Zero-Order Release and Bioavailability Enhancement of Poorly Water Soluble Vinpocetine from Self-Nanoemulsifying Osmotic Pump Tablet

Pharmaceutical Development and Technology

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Zero-order release and bioavailability enhancement of poorly water soluble Vinpocetine from self-nanoemulsifying osmotic pump tablet

Sally A. El-Zahaby, Mohamed H. H. AbouGhaly, Ghada A. Abdelbary & Omaima N. El-Gazayerly

To cite this article: Sally A. El-Zahaby, Mohamed H. H. AbouGhaly, Ghada A. Abdelbary & Omaima N. El-Gazayerly (2018) Zero-order release and bioavailability enhancement of poorly water soluble Vinpocetine from self-nanoemulsifying osmotic pump tablet, Pharmaceutical Development and Technology, 23:9, 900-910, DOI: 10.1080/10837450.2017.1335321 To link to this article: https://doi.org/10.1080/10837450.2017.1335321

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Accepted author version posted online: 25 May 2017. Published online: 08 Jun 2017.

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Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iphd20 PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 2018, VOL. 23, NO. 9, 900–910 https://doi.org/10.1080/10837450.2017.1335321

RESEARCH ARTICLE Zero-order release and bioavailability enhancement of poorly water soluble Vinpocetine from self-nanoemulsifying osmotic pump tablet

a b b b Sally A. El-Zahaby , Mohamed H. H. AbouGhaly , Ghada A. Abdelbary and Omaima N. El-Gazayerly aDepartment of Pharmaceutics, Faculty of Pharmacy and Drug Manufacturing, Pharos University in Alexandria, Alexandria, Egypt; bDepartment of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt

ABSTRACT ARTICLE HISTORY Solid self-nanoemulsifying (S-SNEDDS) asymmetrically coated osmotic tablets of the poorly water-soluble Received 24 January 2017 drug Vinpocetine (VNP) were designed. The aim was to control the release of VNP by the osmotic technol- Revised 15 May 2017 ogy taking advantage of the solubility and bioavailability-enhancing capacity of S-SNEDDS. Liquid SNEDDS Accepted 23 May 2017 loaded with 2.5 mg VNP composed of MaisineTM 35-1, TranscutolVR HP, and CremophorVR EL was adsorbed VR on the solid carrier Aeroperl . S-SNEDDS was mixed with the osmotic tablet excipients (sodium chloride, KEYWORDS AvicelVR , HPMC-K4M, PVP-K30, and LubripharmVR ), then directly compressed to form the core tablet. The 2 1 Vinpocetine; solid self- tablets were dip coated and mechanically drilled. A 3 2 full factorial design was adopted. The independ- nanoemulsifying drug ent variables were: type of coating material (X1), concentration of coating solution (X2), and number of delivery system; osmotic drills (X3). The dependent variables included % release at 2 h (Y1), at 4 h (Y2), and at 8 h (Y3). The in vivo pump tablets; asymmetric performance of the optimum formula was assessed in rabbits. Zero-order VNP release was obtained by coat; zero-order release; the single drilled 1.5% OpadryVR CA coated osmotic tablets and twofold increase in VNP bioavailability was bioequivalence achieved. The combination of SNEDDS and osmotic pump tablet system was successful in enhancing the solubility and absorption of VNP as well as controlling its release.

1. Introduction formed and showed higher solubility when compared to VNP (Hasa et al. 2011; Ma et al. 2016). VNP is a semi-synthetic drug derived from the alkaloid vincamine Another approach to improve VNP solubility is the preparation obtained from the leaves of the lesser periwinkle plant Vinca of solid self-nanoemulsifying drug delivery systems (S-SNEDDS). minor (Jha et al. 2012). It is used for patients suffering from neuro- Nanosized systems help in improving the solubility and dissol- degenerative conditions, such as Parkinson’s and Alzheimer’s dis- ution rate and hence the bioavailability of poorly water soluble ease owing to its anti-inflammatory and cognition improvement properties (Jeon et al. 2010). Unfortunately, VNP usefulness is lim- drugs. This is attributed to the increased surface area available for – ited owing to its poor bioavailability (7%) resulting from both its dissolution as described by the Noyes Whitney (Noyes & Whitney – low aqueous solubility (5 lg/mL) and extensive hepatic first-pass 1897) and Ostwald Freundlich equations (Shchekin & Rusanov metabolism (Mao et al. 2013). This leads to low VNP concentration 2008). SNEDDS are lipid-based systems used for enhancing the in the brain and limited clinical response. VNP is a weak basic solubility and bioavailability of hydrophobic drugs. Another advan- drug whose solubility is pH dependent with higher solubility in tage of SNEDDS is that both long and medium chain fatty acids acidic media (Nie et al. 2011). It shows biphasic elimination with used in their preparation are absorbed into the lymphatic system through Peyer’s patches (Chudasama et al. 2014). Thus, VNP alpha half-life (t1/2) of 0.136 h and beta t1/2 of 4.83 h (Vereczkey avoids passing through the portal circulation and first-pass metab- et al. 1979). As a result of its short t1/2, frequent dosing (three times daily) is required, which is inconvenient for patients with olism. This can further help in enhancing VNP bioavailability. dementia and results in poor compliance (El-Laithy et al. 2011). When these liquid excipients are loaded on solid carriers, Since the bioavailability of VNP is limited in part by its solubil- S-SNEDDS is formed, which is characterized by high stability and ity, several drug delivery systems with improved VNP solubility can be formulated in different dosage forms (Oh et al. 2011). have been developed including cyclodextrin inclusion complexes S-SNEDDS produce oil-in-water nanoemulsions after oral adminis- (Aburahma et al. 2010; Ding et al. 2015), solid dispersions (Chen tration by the GI motility of the stomach and intestine et al. 2009; Kharshoum et al. 2013), nanoparticles (Li et al. 2014; (Constantinides 1995). Wang & Xu 2016), solid lipid nanoparticles (Luo et al. 2006; Morsi Another limitation of VNP is its short t1/2. This makes it a good et al. 2013), nanostructured lipid carriers (Lin et al. 2014), candidate for the preparation of controlled release dosage forms. mixed polymeric micelles (El-Dahmy et al. 2014), and self-micro- Several approaches have been explored to formulate S-SNEDDS emulsifying systems (Chen et al. 2008). Also, new salt forms of into controlled release systems namely; polymer coated and VNP (perchlorate, phosphate, and citrate) have been successfully matrix pellets (Serratoni et al. 2007; Zhang et al. 2012; Miao et al.

