An extended-sustained pulsatile release drug delivery dosageformulation for chronotherapy

Abstract

Morning surge has appealed ample consideration owing to the relation between blood pressure levels and cardiovascular risk due to hypertensive organ damage. The present invention provides a formulation to modulate release profile, to synchronize release profile with chronobiologic antihypertensive therapy focusing primarily on morning surge. A time- controlled and position-controlled extended-sustained pulsatile drug delivery dosage formulation consisting of plurality of core particles, each particle having a base sealing layer of hydrophilic methylcellulose polymer, an intermediate layer comprising of an active drug, a binder and apore forming agent and an outerlayer comprising of an poly(meth)acrylates polymer, emulsifier, plasticizer, anti-tacking agent, wherein the drug release rate controlling polymer is EUDRAGIT FS SOD. The pellets are designed to carry the drugs exhibiting first pass metabolism and have a predetermined span of time of no release.

Description

[0001] AN EXTENDED-SUSTAINED PULSATILE RELEASE DRUG DELIVERY DOSAGEFORMULATION FOR CHRONOTHERAPY

[0002] FIELD OF INVENTION

[0003]

[0001] The present invention relates to a formulation for sustained extended release dosage for Anti arrhythmic, Antianginal and Hypertension drugs. Particularly, the invention describes a formulation to deliver drugs at specific predetermined dosage at time-controlled manner. More particularly the formulations are pH specific and position specific and are resistant to variable pH ambience.

[0004] BACKGROUND OF THE INVENTION

[0005]

[0002] Anti arrhythmic, Antianginal and Hypertension drugs have consistently been in the front line of examination on the grounds that the cardiovascular problems are on an expansion worldwide. A few capacities (for example BP, pulse, stroke volume, heart yield, blood stream) of the cardiovascular framework are dependent upon circadian rhythms. Recent studies have revealed that diseases have predictable cyclic rhythms and that the timing of medication regimens can improve outcomes in selected chronic conditions. The colon- targeted drug delivery systems (CoDDSs) would be advantageous when a delay in absorption is desirable for the treatment of disease that has peak symptoms in the early morning and that exhibit circadian rhythm. This can be portrayed by proportioning drug focus in the early morning hours when the circulatory strain and pulse of both normotensive and hypertensive patients are higher during the morning hours.

[0006]

[0003] Studies have revealed the prevalence of cardiac mortality due to pre-waking surge, especially in hypertensive patients the hazard ratios for a 10 mm-Hg increase in morning surge for a total cardiovascular, stroke and cardiac mortality were 1.38, 1.37 and 1.39 respectively. Also the patients with sleep-trough surge >55 mm Hg (the highest decile) had a higher stroke incidence than those with a surge <55 mm Hg. To serve the purpose of managing the morning surge conventional dosage forms are inappropriate as the patients are asleep and cannot administer just before the symptoms. Hence the current study was aimed at administering the desired candidate before sleep and controlling its release to suit the purpose by adopting a pulsing cap system.

[0004] Propranolol is a non-selective, beta-adrenergic receptor-blocking agent, it undergoes high first pass metabolism by the liver and on average, only about 25% of propranolol reaches the systemic circulation. Propranolol HC1 undergoes extensive and highly variable hepatic first-pass metabolism following oral administration, with a reported systemic bioavailability between 15% and 23%. The clinical ramifications of the first-pass effect are pivotal for the accurate administration and management of pharmacological therapies. This phenomenon predominantly transpires in the liver and small intestine, resulting in considerable losses between the site of administration and the systemic circulation, thereby influencing the quantity of unchanged drug available for systemic absorption. The implications of the first-pass effect are multifaceted. Primarily, drugs that undergo extensive first-pass metabolism exhibit diminished bioavailability when administered orally. To mitigate this challenge, clinicians may opt to escalate the dosage of the administered drug or select alternative routes of administration where applicable. As the colon targeted drug delivery often bypasses this effect, a lower dose is usually administered than that required with oral administration. The antihypertensive activity of propranolol might be due to decreased cardiac output, inhibition of renin release by the kidneys, and diminution of tonic sympathetic nerve outflow from vasomotor centres in the brain.

[0007]

[0005] The pulsatile drug delivery systems are designed to be either or both time-controlled and position-controlled. Additionally they are pH independent as the drug vehicle passes through the digestive tract. This system is explained in detail in many of the prior arts.

[0008]

[0006] US2010 / 0028426 describes a time-specific delayed pulsatile release of drug in the form of tablets. The tablets were designed for immediate release after a pre-defined lag time and is independent of pH in intestinal tract.US70489945 describes a pharmaceutical dosage in the form of capsule designed to release the drug in the form of pellets within six hours of oral administration.

[0009]

[0007] Many of the prior arts mention of time and position controlled sustained pulsatile release of the drugs which is rapid or burst release. But these systems do not address the requirement of small quantities of drug to be released at intervals for treatment of certain health problems.

