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Time and pH dependent colon specific, pulsatile delivery of theophylline for nocturnal asthma. The present study demonstrated a modified chronopharmaceutical formulation based on time and pH for the delivery of theophylline microcapsules to the colon. The formulated system consisted of an insoluble hard gelatin capsule body which was filled with theophylline microcapsules and sealed with a hydrogel plug like guar gum, HPMC and sodium alginate. For overcoming the variability in gastric emptying time, the entire device was coated with an enteric polymer.
Andrea Gazzaniga.et al., "Oral pulsatile delivery systems based on swellable hydrophilic polymers" In this study, the various hydrophilic polymers used in the different pulsatile release formulations like reservoir, capsular and osmotic formulations were studied. The water swellable polymers especially polysaccharidic compounds have been exploited to the greatest extend in the delayed release formulations. These hydrophilic polymers have shown to successfully provide a lag phase required, by undergoing swelling, dissolution or erosion processs and thus enabling its use in chronotherapeutic approaches.
Mohammad Barzegar-Jalali.et al., "Propranolol hydrochloride osmotic capsule with controlled onset of release" Propranolol hydrochloride osmotic capsule was formulated and evaluated. The system consisted of an hard gelatin capsule coated with ethyl cellulose with or without castor oil and was filled with propranolol hydrochloride along with sorbitol which functioned as an osmotic agent. Beeswax plug was used for sealing the capsule body. The various factors like membrane thickness, plug thickness, concentration of cellulose acetate and castor oil was also studied and the system was found to be useful for chronotherapeutic purposes.
Sindhu Abraham.et al., "Development of modified pulsincap drug delivery system of metronidazole for drug targeting" The formulated design consisted of a formaldehyde treated hard gelatin capsule containing the metronidazole pellets and plugged with polymers like guar gum, HPMC-10K, carboxymethylcellulose sodium and sodium alginate at different concentrations. The prepared capsules were further coated with an enteric polymer and a lag time of about 5 hrs was obtained.
Usha Yogendra Nayak.et al., "Chronotherapeutic drug delivery for early morning surge in blood pressure: A programmable delivery system" The study involved the formulation of a system which contained a swellable polymer like xanthan gum, sodium alginate, L-HPC or poly ethylene oxide along with the drug (valsartan) tablet and an erodible tablet of L-HPC or guar gum in a pre coated capsule. The drug release was influenced by the type and amount of polymers and also the erodible tablet. Everted rat intestinal segment was used for the dissolution - absorption study and it indicated a successful delay in absorption of the drug.
Hong-Liang Lin.et al., "Release characteristics and in vitro-in vivo correlation of pulsatile pattern for a pulsatile drug delivery system activated by membrane rupture via osmotic pressure and swelling" The performed study demonstrated that for a Pulsatile drug delivery system based on the principle of membrane rupture, the core and the coating formulation influences the release profile. The thickness, hydrophilicity and the osmotic effect of the semi permeable membrane and the swellability of the excipients determined the lag time of the system. Also the addition of a hydrophilic plasticizer showed a decrease in the lag time.
Akhgari, F. Sadeghi.et al., "Combination of time-dependent and pH-dependent polymethacrylates as a single coating formulation for colonic delivery of indomethacin pellets" In this study a combination of two pH dependent polymers (Eudragit S100 and Eudragit L100) and a time dependent polymer (Eudragit RS) was used for designing a formulation for the delivery of indomethacin pellets to the colon. The lag time of the system was affected by the coating level and its optimum was found to be 10%.
T.Y. Fan.et al., "An investigation of pulsatile release tablets with ethylcellulose and Eudragit L as film coating materials and cross-linked polyvinylpyrrolidone in the core tablets" In the present study, the system formulated for the pulsatile delivery of diltiazem hydrochloride consisted of a coating of ethyl cellulose and Eudragit L and cross linked poly vinyl pyrrolidone was employed as the swelling agent. The PH of above 6 caused Eudragit L to dissolve and created pores in the coating through which water permeated and caused the expansion of the swelling agent which resulted in the burst release of the drug. The in vivo study showed good correlation with the in vitro data.
