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Formulation and evaluation of new oxycodone extended release multiple unit pellet system

Formulation and evaluation of new oxycodone extended release multiple unit pellet system The goal of the present study is to prepare a stable, multiple-unit, extended-release dosage form containing oxycodone pellets coated with aqueous ethylcellulose (EC) dispersion, Surelease E-7-19050. The application of 18% w/w of EC leads to the similar drug release with the hydrophobic, non-swelling, matrix reference product containing 20 mg of oxycodone. Increasing the compression force to 9 kN and including more than 50% w/w of oxycodone pellets into the formulation resulted in faster drug release, indicating the damaging to the EC film coating. The physical appearance of the final formulation, assay of oxycodone, moisture content, and dissolution data over the stability period showed that the multiple-unit pellet system (MUPS) is efficient for the production of highly stable product. Keywords Opioids – Oxycodone - Dissolution – Extended release - Pellets INTRODUCTION Coated pellets are frequently used for oral, controlled-release, most recent and challenging technologies that combine drug delivery. The recent trends indicate that multiparticulate the advantages of both tablets and pellet-filled capsules in drug delivery systems are especially suitable for achieving one dosage form. The multiparticulates spread uniformly controlled- or delayed-release oral formulations with throughout the gastrointestinal tract, resulting in less variable low risk of dose dumping, flexibility of blending to attain bioavailability and a  reduced risk of local irritation. Various different release patterns, as well as reproducible and short drug release profiles can be obtained by simply mixing pellets gastric residence time (Dey et al., 2008). Controlled-release with different release characteristics or incompatible drugs drug delivery systems provide a uniform concentration at can be easily separated (Dashevsky et al., 2004). absorption site, maintain plasma concentration within a Oxycodone hydrochloride is a semisynthetic opioid agonist therapeutic range, reduce the frequency of administration, that provides effective relief for moderate to severe pain in and minimizes the side effects. It is also important to avoid cancer and postoperative patients. The pharmacokinetic and dose dumping after the oral administration of ER dosage steady-state pharmacodynamic studies with immediate- forms, especially for drugs that possess the characteristics of a release (IR) oxycodone have shown it to be well tolerated, higher solubility, higher dose, or a fatal side effect (Uros et al., with adverse effects similar to those of other opioids. The 2014). Furthermore, an alcohol-induced dose dumping effect bioavailability of oral oxycodone in humans is 60% (range: 50– in oral ER dosage forms has gained increased attention in the 87%). The terminal elimination half-life is independent of dose, recent years (Jedinger et al., 2014). with modest interindividual differences (Fukui et al., 2017). Compaction of multiparticulates, commonly called MUPS Ethylcellulose (EC) has been widely used as a barrier (abbreviation for multiple-unit pellet system), is one of the membrane or binder to prepare pharmaceutical, oral, * E-mail: husar.stefan26@gmail.com © European Pharmaceutical Journal OR 4 Eur. Pharm. J. 2019, 66(2), 4-10 Formulation and evaluation of new oxycodone extended release multiple unit pellet system Husár Š. et al. Table 1. Formulation of oxycodone MUPS tablets F1–F3 (weights in mg/tablet) Formulation code Process step Material F1 F2 F3 Oxycodone hydrochloride 20.0 20.0 20.0 Hypromellose (Methocel E5) 1.2 1.2 1.2 Oxycodone drug Polysorbate 80 1.2 1.2 1.2 layered pellets Talc 0.5 0.5 0.5 Sugar spheres with a diameter of 355–425 50.0 50.0 50.0 µm * * * Release modifying 11.7 21.0 30.4 Surelease clear E-7-19050 polymer (7.3 mg EC) (13.1 mg EC) (19.0 mg EC) Microcrystalline cellulose (Comprecel M102) 124.1 137.5 150.8 Compression into Magnesium stearate 2.2 2.4 2.6 MUPS Silica dioxide 1.1 1.2 1.3 MUPS tablet weight in mg 212.0 235.0 258.0 * Surelease clear E-7-19050 contains 62.4% w/w of