Presented By: Prof. Chander Pal Singh Verma HOD, Department of Pharmacognosy

1. Development and characterization of Fast Dissolving Amorphous Drug Composites using Innate Excipients Presented By: Prof. Chander Pal Singh Verma HOD, Department of Pharmacognosy Laureate Institute of Pharmacy Kathog Jawalji Himachal Pradesh , India

2. INTRODUCTION Drugs that are administered orally go through a dissolution process and then permeation across the gastric membrane before they can appear in the blood stream. Some factors that affect the bioavailability (Other than solubility and permeability) • Dissolution rate of the drug, • First-pass effect, • Pre-systemic metabolism of the drug in any other organ, • Susceptibility to efflux mechanisms.

3. Contd…. • Solubility of the drug in the gastric media is a major problem with most drugs, Leading to erratic bioavailability and possible toxicity. Thus, solubility of new drug molecules is the biggest challenge for formulation scientists. • In spite of these issues, the oral route of drug administration has been the most sought after route due to its ease of administration, high patient compliance, cost-effectiveness, least need for maintenance of sterile conditions, and flexibility in design of the dosage form.

4. Contd…. • The first attempt by pharmaceutical companies in making generic drugs is to formulate the drug as an oral dosage form. The pharmaceutical industry is experimenting with various techniques for improving the solubility of the drug post oral administration. • Bioenhancer: The rate and extent to which a therapeutically active substance enters systemic circulation and becomes available at the required site of action is termed as bioavailability Intravenous drugs attain maximum bioavailability. • The concept of using bioenhancers: Based on the ayurvedic system of medicine the concept of using bioenhancer is one feasible approach to reduce treatment costs by increasing the drug bioavailability. Global focus today is on methods aimed at reducing drug dosage, and thus drug treatment cost so that medicines become affordable for wide sections of society, including the financially challenged.

5. Contd…. • The techniques used for improving the solubility characteristics of a drug can be very broadly classified as either physical or chemical processes. • Solid dispersions, a dispersion of one or more active ingredients in an inert carrier or matrix in the solid state prepared by co-melting or solvent extraction or by the solvent-melt method. Solid dispersion technology is a technique which has comparatively fewer problems.

6. Contd…. Disadvantages associated with it such as • Possibility of recrystallization upon storage or during the various pharmaceutical processes. • Moisture might increase the mobility of the drug, thereby increasing the chances of recrystallization. • Some other draw backs include not being able to scale up the process satisfactorily and requiring extra processing stepsbefore the product can be put through any other process5.

7. Contd…. • Some of the problems associated with the properties of the solid dispersions and the need for more processing can be easily overcome by using an adsorbent and forming a ternary solid dispersion, a Drug Composite.

8. Contd…. • The concept of ‘bioavailability enhancers’ is derived from the traditional age old system of Ayurveda (science of life). • Enhancers not only improve the solubility of drug but also significantly have effect on our biological systems. • These effects are generally beneficial either in providing efficacy or safety of the drug. • Aloe Vera gel or Piperine has shown improved bioavailability of various drugs.

9. Contd…. • Low aqueous solubility is a major problem faced during formulation development of new drug molecules. A drug having problems associated with low aqueous solubility, poor bioavailability and slow onset of action will be selected as model drug. • Hence, purpose of this research is to provide fast dissolving composites of Model Drug using natural bioavailability enhancers. 

10. Classification of bioenhancer

11. AIM The ultimate aim of this study is to enhance the solubility, dissolution characteristic of selected drug and thus improve bioavailability with dose reduction using natural bioenhancers.

12. OBJECTIVE • To formulate and evaluate the solid dispersions and converting in to a fast dissolving drug composites using herbal excipients. • To carry out pre-formulation studies for the possible drug/polymer/excipient interaction and micromeritics. • To develop analytical methods for the estimation of drug in the formulations.

13. OBJECTIVE • To develop and formulate solid dispersion composites. • To evaluate the formulated dosage forms based on physico-chemical characterization and in vitro release studies and Selection of optimal formulation. • To formulate and optimize the fast dissolving tablets using natural herbs as bioavailability enhancers.

14. OBJECTIVE • To carry out short term stability studies on the most satisfactory formulations as per ICH guidelines at 30±2°C (65±5%RH) and 40±2°C (75±5%RH). • To carry out pharmacokinetic studies for the developed optimized formulation using healthy male New Zealand rabbits and assess various pharmacokinetic parameters.

