Diltiazem HCl

Diltiazem HCl

Transdermal delivery of Diltiazem HCl from matrix film: Effect of penetration enhancers and study of antihypertensive activity in rabbit model.[Pubmed:27222758]

J Adv Res. 2016 May;7(3):539-50.

The present investigation focused on the development of Diltiazem HCl (DTH) matrix film and its characterization by in-vitro, ex-vivo and in-vivo methods. Films were prepared by solvent casting method by taking different ratios of hydroxypropyl methylcellulose K4M (HPMC K4M) and Eudragit RS100. Various parameters of the films were analyzed such as mechanical property using tensile tester, interaction study by Fourier transform infrared spectroscopy (FTIR) and Thermogravimetric analysis (TGA), in-vitro drug release through cellulose acetate membrane, ex-vivo permeation study using abdominal skin of rat employing Franz diffusion cell, and in-vivo antihypertensive activity using rabbit model. The FTIR studies confirmed the absence of interaction between DTH and selected polymers. Thermal analysis showed the shifting of endothermic peak of DTH in film, indicating the dispersion of DTH in molecular form throughout the film. Incorporation of 1,8-cineole showed highest flux (89.7 mug/cm(2)/h) of DTH compared to other penetration enhancers such as capsaicin, dimethyl sulfoxide (DMSO), and N-methyl pyrrolidone (NMP). Photomicrographs of histology study on optimized formulation (DF9) illustrated disruption of stratum corneum (SC) supporting the ex-vivo results. The in-vivo antihypertensive activity results demonstrated that formulation DF9 was effective in reducing arterial blood pressure in normotensive rabbits. SEM analysis of films kept for stability study (40 +/- 2 degrees C/75% +/- 5%RH for 3 months) revealed the formation of drug crystals which may be due to higher temperature. The findings of the study provide a better alternative dosage form of DTH for the effective treatment of hypertension with enhanced patient compliance.

Effect of solvent type on retardation properties of diltiazem HCl form liquisolid tablets.[Pubmed:24060925]

Colloids Surf B Biointerfaces. 2014 Jan 1;113:10-4.

Liquisolid technique is a new approach to formulate sustained release dosage forms. It seems that the solubility of an active ingredient in solvent plays an important role in drug release profile. The aim of present study was to investigate the effect of solvent type on diltiazem hydrochloride release profile from liquisolid compacts. To examine aforementioned idea, the drug solubility was studied in several conventional nonvolatile solvents. Liquisolid formulations of Diltiazem HCl in the different solvents were prepared and their release profiles were also obtained. Effect of aging on the hardness and drug release profile was studied as well. X-ray crystallography and differential scanning calorimetry (DSC) were used to investigate the formation of any complex between drug and carrier or any crystallinity changes during the manufacturing process. The results showed that Diltiazem HCl had lowest solubility in polysorbate 20. Highest amount was devoted to polysorbate 80 and propylene glycol. Type of nonvolatile solvent and its physicochemical properties as well as solubility of the drug in the applied solvent found to have important role on release profile of the drug from liquisolid compacts. Hardness and dissolution profile of the drug were not affected by aging. Amorphous form was obtained during the process of liquisolid formulation. It follows that the optimized new technique can be used to prepare sustained release formulations of water-soluble drugs.

Effect of solvent on retarding the release of diltiazem HCl from Polyox-based liquisolid tablets.[Pubmed:27714817]

J Pharm Pharmacol. 2016 Nov;68(11):1396-1402.

OBJECTIVES: The aim of this work was to investigate the use of liquisolid technique to sustain the release of a model highly soluble drug, Diltiazem HCl, from liquisolid matrices containing Polyox, a recently proposed matrix-forming hydrophilic polymer as an alternative to hypromellose. METHODS: Polyox-based liquisolid formulations prepared using several non-volatile solvents (i.e. polysorbate 80, polyethylene glycol, polyethylene glycol 200 and polyethylene glycol 600) and then characterised using differential scanning calorimetry and powder X-ray diffraction. The influence of solvent on retarding the release of Diltiazem HCl from Polyox-based liquisolid tablets compared to conventional physical mixture tablets was studied. KEY FINDINGS: Liquisolid tablets exhibited greater retarding properties compared to conventional tablets. The use of polysorbate produced a slower release pattern of the drug from diltiazem hydrochloride (DTZ) liquisolid tablets compared to propylene glycol and polyethylene glycol (200 and 600). The release retardation was decreased with the increase in the concentration of the drug within drug:solvent liquid medication used. Solid-state analysis suggested the presence of a fraction of the drug mass in a solubilised state within polysorbate in liquisolid powders. CONCLUSION: Polyox-based matrix tablets prepared using liquisolid technique in the presence of a carefully selected non-volatile solvent could produce desirable, more sustained release profiles of highly water-soluble drugs compared to conventional physical mixture tablets.