[0008] The foremost concern associated to CoDDS development is the lack of safety of rhythmic materials due to their reversible properties. Some trials have designed to overcome this issue but real breakthroughs can only be achieved by the application of smarter polymers. Significant efforts have been made to design smart systems but the main challenge are related to non -responsiveness to specific biological rhythms. The safety and efficacy of the drug is achieved by coordinating the peak plasma concentration of the drug with circadian rhythm of the body. The capability to engineer rhythms and use reliable models is another major problem. Generally, any model designated should be capable of predicting the physicochemical nature of a system and its biological response.

[0010]

[0009] However none of these pulsatile systems describe a extended-sustained release drug delivery systems which is both positioned-controlled and time-controlled through a formulation of drug- loaded pellets within a pulsincap. The novel chronopharmaceutical drug dosage forms developed in the present invention is safe, effective, easy to use, robust (predictable drug release rate in biological systems) and pre-clinically justified, biocompatible, ease of administration by patients in order to enhance compliance to dosage regimen, and non-toxic.

[0011] OBJECTIVE OF THE INVENTION

[0012]

[0010] The main object of the present invention is to provide a formulation of a time and position-controlled, extended-sustained-release of drug.

[0013]

[0011] Another object of the invention is to provide a formulation programmed through optimised polymer coating of drug loaded pellets with the insoluble capsule plugged with an uniquely designed HPMC4 lactose formulation.

[0014]

[0012] Yet another object of the invention is to provide a formulation of pellets designed to carry the drugs exhibiting first pass metabolism. The coated pellets possess the requisiteparticle size distribution, flow properties, lag time encapsulated in a designed pulsincap having a predetermined span of time of no release.

[0015] SUMMARY OF THE INVENTION

[0013] The present invention provides a time-controlled and position-controlled extended- sustained pulsatile drug delivery dosage formulation consisting of plurality of core particles, each particle having a base sealing layer of hydrophilic methylcellulose polymer; intermediate layer comprising of an active drug, a binder and a pore former; an outer layer comprising ofpoly(meth)acrylates polymer, an emulsifier, a plasticizer and an anti-tacking agent, wherein the drug release rate controlling polymer at 35% w / w polymeric coating is an anionic copolymer based on methyl acrylate, methyl methacrylate and meth acrylic acid and encompassed at a concentration of 10% w / w with respect to pellets weight.

[0016] ADVANTAGES OF THE INVENTION

[0017]

[0014] The present invention provides a formulation for time and position-controlled, extended-sustained-release of drug optimised through polymer coating of drug loaded pellets within the insoluble capsule plugged with an uniquely designed HPMC4 lactose formulation. The pellets are designed to carry the drugs exhibiting first pass metabolism and have a predetermined span of time of no release.

[0018]

[0015] BRIEF DESCRIPTION OF FIGURES

[0019] Fig. 1 : Comparative Invitro Drug release profile Propranolol HC1 pellets coated with Eudragit NM 30 D, Eudragit FS 30D and Eudragit RL 30 D.

[0020] Fig.2: Comparative Zero order plots of pulsatile device consisting of Propranolol hydrochloride pellets coated with Eudragit FS 30 D in different concentrations.

[0021] Fig. 3: Comparative Peppa’s plots of Propranolol hydrochloride pellets coated with Eudragit FS 30 D in different concentrations.

[0022] Fig. 4: X-ray view of the gastrointestinal tract after ingestion of the pulsatile device consisting of pellets containing 80mg of barium sulphate as core material.

[0023] Fig 5: Plasma Concentration-Time Curve of PPL HC1 following oral administration of MF Fig 6 : Plasma Concentration-Time Curve of PPL HC1 following oral administration of PF’s

[0024] DESCRIPTION OF THE INVENTION

[0016] A pulsatile drug delivery system is known to release dosage of drugs after certain lag periods and position-controlled to be released at specific predetermined areas within the stomach or colon. The pulsatile delivery system is capable of providing one or more immediate release pulses. These pulsatile delivery systems are programmed to do so through various coatings of polymers. In recent times such pulsatile release systems finds most importance when it comes to treatment of problems that align with the circadian rhythm such as cardiovascular related problems. Nevertheless, the orally applicable pulsatile release systems due to the potential limitation of the size or materials used for dosage forms encounter problem of passage through first pass metabolism. Pharmaceutical pellets are a brilliant carrier system for the controlled oral administration of low and high doses. Notably, pellets are tiny, free-flowing particulates with not more than 2.0mm in size. From the pharmaceutical perspective, the shape, size, and strength of the pellets play a great role in drug administration. Generally, oral dosage forms follow Zero order or First order release kinetics. However, maintenance of a required levelof drug in the blood for different diseases is still a challenge. Especially for chronic diseases such as ischemic heart disease, asthma, arthritis, where absorption windows exist, an extended-sustained pulsatile release of drug is desirable. It will be even more effective when the extended-sustained pulsatile release is also programmed to be position-controlled such as in colon for better absorption.

[0025]

[0017] Additionally, First pass metabolism is a phenomenon where the drug is metabolized in specific organs such as liver leading to reduction of the active drug concentration before it reaches the target location of action. This first pass metabolic effect is augmented, apart from liver metabolism, by variety of factors such as plasma protein concentration and gastrointestinal motility. This effect attracts the concern of clinical fraternity due to its variability among different human metabolism, which is very important to keep the patient within the therapeutic window of the appropriate drug. Inorder to address this concern, various drug delivery systems such as pulsatile release and sustained release are studied.