15. Scope • The developed formulation can be effectively used for schizophrenic patients with reduced dose. • The formulation has got wide scope of getting patented nationally /internationally.

16. Limitation • The Developed formulation needs to be evaluated clinically which require ethical permissions and consent of patients.

17. PLAN OF WORK • To carry out the preformulation studies for the selected drugs • Standardization of method of estimation (UV & HPLC) • Solubility studies & Partition coefficient • Drug -excipient compatibility studies (IR & DSC) • To prepare and evaluate Solid Dispersion Composite of selected drug • Preparation of solid dispersion • Evaluation of solid dispersion • In-vitro drug release studies • Selection of optimized formulation for further studies • Stability studies as per ICH guidelines

18. Contd…. To develop and evaluate fast dissolving tablets of optimized solid dispersion composite • Preparation of fast dissolving tablets (FDTs) using varying concentration of natural solubility enhancers • In-vitro drug release studies for formulated FDTs • In-vivo studies (Pharmacokinetics & Pharmacodynamic studies) • Stability studies as per ICH guidelines

19. Time schedule

20. REVIEW OF LITERATURE • Vojinovic´, T., et al. (2018), has prepared solid dispersions of carbamazepine in the hydrophilic Kollidon VA64 polymer, adsorbed onto Neusilin UFL2 adsorption carrier in order to improve carbamazepine dissolution rate. From all prepared solid dispersion formulations, significantly faster carbamazepine dissolution was observed compared to pure drug. Ternary solid dispersions containing carbamazepine, Kollidon VA64 and Neusilin UFL2 showed superior dissolution performances over binary ones, containing only carbamazepine and Neusilin UFL2.

21. Contd…… • Sunny Shah et. al., (2016) investigated lurasidone hydrochloride nanocrystals for improving its solubility and dissolution characteristics. Nanocrystals were prepared by media milling technique using zirconium oxide beads with 0.1 mm diameter. Various stabilizers, viz. poloxamer 188, PVP K30, SLS, HPMC E15, and PVP S 630 D, were evaluated to stabilize the nanocrystals. The optimized formulation showed mean particle size of 228 nm and released almost all the drug within first 5 min. Since the crystallinity of the drug is maintained, improvement in saturation solubility and dissolution efficiency could be attributed to decrease in mean particle size of the drug.

22. Contd…… • Rahman H, Chungath TT, Selvakumaraswamy K, Chandrasekar R (2016), Studied the development of water insoluble compound into a sustained release matrix tablets and the influence of Aloe vera gel powder in the dissolution and other physical properties of the SR matrix tablets. The HPMC and ethyl cellulose were used as polymer and different concentration of Aloe vera gel powder used as dissolution enhancer. The results suggest that Aloe vera is improved the dissolution of curcumin. In conclusion, authors suggested that the Aloe vera gel powder can be used as dissolution enhancer for improving the drug absorption of water insoluble drugs .

23. Contd…… • VinayPandit et. al., (2012) Investigated in vitro/in vivo behavior of fast-dissolving tablets containing solid dispersions of pioglitazone hydrochloride (PIO). The effect of various hydrophilic polymers on the aqueous solubility of PIO was studied. Poly vinyl pyrrolidine K 30 (PVPK 30) carrier was selected and solid dispersions were prepared by various methods. In vivo studies of pure drug, selected formulation, and marketed product were carried out in male Wistar rats and pharmacokinetic parameters were calculated using Kinetica software 2000. Therefore, the solid dispersions prepared by kneading method using PVPK 30 as hydrophilic carrier can be successfully used for improvement of dissolution of PIO and resulted in faster onset of action as indicated by in vivo studies.

24. Natural Bioenhancer • Piperine: Piperine, the major plant alkaloid present in Piper nigrum Linn (Black pepper) and Piper longum Linn (Long pepper), has bioavailability enhancing activity for some nutritional substances and for some drugs . The bioenhancing dose of piperine is approximately 15 mg/person/day and no more than 20 mg/day in divided doses. • It also showed enhanced bioavailability when combined with Nevirapine , a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase. • Piperine also increases the bioavailability of curcumin, the active principle of Curcuma longa (turmeric). A 20 mg dose of piperine can increase the bioavailability of curcumin by 20 fold in humans . Acts by inhibiting the drug metabolizing enzymes CYP 450. • Allicin: ALLICIN 27 It is an allyl sulphur compound obtained from garlic (Allium sativum ). Allicin enhances the fungicidal activity of Amphotericin B against pathogenic fungi such as Candida albicans , Aspergillus fumigatus and yeast Saccharomyces cerevisiae. • Naringin: Naringin, a flavonoid glycoside is capable of inhibiting intestinal CYP3A4, CYP3A1, CYP3A2, P-gp and thus acts as a bioenhancer. • Genistein: Genistein (5, 7-Dihydroxy-3-(4-hydroxyphenyl) chromen-4-one) known as a phytoestrogen belongs to the isoflavone class of flavonoids. Since genistein was reported to be able to inhibit P-glycoprotein, BCRP and MRP2 efflux function, the intestinal absorption of paclitaxel, a substrate for efflux transports such as P-glycoprotein, BCRP and MRP2 was dramatically increased, co-administered with genistein.

