Enhancement of Solubility and Dissolution Profile of Telmisartan and Candesartan Cilexetil from Solid Dispersion Systems

Tracks: Contributed Papers: Drug Delivery - Pharmaceutical Technologies (Small Molecule) / Solubility Enhancement / Formulation Date/Time: Tuesday, November 10, 2009 1:00 PM - 5:00 PM Location: T3303

Description: To enhance and improve the Solubility and dissolution profile of poorly soluble antihypertensive drugs Telmisartan and Candesartan Cilexetil using Solid Dispersion Systems. Solid dispersions of Telmisartan and Candesartan Cilexetil were prepared by solvent evaporation, melt agglomeration and spray drying methods using Gelucire50/13, Gelucire 44/14, Poloxamer 188, Poloxamer 407, PEG-6000 and Hydroxypropyl betacyclodextrin as carriers in various proportions. Saturation solubility of dispersions was determined in distilled water using sonication method. Dissolution of optimised formulations was studied using USP XXVIII Dissolution apparatus II. Fourier Transform Infra Red spectroscopy (FTIR), X-Ray powder Diffraction (XRD) and Differential Scanning Calorimetry (DSC) analyses were also performed for optimised formulations. The saturation solubility studies revealed that solid dispersions of Telmisartan-Gelucire 50/13 [in 1:0.3 (drug: carrier weight ratio) prepared by melt agglomeration] and Candesartan Cilexetil-PEG 6000 [in 1:5 (drug: carrier weight ratio) prepared by melt agglomeration] showed greater solubilization of drug than other drug: carrier combinations hence these were taken as optimised formulations. Also it was evident from the in vitro dissolution data of samples, that the Telmisartan-Gelucire 50/13 and Candesartan Cilexetil-PEG-6000 solid dispersions exhibited a higher dissolution rate as compared to the drug alone and other drug: carrier combinations. About three to five fold increase in drug release was obtained with the optimised formulations as compared to the drug alone. FTIR, DSC and XRD studies showed that there were no interactions between the drug and carriers in either case. The prepared solid dispersions showed good physical properties. The solubility and extent of dissolution of Telmisartan from Gelucire 50/13 solid dispersion and that of Candesartan Cilexetil from PEG-6000 was found to be significantly higher than drug alone in either case. Thus, solid dispersions of Telmisartan and Candesartan Cilexetil with increased dissolution efficiency were successfully developed.

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA ANNEXURE- II PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1.

Name of the Candidate and Address:

MOHAN KUMAR.V #317 ,9th main, Prashanthnagar, Vijaynagar, Bangalore-560079 Government College of Pharmacy, Bangalore - 560027

2.

Name of the Institute:

3.

Course of Study and Subject: Date of admission to course

Master of Pharmacy in Pharmaceutics

4.

25 JULY 2011

5.

Title of the topic : SOLUBILITY ENHANCEMENT OF A POORLY WATER SOLUBLE MODEL ANTI- HYPERTENSIVE DRUG

6.

Brief Resume of Intended Work: 6.1: Need for the Study: Hypertension is multifaceted, insidious disorder associated with cardiovascular cerebral and renal vascular abnormalities. A number of oral antihypertensive drugs have been developed in order to improve bioavailability. Calcium channel blockers are widely used in the treatment of hypertension, and enhancement of dissolution rates of water insoluble drugs remains one of the most challenging tasks of drug development. Solubility enhancement is important approach to improve the bioavailability of drugs. This is an attempt to enhance solubility of a model anti hypertensive drug by using hydrophilic binders. Another important technique to enhance solubility is solid dispersion, which was developed by Chiou and Reigelman; this may result in improved solubility and dissolution rates as compared with crystalline material.

 Improving bioavailability of drug those given as solid dosage forms remains a great challenge for the formulation scientists, so this is an attempt to increase the solubility and bioavailability of poorly water soluble anti hypertensive drug.

6.2: Review of literature 1. V K Rai, Brajendra Singh Rajput, Manoj Sharma, Ashish Agarwal, Anil Gupta,and Narendra Singh.,Studied the enhancement of dissolution of a poorly soluble drug, Raloxifene Hydrochloride (RLX-HCl), using solid oral dosage form.Solubility study for pure drug was done in different relevant media, which results in poor solubility of drugs. Hydrophilic binders likePolyvinylpyrrolidone, Hydroxy propyl methyl Cellulose, Hydroxypropyl cellulose were investigated for the purpose to improve the solubility in the formulation. Comparison was made with Hydrophobic binder viz Ethyl cellulose. Dissolution behavior of different formulation and pure drug was studied in different relevant media, which reveals significant improvement in dissolution behavior of drug with hydrophilic binder5. 2. Vijay Kumar, M M Shankaraiah, J S Venkatesh, D Rangaraju, C Nagesh., Studied the solid dispersion of poorly water soluble drug Fenbendazole as a model drug. The purpose of this study was to enhance the dissolution of fenbendazole by solid dispersions consisting of the drug,and a

polymeric carrier ,Binary and ternary system were prepared by kneading method using hydrophilic polymers like polyvinylpyrrolidine K-25( PVP-K25),betacyclodextrin (BCD), mannitol and urea.

The prepared formulations were charecterised by polymer compatibility by using FT-IR and the drug content uniformity was found to be good in all formulations. The solubility of Fenbedazole were greater with fenbendazole-BCD-PVP K25 system. Dissolution rates of fenbendazole were significantly increased by binary and ternary system. The result confirmed that ternary system showed better solubility and dissolution characteristics when compared to binary system8. 3. Bhanudas Shankar Kuchekar, Minal Raghunath Narkhede., Studied the effect of the presence of the water soluble polymers like HPMC, PVP and PEG 6000 on aqueous solubility and complexation abilities felodipine with or without presence of -cyclodextrin and HPCD by phase solubility studies. Addition of water soluble polymer to CD solution improved CD solubilizing efficiency due to increase in CD complexing power toward felodipine. In binary system solubility was found to be 2.5 to 10 times higher than in water which was further improved in the presence of 0.25% w/v water soluble polymer. Ternary systems with CD showed highest increments in solubility towards felodipine, with 78.8%, 81.8% and 74% improvement after the addition of 0.25% w/v HPMC, PVP and PEG6000 , respectively. All the polymers under study showed synergistic effect on felodipine cyclodextrin solublization by increasing complexation efficiency. The highest solubility improvement up to 81.8% was obtained for ternary system when 0.25% w/v of PVP was used3.

4. V P Patel, M C Gohel, R K Parikh, Studied about the increase dissolution rate of felodipine by complexation process. Complexes were prepared using cyclodextrin by employing various techniques like physical mixture, cogrinding, kneading technology, solvent coevaporation.

The physical properties of the prepared solid mass of FDP was characterized by in vitro dissolution studies, UV- spectroscopy, FT-IR, DSC and X-ray powder differaction spectroscopy. Additionaly, phase solubility studies were performed to support the in vitro dissolution study. The results of Fourior transform infrared spectroscopy shows the compatibility of drug with cyclodextrin, while differential scanning calorimetry (DSC) and X-ray powder differaction spectroscopy showed the confirmation of complexation of cyclodextrin with felodipine9. 5. Dong-Han Won, Min-Soo Kim, Sibeum Lee, Jeong-Sook Park, Sung-Joo Hwang.,Prepared Solid dispersions of felodipine with HPMC and surfactants by the conventional solvent evaporation (CSE) and supercritical anti-solvent precipitation (SAS) methods. The solid dispersion particles were characterized by particle size, zeta potential, SEM, DSC, powder X-ray diffraction (XRD), solubility and dissolution studies. The effects of the drug/polymer ratio and surfactants on the solubility of felodipine were also studied. , the particle sizes of solid dispersions from the SAS process were maintained for 6 h due to the increased solubility of felodipine. The physical state of felodipine changed from crystalline to amorphous during the CSE and SAS processes, confirmed by DSC/XRD data2.

6. K P R Chowdary, K Surya Prakasa Rao and Udaya Sree Datla., Studied the individual and combined effects of hydroxy propyl cyclodextrin (HPCD), surfactant (Poloxamer 407) on the solubility and dissolution rate of piroxicam, a BCS class II drug in a series of 22 factorial experiments. The solubility of piroxicam in four selected fluids containing HPCD and Poloxamer 407 as per a 22 factorial study was determined. HPCD and Poloxamer 407 alone gave an increase of 1.55 and 1.86 fold respectively in the solubility of piroxicam in combination they gave only 1.33 fold increase

in the solubility of piroxicam. Combination of HPCD with Poloxamer 407 gave much higher enhancement in the dissolution rate and efficiency (DE30) of piroxicam than is possible with them individually. Hence a combination of HPCD and Poloxamer 407 is recommended to enhance the dissolution rate of piroxicam10. 7. Tao Taoa, Yan Zhaoa, JinjinWua, Beiyi Zhoub., have prepared and evaluated itraconazole dihydrochloride for solubility and dissolution rate enhancement. Itraconazole dihydrochloride was synthesized by bubbling anhydrous hydrogen chloride gas into acetone suspension of itraconazole. Its structure was confirmed by FT-IR, TGA, DSC, powder X-ray diffraction, SEM and Dynamic light scattering. It is concluded that hydrochloride formation increases solubility with beta cyclo dextrin(1/3)1. . 8. S Muralidhar, G Devala Rao, Syed Azhar,Nizami, Karunakara reddy, S Ravindra reddy., Studied about solid dispersions, which were prepared

in differentproportions using hydrophilic carriers like polyethylene glycol 6000 and poly vinyl pyrrolidone K30. The differential scanning calorimetry (DSC) thermograms and infrared (IR) spectra revealed that there was nointeraction of celecoxib with additives and no degradation in celecoxib molecule. The drug release profile was studied in water containing 2% SLS, solid dispersions exhibited superior dissolution profile and improved anti-inflammatory activity in rat paw oedema model. The increase in the dissolution rate and consequent enhancement of anti-inflammatory effect of celecoxib in rats were attributed to wettability, solubilization of the drug by the carriers and possibility due to reduction in the particle size6.

9. Renu Kalyanwat, Stuti Gupta, Rajendra Kr Songara, Dolly Jain and Sushma Patel., Studied about enhancement of dissolution rate of carbamazepine by solid dispersion. This solid dispersion of carbamazepine was prepared by modified solvent evaporation method. Two types of superdisintegrants croscarmellose sodium and sodium starch glycolate were incorporated. Different batches of solid dispersion were prepared and evaluated by drug content determination, saturation solubility study and dissolution study. Thus dissolution rate of carbamazepine was found to be increased with super disintegrant addition11 . 10. Jessy Shaji , Digambar Jadhav., They studied about development of solid dispersion self emulsification pellets (SDSEP). This is a recent technique for poorly water soluble drugs, where it increases water solubility and enhances the

bioavailability. A full factorial design approach was used for the optimization of MCC: Lactose (X1) and % of croscarmellose sodium (X2) were taken as an independent variable. Cumulative % drug release (Y1), Disintegration Time (Y2) and Friability (Y3) were studied as response variables. The differential scanning calorimetry and x-ray diffraction studies demonstrated that enhanced dissolution of Ibuprofen from SDSEP might be due to a decrease in the crystallinity of IBU. In conclusion, dissolution enhancement of Ibuprofen was obtained by preparing a solid dispersion self emulsion using melt technique. The use of a factorial design approach helped in identifying the critical factors in the preparation and formulation of SDSE7 . 11.V K Rai, N Pathak, N Bhaskar, B C Nandi, S Dey, L K Tyagi., They studied about Raloxifene HCL immediate release tablets by wet granulation technique, in order to obtain the best, optimized 6 different formulation were developed.