Ina Krogel.et al., "Pulsatile drug release from an insoluble drug body controlled by an erodible plug" The formulated system consists of an impermeable capsule body housing the drug and an erodible plug which is prepared by either direct compression or by the congealing of a meltable plug material. With increasing molecular weight of the hydrophilic plug material and decreasing concentration of the filler, the erosion time increased. Congealable lipid plugs and surfactants decreased the erosion time. The effect of various excipients like effervescent agents on the rapid release of drug was also demonstrated.
Pedro R. Petrovick.et al., "Influence of adjuvants on the in vitro dissolution of hydrochlorothiazide from hard gelatin capsules" The aim of the study was to determine the influence of various excipients like fillers, lubricants and surfactants on the dissolution of hydrochlorothiazide from hard gelatin capsules. The formulations with no surfactant showed the lowest dissolution profile. The greatest effect on the dissolution profile was due to lubricants and then by the filler. Hydrophobic lubricants like magnesium stearate showed lesser dissolution efficiency than aerosil. Though both micro crystalline cellulose and lactose are hydrophobic, because of the water incorporation property of the micro crystalline cellulose, it showed better dissolution efficiency than lactose.
Rebecca L. Carrier.et al., "The utility of cyclodextrins for enhancing oral bioavailability" The ability of Î²- cyclodextrin to enhance the oral bioavailability of drugs was examined in this study. The complexation of the drug with Î²- cyclodextrin improved the bioavailability better than the physical mixture. The dissolution and absorption of the inclusion complex was found to be related to the physical and chemical property of the drug, Î²- cyclodextrin and also the dosage form.
A.Gazzaniga.et al., "Different HPMC viscosity grades as coating agents for an oral time and/or site-controlled delivery system: a study on process parameters and in vitro performances" The study involved the development and optimization of a formulation devised to release drug after a lag time or to deliver the drug to the colon using different grades oh HPMC. Methocel® E50 was found to be the better hydrophilic polymer as it was least affected by the concentration of the coating solution, medium ph and ionic strength.
Julie Binns.et al., "The tolerability of multiple oral doses of Pulsincap TM capsules in healthy volunteers" The peformed study was double-blind and had a placebo-controlled parallel group. Twelve healthy subjects were involved in the study of which eight subjects were given Pulsincap TM capsules and four subjects were given a matching placebo capsule. The eight subjects who received the Pulsincap TM capsules showed no evidence of adverse events and the formulation was well tolerated. The results of the study showed that Pulsincap TM capsules can be formulated for the delivery of therapeutic agents.
Howard N.E. Stevens.et al., "Evaluation of Pulsincapâ„¢ to provide regional delivery of dofetilide to the human GI tract" The study was designed to formulate a delivery system to release dofetilide, a well absorbed drug following a 5hr delay or to target its release to the lower gastrointestinal tract. Dofetilide showed a reduced bioavailability when delivered from the Pulsincapâ„¢ formulations. The site of drug release and in vitro in vivo correlation was determined from the scintigraphic analysis.
T. Bussemer.et al., "A pulsatile drug delivery system based on rupturable
coated hard gelatin capsules" In the present study, the system formulated consisted of a hard gelatin capsule which was coated first with a swelling layer, and then with an outer insoluble water-permeable polymer. The lag time increased with increasing coating thickness and decreased on the addition of a hydrophilic pore former. The swelling caused due to the water ingress through the outer polymer resulted in the rupturing of the coating and there by the drug release. The extent of medium uptake was almost the same for the different coating levels. The addition of the hydrophobic particulate material to the coating resulted in a reduced lag time.
Jason T. Mc Convillea.et al., "The effect of wet granulation on the erosion behavior of an HPMC-lactose tablet, used as rate controlling component in a pulsatile drug delivery capsule formulation" In the study it was demonstrated that the HPMC tablets prepared by wet granulation showed longer lag times compared to those prepared by direct compression. This was more prominent at low concentrations of HPMC. Microwave dielectric analysis was used for determining the degree of polymer spreading in the aqueous system.