25. Natural Bioenhancer • Quercetin: Quercetin is a dual inhibitor of CYP3A4 and Pgp. It influences the bioavailability of dilitiazem, paclitaxel, digoxin, doxorubicin and tamoxifen and also significantly increased the bioavailability. • Carum carvi is a prized culinary herb used extensively in India for flavouring of food and medicinally it is an effective gastric stimulant, carminative and anthelmintic. The extracts of Carum carvi are used as bioenhancers, either alone or in combination with piperine. • Cuminum cyminium: The essential oil from Cuminum cyminium is being used as bioenhancer and a lot of information is available in patent literature. Patent No. [67] relates to the use of Cuminum cyminium as bioenhancer to decrease the resistance of microbial strains to anti-infective.

26. Natural Bioenhancer • Lysergol:Lysergol (9, 10-Didehydro-6-methylergoline-8-α-methanol) is a promising herbal bioenhancer phytomolecule obtained from morning glory plant (Ipomoea spp.) which enhances the killing activities of different antibiotics on bacteria. • Nitrile glycoside: A new nitrile glycoside, Niaziridin has been isolated from the pods of Moringa oleifera plant. The biomolecule enhances the absorption of drugs, vitamins and nutrients through the gastrointestinal membrane increasing their bioavailability. • Ginger (Zingiber officinale):Ginger is the dried underground stem or rhizome of the zingiberous, herbaceous plant Zingiber officinale Linn, which constitutes one of the most important major spices of India. Traditionally it is used as a carminative and stimulant to the gastro-intestinal tract. • Garlic (Allium sativum) Allicin, the phytomolecule in garlic (Allium sativum) enhances the activity of amphotericin B against yeast (Sacchromyces ceriviciae) and fungal (Candida albicans, Aspergillus fumigatus) infection.

27. Methodology PREFORMULATION STUDIES • Determination of λmax for pure drug in different media • Preliminary Solubility studies of selected drug • Development of Calibration curve for pure drug using UV spectrophotometer and HPLC • Determination of Partition coefficient of pure drug • Phase solubility studies • Compatibility studies such as FTIR • SEM (Scanning Electron microscopy) studies of selected drug • DSC (Differential Scanning calorimetry) studies of selected drug • X-ray powder diffraction (XRPD) studies of selected drug

28. Methodology • Solubility studies of pure drug in distilled water and buffers : Solubility studies were carried out by Higuchi and Connors method. • Screening of appropriate carrier for solid dispersion: The physical mixtures (PMs) of pure drug and different water-soluble polymers viz., mannitol, citric acid, urea, PEG 4000, PEG 6000, PEG 20 K, and PVP K30 in the ratio 1 : 1 were subjected for solubility studies, in distilled water by Higuchi and Connors method. • Preparation of solid dispersions: Solid dispersions were prepared by three different methods viz., hot-melt and solvent evaporation method. The solid dispersion will be prepared as ternary systems using adsorbent • Evaluation of Solid Dispersions: The prepared solid dispersions will be evaluated for percentage yield, Drug content, Solubility Studies, Fourier Transform Infrared Spectroscopy, In vitro Release Studies and  in vitro Data analysis by using PCP disso v2.08 software

29. Preparation & Evaluation of fast dissolving Tablets • The solid dispersion having the maximum solubility and dissolution rate will be selected for preparation of fast-dissolving tablets. • The concentration of Bioavailability Enhancers viz., anhydrous Aloe vera gel (in powder form) and anhydrous Amla Juice (Powder form) in combination and alone will be optimized along with other ingredients for fast dissolution.