[0026]

[0018] The colon is a site where both local and systemic delivery of drugs can take place. Treatment is more effective if it were possible for drugs to be targeted directly on the colon. Colon-specific system is used in diseases that have diurnal rhythms. In the present study, attempt was made to target the drug to the colon, and intentionally delaying the drug absorption from therapeutic point of view in the treatment of hypertension, where peak symptoms are observed in the early morning.

[0019] Compared to capsules and other forms, pellets provide development of formulation with high degree of flexibility due to free-flowing characteristic and avoids individual dosage variability. Hence, they are packed easily without any difficulties. The spherical shape and a low surface area to volume ratio of pellets allow uniform film coating. Pellets offer biopharmaceutical advantages in terms of more even and predictable distribution and transportation in the gastrointestinal tract, which is independent of the nutritional state. The interest in pellets as a dosage form (filled into hard capsules) has increased, for their multiparticulate nature offers important pharmacological and technological advantages over conventional single-unit solid dosage forms.

[0027]

[0020] The present invention describes formulation of such a time and position-controlled, extended-sustained-release of drug programmed through optimised polymer coating of drug loaded pellets within the insoluble capsule plugged with an uniquely designed HPMC4:lactose formulation. These pellets formulation is designed to carry the drugs exhibiting first pass metabolism. The dosage forms may also be applicable as colon targeting dosage forms by prolonging the lag time of about 5 to 6 h.

[0028]

[0021] The main embodiment of the present invention is a formulation of time and position controlled extended-sustained release pulsatile capsule carrying drug-loaded pellets optimised through polymer coating to overcome the problem related to first pass metabolism. The pellet is designed to provide a time and position-controlled extended-sustained pulsatile release of the drug at predetermined intervals rather than a burst release of the drug in one shot. The pulsatile delivery system is fabricated through optimized layers of coating of the pellets carrying the drug with enteric polymers, which are pH independent, whereas the capsule loaded with the pellets are pH dependent to enable the slow release of the pellets.

[0029]

[0022] The polymeric coatings of the pulsatile system may be chosen from a wide range of enteric and water-soluble polymers. In the present invention, the Eudragit polymer is chosen attributing to its versatile site-specific delivery of drugs and pH independent nature. The preferred coating is with EUDRAGIT FS 30D as it poses certain technical advantages such as Highly Flexible Coatings, Aqueous Processing over other EUDRAGIT variants. Hence, the present invention employs EUDRAGIT FS 30D for coating of the pellets and filled into the Pulsincap capsules.

[0023] Pellets are generally the preferred mode of delivering drugs due to the flowability property and reduction in time for dispersion of drugs. These cores are prepared by any known standard techniques such as Fluidized Bed Wurster (bottom spray) Technology, Extrusion Spheronization., Spray drying and congealing. The release kinetics of the drug is tailored to conform with the Zero or First Order kinetics following the mechanism according to Higuchi or Krosemeyer and Peppas Equation for a steady and regular release.

[0030]

[0024] In one embodiment of the inventionthe formulation of the active core is in the form of pellets. The active core consists of seal coated sugar spheres, active principle drug, pelletizing adjuvants such as binding agent, Fillers, Lubricants and pore former such as Cross Povidone, Sodium Starch Glycolate. In the present invention the preferred adjuvant is Povidone K30 and the preferred pore former is Cross povidone. The binding and pore forming properties are very crucial for the extended drug release. In the present invention the weight percentage of the active principle drug with respect to the final weight of drug loaded pellets is 22.8 to 24.61% by weight, the binder present in an amount of between 10.2 to 11.07% by weight and the pore former present in an amount of between 9.71 to 10.46% by weight.

[0031]

[0025] The seal coating of the sugar spheres is carried out to prevent agglomeration and erosion. The polymers for the seal coating are selected from alkylcelluloses having low molecular weight such as hydroxypropylmethylcellulose, hydroxylpropylcellulose, hydroxy ethyl cellulose, methylcellulose, ethylcellulose, cellulose acetate, carboxymethyl cellulose, their derivatives and mixtures thereof.

[0032]

[0026] The Hydroxypropyl methylcellulose (HPMC) E5 has an apparent viscosity in the range of 4 mPas to 6 mPas, preferably from 4.5 to 5.5 mPas. 10% w / v of the HPMC E5 is preferably used in this invention. In a fluidized bed coater, the HPMC E5 fluidized by air at a flow rate of 2000-4500 CFM for an optimum time to coat the loaded sugar spheres and dried by spreading uniformly.

[0033]

[0027] Similarly, the active principle drug is loaded onto the sealed sugar spheresalong with binder and pore former through Wurster coating technique. The binder and pore former are selected from the group of polyvinylpyrrolidone, copovidone, polyethyleneglycols, polyvinylalcohol-polyethylene glycol copolymer, polyvinyl acetate, povidone etc., Preferably the Polyvinylpyrrolidone K-30 and Cross Povidone are used in the present invention. The formulation of designed drug loaded-controlled release pellets is given in Table I.