CONTACT Mohamed H. H. AbouGhaly [email protected] Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt Current affiliation: Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, Heine Pharmacy Building, 575 Stadium Mall Drive, West Lafayette, IN 47907-2091, USA Supplemental data for this article can be accessed here. ß 2017 Informa UK Limited, trading as Taylor & Francis Group PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 901

2014), microspheres (You et al. 2006; Yi et al. 2008), microcapsules containing 10% of the non-solvent glycerol. The coating materials (Zvonar et al. 2010, 2012), nanocapsules (Zvonar et al. 2012; Park used were CA (2.5%, 5%, or 10%), OpadryVR CA (2.5% or 5%), or a V et al. 2013), molded tablets (Patil et al. 2009), matrix tablets mixture of CA and PEG (80:20) similar to Opadry R CA. The tablets (Nazzal & Khan 2006; Wang et al. 2011), and osmotic pump tablets were coated to a weight gain of 10%. In another preliminary (Wei et al. 2007; Zhang et al. 2013). Osmotic systems are charac- experiment, the core tablets were coated using 2.5%, 5%, or 7.5% V terized by zero-order release kinetics unaffected by pH changes, Opadry R CA solutions by fixing the number of dippings to 2 10 s which is a very beneficial feature for pH sensitive drugs like VNP. dippings All tablets were air-dried for 5 s and then immersed in a Herein, we discuss the formulation of VNP solid self-nanoemul- water quench bath for 3 min. The tablets were then air-dried at sifying osmotic pump tablet (VNP-SNEOPT). The formulation of room temperature (25 C) for 12 h. A small orifice was drilled SNEDDS will help in dissolving VNP and will increase the rate of through the coated tablet using a standard 800 lm diameter drug absorption. Also, the dispersion of VNP in the oil globules mechanical micro-drill (dental bur FG 330, Midwest Dental, will help in evading first-pass metabolism by enhancing the Wichita Falls, TX). The coated tablets had either one drill on one absorption through the lymphatic system. This can improve the side or two drills with one on each side. bioavailability of VNP. Formulating SNEDDS into solid S-SNEDDS The coat was examined under projection microscope (PRM-18T, VR and then into SNEOPT will control the release rate and make the Radical Instruments, Haryana, India) before and after immersion plasma concentrations more stable (Barzegar-Jalali et al. 2008). into the release media to check the membrane porosity. Briefly, A powder has very limited ability to retain liquids while maintain- the coating membrane was removed from the tablet core, fixed ing acceptable compaction characteristics and good flow proper- on a slide using a glass cover and examined under the ties (Nokhodchi et al. 2011). Hence, it is very challenging to microscope. formulate a successful tablet formulation from the liquid S-SNEDDS. In this work, we describe the preparation, evaluation, 2.3. Statistical design of the study and optimization of VNP-SNEOPT. We also investigate the effect of 2 1 changing OPT coating parameters on the in vitro release and the A3 2 full factorial design was employed to compare the for- in vivo pharmacokinetic performance of VNP from SNEOPT. mulation variables. Generation and analysis of the experimental design were carried out using SPSS 17.0 software (SPSS Inc., Chicago, IL). The independent variables selected were the type of 2. Materials and methods VR coating material (X1); CA, CA with PEG (80:20), and Opadry CA, X 2.1. Materials concentration of the coating solution ( 2); 1%, 1.5%, and 2%, and the number of drills (X3); either single or twin drill. The dependent Vinpocetine (VNP), manufactured by Covex (Madrid, Spain), was variables included % release at 2 h (Y1), at 4 h (Y2), and at 8 h (Y3) kindly supplied by Amriya Pharmaceutical Industries (Alexandria, denoted Q2h, Q4h and Q8h, respectively. In addition, the coefficient Egypt). Cremophor EL and polyvinylpyrrolidone (PVP-K30) were of determination, R2, of fitting the data to zero-order release pro- kind gifts from BASF (Ludwigshafen, Germany). Transcutol HP and file was chosen as an additional factor for comparison. All formu- TM – Maisine 35 1 were kind gifts from Gattefosse (Lyon, France). lae contained 2.5 mg VNP/250 mg SNEDDS incorporated into the VR Aeroperl 300 Pharma was supplied by Evonik Industries AG tablet core. (Rheinfelden, Germany). Cellulose acetate (CA) was provided by Prolabo (Paris, France). OpadryVR CA (a mixture of CA and polyethylene glycol 3350 in a ratio of 80:20) and hydroxypropyl 2.4. In vitro evaluation of VNP-SNEOPT methyl cellulose K4M (HPMC-K4M) were kind gifts from Colorcon (Indianapolis, IN). Polyethylene glycol 4000 (PEG) was supplied by 2.4.1. Thickness and diameter Winlab Ltd. (Leicestershire, UK). Microcrystalline cellulose (AvicelVR The thickness and diameter of 10 tablets from each formula were PH101) was purchased from FMC Corporation (Philadelphia, PA). measured using a Vernier caliper and the means [± standard devi- LubripharmVR was a kind gift from SPI Pharma (Septemes- ation (SD)] were calculated. les-Vallons, France). Sodium chloride was purchased from El-Gomhouria Co. (Cairo, Egypt). Hydrochloric acid, glycerol and 2.4.2. Weight variation after coating acetone were obtained from El-Nasr Pharmaceutical Chemicals Co. After the core tablets were coated, the weight variation test was (Qaliubiya, Egypt). All other chemicals used were of pharmaceut- conducted by weighing 20 randomly selected tablets individually. ical grade. The average weight (± SD) was calculated.