Different fillers, binders, lubricants were taken as variables. Evaluation of tablets was studied as response variables. Sticking was observed in the formulation containing stearic acid and sodium stearyl fumerate.The different physical properties and in vitro release profile showed best comparable with reference product4. 6.3:Main objective of the study: The present work is an attempt to, *Enhancing the dissolution rate or solubility in vivo by using hydrophilic binders in different gastrointestinal fluids and also by solid dispersion in

solid dosage form by the one of the following method ; Kneading method Solvent evaporation method Fusion method Wet granulation

Evaluation of the formulation Drug-polymer incompatibility studies Drug content . Uniformity of weight Friability and Hardness Disintegration time Stability studies Dissolution studies.

Characterization of Solid dispersion : FT-IR DSC X-Ray Diffraction

Materials & methods : Drug: Calcium Channel Blockers (Felodipine)

, Polymers used : Hydroxypropyl methyl cellulose, Hydroxypropyl cellulose, Polyvinyl pyrolidine, Ethyl cellulose, etc.., 7.1 Source of the data : The data required for the work will be collected from different books , Journals and articles available in the Library of Govt. college of Pharmacy, Journals available at Jgate Helinet of the Rajiv Gandhi University of Health Sciences, website and through various internet sources. 7.2 Method of collection of data: The data will be collected from the designed formulation, then subjecting the formulation to different studies like, invitro drug release studies, drug content, drug polymer compatibility studies, general appearance, size, shape, tablet thickness, hardness, friability, stability studies, on the selected formulation and other tests as necessary during the evaluation part of formulation.

7.3 Does the study require any investigations or interventions to be Conducted on patients or other humans or animals? If so, please describe in brief.
Not applicable

7.4 Has ethical clearance been obtained from your institute in case 7.3?

Not applicable

8. List of references: 1. Tao Taoa, Yan Zhaoa, JinjinWua, Beiyi Zhoub; Preparation and evaluation of Itraconazole dihydrochloride for the solubility and dissolution rate enhancement; International journal of Pharmaceutics;2009;367;109-114.

2. Dang Han won, Min soo kim, Sibuem lee, Jeong sook park Sung joo Hong; Improved physicochemical characteristics of felodipine solid dispersion particles by super critical anti- solvent precipitation process. IIJ.Pharm;2005(;1-2);199208. 3. Bhanudas Shankar Kuchekar, Minal Raghunath Narkhede., The effect of water soluble polymers on Felidipine solubility and complexing abilities with modified cyclodextrin. Iranian journal of pharmaceutical sciences. 2007;3(4);197-202. 4. Rai V.K, Pathak.N, Bhaskar.R, Nandi.B.C, Dey.S, Tyagi.L.K; Optimization of immediate Release tablet of Raloxifene hydrochloride by wet granulation method; International journal of pharmaceutical sciences and drug research; 2009;1(1);51-54 5. V K Rai, Singh Rajput, Manoj Sharma, Ashish Agarwal, Anil Gupta and Narendra Singh,; Solubility enhancement of poorly water soluble drug using different Hydrophillic binders in solid dosage form; International journal of comprehensive pharmacy;2010;3;05.

6. S Muralidhar, G Devala Rao, Syed Azhar Nizami, Karunakara reddy, S.Ravindra Reddy; Enhancement of dissolution rate and anti inflammatory potential of celecoxib using solid dispersion; pharmaceutical research; 2010;1;74-81. 7. Jessy Shaji , Digambar Jadhav; Statistical developement and optimization of solid dispersion self Emulsifying Pellets; International journal of pharmaceutical sciences;2010;4(3);156-167. 8. Vijay Kumar, M M Shankaraia, J S Venkatesh, D Rangaraju , C.Nagesh, Characterization of ternary system poorly soluble drugs in various Hydrophilic carriers International research journal of pharmacy; 2011;2;143-145. 9. V P Patel, M C Gohel, R K Parikh, Invitro Dissolution enhacement of Felodipine bu using cyclo dextrin; Indo-Global Journal of pharmaceutical sciences;2011;1(2);194-205. 10. K P R Chowdary, K Surya prakash rao, and Udaya Sree Datla; A Factorial study on the effects of hydroxyl propyl beta cyclodextrin and Poloxamer on the solubility and dissolution rate of piroxicam; International journal of advances in pharmaceutical research; 2011;2(8);412-417. 11. Renu Kalyanwat, Stuti Gupta, K R Rajendra Songara, Dolly Jain and Sushma Patel; Study of enhancement of dissolution rate of carbamazipine by solid dispertion technique; International journal of comprehensive pharmacy;2011;5(09);1-4. journal of advanced

Signature of the Candidate: (MOHAN KUMAR.V.) Remarks of the Guide:

Name and Designation of: 11.1 Guide: Mrs. MANJULA. B. P., ASST. PROFESSOR, DEPT. OF PHARMACEUTICS, GOVT. COLLEGE OF PHARMACY, BANGALORE 560027

11.2 Signature: 11.3 Co-Guide: 11.4 Signature: 11.5 Head of the Department: NOT APPLICABLE NOT APPLICABLE Dr N. G. NANJUNDASWAMY, PROFESSOR, DEPT. OF PHARMACEUTICS, GOVT. COLLEGE OF PHARMACY, BANGALORE- 560027

11.6: Signature: 12.1 Remarks of the Chairman and Principal: 12.2 Signature: Dr. S. SHASHIDHARA, PRINCI PAL, GOVT. COLLEGE OF PHARMACY, BANGALORE

 560027

FORMULATION AND EVALUATION OF SOLID LIPID MICROPARTICLES FOR ANTIHYPERTENSIVE DRUG

M.PHARM DISSERTATION PROTOCOL

SUBMITTED TO

SUBMITTED TO RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA BY SIVANAGARAJA DEVARAMPATI I M.PHARM

UNDER THE GUIDANCE DR.B.PRAKASH RAO PROFESSOR AND HOD DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY KARNATAKA COLLEGE OF PHARMACY BENGALURU-560064 (2011-2012)

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES BENGALURU, KARNATAKA ANEXURE-II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1 Name of the Candidate and

Address

SIVANAGARAJA DEVARAMPATI KARNATAKA COLLEGE OF PHARMACY #33/2, THIRUMENAHALLI HEGDE NAGAR MAIN ROAD BENGALURU-560064. PERMANENT ADDRESS S/O RAMANAIAH D HOUSE NO:2-65 RAMAKRISHNAPURAM, CHIRALA, PRAKASAM(DT), ANDHRA PRADESH-523125

2 Name of the Institute

KARNATAKA COLLEGE OF PHARMACY, #33/2, THIRUMENAHALLI HEGDE NAGAR MAIN ROAD BENGALURU-560064.

3 Course of the Study & Subject

Master of Pharmacy (Pharmaceutical technology)

4 Date of the Admission to the

Course

JULY 7TH 2011

Title of the topic FORMULATION AND EVALUATION OF SOLID LIPID MICROPARTICLES FOR ANTIHYPERTENSIVE DRUG

6 6.1

BRIEF RESUME OF THE INTENDED WORKTIVIT Need of Study:

Oral drug delivery has taken a new dimensions with the increasing application of lipid as a carrier for the delivery of poorly soluble lipophilic drugs. The unique properties of lipids like their inertness, physicochemical diversity, biocompatibility and proven ability to enhance oral bioavailability of poorly water soluble drugs. There are various approaches in formulating lipid based oral formulations. One among them is solid lipid micropaaticles. The size of solid lipid microparticle range from 1-1000 m. The amount of drug encapsulated can vary upto 80% for lipophilic compounds and they are well tolerated in living systems because they are made from physiological or physiologically made materials. Solid lipid microparticles attract increasing attention as alternative delivery systems. They combine the advantages of different traditional carriers, for example, they can be produced on a industrial scale and allow the control of drug release. Hypertension is a chronic condition which requires treatment for life time. It is very important in case of antihypertensive drugs to maintain constant blood levels, otherwise dose dumping may cause hypotension or sub-therapeutic levels may cause hypertension. Angiotensin converting enzyme inhibitors are a type of drugs used for treating hypertension. The main aim of the present work is to formulate, characterize and in-vitro drug release from solid lipid microparticle system containing a anti-hypertensive drug for controlled release to reduce dosage regimen and to increase bioavailability of the lipophilic drug by solubilising in lipid.

6.2

Review of Literature
Gives review on lipid based drug delivery which has developed over the past decade fuelled by a better understanding of the multiple roles lipids may play in enhancing oral bioavailability.the recent aaproaches in selecting the most appropriate lipid system, methods for characterization of their behaviour in vitro and in vivo, the current formulation and processing techniques to obtain various solid dosage forms.1 Gives review on the different ways of solid lipid nanoparticle production such as high pressure homogenization, ultrasonification, microemulsion, spray

CARVEDILOL

Fast Dissolving Tablet: A Novel Approach for Delivery of Carvedilol

Shailesh Sharma*, G.D. Gupta, C.P. Jain1, P.S. Naruka1 *Pharmaceutics Research Laboratory, Department of Pharmaceutics ASBASJS Memorial College of Pharmacy, Bela, Ropar, Punjab. 1Department of Pharmaceutics B. N. College of Pharmacy, Udaipur, Rajasthan.

ABSTRACT

Carvedilol is a poorly water-soluble oral antihypertensive agent, with problems of variable bioavailability and bio-inequivalence related to its poor water-solubility. This work investigated the possibility of developing Carvedilol tablets, allowing fast, reproducible, and complete drug dissolution, by using drug solid dispersion in polyethylene glycol. Solubility studies were performed to investigate the drug-carrier interactions in solution, X-ray powder diffraction, were used to characterize the solid state of solid dispersions. The tablets were prepared by direct compression technique. The prepared tablets were evaluated for thickness, uniformity of weight, content uniformity, hardness, friability, wetting time, in vitro disintegration time and in vitro drug release. The tablets apart from fulfilling all official and other specifications, the Carvedilol dissolution profile from the newly developed tablets was clearly better than those from various conventional tablets at the same drug dosage. The stability studies conducted as per ICH guidelines at 40 and 75% RH showed insignificant loss in drug content and on physical evaluations at the end of six months.