[0034] Table TPropranolol hydrochloride formulations withEudragit NM 30 D, Eudragit RL 30 D, EUDRAGIT FS 30 D in different concentration.

[0035] Note: PF 1 -Pellets coated with 35 mg of Eudragit NM 30 D

[0036] PF2 -Pellets coated with 26.25 mg of Eudragit NM 30 D PF3- Pellets coated with 17.5 mg of Eudragit NM 30 D PF4- Pellets coated with 35 mg of Eudragit RL 30 D PF5- Pellets coated with 26.25 mg of Eudragit RL 30 D PF6- Pellets coated with 17.5 mg of Eudragit RL 30 D PF7- Pellets coated with 35 mg of Eudragit FS 30 D

[0037] PF8- Pellets coated with 26.25 mg of Eudragit FS 30 D PF9- Pellets coated with 17.5 mg of Eudragit FS 30 D

[0038]

[0028] In an embodiment of the invention the extended-sustained-release coating is performed by the standard Wurster coating technique. The polymer for extended and sustained release coating over the drug loaded cores is selected from a group of soluble or insolublepoly(meth)acrylates. The soluble poly(meth)acrylates are soluble in digestive fluids whereas the insoluble Poly(meth)acrylates are permeable in digestive fluids. Poly(meth)acrylates which exhibit pH dependent release of active drug from the core. The polymer Eudragit FS releases active drug with acidic or alkaline groups, Eudragit RL with alkaline groups and Eudragit NM with neutral groups in the colon region. In the present invention aqueous dispersion of Eudragit NM 30 D / Eudragit RL 30D / Eudragit FS 30D is prepared at 35% w / w, 26.25% w / w and 17.5% w / w concentrations of polymeric coating. Preferably, the 35% w / w concentration polymeric coating exhibits longer hours of extended and sustained release of the active core drug compared to 26.25% w / w and 17.5% w / w concentration amongst all the three polymers. More preferably, the 35% w / w concentration polymeric coating of Eudragit FS 30D exhibits extended-sustained release of the active core drugs for a duration of 12 hours releasing a maximum of 99.827% (Table II). This is enabled by adding of 5 cps Hydroxypropyl methylcellulose as pore former in the polymeric coating solution along with the required quantity of polysorbate 80 and talc as plasticizer and antitacking agent, respectively. The mean molecule size of the pellet is affected by the kind of polymer utilized and the concentration used, as the mean size is expanded with expanding polymer fixation. The molecule size of the pellets with 35% w / w concentration polymeric coating ofEudragit FS 30D is 691.31 ±0.03.

[0039] Table II : Invitro Dissolution data of pulsatile device consisting of Propranolol hydrochloride pellets coated with Eudragit NM 30 D, Eudragit RL 30 D, EUDRAGIT FS 30 D in different concentrations

[0040]

[0029] Additionally the pellets are evaluated to verify the stream properties of required standards for the flowability. The stream properties are expressed in terms of Angle of Repose, Carr’s record and Hausner proportion (Table III). The pellets coated with 35% w / w concentration of Eudragit FS 30Dloaded with 97.68% of drug displays an Angle of Repose of 25°.42”, Carr’s index of 14.82±0.04 and Hausner Ratio of 1.17±0.03. Generally, an angle of repose between 25°-30°, Carr’s index of 12-16% and a lower Hausner proportion of <1.25 shows good stream property of the pellets.

[0041] Table III: Flow Properties of Propranolol hydrochloride pellets coated with Eudragit NM 30 D, Eudragit RL 30 D and Eudragit FS 30 D in different concentrations.

[0042]

[0030] Another embodiment includes the designing of the Pulsincap, which is the specially adapted capsule with an insoluble body filled with drug loaded pellets. It is designed to be pH independent for extended and sustained release of the drug embedded in the pellets. The pulsincap is designed by plugging of the pellets within the capsule body with a HPMC4: lactose hydrogel plug. The joint of the capsule body and cap are sealed with a suitable sealant, 5% ethyl cellulose ethanolic solution. The sealed capsules are completely coated by a dip-coating method with 5% cellulose acetate phthalate in 5:5 (V / V) mixture of acetone: ethanol plasticized with n-dibutyl phthalate (0.75%), to prevent variable gastric emptying. The coating is repeated until an 8-12% increase in weight is obtained. The dissolution testing of the pulsincap in 0.1 M HC1 for 2 h mimicking the average gastric emptying time exhibited no dissolution of the cap. The cap dissolved in pH-7.4 phosphate buffer in 3 h mimicking the average small intestinal transit time exposing the hydrogel plug. After 5 h, the dissolution medium at pH 6.8 phosphate buffers mimicking colonic liquid showed complete release of the pellets from the body of the pulsincap.

[0043]

[0031] The uncovered polymer plug retaining the encompassed fluid, swell and deliver the medication through the swollen pellets into the colon region. The formulation is very effective to contain the medication discharge at pH 1.2, in this way demonstrating the productivity of 5 % CAP for enteric covering. This formulation of hydrogel with enteric polymer coating plays a vital role in the sustained-extended drug release for chronotherapeutic drug delivery. The exponential coefficient (n) values for the pellets coated with Eudragit FS 30 D is found to be between 0.8705 and 0.8800 indicates the drug release to follow non-fickian mechanism. The result also indicates that the release rate is found to decrease with increase in concentration of coating material applied.