2.4.3. Friability 2.2. Preparation of the asymmetrically coated VNP osmotic Ten tablets from each formula were accurately weighed and tablets using the dip-coating technique placed in the drum of a friability tester (Model FR1000, Copley The S-SNEDDS and core tablet were prepared according to our Scientific Ltd., Nottingham, UK), which rotated at 25 rpm for 4 min. previous work (El-Zahaby et al. 2016). Briefly, SNEDDS was com- The tablets were then brushed and reweighed. The percentage posed of 25 mg MaisineTM 35–1, 125 mg CremophorVR EL and loss in weight was calculated and taken as a measure of friability. 100 mg TranscutolVR HP loaded with 2.5 mg VNP. The SNEDDS was loaded on 200 mg AeroperlVR by simple mixing using mortar and 2.4.4. Hardness pestle to form the S-SNEDDS. AvicelVR (133.3 mg), HPMC-K4M Hardness was determined using six tablets from each formulation. (14.2 mg), sodium chloride as osmotic agent (266.7 mg), PVP-K30 Each time the tablet was placed between the two anvils of a (28.5 mg), and LubripharmVR (4.5 mg) were then mixed with the digital tablet hardness tester (Version 4.22, Schleuniger S-SNEDDS to form the core tablet with total weight of 900 mg. Pharmatron Inc., Manchester, NH), force was applied to the anvils, The osmotic tablets were then asymmetrically coated using the and crushing strength that just caused the tablet to break was dip-coating technique. In a preliminary study, the tablets were recorded. The average hardness expressed in Newton (N) (± SD) coated using three different coating solutions dissolved in acetone was calculated. 902 S. A. EL-ZAHABY ET AL.

2.5. In vitro VNP release study at 3000 rpm for 10 min at 4 C (Centurion Scientific Ltd., West Sussex, UK) and stored frozen at 20 C pending VNP analysis. All release studies were carried out in USP apparatus II rotating The liquid chromatography coupled with mass spectrometry paddle (Hanson Research Corporation, Chatsworth, CA) at 50 rpm (LC–MS/MS) method developed and validated by El-Dahmy et al. and at 37 ± 0.5 C. The dissolution was carried out using 130 mL (2014) was used for the analysis of VNP in the collected samples. 0.1 N HCl pH 1.2 (simulated gastric fluid) for the first 2 h. The medium was then changed to phosphate buffer pH 6.8 (simulated 2.8.3. Pharmacokinetic and statistical analysis intestinal fluid) for the next 6 h by adding the required volume of VNP pharmacokinetic parameters after oral administration of the 0.2 M tri-sodium orthophosphate (Jha et al. 2012). The exact total developed formulae compared to the market product were deter- volume of release media (200 mL) was recorded every time and mined by non-compartmental pharmacokinetic models using was taken into consideration in the calculation of the amount of Thermo ScientificTM Kinetica Software version 5 (Waltham, MA). drug released at each time interval. Samples of 5 mL were with- The peak plasma concentration (C ) and the time to reach C drawn at predetermined time intervals (0.5, 1, 1.5, 2, 2.5, 3, 4, 6, max max (t ) were obtained from the plasma concentration–time data. and 8 h) and analyzed spectrophotometrically at 269 nm using a max The area under the plasma concentration–time curve from time UV–Visible spectrophotometer (UV-1601, Shimadzu, Kyoto, Japan). zero to the last time point and to infinity (AUC – and AUC –1) An equal volume of fresh medium maintained at the same 0 24 0 were calculated using the linear trapezoidal rule. Mean residence temperature was then added. The test was run in triplicate. time (MRT) was calculated from the terminal portion of the ln(concentration)–time curve using regression. 2.6. Mechanism of VNP release 2.8.4. Establishment of in vitro/in vivo correlation An ideal osmotic pump system should be able to release all of its According to FDA guidelines, four categories of in vitro/in vivo cor- drug content at a constant release rate (i.e. zero-order kinetics). In relation (IVIVC) can be established namely, levels A, B, C and mul- order to study the mechanism of drug release from VNP osmotic tiple level C. The latter relates one or multiple pharmacokinetic tablets, release data were analyzed according to zero-order, first- parameters [such as C , t , K , or AUC (total or cumulative)] to order, and Higuchi kinetic equations. The latter was applied to the max max a the amount of drug dissolved at different time points of the first 60% drug released (Ribeiro et al. 2012). DDSolver add-in was release profile (U.S. Department of Health and Human Services used for modeling and comparison of drug release profiles (Zhang 1997). To estimate the multiple level C correlation, the cumulative et al. 2010). The model with the highest coefficient of determin- AUC –t was plotted against the percent of VNP released at the ation (R2) was considered to be the best-fitting one. 0 same time points and the coefficient of determination (r2) was determined. 2.7. Statistical analysis The resulting data were analyzed by using SPSS software applying 3. Results and discussion univariate analysis of variance. Post hoc multiple comparisons 3.1. Preliminary prepared VNP S-SNEOPT (Duncan test) were applied when necessary. Differences between formulations were considered to be significant at p < .05. The core tablets used in this study were prepared according to the composition developed in our previous work (El-Zahaby et al. 2016). The core tablets were then dip coated to produce the 2.8. In vivo pharmacokinetic study in rabbits SNEOPT. Preliminary studies were performed to choose the proper 2.8.1. Study design polymers, polymer concentration and number of coat drills to be A study was designed in order to compare the pharmacokinetic used in the coating process. The aim was to select the appropriate parameters of VNP from the optimized S-SNEOPT to the commer- parameters to construct the factorial design to produce formula- cially available VinporalVR tablets (Amriya Pharmaceutical tions with near zero-order release and high extent of drug release. Industries) following single oral dosing administration and a wash Figure 1 illustrates the dissolution profile of some of the prepared out period of 1 week. Two-treatment, two-period, randomized formulae. All of the tablets did not release most of the drug cross-over design was adopted using six healthy male albino rab- included and the maximum amount released (58% after 8 h) was bits (2–2.25 kg) purchased from the laboratory animal center of obtained from the tablets coated with 2.5% OpadryVR CA and the National Research Center (Cairo, Egypt). The experimental drilled twice. In general, VNP released from tablets was higher protocol was approved by the Animal Ethics Committee (Faculty when the tablets were coated using 2.5% OpadryVR CA by fixing of Pharmacy, Cairo University), and the handling of the animals the number of dippings into coating solution to 2 10 s dippings was in accordance with international guidelines (European compared to coating until a 10% weight gain was obtained. This Commission 2010). The rabbits were divided into two groups of is due to the lower amount of coat depositing on the surface of three rabbits; group I received the test formula and group II the tablets. Therefore, two times dipping into coating solution V received the marketed product (Vinporal R ). Rabbits were fasted was the method of choice in further work. Also, since none of the overnight with water ad libitum. Tablets were swallowed intact by prepared preliminary formulae reached full drug release, lower pushing them to the back of the pharynx with a flexible gastric polymer concentration was adopted in the full factorial design to tube. Then, 10 mL of water was given orally with a syringe to ensure complete drug release from the SNEOPT. avoid tablet adherence to the throat and to help swallowing. 3.2. Quality control tests of VNP SNEOPT prepared using the 2.8.2. Sample collection and analysis factorial design Blood samples (3 mL) were taken at zero time (predose) and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10 and 24 h postdose. The The diameter and thickness of the prepared VNP SNEOPT ranged samples were withdrawn via the marginal ear vein into hepari- between 12.02–12.05 mm and 0.811–0.814 mm, respectively. The nized tubes. Plasma was separated immediately by centrifugation weight gain per tablet reached after coating was found to be PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 903