KEYWORDS Carvedilol, Fast Dissolving Tablet, Superdisintigrates, Solid dispersion, Enhance bioavailability. INTRODUCTION

The concept of Fast dissolving Drug Delivery System emerged from the desire to provide patient with more conventional means of taking their medication. It is difficult for many patients to swallow tablets and hard gelatin capsules. Hence they do not comply with prescription, which results in high incidence of non-compliance and ineffective therapy1. In some cases such as motion sickness, sudden episodes of allergic attacks or coughing and

unavailability of water, swallowing conventional tablets may be difficult2. Particularly the difficulty is experienced by pediatric and geriatric patients. Such problems can be resolved by means of Fast Dissolving Tablet. When put on tongue, this tablet disintegrates instantaneously, releasing the drug, which dissolves or disperses in the saliva. Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. In such cases, bioavailability of drug is significantly greater than those observed from conventional tablet dosage form3. Carvedilol is both an alpha and a beta adrenoreceptor-blocking agent used in the treatment of various cardiovascular disorders such as angina pectoris, cardiac arrhythmia and hypertension. Its biological half-life (2.2 hours) is very short and it is 90% absorbed from GIT, but its bioavailability is only 10-20% indicating extensive first pass metabolism in liver. In view of substantial first pass effect and its shorter plasma half-life, therefore is an ideal drug candidate for rapid release drug delivery system.

MATERIALS AND METHODS

Materials Carvedilol was obtained from Sun Pharma (Silvasa) Ac-Di-Sol, Crosspovidone, Xylitol, Sorbitol were obtained as gift samples from Signet Chemicals (Mumbai). Methods Preparation and Evaluation of Solid Dispersion Solid dispersions were prepared with PEG 4000 in various ratios (1:1 to 1:8) by using melt fusion method. The fused mixtures were prepared by heating the corresponding ground mixture in a porcelain dish to about 50C above the melting point of PEG 4000 with continuous stirring for a minute. The samples were immediately quenched to 40C, the resulting solid was scraped out and stored in a desiccators at room temperature. The solid dispersions were evaluated for saturation solubility, drug content and X-Ray Diffraction studies.

Preparation and Evaluation of Tablet 4,5 Tablets were made from blends by direct compression method. All the ingredients (shown in Table 01) were passed through mesh no. 60. All the ingredients were co ground in a pestle motor. Finally talc and magnesium stereate were added and mixed for 5 minutes. The quality of tablet, once formulated by rule, is generally dictated by the quality of physicochemical properties of blends. The mixed blend of excipients was compressed using a single punch machine to produce convex faced tablets weighing 125 mg each with 2.85 mm thickness and 7.8 mm in diameter. The tablets were evaluated for General Appearance, Size and Shape, Uniformity of weight, Tablet hardness, Friability, Disintegration time, Wetting time, In vitro dispersion time, Content Uniformity.

RESULT AND DISCUSSION

The prepared solid dispersions were evaluated for drug content, saturation solubility and X Ray diffraction studies (Table 02).

Table 01: Formulation of Fast dissolving Tablet of Carvedilol

Ingredients Carvedilol Carvedilol FDT1 FDT2 12.5 12.5 FDT3 FDT 4 FDT 5 FDT 6 FDT 7 FDT 8 12.5 12.5 -

+ PEG 4000(1:4) Ac Di Sol 3.75

62.5

62.5

62.5

62.5

5 18 18 25

3.75 18 18 25

5 18 18 25

1.25 -

2.5 -

1.25 -

2.5 -

Crosspovidone Dextrose Lactose Sorbitol Xylitol 18 18 25 19

18.75 18.75 18.75 18.75 11.25 12.5 11.25

17.75 19

17.75 12.5

Avicel pH 102 Talc Magnesium

25 1.25

25 1.25

25 1.25

25 1.25

25 2.5

25 2.5

25 2.5

25 2.5

2.5 Stereate

2.5

2.5

2.5

2.5

2.5

2.5

2.5

Table 02: Evaluation of Solid Dispersion

Parameters Ratio Pure Drug 1:1 1:2 1:3 1:4 1:5 1:6 1:7 1:8 Drug content (%) 100 99.911.302 98.611.294 97.250.416 99.920.256 99.250.419 97.941.253 98.261.035 99.650.983 Saturation solubility (mg/ml) 0.3230.0215 23.3411.257 24.8371.072 26.3590.986 29.9570.549 29.9981.024 30.0011.002 28.0980.458 32.2141.914

Table 03 Evaluation of Fast Dissolving Tablets

Formulation FDT1 Parameters Bulk Density 0.428 (gm/cm3) Tapped 0.459 FDT2 FDT3 FDT4 FDT5 FDT6 FDT7 FDT8

0.461

0.418

0.447

0.392

0.397

0.379

0.382

0.491

0.431

0.473

0.419

0.421

0.419

0.417

Density (gm/cm3) Hausners 1.072 Ratio Compressibil ty (%) Angle of 25.34 Repose (O) Index7.242 6.507 3.11 5.816 6.887 6.045 8.554 9.162 1.065 1.031 1.058 1.068 1.06 1.105 1.091

24.42

26.34

28.24

27.66

29.47

29.98

28.64

124.610. 125.100. 125.48 124.89 125.38 125.54 125.21 126.25 Weight (mg) 39 Hardness 2.30.1 (kg/cm2) Friability 0.55 0.23 0.62 0.51 (%) Disintegratio 282 n Time (sec) Swelling 156 Time (Sec) % Release (5 min) Drug 90.671 92.063 77.789 85.323 97.042 99.266 90.693 94.948 123 172 144 162 141 203 171 214 312 245 544 426 603 445 7 4 3 9 1 7 0.410.3 0.550.2 0.770.1 0.480.2 0.430.1 0.770.2 2.20.3 2.50.1 2.50.4 3.10.1 3.20.2 3.10.3 3.10.2 12 0.19 0.41 0.87 0.28 0.18 0.83

Drug content from solid dispersion of Carvedilol:PEG 4000 (1:1 to 1:8) was found to be 97.94 % to 99.92%. It was observed that the saturation solubility of the drug was increased in

(Sorensons Buffer pH 6.8) by converting the drug Carvedilol into solid dispersions which may be due to change in physical state of Carvedilol from crystalline to amorphous state, which was confirmed by XRD studies. The X- Ray diffraction pattern of solid dispersion of Carvedilol: PEG 4000 (1:4) showed no defined peak attributes to Carvedilol, this implies the absence of apparent crystalline in solid dispersion. However in the pure Carvedilol powder typical peak of Carvedilol was present, so confirming the satisfactory sensitivity of the method. The peaks are shown in Figure 01. On the basis of the obtained results the ratio of Carvedilol: PEG 4000 (1: 4) was optimized for further development of the fast dissolving tablet of Carvedilol.

Figure 1 X-Ray Diffraction Spectrums

Figure 2 Different stages of Swelling of Fast Dissolving Tablet

Figure 3 In Vitro Drug Release Profile (Zero Order Release)

Figure 4 In Vitro Drug Release Profile (First Order Release)

All the tablets were exhibit in white color, odorless, convex in shape with smooth surface with zero defects. The average weight of the prepared tablet was found 123.11 to 126.68 mg. The thickness and diameter of the tablet was found 2.85 mm, 7.8 mm respectively. A tablet requires certain amount of hardness to withstand the mechanical shocks in handling,

packaging and at the time of application. The hardness of the prepared tablet varied from 2.1 to 3.3 Kg/cm2 which have satisfactory strength to withstand the mechanical shocks.

The friability of all the formulation was found to be less than 1.0 %. The results shows resistance to loss of weight indicates the tablets ability to withstand abrasion in handling, packaging and shipment. The disintegration time of the tablets was varied form 19 to 60 seconds. The tablets with Ac-Di-Sol may disintegrate faster then the tablets with the crosspovidone. The in vitro swelling time of all the formulations were varied between 09 to 20seconds. The drug content of all the formulations was varied from 12.293 to 12.600 mg per tablet. The correlation of variation was found to be less than 0.054 %, indicating uniformity of the drug content in the prepared tablets. The release found to be at the end of five minutes 77.789 - 96.063% by using of superdisintegrates. The formulations with Ac Di- Sol shows more release than the tablets with Crosspovidone. An increase (4 -5%) in the drug release was observed when the drug used as solid dispersion with PEG 4000 in ratio of 1:4 with low concentration of disintegrates (1 and 2%). From the in-vitro drug release profile it is evident that the kinetics of drug release is first order for all the prepared fast dissolving tablets as the plot between log percent drug retained versus time showed good linearity. The coefficient of determination of R2 values much closer to 1. The good relationship was evidenced in the Hixon Crowell's Cube Root Law which signifies the drug is assumed to dissolve out from matrix or from surface of the device. All the formulations showed no significant variation in all the parameters under the test period. The drug degradation was found to follow first order kinetics the data obtained from accelerated stability studies, when fitted to the Arrhenius studies, the shelf life of prepared tablet was found to be 520 to 832 days.

CONCLUSION

The prepared tablet gives benefit in terms of patient compliance, low dosing, rapid onset of

action, increased bio-availability, low side effect and good stability which make these tablets popular as a dosage form for the treatment of hypertension.

REFERENCES

1. Seager H. Drug-deliver products and the zydis fast-dissolving dosage form. J. Pharm. and Pharmacol. 1998; 50: 375-382. 2. Habib W, Khankari R, Hontz J. Fast-dissolving drug delivery systems. Critical Reviews Therapeutic Drug Carrier Systems. 2000; 17(1): 61-72. 3. Corveleyn S, Remon, J P. Formulation and production of rapid disintegrating tablets by lyophilization using hydrochlorthiazide as a model drug. Int. J. Pharm. 1997; 152: 215-225. 4. Ringard J, Guyot-Hermann AM, Calculation of disintegrant critical concentration in order to optimize tablets disintegration. Drug Dev. Ind. Pharm. 1997; 14 (15-17): 2321-2339. 5. Bi, Y. et al. (1996) Preparation and evaluation of a compressed tablet rapidly disintegrating in the oral cavity. Chem. Pharm. Bull. 44 (11), 2121-2127.

ACKNOWLEDGEMENT Author(s) is thankful to Sun Pharmaceuticals, Silvasa for providing Carvedilol, and for Signet Chemicals, Mumbai for providing drug, polymer and other ingredients.

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IMPROVEMENT OF THE ORAL BIOAVAILABILITY OF TWO ANTIHYPERTENSIVE DRUGS BY THE USE OF DIFFERENT GALENICAL FORMULATIONS. B. Bittner1

Pharma Division, Preclinical Cardiovascular Research, Hoffmann-La Roche Ltd,

Basel, Switzerland, Sweden

Purpose. Different experimental formulations were investigated for their potential to improve the oral bioavailability (F) of two low solubility and high intestinal permeability antihypertensive compounds Ro XXX1 and Ro XXX2. PK studies using the two compounds formulated as aqueous solutions demonstrated comparatively low systemic F in dog (Ro XXX1: 6%, Ro XXX2: 17%). Possible explanations could be enzymatic instability in the GIT, incomplete/slow solubilization in the GIT, presystemic metabolism, intestinal efflux, and/or liver first pass metabolism/bilary excretion. Moreover, the compounds in their free base form are very lipophilic (logD7.4 = 5.6 and 3.4 for Ro XXX1 and Ro XXX2, respectively). Methods. Several formulations based on aqueous or oily systems, as well as on water miscible solvents and solid dispersions in Eudragit were prepared to improve the amount of compound dissolved. PK experiments were performed in dogs (single oral dose 3 mg/kg). Results. The F of Ro XXX1 in aqueous solution could not be improved significantly, neither using a mixed micellar formulation or a solution in PEG400/Cremophor, nor using a solid dispersion in Pluronic F-68 or an emulsion pre-concentrate. By contrast, oily formulations could enhance its F by a factor of at least 2, with the best result being achieved with the compound formulated in Capmul. A decrease in F was observed with a solid dispersion in Eudragit L 100-55. In the case of the less lipophilic Ro XXX2, the highest F could be achieved using either a solution in water or in Capmul. Administration of the compound in oily systems or in cosolvents resulted in a decrease in F. Again the pH-sensitive Eudragit formulation showed the lowest F. Conclusions. The current studies demonstrated that the fraction absorbed of the two antihypertensive drugs could be increased by increasing the solubility in the formulation. Thus, solubility seems to be one of the rate limiting steps for oral

absorption of the compounds. The effects of formulations on P-glycoprotein and intestinal enzymes will be investigated in further studies.