[0044] Examples

[0045] Example 1 : Preparation of Propranolol hydrochloride Pellets by Fluidized Bed Wurster (Bottom spray) Technology

[0046]

[0032] The fabrication of Propranolol hydrochloride pellets is initiated with seal coating of sugar spheres with 10% w / v of HPMC E5 and sifted through Mesh# 30 followed by Mesh# 35, to prevent agglomeration, reduce fine generation. Also includes consecutive operations such as drug loading and extended-release coating by Wurster coating technique.

[0047] Step 1 - Seal Coating:

[0048]

[0033] 10% w / v solution of HPMC E5 is prepared by slow dispense and continuous stirring for approximately 45min.In a fluidized bed coater HPMC E5 is fluidized by air at a flow rate of 2000-4500 CFM for a span of lOmin to coat the loaded sugar spheres. The seal coated pellets are dried for 3 h at 60°C by spreading uniformly over trays and the uniform sized pellets are collected after sifting over vibro-sifter. Step 2 - Drug Loading:

[0049]

[0034] Polyvinyl pyrrolidone K-30 dispersion is prepared by stirring in vortex of water for a span of 20min.The prepared dispersion is passed using nylon cloth (mesh number 20). The drug Propranolol hydrochloride and cross Carmellose powder blend is prepared my hand mixing of different aliquots and finally with a blender for lOmin. Sugar pellets and drug-cross Carmellose powder blends are charged into a fluidization basket and povidone dispersion is fluidized by air at a flow rate of 2000-4500 CFM for a span of lOminto coat the materials. The drug loaded pellets are dried for 3h at 60°C by spreading uniformly over trays and the uniform sized pellets are collected after sifting over vibro-sifter.

[0050] Step 3 - Extended-Release Coating:

[0051]

[0035] Aqueous dispersion of Eudragit NM 30 D / Eudragit RL 30D / Eudragit FS 30D are prepared by diluting with water to get different levels of polymeric coating (35% w / w, 26.25% w / w and 17.5% w / w respectively). Hydroxypropyl methylcellulose 5 cps is added as pore former in the coating solution. The required quantity of polysorbate 80 and talc is also added to the aqueous dispersion as plasticizer and anti-tacking agent, respectively. The drug- coated pellets are charged into a fluidization basket. An aqueous dispersion of polymer solution is atomized on to the materials while the air is allowed to circulate into the basket to keep the materials under the fluidized state. The process of fluidization is continued for 10 min. The finally coated pellets are dried at ambient conditions for 2 h and sifted through vibro sifter to collect uniform sized pellets.

[0052] Example 2: Designing of Pulsincap

[0053]

[0036] The pellets equivalent to 90 mg of Propranolol hydrochloride manually filled into the formaldehyde-treated bodies. The primary reaction of formaldehyde with gelatin (main constituent of capsule) probably is the formation of methylamines. The linkage is resistant to acid hydrolysis (Fraenkel & Olcott, J Biol Chem, (1948) Jul; 174(3):827-43.) that was formed due to condensation reaction which transforms methyl groups to cross linking methylene bridges. This is an irreversible reaction. The capsule bodies exposed to formaldehyde vapors for 12hrs did not dissolve in pH 7.4 phosphate buffer medium even after 48hrs (hardened capsule bodies reversed to softened only after 24hrs). Thus, for the present study, capsule bodies exposed to formaldehyde vapors to 12hrs are chosen for the preparation of pulsincaps. It is sealed with unhardened cap of the capsule. Exposure to formaldehyde vapors results in decrease in solubility of gelatin owing to the cross-linkage of the amino groups in the gelatin molecular chain with aldehyde groups of formaldehyde by Schiff s base condensation. Physical characteristics of empty gelatin capsules with or without formaldehyde treatment were shown in Table VI (Supporting data).

[0054] Table VI : Physical characteristics of empty gelatin capsules with or without formaldehyde treatment.

[0055] * (Mean ± SD) (n=3).

[0056]

[0037] The capsule bodies after formaldehyde treatment slightly reduced in their size and apart from this no other visual defects were observed. The formaldehyde treatment of the capsule bodies significantly altered their solubility compared to the untreated cap of the capsule. The untreated caps were dissolved within 12 minutes and the treated bodies remained intact over a period of 24 hrs and thus indicating the suitability for the colonic delivery.

[0057]

[0038] The capsules containing the pellets are then plugged with 150mg (of HPMC K4: lactose :: 1 : 1) hydrogel plug. The joint of the capsule body and cap is sealed with a small amount of 5% ethyl cellulose ethanolic solution. The sealed capsules are completely coated by a dip-coating method with 5% cellulose acetate phthalate in 5:5 (V / V) mixture of acetone: ethanol plasticized with n-dibutyl phthalate (0.75%), to prevent variable gastric emptying. The coating is repeated until an 8-12% increase in weight is obtained. The dissolution testing of Pulsincaps is carried out through the rotating paddle method (USP 23) with a dissolution test apparatus. The media used for testing is 0.1 M HC1 for 2 h, followed by pH-7.4 phosphate buffer for 3 h and pH 6.8 phosphate buffers tested for subsequent hours. The temperature is maintained at 37±0.5°C and the rotating speed was lOOrpm.At appropriate time intervals 5 mL of the solution is withdrawn, filtered, and assayed by a UV spectrophotometer at 290 nm, while an equal volume of fresh dissolution medium is added into the apparatus and the aggregate percent release is measured across the sampling times. The lag time is determined as the time span of no release from the dosage form. Table IV depict the weights at multiple stages of coating and resulted in the enteric coated pellets loaded capsules. The final weight were uniform and are in the range of 574.08- 598.95 mg.

