methylcellulose and Hypertension

Using fixed dose combinations of drugs instead of administering drugs separately can be beneficial for both patients and the health care system, but the current understanding of how multidrug formulations work at the molecular level is still in its infancy. Here, we explore dissolution, solubility, and supersaturation of various drug combinations in amorphous formulations. The effect of chemical structural similarity on combination behavior was investigated by using structurally related compounds of both drugs. The effect of polymer type on solution behavior was also evaluated using chemically diverse polymers. Indapamide (IPM) concentration decreased when combined with felodipine (FDN) or its analogues, which occurred even when the IPM solution was undersaturated. The extent of solubility decrease of FDN was less than that of IPM from the dissolution of an equimolar formulation of the drugs. No significant solubility decrease was observed for FDN at low contents of IPM which was also observed for other dihydropyridines, whereas FDN decreases at high contents of IPM. This was explained by the complex nature of the colloidal precipitates of the combinations which impacts the chemical potential of the drugs in solution at different levels. The maximum achievable concentration of FDN and IPM during dissolution of the polyvinylpyrrolidone-based amorphous solid dispersion was higher than the value measured with the hydroxypropyl methylcellulose acetate succinate-based formulation. This emphasizes the significance of molecular properties and chemical diversity of drugs and polymers on solution chemistry and solubility profiles. These findings may apply to drugs administered as a single dosage form or in separate dosage forms and hence need to be well controlled to assure effective treatments and patient safety.

Topics: Antihypertensive Agents; Chemistry, Pharmaceutical; Crystallization; Drug Combinations; Drug Compounding; Drug Interactions; Drug Liberation; Felodipine; Humans; Hypertension; Indapamide; Methylcellulose; Patient Safety; Povidone; Solubility; Solutions

Captopril granules of controlled release with different polymers as ethylcellulose, ethyl/methylcellulose, and immediate release with polyvinylpyrrolidone (PVP) were developed by fluid bed dryer technique. The formulations were analyzed by scanning electron microscopy, X-ray powder diffraction, and dissolution profiles. To compare the formulations an in vivo setting rat blood pressure assay was performed, using angiotensin I as a vasoconstrictor agent. The scanning electron microscopy of granules showed differences in morphology, and X-ray powder diffraction technique presented some modification in crystalline structure of captopril in granules coated with PVP and ethyl/methylcellulose. The dissolution profile of granules coated with ethylcellulose showed a median time release of 4 hr whereas for granules coated with ethyl/methylcellulose, this time was 3.5 hr. The blockage of angiotensin I-induced hypertensive effect lasted 8 hr in granules coated with PVP and of more than 12 hr in the granules coated with ethylcellulose and ethyl/methylcellulose.

Topics: Administration, Oral; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Captopril; Cellulose; Chemistry, Pharmaceutical; Crystallography, X-Ray; Delayed-Action Preparations; Disease Models, Animal; Drug Compounding; Female; Hypertension; Kinetics; Methylcellulose; Microscopy, Electron, Scanning; Models, Chemical; Povidone; Powder Diffraction; Powders; Rats; Rats, Wistar; Solubility; Technology, Pharmaceutical

The cardiovascular effects of a new class of potent inhibitors of dopamine beta-hydroxylase (DBH) were evaluated in spontaneously hypertensive rats (SHR). SK&F 102698 [1-(3,5-difluorobenzyl)imidazole-2-thiol] is the prototype molecule of this class of substituted 1-benzylimidazole-2-thiols and is one of the most potent inhibitors of DBH yet described. After acute p.o. administration in conscious unrestrained SHR, SK&F 102698 elicited a dose-dependent decrease in mean arterial blood pressure. The antihypertensive effect was marked by a gradual onset with long duration of activity. The antihypertensive effect produced by SK&F 102698 was accompanied by bradycardia. SK&F 102698 inhibited DBH in vivo as demonstrated by its ability to increase vascular levels of dopamine (DA) while concomitantly decreasing vascular levels of norepinephrine (NE), thus increasing the overall DA/NE ratio. The chronic cardiovascular effects of SK&F 102698 were evaluated in developing SHR. SHR were administered SK&F 102698 p.o. once daily for 9 weeks beginning when animals were 4 weeks of age. SK&F 102698 (50 mg/kg) significantly attenuated the development of hypertension of these SHR. Tolerance to the chronic effects of DBH inhibition was not observed and blood pressures in drug-treated animals were still reduced significantly 20 hr after drug administration. Vascular catecholamine levels were determined in the mesenteric artery of these chronically treated animals. Vascular DA levels were increased 290%, vascular NE levels were decreased 36% and the DA/NE ratio was increased 520%, as compared to controls. Furthermore, hearts weights of SHR receiving SK&F 102698 were approximately 10% lower than controls. The present study demonstrates that in SHR SK&F 102698 is an effective antihypertensive whose effects are mediated by the novel mechanism of DBH inhibition.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Cardiovascular System; Dopamine beta-Hydroxylase; Hypertension; Imidazoles; Male; Methylcellulose; Norepinephrine; Rats; Rats, Inbred SHR

Topics: Animals; Hypertension; Kidney Glomerulus; Methylcellulose; Microscopy, Electron; Polysaccharides; Polyvinyls; Rats

Topics: Angiotensins; Blood Chemical Analysis; Blood Pressure; Blood Pressure Determination; Bradykinin; Hypertension; Hypertension, Renal; Kidney; Metabolism; Methylcellulose; Nephrectomy; Peptides; Rats; Research; Serum; Tissue Extracts

Topics: Glomerulonephritis; Hypertension; Methylcellulose

Topics: Humans; Hypertension; Methylcellulose; Nephritis

Topics: Humans; Hypertension; Methylcellulose; Polyvinyl Alcohol; Polyvinyls; Sodium Chloride

Topics: Hypernatremia; Hypertension; Hypertension, Renal; Kidney; Methylcellulose; Sodium; Sodium Chloride

Topics: Adrenal Glands; Cardiomegaly; Humans; Hypertension; Kidney; Liver; Methylcellulose; Splenectomy

Topics: Humans; Hypertension; Injections; Methylcellulose