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Yousef Javadzadeh ,Ph.D

Title:Associate Professor Department:Pharmaceutics Office Phone:+98(411)3392606 Fax:+98(411)334-4798 Email:javadzadehy@tbzmed.ac .ir Alternative E-mail: javadzadehy@yahoo.com

Educational Background

PharmD: 1998, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Research Fellow: 2004, School of Pharmacy, Aston University, Birmingham, UK PhD: 2005, in Pharmaceutics, School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

Description of Research Program

Improvement of drug dissolution characteristics and bioavailability Formulation of topical dosage forms and enhancing of their transdermal absorption by enhancers Formulation of hygienic and cosmetic products Development of sustain release formulations

Teaching experiences
Pharmaceutical technology- Drug Information- Hygienic and cosmeticsComputer science

Books
Pharmaceutical solid dosage forms coating technology

Reviewer for following journals

Drug Development and Industrial Pharmacy Journal of Pharmacy and Pharmaceutical Sciences Iranian Journal of Pharmaceutical research Pharmaceutical Sciences Bulletin of the Chemical Society of Ethiopia

Research experiences

Preparation and evaluation of novel metronidazole floating and sustained release matrix tablet as local anti-H. pylori therapy. Preparation and evaluation of metronidazole floating drug delivery system using alginate beads as local anti-H. pylori therapy Evaluation of effect of different grades of cellulose microcrystalline on flowablity, compressibility and hardness of piroxicam liquisolid systems and comparison of drug release Evaluating solubility of sodium diclofenac in binary and ternary solvent systems to obtain best solvent system for preparation of injectable dosage form Evaluation of the enhanced solubility of Piroxicam using of Liquisolid technique. Formulation of sustained release tablets of propranolol hydrochloride using liquisolid technique. Formulation of methotrexate topical formulation ( gel ) and evaluation of its exvivo transdermal absorption Evaluation of physicomechanica properties of crystallized carbamazepine in different pHs. Enhancing dissolution rate of high dose water-insoluble drug (carbamazepine) using liquisolid technique. The use of granulation method to improve physicomechanical properties of piroxicam liquisilid systems Study on content uniformity of antiepileptic drugs from Iranian pharmacy marketing. Study of anti-inflammatory and analgesic effect of eremostachys laciniata on the arthritis, tendonds and ligaments injuries, muscles crushing and acute and chronic low back pains and formulation of pharmaceutical dosage form. Evaluation of enhanced dissolution rate of Indometacin using Liquisolid technique. Formulation of topical finasteride for treatment of androgenetic alopecia and evaluating of its transdermal absorbtion. Clinical evaluation of two topical formulation of finasterid and comparion of it with placebo Formulation of oral solid dosage form of Clofibrate and evaluation of its release.

Evaluation of effect of oral ketamin in dog. formulation of oral dosage form of lorazepam and evaluation of its efficacy in cat. Evaluation of sedative effect of ketamin and hydroxyzine in cat Formulation of rectal diazepam gel. Formulation of Minoxidil Shampoo. Understanding of mechanism of enhanced dissolution rate of ibuprofen using solid dispersion technique. Understanding of mechanism of interaction between Ibuprofen and Glucosamine. Evaluation of effect of different commercial grades of cellulose microcrystalline on flowablity, compressibility and hardness of liquisolid systems and comparison of drug release. Evaluating solubility of diclofenac sodium in binary and ternary solvent systems to obtain best solvent system for preparation of liquid dosage form

Publications
1-Asnaashari S, Khoei NS, Zarrintan MH, Adibkia K, Javadzadeh Y., Preparation and evaluation of novel metronidazole sustained release and floating matrix tablets, Pharm Dev Technol. 2010 Apr 30, in press. 2-Nokhodchi A, Aliakbar R, Desai S, Javadzadeh Y., Liquisolid compacts: The effect of cosolvent and HPMC on theophylline release, Colloids Surf B Biointerfaces. 2010 Apr 21, in press. 3-Javadzadeh Y., Shokri J., Halaj-Nezhadi S., Hamishekar H., Nokhodchi A., Enhancement of percutaneous absorption of finasteride by cosolent, cosurfactant

and surfactants, Pharmaceutical development and technology, in press 4- Javadzadeh Y., Hamedeyazdan S., Adibkia Kh., Kiafar F., Zarrintan M.H., Barzegar-Jalali M., Evaluation of drug release kinetics and physicochemical characteristics of metronidazole floating beads based on calcium silicate and gas forming agents, Pharmaceutical development and technology, in press. 5- Yousef Javadzadeh, H. Shariaati., E. Movahhed danesh, A. Nokhodchi, Effect of some commercial grades of cellulose microcrystalline on flowablity,

compressibility and dissolution profile of piroxicam liquisolid compacts, Drug Development and Industrial Pharmacy, 35; 243-251 (2009). 6-Javadzadeh Y, Mohammadi A., Seyedkhoei N., Nokhodchi A., Improvement physicomechanical properties of carbamazepine by recrystalization in different pH values, Acta Pharmaceutica, 59, 187-197 (2009). 7-Yousef Javadzadeh, Leila Musaalrezaei, Ali Nokhodchi, Liquisolid technique as a new approach to sustain the drug release from compacts, International Journal of Pharmaceutics, 362(1-2), 102-8 (2008). 8- Shabanloei R., Ahmadi F., Vaez J., Ansarin K., Hajizadeh E., Javadzadeh Y., Dolatkhah R., Gholchin M., Alloporinol, chemomile and normal saline mouthwashes for the prevention of chemotherapy-induced stomatitis, Journal of Clinical and Diagnostic Research (JCDR), 5th May 2009. 9- M.Sohrabi, F.A. Kalati, S. Vatansever, M.M. Abbasi, L. Roshangar, A.A. Khaki, I.M. Tuglu, I. Aydemir, Y. Dustar, Y. Javadzadeh, J. Soleimani Rad, Effect of dietary and topical celecoxib on expression of bcl-2, bax, c-erb-B2 and Ki67 in carcinogen-induced tongue carcinoma in rat, Pakistan Journal of Biological Sciences, 1-8 (2009). 10-Javadzadeh Y., Siahi M.R., Asnaashari S., Nokhodchi A., Liquisolid technique as a tool for enhancement of poorly water-soluble drugs and evaluation of their physicochemical properties, Accta Pharm., 57, 99-109 (2007). 11-Javadzadeh Y., Jafari-Navimipour B., Nokhodchi A., Liquisolid technique for dissolution rate enhancement of high dose water-insoluble drug (carbamazepine), International Journal of Pharmaceutics, 341, 26-34 (2007). 12-Javadzadeh Y., Siahi M.R., Asnaashari S., Nokhodchi A., Investigation on

physicochemical properties of piroxicam liquisolid formulations, Pharmaceutical development and technology, 12, 337-343 (2007). 13-Nokhodchi A., Javadzadeh Y., The effect of storage condition on the physical stability of tablets, Pharmaceutical Technology Europe, January 2007, 20-26 (2007). 14-Y. Javadzadeh, M.R. Siahi, M. Barzegar Jalali, A. Nokhodchi, Enhancement of dissolution rate of piroxicam using liquisolid compacts, IL FARMACO, 60(4): 361365 (2005). 15-Ali Nokhodchi, Yousef Javadzadeh, Mohammad Reza Siahi, Mohammad barzegar Jalali, The effect of type and concentration of vehicles on the dissolution rate of a poorly soluble drug (indomethacin) from liquisolid compacts, Journal of pharmacy and pharmaceutical sciences, 8(2): 18-25 (2005). 16-Solmaz Esnaashari, Yousef Javadzadeh, Hanna K. Batchelor, Barbara R. Conwey, The use of micriviscometry to study polymer dissolution from solid dispersion drug delivery systems, International Journal of Pharmaceutics, 292(12):227-230(2005). 17-J. Hanaee, Y. Javadzadeh, S. Taftachi, J. Farid, A. Nokhodchi, The role of various surfactants on the release of salbutamol from suppositories, IL FARMACO, 59(11): 903-906(2004). 18-Javadzadeh Y. , Nokhodchi A., Flowability, compressibility, dissolution and hardness of piroxicam liquisolid systems prepared by cellulose microcrystalline, Pharmaceutical Sciences, 2010, Vol.15, No4, Page 361- 374 19-Adibkia K. , Barzegar-Jalali M. , Nokhodchi A., Siahi Shadbad MR., Omidi Y. , Javadzadeh Y. , Mohammadi G., A review on the methods of preparation of pharmaceutical nanoparticles, Pharmaceutical Sciences, 2010, Vol.15, No4, Page

303- 314. 20-Hasanzadeh D., Nokhodchi A., Javadzadeh Y. , Darsazan B., Siahi M.R., Sustained release formulation of propranolol hydrochloride by solid dispersion technique, Pharmaceutical sciences, Spring( 2005); 67-74. 21-Yousef Javadzadeh- Ali Nokhodchi - Solmaz Asnaashari- Ahdieh BafandehMohammad Reza Siahi, Evaluation of enhanced dissolution rate of indomethacin using liquisolid technique, Pharmaceutical sciences, Summer( 2005); 57-64. 22-Siahi M.R., Javadzadeh Y., Mahdavizadeh F., Nokhodchi A., Studies on the effect of solvent on the efficiency of sunscreen products, Pharmaceutical sciences, autumn (2005), 1-7. 23-Yousef Javadzadeh- Solmaz Asnaashari-Ali Nokhodchi - Barbara Conway, Evaluating effect of glucosamine on dissolution, protein binding and partition coefficient of ibuprofen, Pharmaceutical sciences, autumn(2005), 21-25. 24-Shokri j., Nokhodchi A., Javadzadeh Y., Ayatollahi M., Formulation of topical finasteride for treatment of androgenetic alopecia and evaluating of its transdermal absorbtion, Pharmaceutical sciences, No 1(2004), Spring and Summer, 65-78 25-Farid J., Azarmi Sh., Javadzadeh Y., Bahari m., Evaluation of release of Indomethacin from matrices of acrilic polymers, Pharmaceutical sciences, No 1(2002), Spring and Summer, 69-78. 26-Farid J., Azarmi Sh., Javadzadeh Y., Hargoli S, Evaluation of base type and surface-active agents in release rate of naproxen from suppositories, Pharmaceutical Sciences, No 1(2001), Spring and Summer, 75-84 27-Shabanloei R., Ahmadi F., Vaaz garamalaky J., Hajizadeh E., Javadzadeh Y, The effects of Allopurinol and Normal Saline mouthwashs in the prevention of

chemotherapy-induced stomatitis, Pharmaceutical sciences, spring (2006), 27-33. 28-Shabanlouie R., Ahmadi F., Vaez Gharamaleki, Hajizadeh E, Javadzadeh Y., Effect of chamomile mouthwash in the prevention of chemotherapy-induced stomatitis , Journal of rehabilitation, Summer 2006; 7(2), 70-75. 29-Shabanloei R., Ahmadi Gharamaleki J., Hajizadeh E., Javadzadeh Y., The effect of allopurinol mouthwash in the prevention of chemotherapy-induced dtomatitis, Tehran University Medical Journal, Vol. 65, No. 9, Dec 2007, 71-76. 30- Javadzadeh Y., Hasanzadeh D., Hasani S., Evaluating solubility of sodium diclofenac in binary and ternary solvent systems to obtain a suitable solvent system for preparation of injectable dosage form, Pharmaceutical sciences, autumn ( 2007); 27-35. 31- Yousef Javadzadeh, M.R. Siahi, Z. Rajabi, I. Keivan, O. Asnaashari, R. Safdari, Formulation of methotrexate topical formulation (gel) and evaluation of its in vitro transdermal absorption, Pharmaceutical sciences, winter ( 2008); 1-14. 32- Yousef Javadzadeh, Davood Hasanzadeh, , Sepideh Ghafourian, Somayeh Hallaj Nezhadi, Ali Nokhodchi, Comparison of the natural polymer of Plantago psyllium as tablet binder and disintegrant with other common pharmaceutical excipients, Pharmaceutical Sciences, 15(1), 53-66 (2009).