R.Bodmeier.et al., "Evaluation of the swelling, hydration and rupturing properties of the swelling layer of a rupturable pulsatile drug delivery system" The study exhibited a linear correlation between the water uptake and the swelling layer. The ionic strength and the pH of the medium was shown to influence the swelling behavior of Ac-Di-Solw which was due to the acidic nature of the polymer and the competition for free water. The analysis of the time dependent swelling force data confirmed that the penetration rate of the medium controlled the diffusion controlled swelling force development.
Gordon L. Amidonc.et al., "Pharmacokinetics of an immediate release, a controlled release and a two pulse dosage form in dogs" In the present study, for each dosage form the pharmacokinetic parameters were determined. On comparing the plasma time curves, it was found that there was a significant difference in the drug plasma levels for each dosage form. For each dose between 1 - 1.75 and 2.5 - 3.5 hr, two defined Cmax values were obtained.
Roland Bodmeier.et al., "Floating or pulsatile drug delivery systems based on coated effervescent cores" In the present study it was demonstrated that the time of floatation depended on factors like the concentration of the effervescent agent, the type of filler, hardness of the core tablet and the thickness and composition of the polymer like the type of polymer and plasticizer used. In order to facilitate a rapid drug release after the lag phase, a quick release core was formulated. The lag time increased with increasing coating level and core hardness.
Joseph Kosta.et al., "Responsive polymeric delivery systems" In the present study, the fundamental principles of the self regulated delivery systems and the externally regulated delivery systems were studied. According to the physiological need these systems are capable of adjusting the release rate of the drugs. The advantages and disadvantages of the different approaches according to the different clinical conditions like diabetes were also evaluated.
Ross AC.et al., "Chronopharmaceutical drug delivery from a pulsatile capsule device based on programmable erosion" The present study involved the development of a pulsatile drug delivery device which consisted of an insoluble capsule body containing the drug formulation (propranoloI hydrochloride) and sealed with an erodible tabet. With the increasing concentration of dibasic calcium phosphate ( insoluble excipient) and HPMC( gel-forming excipient), the lag time was also found to increase. The time release was influenced by the composition and weight of the erodible tablet. The formulated system can be used for the development of a chronopharmaceutical delivery system with a lag time ranging from 2-12 hrs by manipulating the erodible tablet formulation.
Björn Lemmer.et al., "Circadian rhythms and drug delivery" The functions of the body are found to follow circadian rhythm eg. Blood pressure, heart rate, blood flow, pulmonary, hepatic and renal functions. Therefore the onset of diseases and also their symptoms show a variation within the 24 hrs of a day. The pharmacokinetics and pharmaco-dynamics of the different drugs like anti-asthmatics, H-2 blockers and cardiovascular drugs also show daily variation. So it can be summarized that while evaluating a drug delivery system, the biological rhythm of the body functions has to be taken into account.
Hermida RC.et al., "Administration-time-dependent effects of antihypertensive treatment on the circadian pattern of blood pressure" The study was performed to develop a methodology for the treatment of hypertension taking into account the circadian blood pressure pattern. The difference in the time of administration of a drug has shown a difference in its anti-hypertensive action. Nifedipine gastrointestinal therapeutic system showed better anti-hypertensive action and a significant reduction in blood pressure when administered at bedtime than when compared to the early morning administration.
Nayak UY.et al., "Chronotherapeutic drug delivery for early morning surge in blood pressure: a programmable delivery system" The objective of the study was to formulate a pulsatile delivery system for valsartan. . The formulated system contained swellable polymer like L-HPC, polyethylene oxide, xanthan gum or sodium alginate along with the drug tablet and an erodible tablet (L-HPC or guar gum)enclosed in a pre-coated capsule. The various formulation parameters were investigated. The drug release was influenced by the type and amount of polymers and the erodible tablets. A delayed absorption of drug was observed from the continuous dissolution-absorption study performed using everted rat intestine.
DRUG AND POLYMER PROFILE
Chemical name : 6-Chloro-3,4-dihydro-2H-1,2,4- benzothiadiazine-7-sulfonamide 1,1-dioxide
Molecular formulae : C7H8ClN3O4S2
Molecular weight : 297.73
Description : white or almost white, crystalline powder, odourless
Solubility : soluble in acetone; sparingly soluble in ethanol(95%); very slightly soluble in water. Dissolves in dilute solutions of alkali hydroxide.
