Formulation development and optimization studies of mouth dissolving tablets of tizanidine HCl.

The purpose of this research was the development and optimization of mouth dissolving tablets (MDT) of Tizanidine hydrochloride using superdisintegrant. MDTs of Tizanidine (4mg) were manufactured by direct compression method. Formulations comprised of Tizanidine and excipients including croscarmellose sodium, Avicel PH 102, aspartame, orange flavor and magnesium stearate. Blends of powder were assessed for flow characterization and then compressed by direct compression. During post compression stage, a detail evaluation of tablets with respect to weight variation, hardness, thickness, disintegration time, wetting time, friability, drug content analysis, content uniformity, palatability and dissolution studies was carried out. All the formulations complied with the pharmacopeial requirements of weight, disintegration time and assay. Amongst the trial formulations F4 with concentration of croscarmellose sodium i.e. 5% was proved as best optimized due to satisfactory quality attributes such as least disintegration time and sufficient hardness. Hence, it was concluded that manufacturing of mouth dissolving tablets by addition of superdisintegrant is beneficial for treating patients with dysphagia.

[Study of analgesic effect of novel imidazoline derivatives and their effect on arterial pressure during pain]. / Izuchenie boleutoliaiushchego deistviia novykh proizvodnykh imidazolina i ikh vliianiia na arterial'noe davlenie v usloviiakh bolevogo vozdeistviia.

In rat experiments new imidazoline derivatives caused a pain-relieving effect and inhibited a rise in arterial pressure in pain. Fluoride derivatives of imidazoline in doses of 1, 2, and 4 mg/kg induced long-term analgesia, had no effect on the background arterial blood pressure (AP), and significantly reduced its nociceptive pressor responses. The bromide derivatives of imidazoline showed no noticeable pain-relieving activity but reduced the nociceptive AP shifts. The background AP parameters did not change in this case. The prospects of directed chemical modification of imidazoline derivatives to obtain new analgesics capable of reducing the undesirable hemodynamic manifestations of pain are discussed.

Radioiodinated p-iodoclonidine: a high-affinity probe for the alpha 2-adrenergic receptor.

The chemical synthesis of 2-[(2,6-dichloro-4-iodophenyl)imino]imidazolidine (PIC) and its radioiodinated analogue [125I]PIC is described. PIC was synthesized from 2,6-dichloroaniline in five synthetic steps. This agent displayed a high affinity for the alpha 2-adrenergic receptor (IC50 = 1.5 nM) in competitive binding assays conducted with purified human platelet plasma membrane fractions. For the synthesis of radioiodinated PIC the triazene intermediate 11 was synthesized from 2,6-dichloro-4-nitroaniline in five synthetic steps. Acid-catalyzed decomposition of 11 with no-carrier-added Na125I afforded high specific activity [125I]PIC. In view of its high affinity for the alpha 2-adrenergic receptor, [125I]PIC is a potentially useful probe for studies in adrenergic pharmacology.

Two stereoisomeric imidazoline derivatives: synthesis and optical and alpha 2-adrenoceptor activities.

Two eight-step pathways for synthesizing the stereoisomeric compounds (-)-2-[1-(2,6-dichlorophenoxy)ethyl]-2-imidazoline hydrochloride ("levlofexidine" hydrochloride; (-)-lofexidine hydrochloride) and (+)-2-[1-(2,6-dichlorophenoxy)ethyl]-2-imidazoline hydrochloride ("dexlofexidine" hydrochloride; (+)-lofexidine hydrochloride) and the optical resolution of (+/-)-lofexidine are described. (-)-Lofexidine, a stereoselective alpha 2-adrenoceptor agonist, due to its center of asymmetry, is demonstrated to be a potent drug for the treatment of hypertension (doses 0.561 microgram/kg) and to have the highest affinity and a concentration dependency for alpha 2-adrenoceptors in direct binding studies (0.36 nmol/L). (+)-Lofexidine is 10 times less potent.

p-Azidoclonidine: a photoaffinity label for the alpha 2-adrenoceptor.

We have synthesized and characterized p-azidoclonidine (AZC) as a putative alpha 2-adrenoceptor photoaffinity label. [3H]AZC demonstrated high affinity (KD = 11.8 +/- 2.5 nM), saturability (Bmax = 171 +/- 21 fmol/mg protein), stereo-specificity, and rank order of potency expected of a specific alpha 2-receptor label when used as a reversible ligand in the rat cerebral cortex. The pharmacologic profile of AZC was similar to p-aminoclonidine (PAC), an established alpha 2-adrenoceptor partial agonist. Membranes covalently prelabeled with nonradioactive AZC showed a dose dependent decrease in the number of alpha 2-receptor sites subsequently detected by [3H]PAC and [3H]yohimbine. Specific covalent [3H]AZC binding to rat cerebral cortical alpha 2-receptors represented 35 +/- 7% of the total [3H]AZC bound. These data indicate that AZC is a selective alpha 2-adrenoceptor photoaffinity label which may be useful in the identification and purification of the alpha 2-Adrenoceptor.

An affinity label for alpha 2-adrenergic receptors in rat brain.

Clonidine, a potent and highly selective alpha 2-adrenergic agonist of the central nervous system, was modified. Insertion of the strong alkylating isothiocyanate group (NCS) group, at its aromatic residue, makes clonidine a potential affinity label of the alpha 2-adrenergic receptors. In displacement of [3H]clonidine and p-[3H]aminoclonidine from rat brain membrane preparations, clonidine-NCS demonstrates high affinity for the alpha 2-adrenergic receptors (Kd = 50 mM). The covalent labelling of the central alpha 2-receptors requires higher concentrations of the irreversible ligand (1-70 microM), thus indicating possible non-productive interactions at the environment of the receptor site. Only partial protection of the receptors is observed with a reversible alpha 2-agonist. The new clonidine analog appears to be a general ligand for the alpha 2-adrenergic receptors and might serve as a potential affinity probe for these receptors.

Chemistry of lofexidine.

The systematic syntheses and pharmacological studies of numerous imidazolines aryloxyalkyl-substituted in the 2-position show that substitution of the aryl residue in the 2,6-position by halogen and addition of a side-chain to the alkyl residue results in compounds with marked antihypertensive activity. 2-[1-(2,6-Dichlorphenoxy)-ethyl-2-imidazoline hydrochloride (lofexidine, Lofetensin and Loxacor) exhibits the most marked hypotensive activity. The synthesis and physico-chemical properties of lofexidine are described.

Clonidine and related analogues. Quantitative correlations.

Twenty-two structural derivatives of clonidine [2-(2,6-dichlorophenylimino)imidazolidine] have been synthesized and their main physicochemical parameters (log P, deltaRM, pKa) determined. Quantitative correlations between the peripheral alpha-mimetic action (pithed rats) and physicochemical parameters pointed out the critical role of the steric effect in the ortho positions. On the other hand, attempted quantitative correlations between physicochemical parameters and central hypotensive activity were unsuccessful. These results are discussed in the light of the postulated mechanism of action of clonidine.