Congress Attended,Lectures
1- Javadzadeh Y., Mohammadi A., Asnaashari S., Nokhodchi A., Effect of pH of the crystallization medium on the physicomechanical properties of carbamazepine crystals, The British Pharmaceutical Conference & Exhibition(BPC), 10-12 September 2007, Manchester, UK. (this poster was awarded as best poster in Pharmaceutical Technology section)

2- Javadzadeh Y., Shariati H., Asnaashari S., Nokhodchi A., Effecdt of some commercial grades of cellulose microcrystalline on flowability, compressibility and dissolution profile of piroxicam liquisolid compacts, 68th International Congress of FIP, 29 August until 4 September 2008, Basel Switzerland. 3- Javadzadeh Y., Siahi MR., Rajabi Z., Iman K., Ansaashari S., Safdari R., Formulation of methotrexate topical formulation (gel) and evaluation of its in vitro transdermal absorption, The 11th Iranian Pharmaceutical Sciences Conference, 1821 August 2008, Kerman, Iran. 4- Seyedkhoei N., Javadzadeh Y., Preparation and evaluation of novel metronidazole floating and sustained release matrix tablet, The 11th Iranian Pharmaceutical Sciences Conference, 18- 21 August 2008, Kerman, Iran. 5- Tamizi E., Jouyban A., Javadzadeh Y., Study on physicochemical properties of antiepileptic drugs from Iranian marketing, The 11th Iranian Pharmaceutical Sciences Conference, 18- 21 August 2008, Kerman, Iran. 6- Rafie F., Javadzadeh Y., Hasanzadeh D., Hasani S., Evaluation of effect of different commericial grades of cellulose microcrystalline on flowability, compressibility, hardness and dissolution of liquisolid systems and comparison of drug release, The 11th Iranian Pharmaceutical Sciences Conference, 18- 21 August 2008, Kerman, Iran. 7- Javadzadeh Y., Shokri S., Ayatollahi M., Hallaj Nezhad S., Nokhodchi A., Topical finasteride for androgenic alopecia treatment, The 11th Iranian Pharmaceutical Sciences Conference, 18- 21 August 2008, Kerman, Iran. 8- Saffaei E., Javadzadeh Y., Hasanzadeh D., Hasany S., Evaluating solubility of diclofenac sodium in binary and ternary solvent systems to obtain a suitable solvent

system for preparation of injectable solution form, The 11th Iranian Pharmaceutical Sciences Conference, 18- 21 August 2008, Kerman, Iran. 9- Safaei E., Javadzadeh Y., The role of various surfactants on the release of salbotamol from suppositories, The 11th Iranian Pharmaceutical Sciences Conference, 18- 21 August 2008, Kerman, Iran. 10- Salarmand K., Javadzadeh Y., Zarrintan MH., Improvement physicochemical properties of piroxicam liquisolid compacts using granulation technique, The 11th Iranian Pharmaceutical Sciences Conference, 18- 21 August 2008, Kerman, Iran. 11- Nokhodchi A., Hasanzadeh D., Javadzadeh Y., Ghafourian T., Hallaj Nazhad S., Comparison of the natural polymer of Plantago psyllium as tablet binder and disintegrant with other common pharmaceutical excipients, The 11th Iranian Pharmaceutical Sciences Conference, 18- 21 August 2008, Kerman, Iran. 12- Bazmani A., Mazlumi A., Babaei H., Delazar A., Javadzadeh Y., Amini MH., Rostamzadeh S., Hosein poor T., Repellant effect of herbal drugs (Peganum harmala and Sabucus ebulus) on Phlebotomus sand flied, the vectors of leishmania, The 11th Iranian Pharmaceutical Sciences Conference, 18- 21 August 2008, Kerman, Iran. 13- Bazmani A., Mazlumi A., Babaei H., Delazar A., Javadzadeh Y., Amini MH., Rostamzadeh S., Esnaashari S., Repellant effect of herbal drugs (Eugenia caryophyllus and Menthe piperita) on Phlebotomus sand flied, the vectors of leishmania The 11th Iranian Pharmaceutical Sciences Conference, 18- 21 August 2008, Kerman, Iran. 14- Bazmani A., Mazlumi A., Babaei H., Delazar A., Javadzadeh Y., Amini MH., Rostamzadeh R., Repellant effect of herbal drugs (Hesperis persica and Ailanthus altissima) on Phlebotomus sand flied, the vectors of leishmania The 11th Iranian

Pharmaceutical Sciences Conference, 18- 21 August 2008, Kerman, Iran. 15- Nokhodchi A., Javadzadeh Y., Mosaalrezaei L., Liquisolid technique for sustaining the drug release from compacts, 10-12 September 2007, Manchester, UK. 16- Javadzadeh Y., Siahi M.R., Iman K., Rajabi Z., Enhancement of transdermal absorption of methotrexate from topical formulation for treatment of psoriasis, The third Iranian conference of novel drug delivery systems, 20-21 June 2007, Tehran, Iran. 17- Mahmoodi-Yamchi L., Nokhodchi A., Javadzadeh Y., Siahi-Shadbad M.R., An in vitro evaluation of psyllium powder as a potential excipient for oral controlledrelease matrix tablet, The third Iranian conference of novel drug delivery systems, 20-21 June 2007, Tehran, Iran. 18- Mazlumi AS., Delazar A., Babaei H., Javadzadeh Y., Bazmani A., Amini MH., Ghazanchaei A., Rostamzadeh S., Bamdad S.,Esnaashari S., Mesgari M., Study of Hesperis persica and Eugenia caryophyllus extracts effects as a mosquito repellent for leishmania control, The 3rd congress of medical plants, 24-25 October 2007, Tehran, Iran. 19- Yousef Javadzadeh, Mohammad Reza Siahi-Shadbad, Mohammad BarzegarJalali, Ali Nokhodchi , Study of Physichochemical Properties of Piroxicam Liquisolid Compacts, The Second International Conference of Pharmaceutical and Drug Industries Division- Applied Research for Drug Industries Conference, 7-9 March 2005, Cairo, Egypt. 20- Ali Nokhodchi, Yousef Javadzadeh, Mohammad Barzegar-Jalali, Mohammad Reza Siahi-Shadbad, Liquisolid compacts as a tool for dissolution enhancement of poorly soluble drugs, 12th Iranian Researchers Conference in Europe(IRCE2004), 3rd

-4 th July 2004, Manchester- UK . 21- Solmaz Asnaashari, Hadi Moazzen, Javad Farid, Yousef Javadzadeh, Evaluation of diazepam release from rectal gel formulation of it, The 2nd International congress of pharmaceuticals & Drug Industries Division, Cairo, Egypt, 7-9 March 2005 22- Yousef Javadzadeh, Mohammadreza Siahi, Mohammad Barzegar Jalali, Solmaz Asnaashari, Ali Nokhodchi, Study on the mechanism of enhanced dissolution rate of indomethacin from liquisolid tablets, 26th Annual conference of the academy of pharmaceutical siences, port Elizabets, South Africa, 29 September to 1 October 2005. 23-Javadzadeh Y., Jafari Navimi pour B., Asnaashari S., Nokhodchi A , Enhancing dissolution rate of high dose water- insoluble drug carbamazepine) using

liquisolid technique, 8th International Symposium on Pharmaceutical Sciences (ISOPS-8), Ankara, June 13-16, 2006 24- Yousef Javadzadeh,, Mohammad Reza Siahi, Solmaz Asnaashari, Ali Nokhodchi, Evaluation of physicochemical properties of indomethacin liquisolid compacts, 8th International Symposium on Pharmaceutical Sciences (ISOPS-8), Ankara, June 13-16, 2006. 25- Javadzadeh Y., Musaalrezaee L., Asnaashari S.., Nokhodchi A., Evaluation on capability of liquisolid technique in preparation of sustain release formulation of propranolol hydrochloride, 8th International Symposium on Pharmaceutical Sciences (ISOPS-8), Ankara, June 13-16, 2006. 26- Ghazanchaei A., Babaei H., Delazar A., Mazloumi A.S., Javadzadeh Y., Bazmani A., Amini M.H., Rostamzadeh S., Bamedad S., Esnaashari S., Mesgari M.,

Study of Peganum harmala and Menthe piperita extracts effect as a mosquito repellent for leishmania control, The 3rd congress of medical plants, 24-25 October 2007, Tehran, Iran. 27- Babaei H., Delazar A., Javadzadeh Y., Mazloumi A.S., Bazmani A., Amini M.H., Ghazanchaei A., Rostamzadeh S., Bamedad S., Esnaashari S., Mesgari M., Study of Ageti and Arar extracts effect as a mosquito repellent for leishmania control, The 16th Iranian congress on infectious disease and tropical medicine, 15-19 Dec. 2007, Tehran, Iran. 28- J. Shokri, A. Nokhodchi, Y. Javadzadeh, M. Ayatallahi, A. Nazari, Formulation of topical finasteride for treatment of androgenetic alopecia and evaluation of its transdermal absorption, 9th Seminar of Pharmaceutical Sciences, Tabriz, Agu 23-26, 2004 . 29- Y. Javadzadeh, M. R. Siahi, M/ Barzegar Jalali, A. Nokhodchi, Enhancement of dissolution rate of piroxicam using liquisolid compacts, 9th Seminar of Pharmaceutical Sciences, Tabriz, Agu 23-26, 2004 . 30- Y. Javadzadeh, J. Farid, H. Moazzen, Formulation of diazepam rectal jel for treatment of seizure, secon congress of medical sciences, Young researcher club, Ardabil, Iran, 2003 . 31- Y. Javadzadeh, J. Farid, J. Hanaee, S. Taftachi, evaluation of effect of the concentration of surface active agents on release of naproxen from suppositories, 8th Iranian seminar of pharmaceutical sciences, Shiraz, Agu 26- 28, 2002 . 32-Y. Javadzadeh, A. Nokhodchi, M.R. Siahi, M. Barzegar Jalali, Enhancement of Prednisolon Dissolution properties utilizing liquisolid technique,9th Iranian pharmaceutical congress,2003, Tabriz, Iran.

