (A) and/or (R) and their different degrees of substitution (n) on the sustained drug release from matrix tablets prepared by direct compression. CONCLUSIONS: SA polymers are interesting excipients for the preparation of controlled drug release tablets.