Sustained release of diltiazem HCl tableted after co-spray drying and physical mixing with PVAc and PVP.[Pubmed:26035331]

Drug Dev Ind Pharm. 2016;42(2):270-9.

In this work, aqueous Diltiazem HCl and polyvinyl-pyrrolidone (PVP) solutions were mixed with Kollicoat SR 30D and spray dried to microparticles of different drug:excipient ratio and PVP content. Co-spray dried products and physical mixtures of drug, Kollidon SR and PVP were tableted. Spray drying process, co-spray dried products and compressibility/compactability of co-spray dried and physical mixtures, as well as drug release and water uptake of matrix-tablets was evaluated. Simple power equation fitted drug release and water uptake (R(2) > 0.909 and 0.938, respectively) and correlations between them were examined. Co-spray dried products with PVP content lower than in physical mixtures result in slower release, while at equal PVP content (19 and 29% w/w of excipient) in similar release (f2 > 50). Increase of PVP content increases release rate and co-spray drying might be an alternative, when physical mixing is inadequate. Co-spray dried products show better compressibility/compatibility but higher stickiness to the die-wall compared to physical mixtures. SEM observations and comparison of release and swelling showed that distribution of tableted component affects only the swelling, while PVP content for both co-spray dried and physical mixes is major reason for release alterations and an aid for drug release control.

Molecular mechanism of diltiazem interaction with L-type Ca2+ channels.[Pubmed:9765241]

J Biol Chem. 1998 Oct 16;273(42):27205-12.

Benzothiazepine Ca2+ antagonists (such as (+)-cis-diltiazem) interact with transmembrane segments IIIS6 and IVS6 in the alpha1 subunit of L-type Ca2+ channels. We investigated the contribution of individual IIIS6 amino acid residues for diltiazem sensitivity by employing alanine scanning mutagenesis in a benzothiazepine-sensitive alpha1 subunit chimera (ALDIL) expressed in Xenopus laevis oocytes. The most dramatic decrease of block by 100 microM diltiazem (ALDIL 45 +/- 4.8% inhibition) during trains of 100-ms pulses (0.1 Hz, -80 mV holding potential) was found after mutation of adjacent IIIS6 residues Phe1164(21 +/- 3%) and Val1165 (8.5 +/- 1.4%). Diltiazem delayed current recovery by promoting a slowly recovering current component. This effect was similar in ALDIL and F1164A but largely prevented in V1165A. Both mutations slowed inactivation kinetics during a pulse. The reduced diltiazem block can therefore be explained by slowing of inactivation kinetics (F1164A and V1165A) and accelerated recovery from drug block (V1165A). The bulkier diltiazem derivative benziazem still efficiently blocked V1165A. From these functional and from additional radioligand binding studies with the dihydropyridine (+)-[3H]isradipine we propose a model in which Val1165 controls dissociation of the bound diltiazem molecule, and where bulky substituents on the basic nitrogen of diltiazem protrude toward the adjacent dihydropyridine binding domain.

Inhibition of nicotinic receptor-mediated responses in bovine chromaffin cells by diltiazem.[Pubmed:8818357]

Br J Pharmacol. 1996 Jul;118(5):1301-7.

