OMICS INTERNATIONAL CONFERENCES

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1 1 ABOUT OMICS GROUP OMICS Group is an amalgamation of Open Access Publications and worldwide international science conferences and events. Established in the year 2007 with the sole aim of making the information on Sciences and technology Open Access, OMICS Group publishes 500 online open access scholarly journals in all aspects of Science, Engineering, Management and Technology journals. OMICS Group has been instrumental in taking the knowledge on Science & technology to the doorsteps of ordinary men and women. Research Scholars, Students, Libraries, Educational Institutions, Research centers and the industry are main stakeholders that benefitted greatly from this knowledge dissemination. OMICS Group also organizes 500 International conferences annually across the globe, where knowledge transfer takes place through debates, round table discussions, poster presentations, workshops, symposia and exhibitions.

2 2 OMICS INTERNATIONAL CONFERENCES OMICS International is a pioneer and leading science event organizer, which publishes around 500 open access journals and conducts over 500 Medical, Clinical, Engineering, Life Sciences, Pharma scientific conferences all over the globe annually with the support of more than 1000 scientific associations and 30,000 editorial board members and 3.5 million followers to its credit. OMICS Group has organized 500 conferences, workshops and national symposiums across the major cities including San Francisco, Las Vegas, San Antonio, Omaha, Orlando, Raleigh, Santa Clara, Chicago, Philadelphia, Baltimore, United Kingdom, Valencia, Dubai, Beijing, Hyderabad, Bengaluru and Mumbai.

3 FORMULATION OF ANTIPSYCHOTIC DRUGS AND THEIR IN VITRO ANALITICAL TESTS Enikő Borbás Superviser: Dr. Zsombor Kristóf Nagy Dr. György Marosi

4 4 STUCTURE OF THE PRESENTATION I. Case study : formulation development of a poorly watersoluble antipsychotic drug, Aripiprazole II. Importance of in vitro analitical tests in formulation development:formulation screening with different analitical test III. Solubility-permeability interplay and effect of commonly used solubility enhancers on membrane permeability

5 FORMULATION OF POORLY WATERSOLUBLE ANTIPSYCHOTIC DRUGS 5 80% of the newly discovered active pharmaceutical ingredients (API) are poorly watersoluble Are they really taking it? Is there a painless solution for the patient?

6 FORMULATION STRATEGIES Noyes-Whitney equation: dc D A (Cs Ct) = dt h V Amorphisation Amorphous state Orally fast dissolving drug delivery system Fast effect Escaping the first pass metabolism Less harmful for the liver Smaller doses 6 Crystalline form Watersoluble polymer matrix Enhanced bioavailability!!

7 7 PRODUCTION OF ORALLY FAST DISSOLVING DRUG DELIVERY SYSTEM BY ELECTROSPINNING Solution for the technological and therapeutical challenges!

8 8 AIM OF THIS STUDY Aripiprazole containing orally fast dissolving and absorbing drug delivery system Plans for the formulation: Cyclodextrin-based formulation Minimization of the fiber forming polymer contant: poly(ethylene-oxide) Retard effect of the polymer

9 ARP concentration (mol/dm 3 ) 9 OPTIMIZATION OF THE FORMULATION MATRIX osulfobutylether-β-cyclodextrin SBEβCD SB o Optimization of the fiber former polymer concentration in the polymer solution: Molecular weight (g/mol) Concentration w/v % 7 million 4 million 0,5% HPβCD 2 million 0,75% CD concentration (mol/dm 3 ) Content of the formulation matrix 4.5% 2.0% 4.5% ARP concentration hatóanyag tartalom (m/m %) m/m% 89.0% CD tartalom concentration (m/m %) m/m% PEO concentration polimer tartalom (m/m %) m/m% citromsav Citric acid tartalom concentration (m/m %) m/m%

10 Intensity (counts/sec) ANALITCAL TESTS OF THE ELECTROSPUN CYCLODEXTRIN-BASED FORMULATION OF ARIPIPRAZOLE 10 Scanning electronmicroscopic image (800nm-2000nm) Enhancement of surface area ARP Heatflow (W/g) ARP PEO SBECD Citric acid Physical mixture Electrospun fibers Temperature( C) DSC thermogram After 3 months SBECD PEO Citric acid Amorphisation Electrospun fiber X-ray diffractogram

11 Dissolution % IN SYRINGE DISSOLUTION TESTING 11 5ml ph 6,8 phosphate buffer Novel method for testing orally dissolving drug delivery systems! Watersoluble polymer matrix Time(min) Dissolution is fast and efficient! electrospun szálképzett fibers minta fizikai physical keverék mixture tiszta pure ARP Escaping the retard effect of the polymer!

12 12 THE ROUTE OF THE API IN THE HUMAN BODY Dissolution Absorption Formulation Dissolved API API in the blood circuit Cyclodextrin content Precipitation of the API Is it going to absorb?