[0058] Table IV: Composition for pulsatile capsule containing Propranolol hydrochloride pellets coated with various polymers based on design summary.

[0059] Example 3 : Release kinetics

[0060]

[0039] The assessment of drug delivery process from a pharmaceutical dosage form is vital. The order of drug delivery from matrix systems is defined by zero or first order kinetics. The mechanism of drug delivery as of matrix is by Higuchi or Krosemeyer and Peppas equation (Figs 2&3). To ascertain the mechanism of drug release, the dissolution data was analysed by zero order, first order, and Higuchi and peppas equations. When the amount of drug release values were plotted against time straight lines were acquired in all the cases demonstrating that the pace of medication discharge from these miniature particles followed zero order (Fig 2). The plot of log % Drug Released versus log time (peppas plots) were drawn. The plots were discovered to be straight (Fig.3) with all pellets.

[0040] The time required to get 50% drug release (T50) and 90% drug release (T90) was calculated and were shown in table V. The exponential coefficient (n) values were found to be in between 0.8770 to 0.9436, indicating that the drug release followed non-fickian diffusion mechanism. These results indicated that increase in concentration of coating material applied, the release rate was found to decreased.

[0061] Table V: In vitro drug release kinetic data pulsatile device consisting of Propranolol hydrochloridepellets coated with Eudragit NM 30 D, Eudragit RL 30 D andEudragit FS 30 D in different concentrations.

[0062] Example 4: Invivo targeting efficacy evaluation of colon targeting optimized pellets

[0063]

[0041] To render support to the In vitro studies, the dosage form is evaluated in rabbits as it closely simulates the human physiological environment of the colon. The behaviour of Propranolol hydrochloride pellets in rabbit is observed using a radiographic imaging technique. It involves the use of radio-opaque markers such as barium sulphate, in the formulation instead of drug to determine the position of the pellets. Healthy rabbit of 2.8 ±0.2 kg is fasted overnight and on the next day morning pellets are administered followed by 25mL of water. The study is performed using barium sulphate as X-ray opaque material. Capsules containing 80mg of barium sulphate as core material in pellets is administered to rabbits by gastric intubation. Images taken at definite intervals (1sthour, 4thhour and 6thhour) to trace the performance of the formulation and represented in Fig 4. Fig.4 shows the radiographic images taken at different time periods after administration of the barium sulfate- loaded pellets to rabbit under fasting conditions. It was observed that pellets were observed in gastric region after 1 h, and in colon region at the 6th hour. The study is indicative of the efficiency of the pulsatile pellets for its capacity to traverse the intestine intact and deliver the drug for its chronotherapeutic benefit.

[0064] Example 5: Evaluation of Propranolol hydrochloride pellets coated with Eudragit FS 30 D in different concentrations:

[0065]

[0042] Invitro drug discharge profiles plot of Propranolol hydrochloride pellets covered with Eudragit NM 30 D, Eudragit RL 30 D and Eudragit FS 30D in various fixations were represented in Table II and Fig 1. Aqueous dispersion of Eudragit NM 30D / Eudragit RL 30DZEudragit FS 30D were prepared by diluting with water to coat over drug layered beads along with Hydroxy propyl methyl cellulose 5 cps as binder in coating solution & formulation variable selected was % weight buildup (% coating) of extended-release polymer. To optimize % coating of extended-release polymer, three formulations with different levels of polymeric coating (35% w / w, 26.25% w / w and 17.5. %w / w respectively) were manufactured.

[0066]

[0043] The drug release from pellets was impacted by the kind of polymer utilized and its extent in the formulation. Among the three polymers (Eudragit NM 30 D, Eudragit RL 30D and Eudragit FS 30D), the pellets coated with Eudragit FS 30Dshown extended drug release than the pellets coated withEudragit NM 30 D andEudragit RL30D.

[0067] Eudragit FS30D > Eudragit NM30D > Eudragit RL30D

[0068]

[0044] Among the three polymers concentrations (35%w / w, 26.25%w / w and 17.5%w / w) the pellets coated with 35% w / w concentrations indicated prolonged drug release than the pellets covered with 26.25% w / w and 17.5 %w / w concentration. Among all the formulations, the formulations prepared with 35%w / w concentrations of Eudragit FS 30D shown extended drug release for a period of 12 hours. Hence that formulations (PF7) was selected for further studies. Example 6: Studies on therapeutic efficacy compared to marketed formulation

[0069]

[0045] The results of the in vivo studies carried out as part of the study to prove the therapeutic efficacy of the Pulsatile formulation of present invention compared to the Marketed Formulation, PROLOL TR 80. The in vivo results indicated that the pharmacokinetic parameters significantly differed following pulsatile formulations compared to oral marketed sustained release formulation.