1. The effects of diltiazem on various functional parameters were studied in bovine cultured adrenal chromaffin cells stimulated with the nicotinic receptor agonist dimethylphenylpiperazinium (DMPP) or with depolarizing Krebs-HEPES solutions containing high K+ concentrations. 2. The release of [3H]-noradrenaline induced by DMPP (100 microM for 5 min) was gradually and fully inhibited by increasing concentrations of diltiazem (IC50 = 1.3 microM). In contrast, the highest concentration of diltiazem used (10 microM) inhibited the response to high K+ (59 mM for 5 min) by only 25%. 3. 45Ca2+ uptake into cells stimulated with DMPP (100 microM for 1 min) was also blocked by diltiazem in a concentration-dependent manner (IC50 = 0.4 microM). Again, diltiazem blocked the K(+)-evoked 45Ca2+ uptake (70 mM K+ for 1 min) only by 20%. In contrast, the N-P-Q-type Ca2+ channel blocker omega-conotoxin MVIIC depressed the K+ signal by 70%. In the presence of this toxin, diltiazem exhibited an additional small inhibitory effect, indicating that the compound was acting on L-type Ca2+ channels. 4. Whole-cell Ba2+ currents through Ca2+ channels in voltage-clamped chromaffin cells were inhibited by 3-10 microM diltiazem by 20-25%. The inhibition was readily reversed upon washout of the drug. 5. The whole-cell currents elicited by 100 microM DMPP (IDMPP) were inhibited in a concentration-dependent and reversible manner by diltiazem. Maximal effects were found at 10 microM, which reduced the peak IDMPP by 70%. The area of each curve represented by total current (QDMPP) was reduced more than the peak current. At 10 microM, the inhibition amounted to 80%; the IC50 for QDMPP inhibition was 0.73 microM, a figure close to the IC50 for 45Ca2+ uptake (0.4 microM) and [3H]-noradrenaline release (1.3 microM). The blocking effects of diltiazem developed very quickly and did not exhibit use-dependence; thus the drug blocked the channel in its closed state. The blocking effects of 1 microM diltiazem on IDMPP were similar at different holding potentials (inhibition by around 30% at -100, -80 or -50 mV). Diltiazem did not affect the current flow through voltage-dependent Na+ channels. 6. These data are compatible with the idea that diltiazem has little effect on Ca2+ entry through voltage-dependent Ca2+ channels in bovine chromaffin cells. Neither, does diltiazem affect INa. Rather, diltiazem acts directly on the neuronal nicotinic receptor ion channel and blocks ion fluxes, cell depolarization and the subsequent Ca2+ entry and catecholamine release. This novel effect of diltiazem might have clinical relevance since it might reduce the sympathoadrenal drive to the heart and blood vessels, thus contributing to the well established antihypertensive and cardioprotective effects of the drug.

Block of P-type Ca2+ channels in freshly dissociated rat cerebellar Purkinje neurons by diltiazem and verapamil.[Pubmed:8574653]

Brain Res. 1995 Oct 9;695(1):88-91.

We investigated the effects of organic Ca2+ channel blockers, diltiazem and verapamil, on the high voltage-activated P-type Ca2+ channels in freshly isolated rat Purkinje neurons. Both diltiazem and verapamil blocked P-type Ca2+ channel current without any change in the current-voltage relation. The block was concentration-dependent. In the presence of these agents, the inactivation curve was shifted to hyperpolarizing potentials. The characteristics of block of P-type Ca2+ channels by diltiazem and verapamil are similar to that of L-type Ca2+ channels. These results indicate that both benzothiazepine and phenylalkylamine react with P-type Ca2+ channels and suggest that some structural features common to which operate in both L-type and P-type Ca2+ channels may be involved in drug binding to these channels.

Effects of diltiazem on bioenergetics, K+ gradients, and free cytosolic Ca2+ levels in rat brain synaptosomes submitted to energy metabolism inhibition and depolarization.[Pubmed:2795006]

J Neurochem. 1989 Nov;53(5):1379-89.

Diltiazem was able to decrease the oxygen consumption rate and lactate production in synaptosomes isolated from rat forebrains, both under control and depolarized (40 microM veratridine) conditions, starting from a concentration of 250 microM. This effect was particularly evident when synaptosomes were depolarized by veratridine. This depolarization-counteracting action was evident also when transplasma membrane K+ diffusion potentials were measured after depolarization induced by veratridine and by rotenone with a glucose shortage. The concentrations of ATP, phosphocreatine, and creatine were less sensitive to diltiazem action. The concentration/response relationships were the same as those found for the oxygen consumption were the same as those found for the oxygen consumption rate, lactate production, and K+ diffusion potentials. The effects of 0.5 mM diltiazem in counteracting inhibition of energy metabolism induced by rotenone without glucose were no longer detectable when either Ca2+ or Na+ was absent from the incubation medium of synaptosomes. Diltiazem at the same concentrations (starting from 250 microM) was able to inhibit both the veratridine-induced and the rotenone-without-glucose-induced increase in intrasynaptosomal free Ca2+ levels evaluated with the fluorescent probe quin2. The results are discussed in view of a possible effect of diltiazem on voltage-dependent Na+ channels and the possibility of utilizing this approach for counteracting neuronal failure due to derangement of energy metabolism or hyperexcitation.