13 PERMEABILITY TESTS:IT DISSOLVES, BUT IS IT GOING TO ABSORB? 13 Donor Used in drug development μl artificial membrane Acceptor PAMPA (Parallel Artificial Membrane Permeability Assay ) Microflux Novel method in the formulation development! 10-20ml

14 ph Sum of ranking differences% Relative frequency of random numbers 14 PAMPA AND MICROFLUX OPTIMIZATION TO MODELL BUCCAL ABSORPTION Optimization of donor buffer ph, and buffercapacity Membrane composition: Reference: permeation through porcine buccal mucosa (ex vivo) 100 XX1 Med XX buccal lipid 15 Citric acid concentration mg/ml GI lipid n-dodekane 10 5 ph and buffercapacity of the buffer and human saliva is the same! rank= difference from the reference ranking *Kokate, Amit, et al. "In silico prediction of drug permeability across buccal mucosa." Pharmaceutical research 26.5 (2009)

15 Flux (µg/h*cm 2 ) DISSOLUTION-ABSORPTION TEST OF THE ARIPIRAZOLE CONTAINING ELECTROSPUN FIBERS 15 Donor Acceptor Flux m= weight(µg), t=time(h), A=membrane surface (cm 2 ) Membrane surface=8,55cm szálas minta fizikai keverék tiszta hatóanyag Electrospun fibers Physical mixture pure API

16 SUMMERY OF THE CASE STUDY 16 Technological results Therapeutical results Aripirazole containing cyclodextrin based formulation Modelling the oral cavitiy in dissolution-absortion testing Biorelevant analitical testing Less animal tests are needed o Ensuring the treatment of psychiatric patients o Fast effect o Painless treatment

17 17 II. IMPORTANCE OF IN VITRO ANALITICAL TESTS IN FORMULATION DEVELOPMENT: FORMULATION SCREENING USING CONVENTIONAL AND NOVEL ANALITICAL TESTS

18 IN VITRO ANALITICAL TESTS PAST -PRESENT FUTURE IN FORMULATION SCREENING 18 Dissolution testing PAMPA Microflux 37 ºC Dissolving formulation Small volume 150µl ph=6.8 buffer 37 ºC Gradient ph 900 ml Membrane 300 µl ph=7.4 buffer

19 19 FORMULATION SCREENING USING DISSOLUTION, PAMPA AND MICROFLUX ASSAYS Model compound: Risperidone, poorly watersoluble antipsychotic drug Electrospinning Film casting Formulation API content (w/w%) polimer content (w/v%) Cyclodextrin content (w/w %) Solvent Casted film: PVP/HPBCD EtOH Electrospun fiber: PVP/HPBCD EtOH Electrospun fiber: PVP EtOH

20 COMPARISON OF DISSOLUTION, PAMPA AND MICROFLUX TEST RESULTS BY NONPARAMETRIC RANKING 20 Formulation Dissolution PAMPA Microflux Casted Film: PVP/HPBCD Electrospun fiber: PVP/HPBCD Electrospun fiber: PVP Untreated Risperidone Ranking of the formulations by different analitical test results Dissolution Bioavailability The best formulation from bioavalabitlity point of view cannot be found by only dissolution tests!

21 21 III. SOLUBILITY-PERMEABILITY INTERPLAY AND EFFECT OF COMMONLY USED DISSOLUTION ENHANCERS ON MEMBRANE PERMEABILITY

22 22 SOLUBILITY-PERMEABILITY INTERPLAY Solubility/ Dissolution Bioavailability Permeability

23 23 EXCEPIENT EFFECT ON PERMEATION Cyclodextrins can form inclusion complexes with cholesterine, affecting membrane integrity! Phospholipid membrane Unstirred water layer Surfactants can thinner UWL!

24 CASE STUDY: DO POLYMERS EFFECT MEMBRANE PERMEATION? Dissolution enhancement of Meloxicam, a poorly watersoluble anti-infammatory model compound Formulation screening using several PVP derivatives and Soluplus Describing a novel analytical method for testing dissolution and permeation profile of drugs from formulations 24

25 25 POLYVINILPIRROLIDONE DERVATIVES AND SOLUPLUS PVP K30 PVP K90 K value refers to instrinsic viscosity and molar mass PVP VA 64 Vinylpyrrolidone-vinyl acetate copolymer Soluplus polyvinyl caprolactampolyvinyl acetatepolyethylene glycol graft copolymer HPBCD Hydroxypropyl-beta-cyclodextrin

26 Concentration (µg/ml) DISSOLUTION TEST RESULTS pure MEL PVPK90HPBCD 85% PVPK90 Soluplus time (min) PVP VA 64 PVP K30 26

27 CONCENTRATION (µg/ml) concenctration (µg/ml) MICROFLUX TEST RESULTS untreated Meloxicam PVPK90, HPBCD PVP K90 Soluplus Donor concentration time (min) untreated Meloxicam Soluplus PVPK90, HPBCD PVP K90 PVP 8.0 VA 64 PVP K30 DMSO stock ACCEPTOR CONCENTRATION TIME (MIN) 27

28 Auc of acceptor (µg/min*cm2) DISSOLUTION-ABSORPTION TEST OF THE AUC of donor and dissolution curve ELECTROSPUN FIBERS AUC of donor AUC of dissolution curve UNTREATED MELOXICAM 85%PVPK90 PVPK90HPBCD SOLUPLUS PVP K30 PVP VA 64 DMSO STOCK SOLUTION AUC of acceptor UNTREATED MELOXICAM 85%PVPK90 PVPK90HPBCD SOLUPLUS PVP K30 PVP VA 64 DMSO STOCK SOLUTION

29 AUC of acceptor CORRELATION OF DONOR AUC AND ACCEPTOR AUC Correlation of donor AUC and acceptor AUC Surfactant effect! y = x R² = y = x R² = PVP derivatives soluplus y = x R² = DMSO AUC of donor Solubility-permeability interplay! untreated meloxicam 29

30 SUMMERY 30 I. Case study : formulation development of a poorly watersoluble antipsychotic drug, Aripiprazole II. Importance of in vitro analitical tests in formulation development:formulation screening with different analitical test III. Solubility-permeability interplay and effect of commonly used solubility enhancers on membrane permeability

31 31 LET US MEET AGAIN.. We welcome you all to our future conferences of OMICS International 7 th Annual Global Pharma Summit On June 20-22, 2016 at New Orleans, USA

32 THANK YOU FOR YOUR KIND ATTANTION! 32