33- Y. Javadzadeh, M.R. Siahi, K. Iman, Z. Rajabi, Enhancement of transdermal absorpsion of methotrexate from topical formulation for treatmen of psoriasis, 3rh Iranian Conference of Novel Drug Delivery Systems, 20-21 June 2007, Tehran, Iran. 34-L. Mahmudi-yamchi, A. Nokhodchi, Y. Javadzadeh, M.R. Siahi-Shadbad, An in vitro evaluation of psyllium powder as a potential excipient for oral controlledrelease matrix tablet, 3rh Iranian Conference of Novel Drug Delivery Systems, 2021 June 2007, Tehran, Iran. 35-"Shampoos", Tabriz University of Medical Sciences, 14th Training course for Iranian Pharmasists, 2000. 36-OTC Drugs Tabriz University of Medical Sciences, 22th Training course for Iranian Pharmasists, 2004. 37-Bioequivalency Tabriz University of Medical Sciences, Training course for Iranian Pharmasists, 2006. 38-toothpastes Tabriz University of Medical Sciences, Training course for Iranian Pharmasists, 2006. 39-Shampoos and soaps Tabriz University of Medical Sciences, Training course for Iranian Pharmasists, 2006. 40- Novel oral drug delivery systems Urumieh University of Medical Sciences, Training course for Iranian Pharmasists, 2006. 41-toothpastes Urumieh University of Medical Sciences, Training course for Iranian Pharmasists, 2006. 42-Shampoos and soaps Tabriz University of Medical Sciences, Training course for Iranian Pharmasists, 2006.

Presentations

Yousef Javadzadeh, Mohammad Reza Siahi-Shadbad, Mohammad Barzegar-Jalali, Ali Nokhodchi , Study of Physichochemical Properties of Piroxicam Liquisolid Compacts, The Second International Conference of Pharmaceutical and Drug Industries Division- Applied Research for Drug Industries Conference, 7-9 March 2005, Cairo, Egypt.

Ali Nokhodchi, Yousef Javadzadeh, Mohammad Barzegar-Jalali, Mohammad Reza Siahi-Shadbad, Liquisolid compacts as a tool for dissolution enhancement of poorly soluble drugs, 12th Iranian Researchers Conference in Europe(IRCE2004), 3rd -4 th July 2004, Manchester- UK .

Solmaz Asnaashari, Hadi Moazzen, Javad Farid, Yousef Javadzadeh, Evaluation of diazepam release from rectal gel formulation of it, The 2nd International congress of pharmaceuticals & Drug Industries Division, Cairo, Egypt, 7-9 March 2005

Yousef Javadzadeh, Mohammadreza Siahi, Mohammad Barzegar Jalali, Solmaz Asnaashari, Ali Nokhodchi, Study on the mechanism of enhanced dissolution rate of indomethacin from liquisolid tablets, 26th Annual conference of the academy of pharmaceutical siences, port Elizabets, South Africa, 29 September to 1 October 2005.

Javadzadeh Y., Jafari Navimi pour B., Asnaashari S., Nokhodchi A , Enhancing dissolution rate of high dose water- insoluble drug carbamazepine) using liquisolid technique, 8th International Symposium on Pharmaceutical Sciences (ISOPS-8), Ankara, June 13-16, 2006

Yousef Javadzadeh,, Mohammad Reza Siahi, Solmaz Asnaashari, Ali Nokhodchi, Evaluation of physicochemical properties of indomethacin liquisolid compacts, 8th International Symposium on Pharmaceutical Sciences (ISOPS-8), Ankara,

June 13-16, 2006.

o

Javadzadeh Y., Musaalrezaee L., Asnaashari S.., Nokhodchi A., Evaluation on capability of liquisolid technique in preparation of sustain release formulation of propranolol hydrochloride, 8th International Symposium on Pharmaceutical Sciences (ISOPS-8), Ankara, June 13-16, 2006.

J. Shokri, A. Nokhodchi, Y. Javadzadeh, M. Ayatallahi, A. Nazari, Formulation of topical finasteride for treatment of androgenetic alopecia and evaluation of its transdermal absorption, 9th Seminar of Pharmaceutical Sciences, Tabriz, Agu 2326, 2004 .

Y. Javadzadeh, M. R. Siahi, M/ Barzegar Jalali, A. Nokhodchi, Enhancement of dissolution rate of piroxicam using liquisolid compacts, 9th Seminar of Pharmaceutical Sciences, Tabriz, Agu 23-26, 2004 .

Y. Javadzadeh, J. Farid, H. Moazzen, Formulation of diazepam rectal jel for treatment of seizure, secon congress of medical sciences, Young researcher club, Ardabil, Iran, 2003 .

Y. Javadzadeh, J. Farid, J. Hanaee, S. Taftachi, evaluation of effect of the concentration of surface active agents on release of naproxen from suppositories, 8th Iranian seminar of pharmaceutical sciences, Shiraz, Agu 26- 28, 2002 .

Enhancement of Prednisolon Dissolution properties utilizing liquisolid technique,9th Iranian pharmaceutical congress,2003, Tabriz, Iran.

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Olmesartan medoxomil for the treatment of hypertension in children and adolescents Giuliano Tocci1 and Massimo Volpe1,2 1Chair and Division of Cardiology, Department of Clinical and Molecular Medicine, Faculty of Medicine, University of Rome Sapienza, SantAndrea Hospital, Rome; 2IRCCS Neuromed, Pozzilli, Italy Correspondence: Massimo Volpe, Chair and Division of Cardiology, Department of Clinical and Molecular Medicine, Faculty of Medicine, University of Rome Sapienza, SantAndrea Hospital, Via di Grottarossa 1035-9, 00189 Rome, Italy, Tel +39 06 3377 5654, Fax +39 06 3377 5061, Email massimo.volpe@uniroma1.it Received March 30, 2011

This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. This article has been cited by other articles in PMC. Other Sections Abstract Introduction Hypertension management in children and adolescents Pharmacodynamics, pharmacokinetics and clinical efficacy of olmesartan Conclusions and perspectives References Abstract Prevalence of hypertension in children and adolescents has progressively and continuously increased over recent decades. Thus, early and effective control of high blood pressure may be considered an effective therapeutic approach, in order to reduce the burden of hypertension-related cardiovascular disease in future. In the past, due to the absence of prospective, long-term, randomized, controlled clinical trials performed in young hypertensive patients, lifestyle changes have been long seen as the only strategy to reduce high blood pressure levels. More recently, clinical data on the efficacy and safety of five major classes of antihypertensive drugs (including angiotensin converting enzyme inhibitors, angiotensin receptor blockers [ARBs], beta-blockers, calcium-antagonists, and diuretics) have become available. In particular, these trials demonstrated dose-dependent blood pressure reductions and a good tolerability profile of several ARBs in hypertensive children and adolescents. An overview is provided of the clinical benefits of early detection and prompt intervention of high blood pressure levels, with a closer analysis of recent clinical trials, performed with olmesartan medoxomil in young subjects with hypertension. Keywords: hypertension, high blood pressure, children, adolescents, antihypertensive treatment, olmesartan medoxomil Other Sections Abstract Introduction Hypertension management in children and adolescents Pharmacodynamics, pharmacokinetics and clinical efficacy of olmesartan Conclusions and perspectives References Introduction Effective treatment of high blood pressure (BP) represents a key strategy in reducing the burden of cardiovascular (CV) and renal diseases.13 Consistent findings have demonstrated significant reductions in CV and renal morbidity and mortality through the systematic use of different BP-lowering strategies in adult populations.47 In spite of these well-established concepts, hypertension remains poorly controlled in both Western countries8,9 and in developing countries.1012 In view of the progressively increasing prevalence of hypertension in children and adolescents,13,14

early and effective control of BP may be considered an effective therapeutic approach for reducing the burden of hypertension-related CV disease. Observational surveys have demonstrated that high BP levels are frequently associated with other concomitant CV risk factors, including obesity, dyslipidemia, metabolic syndrome, and diabetes in young individuals.1518 This clustering of multiple, concomitant CV risk factors may exert different effects according to target populations: while in adulthood it raises the susceptibility for developing major CV and renal events, including acute myocardial infarction, stroke, and heart and renal failure,19,20 in childhood it may substantially promote an acceleration of the risk of developing established CV disease in adult age.21,22 In other words, young subjects with high BP levels, hypercholesterolemia, metabolic syndrome, or impaired glucose regulation have greater susceptibility to develop these clinical conditions with aging, thus contributing to an increased burden of CV disease in the general population. These features make hypertension a potential target to reduce CV morbidity in young subjects and to improve prevention of CV morbidity and mortality in adult individuals.23 This latter point has prompted the search for agents or strategies that exert an early and effective BP control and that, at the same time, are able to provide benefits in terms of organ protection, beyond BP-lowering effects, with a low incidence of side effects and good tolerability profile, which represents important properties in young individuals.24,25 In view of the progressively large diffusion of hypertension and BP-related clinical diseases in children and adolescents, and of the objective difficulties of applying lifestyle changes in this specific age group, the use of antihypertensive drugs, especially in those patients not controlled with lifestyle changes, may enable improved BP control and reduce the burden of CV disease in young individuals. This paper provides an overview of the main findings of a recent clinical trial, performed with olmesartan medoxomil in young individuals, and discusses the clinical benefits derived from early detection and prompt intervention of high BP levels in children and adolescents. According to the aim of our study, a comprehensive search strategy was performed through online medical databases (Medline and Embase) by using the following search terms: hypertension, high blood pressure, children, adolescents, olmesartan medoxomil. Among the large number of articles made available from this research, only those which have been published in English, in peer-reviewed journals, and with full access to entire contents of the paper have been selected and discussed in this paper. Other Sections Abstract Introduction Hypertension management in children and adolescents Pharmacodynamics, pharmacokinetics and clinical efficacy of olmesartan Conclusions and perspectives References Hypertension management in children and adolescents