Figure 1. In vitro release studies of some of the preliminary prepared VNP S-SNEOPT.

2 1 Table 1. Composition and responses of 3 2 factorial design. Concentration Type of coating of coating Number Friability (%) Hardness (N±SD) a a a Formula material (X1) solution (X2) of drills (X3) n ¼ 10 n ¼ 3 Q2h (Y1) (%±SD) Q4h (Y2) (%±SD) Q8h (Y3) (%±SD) 1 CA 1% 1 9.756 22.33 ± 0.58 28.65 ± 1.99 60.40 ± 1.00 94.27 ± 4.30 2 2 12.195 21.00 ± 1.00 38.79 ± 4.45 61.20 ± 0.73 97.85 ± 0.11 3 1.50% 1 0 23.00 ± 0.00 33.06 ± 1.04 44.29 ± 1.04 60.93 ± 10.10 4 2 0.298 23.00 ± 1.00 34.18 ± 0.87 41.66 ± 1.60 66.01 ± 0.07 5 2% 1 0 24.67 ± 1.53 29.27 ± 0.72 41.55 ± 0.60 50.11 ± 2.16 6 2 0.123 24.33 ± 1.15 29.81 ± 3.88 40.12 ± 2.11 51.79 ± 1.07 7 CA/PEG (80:20) 1% 1 8.791 22.00 ± 0.00 43.36 ± 6.08 75.50 ± 4.14 96.87 ± 0.01 8 2 8.363 23.67 ± 1.53 36.43 ± 1.73 88.29 ± 2.61 96.54 ± 4.99 9 1.50% 1 0.055 29.00 ± 0.00 28.01 ± 1.52 46.88 ± 3.29 92.84 ± 2.03 10 2 0.552 29.33 ± 0.58 33.67 ± 0.96 48.11 ± 5.09 86.93 ± 4.29 11 2% 1 0.332 26.00 ± 2.00 22.40 ± 1.60 34.72 ± 3.00 47.12 ± 1.57 12 2 0.111 24.33 ± 1.15 30.06 ± 4.86 42.66 ± 0.97 68.29 ± 4.82 13 OpadryVR CA 1% 1 7.377 23.00 ± 0.00 42.05 ± 2.15 91.52 ± 0.46 100.58 ± 1.06 14 2 0 24.00 ± 0.00 61.06 ± 0.49 84.57 ± 1.11 101.72 ± 3.34 15 1.50% 1 0.114 42.00 ± 0.00 33.59 ± 0.12 45.56 ± 0.09 77.58 ± 0.06 16 2 0 40.67 ± 0.58 41.80 ± 1.08 69.92 ± 0.66 101.62 ± 2.26 17 2% 1 0 38.00 ± 0.00 32.14 ± 0.15 47.12 ± 0.05 66.53 ± 0.06 18 2 0.159 40.67 ± 1.53 35.49 ± 3.13 57.69 ± 8.25 98.79 ± 4.52 a Q2h, Q4h, and Q8h are the % cumulative VNP released at 2, 4, and 8 h, respectively. between 0.01 and 0.02 g. The low concentrations used in coatings These three points will help in describing the initial release as along with the short dipping time led to the small weight gain well as the rate and extent of drug release. The optimum target observed. The results of the friability and hardness tests are from osmotic pump tablets is to obtain a constant zero-order shown in Table 1. All 1.5% and 2% coated tablets passed friability release independent of time and the conditions in the gastrointes- test. On the other hand, all the 1% coated tablets did not pass fri- tinal tract (Shokri et al. 2008). However, one of the problems ability test except the twin drilled 1% OpadryVR CA coated tablets. encountered with osmotic systems is the lag time associated with The low concentration coatings produced more fragile coats that the initial stage of water imbibition inside the system to start the peeled off easily from the surface of the tablets. OpadryVR CA release. That is why it is beneficial to have a minimal initial drug Q coated tablets had a uniform appearance and were less liable to release as denoted by 2h, when formulating extended release friability. This correlated with hardness results where tablets osmotic systems before majority of the drug being released in a specific time period (Huang et al. 2004). coated with CA or the mixture of CA/PEG showed lower hardness values compared to the core tablet without coating. On the other VR hand, Opadry CA coated tablets possessed hardness values com- 3.3.1. In vitro release profile of VNP from CA coated SNEOPTs parable to the core tablet (the core C4 hardness was 38 N). A reported drawback of osmotic pump tablets is the lag time Collectively, hardness of all coated tablets ranged from 21 to 42 N, encountered before drug release starts especially for water insol- which is acceptable (Mahalaxmi et al. 2009; Ketjinda et al. 2011). uble drugs. This problem also appears when dense tablet coating is used. As shown in Figure 2, the use of asymmetric membrane coating in the preparation of SNEOPT led to more rapid release in 3.3. Optimization of VNP release from osmotic tablets using full the initial phase and relatively higher Q values. This type of factorial design 2h coating was known to have the ability to minimize the lag time In order to compare the prepared formulae, three response variables encountered in the usual dense coatings allowing the drug to be were selected; the percentage of drug released after 2, 4, and 8 h. released from numerous delivery ports (Herbig et al. 1995). 904 S. A. EL-ZAHABY ET AL.