EC. EC, ethylcellulose. modified-release dosage forms. The aqueous dispersion of to the dispersion and mixed for another 45 min. The required EC, for example, Surelease, has been used to manufacture quantity of Talc was added at the end of oxycodone dispersion modified-release multiparticulates for filling into capsules preparation and mixed for 20 min. Required amount of sugar and single-unit tablets or soft-gel capsules through film- spheres with a  diameter of 355–425 µm was loaded into coating applications. In addition, the use of aqueous EC a  fluidized bed coater Glatt GPCG-2 equipped with a 3.0-L dispersion as a release retardant binder for the manufacture Wurster container, air distribution plate type A, and filter bags of inert matrices has been reported. Surelease enhanced with a porosity of below 20 μm (Glatt GmbH, Germany) and the compaction characteristics of the drug, and the drug preheated to a product temperature of 34–36°C. The layering was released from those inert porous matrices by diffusion conditions were given as follows: batch size, 400 g; inlet air (Rajabi-Siahboomi & Farrell, 2008). temperature, 45°C; product temperature, 33°C; air flow, 120 m /h; nozzle diameter, 1.2 mm; atomizing air pressure, 1.5 bar; MATERIALS AND METHODS spray rate, 5 g/min; final drying at 40°C for 20 min. Materials Coating of drug-layered pellets The materials used in this study were oxycodone hydrochloride The oxycodone drug-layered pellets were coated with aqueous (Saneca Pharmaceuticals, Slovakia), sugar spheres with water dispersion of Surelease E-7-19050 (15% w/w solid a diameter of 355–425 µm (Hanns G. Werner, Germany), talc content) using the fluidized bed coater Glatt GPCG-2 (Glatt (Luzenac, China), hypromellose (HPMC, Methocel E5, Dow GmbH, Germany) and preheated to a  product temperature Chemicals, GB), polysorbate 80 (Centralchem, Slovakia), of 36–48°C. Three different quantities of Surelease E-7-19050 Surelease clear E-7-19050 (Colorcon, USA), microcrystalline were applied onto oxycodone pellets (formulations F1–F3, cellulose (Comprecel M102, Mingtai, China), silica dioxide Table 1). The layering conditions were given as follows: batch (Grace GmbH, GB), and magnesium stearate (Faci SPA, Italia). size, 400 g; inlet air temperature, 50°C; product temperature, 35°C; air flow, 140 m /h; nozzle diameter, 1.2 mm; atomizing METHODS air pressure, 1.5 bar; spray rate, 8 g/min; final drying at 45°C for 30 min. Preparation of opiate pellets Compression of coated pellets The spraying of water dispersion method was chosen to prepare the opioid analgesic pellets. The required quantities The composition of MUPS tablets F1–F3 is presented in Table of hypromellose and polysorbate 80 were dispersed in water, 1. Coated pellets were mixed in a slow speed blender RV1 purified to prepare binding suspension, and mixed until clear (Kovymont, Slovakia) for 15 min at 13 rpm with different solution is achieved. Oxycodone HCl powder was then added amounts of microcrystalline cellulose (Comprecel M102). 5 6 Eur. Pharm. J. 2019, 66(2), 4-10 Formulation and evaluation of new oxycodone extended release multiple unit pellet system Husár Š. et al. Table 2. Formulation of oxycodone MUPS tablets F4–F6 (weights in mg/tablet) Formulation code Process step Material F4 F5 F6 Oxycodone hydrochloride 20.0 20.0 20.0 Hypromellose (Methocel E5) 1.2 1.2 1.2 Oxycodone drug Polysorbate 80 1.2 1.2 1.2 layered pellets Talc 0.5 0.5 0.5 Sugar spheres with a diameter of 355–425 50.0 50.0 50.0 µm * * * Release modifying 21.0 21.0 21.0 Surelease clear E-7-19050 polymer (13.1 mg EC) (13.1 mg EC) (13.1 mg EC) Microcrystalline cellulose 214.4 91.3 38.1 (Comprecel M102) Compression into MUPS Magnesium stearate 3.1 1.9 1.3 Silica dioxide 1.6 0.9 0.7 MUPS tablet weight in mg 313.0 188.0 134.0 Surelease clear E-7-19050 contains 62.4% w/w of EC. EC, ethylcellulose. After that 1.0% of magnesium stearate and 0.5% of silica chambers SC-12 Plus (REMI Laboratory Instruments, India): dioxide were added as a  lubricant/glidant (Table 2) and 25°C/60%, 30°C/65%, and 40°C/75%. After each month, mixed in the slow speed blender RV1 for 5 min at 13 rpm. The dissolution, appearance, assay, and LOD (halogen analyser tablets were compressed on a  rotary tablet press Pressima Mettler