Diagnostic criteria for high BP levels in children and adolescents are based on the concept that BP progressively increases according to age, height and body size.26,27 Since a single BP threshold to define hypertension is not applicable in young individuals, BP targets are commonly defined in relation to the distribution of BP in the normal young population. Thus, normal BP in children and adolescents is defined as systolic and diastolic BP levels less than the 90th percentile for age, sex, and height, whereas hypertension is defined as systolic and diastolic BP levels persistently on the 95th percentile or more, measured on at least three separate visits.26,27 As for hypertension definition, BP targets to be achieved with treatment vary according to the characteristics of general population.26,27 In the past, lifestyle changes have been highly recommended to reduce high BP levels in young hypertensive patients. More recently, international guidelines recommend that, when required and usually after a 3- to 6-month period of lifestyle changes, antihypertensive treatment should be started with a single drug administered at a low dose, in order to avoid a rapid fall in BP.2628 When antihypertensive drug therapy is needed, the first choice of antihypertensive agents can be made among all five classes of antihypertensive drugs.26,27 This is mostly based on the fact that only few placebo-controlled studies are available, but almost no head-to-head studies directly comparing the efficacy and safety of different antihypertensive drugs in children or adolescents have been conducted. Since the renninangiotensin system (RAS) is intimately involved in different pathophysiological mechanisms leading to development and progression of hypertension, RAS blocking agents, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), are now viewed as suitable and useful therapeutic tools to antagonize the deleterious consequences of RAS abnormal activity in hypertension-related disease conditions, including metabolic syndrome,29 diabetes,30 and organ damage,31 in the presence of an effective BPlowering efficacy and good tolerability profile. In this regard, a recent analysis of 27 clinical trials performed in young individuals with hypertension reported comparable BP reductions with ACE inhibitors, ARBs, and calcium-channel blockers.32 In particular, clinical data on the efficacy, safety, and tolerability of ARB-based therapy in hypertensive children have become recently available. These trials demonstrated dose-dependent BP reductions and a good tolerability profile of several ARB compounds, such as losartan 0.75 to 1.44 mg/kg, candesartan 0.16 to 0.47 mg/kg, valsartan 2 mg/kg per day, and irbesartan 75 to 150 mg daily.26 More recently, interesting clinical data demonstrating the efficacy and tolerability of olmesartan medoxomil have become available.33 Other Sections Abstract Introduction Hypertension management in children and adolescents Pharmacodynamics, pharmacokinetics and clinical efficacy of olmesartan Conclusions and perspectives References

Pharmacodynamics, pharmacokinetics and clinical efficacy of olmesartan Pharmacodynamics Olmesartan medoxomil is an orally administered prodrug of olmesartan, a nonpeptide ARB that has high selectivity for the AT1 receptor, to which it is highly bound, having a limited affinity to the AT2 receptor.34 Since activation of the AT1 receptor by angiotensin II induces arteriolar vasoconstriction, sympathetic nervous system activation, salt and water retention, and aldosterone secretion,35 olmesartan is presumed to reduce high BP levels mostly by blocking the vasoconstrictor and aldosterone-secreting effects of angiotensin II.36,37 Consistent with this mechanism of action, animal and human studies demonstrated that the effects of olmesartan medoxomil on BP parallel the inhibitory effects on RAS activation.36 In animal models, olmesartan also reduced production of markers of early CV inflammation,38 myocardial remodeling,39 and cardiac fibrosis.40 In addition, it reduced in a dose-dependent fashion urinary protein excretion and the area of plaque lesions and intimal wall thickening in cross sections of the aorta.41 In patients with hypertension, olmesartan produces gradual and sustained dose-dependent reductions in both systolic and diastolic BP levels, without first-dose hypotension, tachyphylaxis during extended treatment or rapid rebound hypertension, when treatment is discontinued.42,43 Pharmacokinetics Olmesartan medoxomil is a prodrug that is rapidly hydrolyzed into olmesartan in the gastrointestinal tract.36,44 It is rapidly absorbed from the gastrointestinal tract, with a maximum plasma concentration (Cmax) of 0.22 to 2.1 mg/L, a time to Cmax of 1.4 ti 2.8 hours, and a mean area under the concentration-time curve (AUC) of 1.6 ti 19.9 mgh/L, following administration of olmesartan medoxomil 10 to 160 mg.45 Olmesartan is the only metabolite of olmesartan medoxomil. It is excreted mainly in the feces (about 60%) and the urine; in children, approximately 3% to 15% was recovered in the urine.46 The mean terminal elimination half-life was 12 to 18 hours for 20 mg olmesartan,45 which compares favorably with the half-lives of some other ARBs: irbesartan (11 to 15 hours), losartan (2 hours) and its active metabolite (4 to 5 hours), and valsartan (6 hours).47 Finally, olmesartan is not metabolized by cytochrome P-450 enzymes and, therefore, it is unlikely to interact with other drugs that inhibit, induce, or are metabolized by cytochrome P-450 enzymes.48,49 The pharmacokinetics of oral olmesartan medoxomil have been investigated in relatively small, open-label studies performed in pediatric patients with hypertension.50 More recently, the antihypertensive efficacy, safety, and tolerability of oral olmesartan medoxomil in the treatment of hypertension in children and adolescents (aged 6 to 16 years) was investigated in a randomized, double-blind, multinational, phase II/III trial.33 The main findings of this study confirmed the potential benefits derived from the use of this drug in the young population, in terms of BP-lowering efficacy and a good tolerability profile.50 Clinical efficacy, safety, and tolerability in children and adolescents The Assessment of Efficacy and Safety of Olmesartan in Pediatric Hypertension (AESOP) study33 was a randomized, multicenter, double-blind, parallel-group, dose-

ranging prospective clinical trial performed in young individuals of any race, aged 6 to 16 years, and presenting with primary or secondary hypertension. The primary endpoint was the efficacy and safety profile of olmesartan medoxomil in children and adolescents with hypertension, defined as systolic BP above the 95th percentile for age, gender, and height.33 This trial was specifically requested by the United States Food and Drug Administration, for approving drug prescriptions in young individuals. The trial was conducted in two distinct periods, with two cohorts in each period. Enrolled individuals were stratified according to ethnicity (cohort A: 62% Caucasian, 18% Black, 10% Asian, and 14% other races; cohort B, 100% Black). In period 1, patients were randomized to receive either low-dose (2.5 to 5 mg) or high-dose (20 to 40 mg) olmesartan daily for 3 weeks. In period 2, patients maintained their olmesartan dose (active treatment) or initiated placebo washout for an additional 2 weeks. Among 422 individuals who were initially screened, 302 were randomly assigned to the two cohorts (cohort A: n = 190 and cohort B: n = 112). In particular, 95 and 56 patients were randomly assigned to each of the olmesartan dose groups in cohort A and B, respectively. During the first period, the primary efficacy analyses were based on the changes from baseline in trough seated systolic and diastolic BP levels at the end of period 1 in cohorts. Reductions in both systolic and diastolic BP levels were consistently greater in the high-dose group than in the low-dose group, and they were smaller in cohort B than in cohort A. These differences were statistically significant, even after adjustment for baseline body weight. Among patients included in period 1 analysis, 13 individuals did not enter period 2, resulting in a total of 182 patients in cohort A and 107 patients in cohort B, respectively. BP changes were analyzed from period 2 baseline (end of period 1) through the end of period 2 (last observation carried forward). Among patients included in cohort A, the mean increase in seated systolic BP was 0.43 mmHg for subjects on active treatment and 4.9 mmHg for subjects receiving placebo (BP difference between active treatment and placebo of 3.6 mmHg; P = 0.0093). Among individuals included in cohort B, the mean seated systolic BP increase (1.4 mmHg) for subjects on active treatment was lower than that reported in subjects on placebo (3.8 mmHg; P = NS). The percentage of patients experiencing a treatment-emergent adverse event within each cohort was low and similar for the low- and high-dose active treatment groups. The majority of adverse effects were mild or moderate in intensity and were considered unrelated to active therapy. Other Sections Abstract Introduction Hypertension management in children and adolescents Pharmacodynamics, pharmacokinetics and clinical efficacy of olmesartan Conclusions and perspectives References Conclusions and perspectives

Hypertension in children and adolescents is a growing epidemiological problem. The progressive rise of average BP levels among young individuals definitely parallels the dramatic increase in overweight, obesity, metabolic syndrome, impaired glucose regulation, and diabetes that we are witnessing. Therefore, a higher commitment to the measurement of BP, diagnosis of hypertension, and therapeutic interventions (virtuous lifestyle changes and drug therapy, when required) should be undertaken and promoted in young subjects. Population strategies to prevent development of hypertension at a young age, with particular regard to the quality of diet, routine exercise or regular physical activity, and banning of cigarette smoking, need to be actively promoted. Similar measures should be also applied at a clinical level in the individual patient, especially when concomitant predisposing risk factors are present. Drug therapy should be undertaken prudently, when required. Drugs that may provide a satisfactory BP control in monotherapy and that have few side effects and do not interfere with the quality of life in children and adolescents are highly recommended.26,27 In this regard, ARBs have been sufficiently explored in young hypertensive patients, and seem to have a substantially good record. Among these drugs, olmesartan medoxomil has been recently tested with a rigorous clinical trial program in a population of children and adolescents aging from 6 to 16 years and belonging to Caucasian or Black ethnic groups.33 The results of this study have been satisfactory in terms of BP reduction and tolerability profile.33 Together with the organ protection and the neutral metabolic effects provided by ARBs through the selective antagonism of RAS, olmesartan appears to hold more than a good promise for an effective and safe treatment of children and adolescents with hypertension. Footnotes Disclosure MV has received research grants from Novartis, has served in international advisory boards of sanofi-aventis, Bayer, Novartis, Boehringer Ingelheim, and Daichii Sankyo, and has lectured in symposia supported by several drug companies producing ARBs; GT has no conflict of interest to disclose. Other Sections Abstract Introduction Hypertension management in children and adolescents Pharmacodynamics, pharmacokinetics and clinical efficacy of olmesartan Conclusions and perspectives References References 1. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) J Hypertens. 2007;25(6):11051187. [PubMed]

2. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):25602572. [PubMed] 3. Williams B, Poulter NR, Brown MJ, et al. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV. J Hum Hypertens. 2004;18(3):139185. [PubMed] 4. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2000;356(9246):19551964. [PubMed] 5. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362(9395):15271535. [PubMed] 6. Turnbull F, Neal B, Algert C, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med. 2005;165(12):14101419. [PubMed] 7. Turnbull F, Neal B, Ninomiya T, et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ. 2008;336(7653):11211123. [PMC free article] [PubMed] 8. Wolf-Maier K, Cooper RS, Banegas JR, et al. Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA. 2003;289(18):23632369. [PubMed] 9. Wolf-Maier K, Cooper RS, Kramer H, et al. Hypertension treatment and control in five European countries, Canada, and the United States. Hypertension. 2004;43(1):1017. [PubMed] 10. Nakamura K, Barzi F, Lam TH, et al. Cigarette smoking, systolic blood pressure, and cardiovascular diseases in the Asia-Pacific region. Stroke. 2008;39(6):1694 1702. [PubMed] 11. Martiniuk AL, Lee CM, Lawes CM, et al. Hypertension: its prevalence and population-attributable fraction for mortality from cardiovascular disease in the AsiaPacific region. J Hypertens. 2007;25(1):7379. [PubMed] 12. Barzi F, Patel A, Woodward M, et al. A comparison of lipid variables as predictors of cardiovascular disease in the Asia Pacific region. Ann Epidemiol. 2005;15(5):405413. [PubMed] 13. Kelishadi R, Ardalan G, Gheiratmand R, et al. Blood pressure and its influencing factors in a national representative sample of Iranian children and adolescents: the CASPIAN Study. Eur J Cardiovasc Prev Rehabil. 2006 Dec;13(6):956963. [PubMed] 14. Genovesi S, Antolini L, Gallieni M, et al. High prevalence of hypertension in normal and underweight Indian children. J Hypertens. 2011;29(2):217221. [PubMed]