Figure 2. In vitro release profiles for VNP core tablets coated with (2%, 1.5%, and 1%) asymmetric CA membrane by fixed number of dipping and either having 1 or 2 drills in 0.1 N HCl for 2 h followed by changing media to pH 6.8 phosphate buffer till 8 h at 37 ± 0.5 C.

According to statistical analysis (Duncan test), there is no sig- As shown in Figure 3, 2% coated single drilled CPOPTs showed nificant difference (p > .05) in the overall % VNP released from the significantly lower (p < .05) rate and extent (47% after 8 h) of VNP single and twin drilled formulae coated by either 1.5% or 2% CA. release among this category of coating; as the coating solution All those formulae released from 50% to 66% VNP after 8 h. concentration increased, the drug release decreased. The higher Changing the number of drills in those membranes had no signifi- polymer concentration led to lower membrane permeability to cant effect (p > .05) on VNP release as well. These results are in the dissolution medium. Therefore, VNP release was slower accordance with the work of Derakhshandehand and Berenji through the tablet coat. An inverse correlation between the rate (2014), where they tested the influence of the number of release of drug release and CA coated CPOPTs was observed in a study orifices on the release of buspirone from oral osmotic pump tab- by Abd-Elbary et al. (2011). In addition, Shokri et al. (2008) let. Their results showed that the drug release rate did not reported that drug release rate decreased as a result of using increase significantly with an increasing number of release orifices thicker coating on CPOPTs which in turn decreased the rate of from 1 to 2 (p > .05) and it is concluded that the main force for water penetration through the membrane. drug release in the prepared osmotic tablets is the osmotic pres- There was no significant difference (p > .05) between VNP sure across the coating membrane. The tablets coated with 2% release from 1% CA/PEG CPOPTs with 1 and 2 drills. The same CA remains intact throughout the release while the tablets coated was observed for 1.5% coated tablets. At lower CA/PEG concentra- with 1.5% CA showed a small rupture in the coat after 8 h. There tions (1% and 1.5%), the membrane permeability is already high was no significant difference (p > .05) between the two 1% CA for- due to the controlled pores formed in the coats. This led to mulations; however, the extent of drug release was significantly decreased effect of the drills on membrane coat permeability. higher (p < .05) than the 1.5% and 2% CA SNEOPT. The tablet Also, a non-significant difference (p > .05) between the mean VNP coating cracked shortly after the tablet was exposed to the dissol- released from the CPOP tablets coated with 1.5% CA/PEG (single ution medium. This was probably due to the lack of resistance of drill) and 2% CA/PEG (twin drills). The twin drilled membrane with the thin layer of coating around the tablet, which was unable to higher polymer concentration (2%) gives the same results as tolerate the building hydrostatic pressure induced by when decreasing polymer concentration to 1.5% and make a sin- polymer swelling (Shokri et al. 2008). This can also explain the gle drill in the membrane. This indicates that when the coat per- non-significant difference between the single- and twin-drilled meability is already high due to presence of pore former, the tablets. It is previously reported that when a low concentration of resistance to water transport in the tablet core is more significant CA in the coating and/or a low coating level was applied to than the transport through the coat. This is in accordance with osmotic tablets, the produced asymmetric membrane tends to the work by Thombre et al. (2004), where changing the CA/PEG rupture during in vitro testing (Am Ende & Miller 2007). ratios between 7/3 and 6/4 yielded similar drug release profiles. Both osmotic tablets coated by either 1.5 or 2% CA/PEG remained 3.3.2. In vitro release profile of VNP from SNE controlled porosity intact during the 8 h period of the release test. osmotic pump tablets coated with CA/PEG The fastest release rate was observed for 1% CA/PEG coated The effect of changing the mixture of CA/PEG concentration and CPOPTs either having 1 or 2 drills, where they released the whole the number of drills on VNP release from the prepared controlled VNP content at 8 h. The membrane coating of these tablets was porosity osmotic pump tablets (CPOPTs) was investigated. PEG ruptured during the release study and the tablets disintegrated was used in many studies as a leachable pore-forming material to partially. This explains the complete VNP release within 8 h. Low change the CA membrane permeability (Makhija & Vavia 2003; polymer concentration along with the presence of the water sol- Abd-Elbary et al. 2011). Also, PEG acts as a plasticizer that enhan- uble PEG made the membrane fragile and highly permeable. So, it ces both the flexibility and the mechanical resistance of the mem- was not able to withstand the pressure inside the osmotic tablets brane coating against internal osmotic pressure (Abd-Elbary et al. and ruptured in the dissolution medium releasing the VNP con- 2011; Adibkia et al. 2014). tents faster than other osmotic tablets under study in this group. PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 905

Figure 3. In vitro release profiles for VNP core tablets coated with (2%, 1.5%, and 1%) asymmetric (CA/PEG) membrane by fixed number of dipping and either having 1 or 2 drills in 0.1 N HCl for 2 h followed by changing media to pH 6.8 phosphate buffer till 8 h at 37 ± 0.5 C.