30. Evaluation • The tablet thickness will be determined by using Vernier caliper, while the tablet hardness and friability will be determined using Monsanto tablet hardness tester and friabilator (Roche), respectively. • The disintegration time will be measured by using tablet disintegrator (Electrolab, India). • Wetting time will be determined by well-reported method. A tissue paper will be folded double and placed in a Petri dish (internal diameter 10 cm) containing 10 ml of Amaranth solution. The tablet will be carefully placed on the surface of tissue paper. The time required for the tablet to get colored completely pink will be noted as wetting time.

31. In vitro Release Studies of prepared fast dissolving tablets • The release rate of fast-dissolving tablets containing pure drug, solid dispersion (Drug Composite), and MF (containing equivalent of amount of drug) (n = 6) will be determined using USP type II apparatus (Paddle method). The dissolution test will be performed using 900 ml of simulated gastric fluid, at 37 ± 0.5°C and 75 rpm. The samples were analyzed spectrophotometrically against similarly treated blank. • In order to evaluate the similarity between the best formulation and MF, the in vitro dissolution profiles of both were compared. Similarity factor (f2) will be calculated by using the following formula: f2 = 50 × log {[1+(1/n) ∑ (Rj – Tj)2 ]- 0.5 × 100 } j=1

32. In vivo Studies • The bioavailability studies for fast dissolving tablets with pure drug, Optimized drug composite, and MF will be carried out using male New Zealand Rabbits. • The results obtained were analyzed for various non-compartmental pharmacokinetic parameters using Kinetica 2000 software. Furthermore, the pharmacokinetic data were analyzed statistically by one way ANOVA followed by Dunett Post Hoc test for multiple comparison using graph pad prism (demo version).

33. In vitro-in vivo correlation • Level A correlation is the highest category of correlation and represents a point-to-point relationship between in vitro dissolution rate and in vivo input rate of the drug from the dosage form. In vitro-in vivo correlation of tablets with Optimized drug composite will be investigated by plotting the percent drug dissolved (Fr) vs percent drug absorbed (Fa). Percent dissolved values will be taken from in vitro release data and percent absorbed was determined by the Wagner-Nelson method using the following equation: Fa= [(Ct+keAUC0-t/ keAUC0-α)] ×100

34. Stability Studies • Stability studies will be performed as per ICH guidelines for 6 months at 40°C ± 2°C / 75% RH ± 5%.

35. References / Bibliography • Savjani, K.T., A.K. Gajjar, and J.K. Savjani, Drug Solubility: Importance and Enhancement Techniques. ISRN pharmaceutics, 2012. 2012. • Sharma, D., et al., Solubility enhancement-eminent role in poorly soluble drugs. Research Journal of Pharmacy and Technology, 2009. 2(2): p. 220-224. • Krishnaiah, Y.S.R., Pharmaceutical technologies for enhancing oral bioavailability of poorly soluble drugs. J BioequivAvailab, 2010. 2(2): p. 28-36. • Moore, M.D. and P.L.D. Wildfong, Aqueous solubility enhancement through engineering of binary solid composites: pharmaceutical applications. Journal of Pharmaceutical Innovation, 2009. 4(1): p. 36-49. • Jinno, J., et al., Effect of particle size reduction on dissolution and oral absorption of a poorly water-soluble drug, cilostazol, in beagle dogs. Journal of controlled release, 2006. 111(1): p. 56-64. • Myoungjin Kwon and Sun-Oh Ju.The Effect of Aloevera for Constipation in Schizophrenia Patients. Indian Journal of Science and Technology, 2016, Vol 9(41):3-5. • Vojinovic´, T., et al. Development of ternary solid dispersions with hydrophilic polymer and surface adsorbent for improving dissolution rate of carbamazepine. Saudi Pharmaceutical Journal (2018), https://doi.org/10.1016/j.jsps.2018.02.017 • Sunny Shah, BhavinParmar, MoinuddinSoniwala, and JayantChavda. Design, Optimization, and Evaluation of Lurasidone Hydrochloride Nanocrystals. AAPS PharmSciTech, Vol. 17, No. 5, October 2016 • Rahman H, Chungath TT, Selvakumaraswamy K, Chandrasekar R (2016) Aloe vera Mucilage as Solubility Enhancer in Tablet Formulation. J Nutr Food Sci 6: 548. doi:10.4172/2155-9600.1000548 • VinayPandit, Roopa S. Pai, Kusum Devi, and Sarasija Suresh.In vitro-in vivo evaluation of fast-dissolving tablets containing solid dispersion of pioglitazone hydrochloride.J Adv PharmTechnol Res. 2012 Jul-Sep; 3(3): 160–170.