[0070]

[0046] Dosage forms: Marketed formulations PROLOL TR 80 and pulsatile formulation of Propranolol hydrochloride with identical amounts of HPMCK4M: lactose plug, formulated in the laboratory conditions and chosen on the basis of drug content, lag time, in-vitro release studies and stability conditions (Table VIII).

[0071]

[0047] Subject selection: Twelve New Zealand healthy rabbits bearing on average age of 10±2 weeks and a mean weight of 3±0.2 kg is utilized in this study. All are separated into two groups, with six in each group and are overnight fastened. Both groups are accommodated in separate cages and thus taken care of no strain on the animals. Food and water are available ad libitum at the whole extent through the study. The study is steered in a crossover design with two weeks of washout periods in among the two experiments. The animal dose of Propranolol hydrochloride computed relevant to the human dose with the below-cited formula.

[0072] Animal dose = Human dose x Animal wei ht

[0073] Human weight

[0074] Human dose of Propranolol hydrochloride = 80 mg.

[0075] = 80x3 / 70= 3.42mg / kg

[0076] Table VIII: Drug dosage for animal studies

[0077] The prescribed dose of PPL HC1 to be processed via gastric intubation approach. Blood sampling:

[0078]

[0048] Approximately 1 ml of blood samples gathered from tracheal lobular vein of rabbit and subsequently stored in screw-top heparinized plastic tubes, the sampling intervals of blood is 0 mins (pre-dose), 1 hr., 2 hr. to 20 hr. (Every 2 hrs. once), 24hr and 48 hr.” The plasma was instantly parted by centrifugation for the duration of 5 mins, a speed of 4000 rpm and the sample was frozen at -20°C, examined by LCMS / MS method.

[0079] Determination & Statistical analysis of Pharmacokinetic Parameters:

[0080]

[0049] “Pharmacokinetic parameters, for instance Area under the curve (AUC), Peak plasma concentration (Cmax), Elimination rate constant (Kel), Time at which peak occurred (Tmax), Biological half-life (ti / 2) and mean residence time (MRT) were determined employing the noncompartmental pharmacokinetic data analysis software PK Solutions 2.0TM (Summit Research Services, Montrose, CO, USA). The pharmacokinetic parameters of the verified designs were statistically analyzed using paired sample’s t-test for normally distributed results of Cmax, Ka, Kei, MRT and AUC0-a value. All tests were accomplished at 0.001 level of significance.”

[0081] Determination of Pharmaco dynamic parameters:

[0082]

[0050] Pharmaco dynamic evaluation of optimized Propranolol hydrochloride formulations:

[0083] In animals, Pharmacodynamic factors since the intake of oral and optimized pulsatile formulation of Propranolol hydrochloride (Table IX) is appraised by % 13 -blockade. The subjects in research have admittance to take water; however, prior to the intake of drug, fasted since 24hrs. All the subjects are sedated with urethane (1 g / kg, i.p.) and subsequent recording of a normal electrocardiogram. Prior intake of drug formulations, isoprenaline (2 mg / kg, iv) in normal saline directed into the marginal ear vein. Electrocardiogram is chronicled instantly and kept as control. The animal dose of Propranolol hydrochloride and its pellets determined pertinent to the human dose. Electrocardiogram is recorded at 1, 2, 4 and 6 h lest of oral and 4, 8, 12, 20 and 24 h lest of optimized pulsatile formulation postadministration, isoprenaline (2 mg / kg, iv) response is recorded as before. Each subject stood as its specific control. The % 13 -blockade acquired from the variance of response with isoprenaline at time “0” and respective interval with intake of the designed formulations. Table IX: Treatment parameters for oral and optimized pulsatile formulation administration of Propranol ol hydrochi ori de .

[0084]

[0051] The outcome from the oral administration of Propranolol hydrochloride demonstrated the maximum plasma concentration (C max) 49.0 ± 0.31ng / ml at 6 hrs (t max). While pulsatile formulation administration showed the greatest plasma concentration of 52.1 ± 0.42ng / ml at 12 hrs (t max) after an underlying lag time 5 hrs. The oral administration of Propranolol hydrochloride resulted in a low and quite variable AUC of 356.2± 1.43ng.hr / ml, whereas the pulsatile formulations resulted in AUC of 951.7±2.07 ng.hr / ml (Tables X & XI, Figs 5 & 6).

[0085] Table X: Plasma Concentration of PPL HC1 following oral administration of Marketed Formulation.

[0086] Table XI: Plasma Concentration of PPL HC1 following oral administration of Pulsatile formulation’s.

[0087]

[0052] The mean residence time of pulsatile formulations administration (23.2 ± 0.14 hrs) is found to be more than oral administration (14.8 ± 0.01 hrs). The mean residence time (MRT) is found to be increased significantly (p<0.001) for pulsatile formulations on comparison with oral sustained formulations. Though both the formulations (marketed sustained formulation and pulsatile formulations of Propranolol hydrochloride) containing an equivalent amount of drug, the AUCO-co values observed with pulsatile formulations (p<0.001) is found to be three fold time than that of oral sustained formulations of propranolol hydrochloride (Table XII), Table XII: Statistical Treatment of Pharmacokinetic Parameters (Mean ± S.D.) following oral administration of MF and PF’s of PPL HC1.