Figure 4. In vitro release profiles for VNP core tablets coated with (2%, 1.5%, and 1%) asymmetric OpadryVR CA membrane by fixed number of dipping and either having 1 or 2 drills in 0.1 N HCl for 2 h followed by changing media to pH 6.8 phosphate buffer till 8 h at 37 ± 0.5 C.

From the previous results, it is clear that more VNP was permeate inside the tablet and thus lower the dissolution rate of released from CPOP than CA coated tablets. During dissolution, the tablet core components which consequently reduces drug water is imbibed by the core from the dissolution medium across release rate from osmotic tablets. These results are similar to membrane. However, although both are asymmetric membranes, those obtained by Abd-Elbary et al. (2011), where the CPOPT the pores formed in the membrane gradually following dissolution coated with solution of higher CA concentration showed more of PEG generated a more porous membrane that helps in releas- prolonged drug release rates than the formulae coated with solu- ing VNP out of the core at a higher rate (Verma et al. 2002). tion of lower CA concentrations. There was a non-significant difference (p < .05) between VNP released from SNEOPTs coated with 1% (single drill) and 1.5% (twin drills) OpadryVR CA. 3.3.3. In vitro release profile of VNP from SNEOPTs coated with Decreasing the polymer concentration by 0.5%, which was OpadryVR CA VR expected to increase the rate of VNP release, was nullified by As illustrated in Figure 4, 1.5% and 2% Opadry CA coated tablets decreasing the number of drills. This highlights the importance of with a single drill showed the slowest VNP release; where they the number of drills for OpadryVR CA as compared to the con- released 66.5% and 77.5% VNP, respectively, at 8 h. While 1% trolled porosity CA/PEG coat. VR Opadry CA coated SNEOPTs with twin drills released VNP rapidly The coating of the 1% OpadryVR CA SNEOPTs partially separated compared to other formulations (101.4% at 8 h). As the concentra- from the tablets' core after 3 h, while a rupture was observed after VR tion of Opadry CA increased, VNP release was more controlled. 8 h for the twin drilled 1.5% OpadryVR CA coated tablets. Twin The membrane of higher polymer concentration might represent drilled tablets coated with 2% OpadryVR CA remained intact a more resistant barrier to drug release than the one of lower throughout the whole release study. The behavior of different coat polymer concentration. Increasing the polymer concentration in concentrations in the release media during the test helped in the coat will produce more resistance for the release medium to explaining the differences and similarities in VNP released from 906 S. A. EL-ZAHABY ET AL.

Table 2. Collective squared correlation coefficient (R2) of zero-order, first-order and Higuchi models. R2