15. Rumboldt M, Pavlicevic I, Kuzmanic M, Rumboldt Z. Prevalence of hypertension in school children. J Hypertens. 2008;26(3):610611. 611612. author reply. [PubMed] 16. Sorof JM, Lai D, Turner J, Poffenbarger T, Portman RJ. Overweight, ethnicity, and the prevalence of hypertension in school-aged children. Pediatrics. 2004;113(3 Pt 1):475482. [PubMed] 17. Sorof JM. Prevalence and consequence of systolic hypertension in children. Am J Hypertens. 2002;15(2 Pt 2):57S60S. [PubMed] 18. Kelishadi R. Childhood overweight, obesity, and the metabolic syndrome in developing countries. Epidemiol Rev. 2007;29:6276. [PubMed] 19. McQueen MJ, Hawken S, Wang X, et al. Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study. Lancet. 2008;372(9634):224233. [PubMed] 20. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364(9438):937952. [PubMed] 21. Bao W, Threefoot SA, Srinivasan SR, Berenson GS. Essential hypertension predicted by tracking of elevated blood pressure from childhood to adulthood: the Bogalusa Heart Study. Am J Hypertens. 1995;8(7):657665. [PubMed] 22. Chen W, Srinivasan SR, Ruan L, Mei H, Berenson GS. Adult hypertension is associated with blood pressure variability in childhood in blacks and whites: the bogalusa heart study. Am J Hypertens. 2011;24(1):7782. [PMC free article] [PubMed] 23. Berenson GS, Wattigney WA, Bao W, Nicklas TA, Jiang X, Rush JA. Epidemiology of early primary hypertension and implications for prevention: the Bogalusa Heart Study. J Hum Hypertens. 1994;8(5):303311. [PubMed] 24. Volpe M, Erhardt LR, Williams B. Managing cardiovascular risk: the need for change. J Hum Hypertens. 2008;22(2):154157. [PubMed] 25. Williams B. Recent hypertension trials: implications and controversies. J Am Coll Cardiol. 2005;45(6):813827. [PubMed] 26. Lurbe E, Cifkova R, Cruickshank JK, et al. Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension. J Hypertens. 2009;27(9):17191742. [PubMed] 27. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114(2 Suppl 4th Report):555 576. [PubMed] 28. Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: a working group report from the National High Blood Pressure Education Program National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Pediatrics. 1996;98(4 Pt 1):649658. [PubMed] 29. Yamada S. Pleiotropic effects of ARB in metabolic syndrome. Curr Vasc Pharmacol. 2011;9(2):158161. [PubMed]

30. Saitoh S, Takeishi Y. Pleiotropic effects of ARB in diabetes mellitus. Curr Vasc Pharmacol. 2011;9(2):136144. [PubMed] 31. Papadopoulos DP, Papademetriou V, Makris TK. On target to dual block RAS? Angiology. 2009;60(6):739749. [PubMed] 32. Simonetti GD, Rizzi M, Donadini R, Bianchetti MG. Effects of anti-hypertensive drugs on blood pressure and proteinuria in childhood. J Hypertens. 2007;25(12):23702376. [PubMed] 33. Hazan L, Hernandez Rodriguez OA, Bhorat AE, Miyazaki K, Tao B, Heyrman R. A double-blind, dose-response study of the efficacy and safety of olmesartan medoxomil in children and adolescents with hypertension. Hypertension. 2010;55(6):13231330. [PubMed] 34. Warner GT, Jarvis B. Olmesartan medoxomil. Drugs. 2002;62(9):13451353. 13541346. discussion. [PubMed] 35. Volpe M, Musumeci B, De Paolis P, Savoia C, Morganti A. Angiotensin II AT2 receptor subtype: an uprising frontier in cardiovascular disease? J Hypertens. 2003;21(8):14291443. [PubMed] 36. Brunner HR. Olmesartan medoxomil: current status of its use in monotherapy. Vasc Health Risk Manag. 2006;2(4):327340. [PMC free article] [PubMed] 37. Puchler K, Laeis P, Stumpe KO. Blood pressure response, but not adverse event incidence, correlates with dose of angiotensin II antagonist. J Hypertens Suppl. 2001;19(1):S41S48. [PubMed] 38. Usui M, Egashira K, Tomita H, et al. Important role of local angiotensin II activity mediated via type 1 receptor in the pathogenesis of cardiovascular inflammatory changes induced by chronic blockade of nitric oxide synthesis in rats. Circulation. 2000;101(3):305310. [PubMed] 39. Takemoto M, Egashira K, Tomita H, et al. Chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade: effects on cardiovascular remodeling in rats induced by the long-term blockade of nitric oxide synthesis. Hypertension. 1997;30(6):16211627. [PubMed] 40. Tomita H, Egashira K, Ohara Y, et al. Early induction of transforming growth factor-beta via angiotensin II type 1 receptors contributes to cardiac fibrosis induced by long-term blockade of nitric oxide synthesis in rats. Hypertension. 1998;32(2):273279. [PubMed] 41. Koike H, Sada T, Mizuno M. In vitro and in vivo pharmacology of olmesartan medoxomil, an angiotensin II type AT1 receptor antagonist. J Hypertens Suppl. 2001;19(1):S3S14. [PubMed] 42. Scott LJ, McCormack PL. Olmesartan medoxomil: a review of its use in the management of hypertension. Drugs. 2008;68(9):12391272. [PubMed] 43. Unger T, McInnes GT, Neutel JM, Bohm M. The role of olmesartan medoxomil in the management of hypertension. Drugs. 2004;64(24):27312739. [PubMed] 44. Brousil JA, Burke JM. Olmesartan medoxomil: an angiotensin II-receptor blocker. Clin Ther. 2003;25(4):10411055. [PubMed]

45. Schwocho LR, Masonson HN. Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects. J Clin Pharmacol. 2001;41(5):515527. [PubMed] 46. Von Bergmann K, Laeis P, Puchler K, Sudhop T, Schwocho LR, Gonzalez L. Olmesartan medoxomil: influence of age, renal and hepatic function on the pharmacokinetics of olmesartan medoxomil. J Hypertens Suppl. 2001;19(1):S33S40. [PubMed] 47. Stumpe KO. Olmesartan compared with other angiotensin II receptor antagonists: head-to-head trials. Clin Ther. 2004;26(Suppl A):A33A37. [PubMed] 48. Wehling M. Can the pharmacokinetic characteristics of olmesartan medoxomil contribute to the improvement of blood pressure control? Clin Ther. 2004;26(Suppl A):A21A27. [PubMed] 49. Laeis P, Puchler K, Kirch W. The pharmacokinetic and metabolic profile of olmesartan medoxomil limits the risk of clinically relevant drug interaction. J Hypertens Suppl. 2001;19(1):S21S32. [PubMed] 50. Muir VJ, Keating GM. Olmesartan medoxomil: in children and adolescents with hypertension. Drugs. 2010;70(18):24392447. [PubMed]

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NO
2

ClCl2,4~Dichlor o nitro benzeneC

6

H
5

CH
2

SHBenzyl mercaptanNO
2

ClSCH
2

C
6

H
5

Cl
2

(O)NO
2

SO
2

ClClNH
4

OHNO
2

SO
2

NH
2

ClH
2

ReductionNH
2

SO
2

NH
2

Cl(CH
3

CO)
2

O (or)Ethyl ortho

acetateClNHNSO OCH
3

The drug at therapeutic dose levels, causes vasodepress ion which

is primarily the outcome of arteriolar dilatation, in order that the ensuingorth

ostatic hypotension is normally minimal. However,cer tain extent of venousdilata

tion invariably occurs, which occasionaly is responsible to

affordorthos tatic hypotension. It has been duly observed that the smooth

musclerelaxing effects are usually caused due to the hyperpolarization

of vascular sm ooth muscle by activating ATPasesensitive Kchannels. Hence, it is

mostlyused in IV as a hypotensive drug in situations arising from acute hypertensive

crises. Diazoxide is found to be 90% proteinbound; however, fast and rapid

IVadministra tion allows quickdistribution to smooth muscle before it gets boundto

protein intimately. Therefore, one may attain a greater and longerlastingdrop

in blood pressure through faster rates of IV injection. Interestingly , thedrug

is found to persist in blood circulation much longer than thecorrespo nding

hypotensive effect. The plasma halflife is 20 to 60 hours insubjects having normal renal

function, whereas the correspondin g hypotensive

Department of Pharmaceut

ical Chemistry, NPC

21

effects lasts only 2 to 15 hours. Mechanism of action :Diazoxide hyperpolarri se arterial

smooth muscle cells by activatingAT P-sensitive K

+

channels; this causes

relaxation of the vascular smootmuscl e. Uses:Used intravenousl y in acute

hypertensive cases. Injection of an IV boluslowers BP within 30 sec, and a maximum

effect is achieved within 3 to 5 min. Dose:0.4 to 1 g per day in 2

or 3 divided doses. HydralazineIU PAC Name 1hydrazinopht halazine. Structure:-

Antihypertens i ve Agents
NNNH NH
2

Synthesis:COOHCHO
+

NNH
2

NHNOPhthalaz onePOCl
3

NNClNH
2

NH
2

NNNH NH

The drug acts on the vascular smooth muscle to afford definiterelax ation. Its

exact mechanism of action is still not quite vivid and clear. It isfound to interfere

with Ca2+ entry and Ca2+ release from the prevailingint racellular reserves ;

besides, causing a specific activation of guanylatecy clase

there by giving rise to an enhanced levels of cGMP. In fact, theconcerte

d effort of all these biochemical events may afford an apparentvas odilation.It gets

excreted rapidly through the kidneys, and within a span of 24hours nearly 75%

of the total quantum administered appears in the urine as its metabolites

or absolutely unchanged form. The drug invariably undergoesm ainly three

types of chemical transformati ons, namely :( a )

benzylicoxida tion ; ( b ) glucuronide formation ; and (

c ) N-acetylation by themicrosom al enzymes invariably found in the

liver and tissues. It has been

Department of Pharmaceut ical

Chemistry, NPC
23

observed that acetylation could pose as a main determinant factor of the rateof

hepatic removal of the drug from the blood in circulation ; and, hence, of

the prevailin g systemic availability of the same.* Consequentl y, the rapidacetyla

tion aids in an extremely high hepatic extraction ratio ensuing from thecirculator y blood,

which is virtually responsible for the greater portion of the

first-pass elimination.M echanism of action :It causes vasodilatati on by stimulating

guanylate cyclase inarteriolar smooth muscle; the stimulant appears to be nitric

oxide (NO)from the local oxidation of the hydrazine moiety. Nitric oxide

is a natural,endo thelinderived relaxing factor. Uses :-

Treatment of hypertensiv e emergencie s, toxemia of pregnancy,a

cute congestive heart failure or after myocardial infarction. Dose :-

Oral, initial, 10 mg 4 times daily for 2 to 4 days, then 25 mg 4 times per day for

the rest of the week.

Antihypertens i ve Agents MinoxidilIUPA C Name 2,6-Diamino6piperidinopyr

imidine 3oxide. Structure :NNNH

2

NH
2

NO ..

Synthesis :-

Department of Pharmaceut ical Chemistry, NPC

25

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