Ultraviolet spectrum : 273nm
Category : Diuretic
Dose : 12.5 to 100mg
Dosage form : capsules, tablets, oral solution
MECHANISM OF ACTION :
Hydrochlorothiazide, belonging to the thiazide class of diuretics, acts by blocking the reabsorption of sodium and chloride ions, and it thereby increasing the quantity of sodium traversing through the distal tubule of the nephron and thus increasing the volume of water excreted.
The three mechanisms proposed for the acute antihypertensive effects of thiazides are reduction in blood volume and cardiac output, natriuretic effect and a direct vasodilatory effect. The plasma volume returns toward normal with its chronic administration but peripheral vascular resistance is decreased.
Bioavailability : 65-75%
Protein binding : 40-60%
Metabolism : does not undergo significant metabolism
(>95% excreted unchanged in urine)
Excretion : Primarily excreted unchanged in urine
Half-life : 6 to 10 hours / 2.5 ± 0.2 hrs
Routes : Oral
CELLULOSE ACETATE PHTHALATE
Synonyms : Cellacefate, Cellulose acetate phthalate, cellulose acetate hydrogen phthalate, Aquacoat cPD
Chemical name : Cellulose acetate 1,2-benzenedicarboxylate
Functional category : Coating agent
Description : White, free-flowing powder or colorless flakes; odourless or with a faint odour of acetic acid; hygroscopic.
Solubility : Freely soluble in acetone; soluble in diethylene glycol and in dioxan; practically insoluble in water, in ethanol (95%), in toluene and in chlorinated and non-chlorinated aliphatic hydrocarbons. It dissolves in dilute solutions of alkalis.
Melting point : 192áµ’C
Density (bulk) : 0.260 g/cm3
Density (tapped) : 0.266 g/cm3
Use : used as an enteric film coating material or as a matrix binder for tablets and capsules.
Synomyms : Aquacoat ECD; Aqualon; Ashacel; E462; Ethocel; Ethylcellulosum; Surelease.
Chemical name : Cellulose ethyl ether
Functional Category : Coating agent; flavoring agent; tablet binder; tablet filler; Viscosity increasing agent
Description : Ethyl cellulose is a tasteless, free-flowing, white to light tan colored powder.
Solubility : practically insoluble in glycerin, propylene glycol and water; freely soluble in chloroform, methyl acetate and tetrahydrofuran, and in mixtures of aromatic hydrocarbons with ethanol (95%).
Density (bulk) : 0.4 g/cm3
Use : Hydrophobic coating agent for tablets and granules; Ethyl cellulose coatings are used to modify the release of a drug, to mask an unpleasant taste, or to improve the stability of a formulation
Synonym : Bleached wax; cera alba
Chemical Name : White beeswax
Functional Category : Controlled-release agent; stabilizing agent; stiffening agent.
Description : Yellowish-white pieces or plates, translucent when thin, with a fine grained, matt, non-crystalline fracture; becomes soft and pliable when warmed by hand. Odour, faint and characteristic.
Solubility : Partially soluble in hot ethanol (90%) and in ether; practically insoluble in water; completely soluble in volatile and fixed oils.
Melting range : 60-67áµ’C
Density : 0.95-0.96 g/cm3
Use : Used to increase the consistency of creams and ointments, and to stabilize water-in-oil emulsions. White wax is used to polish sugar coated tablets and to adjust the melting point of suppositories.
HYDROXY PROPYL METHYL CELLULOSE (HPMC)
Molecular Formula : C56H108O30
Molecular Weight : 3912.39
Description : White to off-white powder
Solubility : Swells in cold water, insoluble in hot water, soluble in most organic solvents.
Melting point : 56.2áµ’C
Density : 1.39 g/cm3
Chemical properties : HPMC is cellulose ether, derived from alkali treated cellulose that is reacted with methyl chloride and propylene.
Uses : Used as an enteric film coating material or a matrix binder in solid dosage forms. Used as a viscosity control agent, gelling agent, film former, stabilizer, dispersant, lubricant, binder, emulsifying agent and suspending agent. End applications include adhesives and glues, agriculture, building materials, personal care products, detergents and surfactants, paints, printing inks and coatings, pharmaceuticals, food products, polymerization and textiles.