Concentration of coating Zero order First order Higuchi diffusion Formula Type of coating material (X1) solution (X2) Number of drills (X3) 1 CA 1% 1 0.917 0.894 0.942 2 2 0.955 0.889 0.972 3 1.50% 1 0.905 0.933 0.962 4 2 0.952 0.944 0.962 5 2% 1 0.882 0.924 0.957 6 2 0.915 0.957 0.981 7 CA/PEG (80:20) 1% 1 0.932 0.971 0.972 8 2 0.868 0.873 0.914 9 1.50% 1 0.981 0.914 0.942 10 2 0.976 0.849 0.952 11 2% 1 0.910 0.947 0.968 12 2 0.963 0.991 0.988 13 OpadryVR CA 1% 1 0.980 0.790 0.933 14 2 0.966 0.945 0.985 15 1.50% 1 0.993 0.970 0.975 16 2 0.989 0.967 0.960 17 2% 1 0.957 0.994 0.993 18 2 0.998 0.982 0.959 2 The model with the highest R value is shown in bold case for each formulation. osmotic tablets. As long as the membrane kept its integrity (2% with the dissolution media makes the drug diffusion through the OpadryVR CA), the VNP release was more controlled. The rupture or created pores the predominant pathway. Similarly, Bi et al. (2007) separation of membranes led to more VNP release. Therefore, the concluded that the drug release from the porous osmotic systems coating membrane composition is crucial to provide the conveni- of theophylline is influenced by micro-environmental osmotic ent quantity of water in the tablet core in the appropriate time and pressure. This pressure is produced by the osmotic agents’ dissol- to assure that the accumulated pressure does not lead to system ution in the water permeating through the membrane and the rupture. Therefore, 1% OpadryVR CA was excluded from further diffusion through the pores produced by the pore formers. consideration. According to Table 2, 6 out of the 18 formulae showed zero-order To investigate the changes in the membrane structure, surface release kinetics. This suggests that the rate of water imbibition of the tablet’s coat (both before and after release studies) was across the coating membrane was perfectly controlled so that a studied using projection microscope. saturated solution of sodium chloride in the tablet core was main- Supplementary Figure S1(A) shows the photograph obtained tained. This would lead to a constant osmotic pressure gradient from projection microscopy of the OpadryVR CA asymmetric tablet’s between the tablet core and the external environment throughout coat before dissolution study revealing the pre-formed pores within the release tests durations (Abd-Elbary et al. 2011). The highest R2 the coat. In Supplementary Figure S1(B), after being in contact with value (0.998) was corresponding to the twin drilled tablets coated V the dissolution medium, the number of pores increased due to the by 2% Opadry R CA but those tablets released the whole VNP con- presence of PEG in the composition of OpadryVR CA, which created tents (98.793%) in 8 h. On the other hand, tablets coated by 1.5% V more pores upon contact with release medium. Many of these Opadry R CA and having a single drill had R2 equal to 0.993 and pores were either enlarged or inter connected to one another dur- VNP release was continued until 24 h (data not shown) which ing the release study. Similar observations were reported by matched the aim of formulating once daily controlled release for- Okimoto et al. (1999) who concluded that the addition of micron- mulation. Based on these results, single drilled tablets coated by V ized lactose as a pore former made the CA membrane surface 1.5% Opadry R CA was selected as the optimum VNP SNEOPT more porous when examined by scanning electron microscopy. In formulation. addition, after dissolution, the exhausted membranes of the single drilled coated tablets were visually observed for any cracks in the 3.3.5. Comparison of the in vitro release profile of the selected V coating. There were no visible cracks in the coating and they were optimum formula and the reference market product (Vinporal R intact after complete release. The integrity of the osmotic system is tablet) important to keep controlling VNP release through the SNEOPT. VNP release from the marketed tablet was complete within the first 30 min of dissolution in acidic medium (pH 1.2) because of its 3.3.4. Modeling of drug release profiles weakly basic nature. Therefore, it was not possible to proceed on Release data of the prepared formulations were fitted to various the following steps of the dissolution experiment where the pH is mathematical models (zero-order, first-order, and Higuchi diffusion changed. This result is in accordance with that found by Ribeiro models) in order to describe the kinetics of drug release. The coef- et al. (2007) where VNP release from the instant release formula ficient of determination (R2) was taken as a criterion for selecting was immediate in the first hour of the dissolution at pH 1.2. Based the most appropriate model. The acceptable fit of the zero-order on this result, the in vitro release of the marketed product was kinetic model to the drug release data indicates that a concentra- made separately in 0.1 N HCl (pH 1.2) and then in phosphate buf- tion independent mechanism is predominant (Barzegar-Jalali et al. fer (pH 6.8). 2008), which is the optimum target of preparing osmotic pump Figure 5 shows a comparison between the in vitro release pro- tablets. files for VNP single drilled tablets coated with 1.5% OpadryVR CA All CA coated tablets followed Higuchi model (Table 2). This which is the selected optimized formulation, and that of the mar- could be explained based on the asymmetric membrane nature keted product in both 0.1 N HCl (pH 1.2) and phosphate buffer used in the study. The produced porous membrane upon contact (pH 6.8). It is obvious that, the marketed product showed rapid PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY 907

Figure 5. Comparison between the in vitro release profiles of VNP from single drilled osmotic tablets coated with 1.5% asymmetric OpadryVR CA membrane and the marketed tablet VinporalVR (in 0.1 N HCl and pH 6.8 phosphate buffer). release in acidic medium (102.258% in 30 min). Based on data in the literature, a sharp decrease in VNP solubility and dissolution at higher pH values was expected. This was clear in the dissolution curve of marketed VNP in phosphate buffer pH 6.8 media where, only 11.741% of drug was released after 8 h. Hence, S-SNEOPT was developed to improve VNP dissolution behavior over a pH range that simulates the fasted GIT. The dissolution profile of the single drilled VNP tablets coated by 1.5% OpadryVR CA clearly indicated a controlled release pattern over 8 h of the experiment, where 77.576% VNP was released. Along with optimized formulation parameters; concentration and type of coat and number of drills that yield zero-order kinetics, the presence of HPMC K4M led to tablet swelling upon contact with the dissolution media and a gel layer was formed on their surfaces. This gel delayed water penetration into the tablet and thus reduced drug release rate. Figure 6. Mean plasma concentration–time curve following the oral administra- VR Still, the extent of drug release was nearly complete at the end of tion of the reference Vinporal tablets and the osmotic tablets of the optimized the dissolution experiment (after 24 h, data not shown). The formulation of VNP. incorporation of VNP into the S-SNEDDS helped in achieving a constant drug release in both media (pH 1.2 and 6.8) because of Table 3. Summary of the pharmacokinetic parameters of VNP following the oral the pH independent solubility and dissolution rate. Also, the dis- administration of VinporalVR tablets and the optimized osmotic tablets. advantage faced with osmotic pump tablets when lipophilic drugs Pharmacokinetic parameter VinporalVR tablet VNP osmotic tablet are formulated and are difficult to be released completely was Cmax (ng/mL) 17.831 ± 8.381 23.862 ± 3.011 a,b resolved. tmax (h) 2.50 0.25 AUC0–t (ng h/mL) 112.525 ± 17.579 130.232 ± 31.256 b AUC0–1 (ng h/mL) 160.314 ± 17.016 378.42 ± 100.033 3.4. In vivo pharmacokinetics study in rabbits MRT (h)a,b 21.28 50.41 aMedian. The pharmacokinetic parameters of VNP following oral administra- bSignificant difference (p < .05). tion of the immediate release VinporalVR tablet as well as the controlled release optimized VNP SNEOPT were evaluated in rabbits. Figure 6 illustrates the mean plasma concentration–time profile of and the enhancement of VNP solubility by incorporation VNP following the administration of the optimum SNEOPT and into S-SNEDDS. The spontaneous formation of VNP loaded nanoe- the marketed product. mulsion in the GI tract presented the drug in a solubilized form Table 3 shows a summary of the pharmacokinetic parameters inside the nanosized oil droplets, which possess large interfacial obtained by non-compartmental fitting of the concentration time surface area for drug absorption (Kang et al. 2004). V data of VNP following the oral administration of Vinporal R and the The significant prolongation (p < .05) of median MRT following optimized VNP SNEOPT. Statistical analysis of the obtained data the administration of VNP osmotic tablets showed evidence for revealed non-significant differences (p > .05) between Cmax and the controlled VNP release achieved by the optimized SNEOPT AUC0–t for the tested formulae. Whereas the AUC0–1 of VNP fol- when compared to the marketed product. This results was also lowing the administration of the osmotic tablets showed signifi- observed by Abd-Elbary et al. ( 2011), where a prolonged MRT cantly higher (p < .05) extent of VNP absorption when compared from 6.62 to 12.12 h was achieved by the etodolac CPOP tablets to the marketed product VinporalVR . compared to NapilacVR capsules. Significantly lower median tmax (p < .05) observed for the The relative bioavailability was found to be 236.048% for the osmotic tablet was due to the high initial drug release achieved tested VNP osmotic tablet, based on the mean AUC0–1 of the 908 S. A. EL-ZAHABY ET AL.