[0088] Values are presented in Mean ± SD (n = 6); *p<0.05, ** p<0.01,*** p<0.001

[0053] For Propanolol hydrochloride formulations, in agreement with pharmacokinetic data, maximum 13 -blockade is obtained at 6 h after oral sustained formulations administration and decreased by 80% after 12 h. In the case of pulsatile formulations administration, maximum 13 -blockade, is observed after 12.0 h and is prolonged over a period of 18 h (Table XIII) Table XIII: Percent 13-Blockade after MF and optimized PF’s administration of PPL HC1 in rabbits.

[0089]

[0054] A timed delayed capsule device for Chrono therapeutic delivery of Propranolol hydrochloride successfully developed. In accordance with the Chrono modulated therapy of Blood Pressure, the lag time criterion of 5hours and sustained release for a period of 12 hours is satisfied. The dosage form can be taken at bed time and will release the contents in the early morning hours when the risk of hypertension is highest.

[0090]

[0055] Hence, the developed dosage formulation has better therapeutic efficacy in delivering the Propranolol hydrochloride during high risk time and also a controlled drug delivery for easy targeting to the colon than conventional colonic drug delivery.

[0091] Table XIV: Comparative Table for Therapeutic Efficacy The above Table XIV shows that the maximum B -blockade extends upto 17h with Tmax at 12 h and MRT of 23.2 in the present invention.

Claims

Claims:We Claim:

1. A time-controlled and position-controlled extended-sustained pulsatile drug delivery dosage formulation consisting of:(a) plurality of core particles, each particle having a base sealing layer of hydrophilic methyl cellulose polymer; intermediate layer comprising of an active drug, a binder and a pore former an outerlayer comprising ofpoly(meth)acrylates polymer, an emulsifier, a plasticizer and an anti-tacking agent, wherein the drug release rate controlling polymer at 35% w / w polymeric coating is an anionic copolymer based on methyl acrylate, methyl methacrylate and meth acrylic acid and encompassed at a concentration of 10% w / w with respect to pellets weight.Wherein, the hydrophilic methyl cellulose polymer is present in an amount of between 3 to 5 %, preferably 4% w / v (or) w / w with respect to weight of pellets after seal coating; the active drug present in an amount of between 22.8 to 24.61% by weight, the binder present in an amount of between 10.2 to 11.07% by weight and the pore former present in an amount of between 9.71 to 10.46% by weight with respect to final weight of drug loaded pellets; the pore former present in an amount of between 0.4 to 0.8% by weight, the plasticizer present in an amount of between 1 to 2% by weight and anti-tacking agent present in an amount of between 0.7 to 1.4% by weight with respect to final weight of Extended coated pellets; and(b) a pulsincap encapsulating the plurality of core particles, the said pulsincap consisting of (i) a top soluble cap and a bottom insoluble body, wherein the mouth of the body holding the plurality of core particles is plugged with a hydrogel plug; (ii) sealing at interface of the cap and body with alkyl cellulose polymer; (iii) a coating on outer surface of pulsincap having a phthalate polymer and a plasticizer mixture at 5:5 (V / V).

2. The extended-sustained pulsatile drug delivery dosage formulation as claimed in claim 1, wherein the drug release is extended upto 12 hours.

3. The extended-sustained pulsatile drug delivery dosage formulation as claimed in claim 1,wherein the hydrophilic methylcellulose polymer is selected from Hydroxy propyl methyl Cellulose E5, Hydroxy propyl methyl Cellulose El 5, preferably Hydroxy propyl methyl cellulose having a viscosity of 5mPa.

4. The extended-sustained pulsatile drug delivery dosage formulation as claimed in claim 1, wherein the active drug is selected from Propranolol HC1, Propranolol , preferably Propranolol HC1.

5. The extended-sustained pulsatile drug delivery dosage formulation as claimed in claim 1, wherein the binder is selected from Povidone K30, Povidone K90, preferably Povidone K306. The extended-sustained pulsatile drug delivery dosage formulation as claimed in claim 1, wherein the pore former is selected from Cross povidone, Sodium Starch Glycolate, preferably Cross povidone.

7. The extended-sustained pulsatile drug delivery dosage formulation as claimed in claim 1, wherein the plasticizer is selected from Polysorbate 80, polyethyleneglycol 400 , preferably Polysorbate 80.

8. The extended-sustained pulsatile drug delivery dosage formulation as claimed in claim 1, wherein the anti-tacking agent is selected from Talc, calcium carbonate , preferably Talc.

9. The extended-sustained pulsatile drug delivery dosage formulation as claimed in claim 1, wherein the hydrogel plug is HPMC K4: lactose in the weight ratio of 1 : 1.

10. The extended-sustained pulsatile drug delivery dosage formulation as claimed in claim 1, wherein the core particle is non-pareil sugar sphere.

Images