can be used as a replacement for bioequivalence studies (El-Mahrouk et al. 2014). In Figure 7, the multiple level C linear

plot of the cumulative AUC0–t versus the percent of VNP dissolved at the same time points is illustrated. Good point to point rela- tionship was established. A coefficient of determination of 0.9748 was obtained which indicate a close linear correlation.

4. Conclusions

Osmotic VNP formulation containing the drug in the form of S- SNEDDS was successfully designed to overcome VNP solubility drawback at higher pH values, extend drug release for a longer period of time without the risk of precipitation, and enhance drug bioavailability. In vitro release of the optimized formula was successful in reaching complete VNP release at a zero-order rate Figure 7. Multiple level C linear plot for the optimized formulation of VNP. throughout the release study. The use of asymmetric membrane coating was successful in reaching more complete VNP release tested formula compared to that of the reference standard mar- when compared to dense coating. The presence of pore forming keted product which represents approximately twofold improve- PEG in the coating material had a prevalent effect in enhancing ment. The possible reasons of the lower bioavailability of VNP VNP release when compared to the effect of the number of drills. In vivo from the marketed product were its poor water-solubility, and experiment in rabbits showed approximately twofold extensive metabolism in the liver (Chen et al. 2008). The substan- increase in bioavailability of VNP from the optimum SNEOPT com- tial bioavailability enhancement of VNP from S-SNEDDS in the cur- pared to the marketed conventional VNP tablet. rent study can be attributed to its promotion of lymphatic transport through the transcellular pathway due to the presence Disclosure statement of the oily phase MaisineTM35–1 (Haus et al. 1994). Long-chain oils TM like Maisine 35–1 promote the lipoprotein synthesis, an effect No potential conflict of interest was reported by the authors. similar to the presence of food, that could apparently enhance the bioavailability of VNP (Charman & Stella 1991; Chen et al. ORCID 2008). Additionally, VNP is a highly lipophilic compound so it has Mohamed H. H. AbouGhaly http://orcid.org/0000-0003-3886- good solubility in triglycerides oils. Consequently, the aforemen- 2450 tioned factors might contribute toward absorption via the lymphatic route, minimizing VNP first-pass effect. Moreover, the high content of CremophorVR EL with intermedi- ate HLB value in the composition of S-SNEDDS improves VNP bio- References availability by enhancing drug dissolution (Chen et al. 2008) and increasing intestinal epithelial permeability by disturbing the cell Abd-Elbary A, Tadros MI, Alaa-Eldin AA. 2011. Development and in membrane that facilitated the transcellular absorption (Swenson & vitro/in vivo evaluation of etodolac controlled porosity osmotic Curatolo 1992). In addition, surfactant monomers can form polar pump tablets. AAPS PharmSciTech. 12:485–495. defects in the lipid bilayer by partitioning into the cell membrane. Aburahma MH, El-Laithy HM, Hamza YE-S. 2010. Preparation and The membrane could be dissolved into surfactant–membrane in vitro/in vivo characterization of porous sublingual tablets con- mixed micelles at high surfactant concentrations in the cell mem- taining ternary kneaded solid system of vinpocetine with brane (Swenson & Curatolo 1992; Kommuru et al. 2001). It was b-cyclodextrin and hydroxy acid. Sci Pharm. 78:363–379. also reported that CremophorVR EL can reversibly open the tight Adibkia K, Ghanbarzadeh S, Shokri MH, Arami Z, Arash Z, Shokri J. junctions in the intestinal wall leading to paracellular transport 2014. Micro-porous surfaces in controlled drug delivery systems: (Lindmark et al. 1995). Additionally, it was reported that it has an design and evaluation of diltiazem hydrochloride controlled effect in decreasing p-glycoprotein drug efflux (Nerurkar et al. porosity osmotic pump using non-ionic surfactants as pore-for- 1996). The S-SNEDDS contains also the absorption enhancer, mer. Pharm Dev Technol. 19:507–512. TranscutolVR HP, which may as well have contributed to the Am Ende MT, Miller LA. 2007. Mechanistic investigation of drug achieved enhancement in VNP bioavailability (Cui et al. 2005). release from asymmetric membrane tablets: effect of media It was also reported that the SNEDDS can modify hydrogen gradients (osmotic pressure and concentration), and potential bonding and ionic forces between the polar head groups of the coating failures on in vitro release. Pharm Res. 24:288–297. lipid bilayers. Also, SNEDDS can disrupt the membrane lipid-pack- Barzegar-Jalali M, Adibkia K, Valizadeh H, Reza Siahi Shadbad M, ing arrangement by inserting itself between the lipophilic tails of Nokhodchi A, Omidi Y, Mohammadi G, Hallaj Nezhadi S, Hasan the bilayers. Previous caco-2 cells studies indicated that VNP- M. 2008. Kinetic analysis of drug release from nanoparticles. SMEDDS was able to open the intestinal tight junctions as JPPS. 11:167–177. opposed to VNP powder (Chen et al. 2008). 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