Toledo HF63, 10 min at 105°C, 5-g samples of crushed AX8 (IMA Pharma, Italy) with different compression forces; tablets) were performed and evaluated. the composition and tablet weight of formulations F1–F6 RESULTS AND DISCUSSION are presented in Tables 1 and 2. The hardness of tablets was tested using a  hardness tester Sotax Tester 8M (Sotax AG, Switzerland), and the disintegration of 6 MUPS tablets in water Compaction of multiparticulates, commonly called MUPS, is (temperature 35–39°C) was performed using a disintegration one of the most recent and challenging technologies that tester Sotax DT2 (Sotax AG, Switzerland). The friability of 6.5g combine the advantages of both tablets and pellet-filled of MUPS tablets was tested using a Sotax friability tester capsules in one dosage form. Ideally, the compacted pellets (Sotax AG, Switzerland) and evaluated after 100 rotations of should not fuse into a nondisintegrating matrix during the drum. The physical characteristics of MUPS fromulations compression and should disintegrate rapidly into individual F1–F6 are reported in Table 3. pellets in gastrointestinal fluids. Importantly, the drug release should not be affected by the compaction process and the In vitro dissolution study polymer coating must be able to resist to the compression force; it can deform, but it should not rupture (Bhad et al., The drug release from the coated and compressed pellets 2010). Most studies on the compression of pellets with was investigated using a  paddle apparatus Sotax AT7 Smart EC revealed damage to the coating layer with a loss of the (Sotax AG, Switzerland) in 900 mL of 0.1N HCl at 75 rpm at extended-release properties. The mechanical properties of 37 ± 0.5°C, n = 6. Samples were withdrawn at predetermined the particular Surelease E-7-19050 polymer coating were time points (sample volume: 1.5 mL) and measured using determined in order to investigate its suitability for the UV spectrophotometer (Cary 50 UV-VIS spectrophotometer, coating of oxycodone pellets, which are intended to be Agilent technologies) at 230 nm. compressed into tablets. Figure 1 shows drug release profiles of MUPS compressed Tablets bulk stability testing using oxycodone coated pellets with different concentration of retarding agent Surelease E-7-19050: 10% w/w (referring to The final formulation of oxycodone MUPS tablets was set the active oxycodone pellets, see composition in Table 1) of for stability study in double PE bags with a dessicant placed EC (EC, Formulation F1), 18% w/w of EC (F2), and 26% w/w of between them and closed in a nontransparent plastic EC (F3). The formulations F1–F3 were compressed at the same container for 3 months at a relative temperature (RT) and main compression force of 4.5 kN. The dissolution profiles relative humidity (RH) conditions in 3 different stability are compared with the commercially available reference 5 6 Eur. Pharm. J. 2019, 66(2), 4-10 Formulation and evaluation of new oxycodone extended release multiple unit pellet system Husár Š. et al. Table 3. Physical characteristics of oxycodone MUPS tablets F1–F6 Formulation Average weight [mg], Hardness [N], Friability Disintegration [s], code n = 20 n = 10 [25 rpm, 4 min, %], n = 3 n = 6 F1 212.2 ± 2.9 51 ± 5.4 0.51 ± 0.08 31 ± 5.8 F2 235.2 ± 2.7 52 ± 6.3 0.47 ± 0.10 24 ± 7.5 F3 258.8 ± 3.6 54 ± 5.8 0.56 ± 0.06 42 ± 4.2 F4 313.0 ± 2.4 76 ± 5.0 0.50 ± 0.07 35 ± 2.8 F5 188.6 ± 2.2 41 ± 4.2 0.35 ± 0.06 161 ± 12.1 F6 134.7 ± 2.9 43 ± 3.6 0.28 ± 0.04 987 ± 9.9 F4 (3 kN) 313.6 ± 3.8 38 ± 4.1 0.91 ± 0.06 24 ± 1.8 F4 (6 kN) 314.2 ± 2.1 54 ± 3.0 0.65 ± 0.02 124 ± 8.2 F4 (9 kN) 313.4 ± 1.2 78 ± 2.6 0.04 ± 0.01 997 ± 13.4 Figure 1. Influence of Ethyl celullose content on oxycodone drug release from MUPS tablets F1-F3 product, Targin (Mundipharma, Austria), containing 20 mg compression. It has been reported that plastically deforming of oxycodone hydrochloride in a hydrophobic, non-swellable excipients are more effective in protecting the coated pellets matrix tablets. As it can be seen, the release decreased with during compression; therefore, the microcrystalline cellulose increasing EC content and the similar dissolution profile (Comprecel M102) was selected to provide a better protective (similarity factor f2 = 84) was achieved with formulation F2 effect to the oxycodone-coated pellets. Figure 2 shows that containing 18% w/w of EC (Surelease E-7-19050). Following increasing the protective excipient to 70% w/w (30% pellet this observation, the effect of filler/pellet content was further content, formulation F4) minimized the damage to the investigated with this concentration of EC. compressed drug pellets, with the f2 between compressed Three formulations, F4, F5, and F6 (containing 18% w/w of and uncompressed pellets being 61. Values for f2 (similarity EC, see composition in Table 2), were prepared with different factor) between 50 and 100 indicate that the two profiles are oxycodone pellet content, 30%, 50% and 70% w/w, mixed similar (Vetchý et al., 2014). Compressing coated pellets with with extragranular excipients and compressed at the same 30% of protective excipient (formulation F6) resulted in the main compression force of 4.5 kN. The oxycodone release loss of their extended-release properties. This is explained from compressed pellets was significantly faster compared by the lower yield pressure of the MCC filler that absorbs with that from the original pellets coated with 18% of EC the energy of compaction and preferentially deforms under as shown in Figure 2. This could be explained by the weak pressure, thus protecting the pellets. A higher level of the mechanical properties of EC films, which ruptured during cushioning excipient also reduces the number of oxycodone 7 8 Eur. Pharm. J. 2019, 66(2), 4-10 Formulation and evaluation of new oxycodone extended release multiple unit pellet system Husár Š. et al. Figure 2. Influence of proportion of coated pellets on oxycodone drug release from MUPS tablets F4-F6 Figure 3. Influence of compression force on oxycodone drug release from MUPS tablets containing 30% w/w proportion of coated pellets pellets coming in direct contact with each other or with the a compression force of 3 and 6 kN were 71 and 62, respectively, punch surface during the compression cycle, which can cause compared with the matrix reference tablets, Targin. Increasing pellets to rupture (Al-Hashimi et al., 2018). the tablet compression force to 9 kN leads to MUPS tablets of Figure 3 shows drug release profile of MUPS compressed greater strength; however, an increase in tablet disintegration at different compression forces using 30% w/w oxycodone time to more than 15 min was also observed (Table 3). Higher pellets content in the formulation. Increasing compression disintegration time could be attributed to a lower penetration force resulted in faster drug release, indicating the damaging of the disintegration test media into the tablet because of the to the EC film coating. The f2 values for tablets compressed at creation of undesirable matrix structure. 7 8 Eur. Pharm. J. 2019, 66(2), 4-10 Formulation and evaluation of new oxycodone extended release multiple unit pellet system Husár Š. et al. Table 4. Stability data* of oxycodone MUPS tablets at different time intervals in three different conditions (formulation F4) 25°C/60% RH 30°C/65% RH 40°C/75% RH Parameters Initial 1M 2M 3M 1M 2M 3M 1M 2M 3M Assay % 98.7 98.4 98.0 97.7 98.2 98.4 98.0 97.4 97.0 97.2 Appearance (white to off- Slightly Comply Comply Comply Comply Comply Comply Comply Comply Comply white, round, yellowish biconvex tablets) Loss on drying % 2.8 3.5 3.8 3.8 3.8 3.8 3.9 4.0 4.2 4.4 Q8 85.91 84.24 84.65 82.17 82.01 82.53 79.85 83.08 81.24 78.66 t 2.14 1.98 2.02 1.89 2.01 2.14 1.80 1.99 1.96 1.78 50% t 6.30 6.14 6.28 6.02 6.24 6.34 5.98 6.27 6.24 5.90 80% r 0.995 0.990 0.997 0.989 0.991 0.994 0.994 0.984 0.986 0.994 k 2.362 2.512 2.378 2.156 2.318 2.305 2.224 1.214 1.105 1.064 n 0.656 0.641 0.652 0.671 0.661 0.663 0.658 0.726 0.741 0.735 Q indicates percentage of oxycodone drug release at 8 h; t , time required for 50% drug release; t , time required for 80% drug 8 50% 80% release; r , correlation coefficient; k, release rate constant; n, diffusion exponent; M, month. MUPS tablets of the formulation F4 (18% EC, 30% oxycodone To study release kinetics, a graph is plotted between log pellets content) compressed at 6 kN were set for the stability cummulative percentage of drug release (log (Qt /Q∞)) versus for 3 months in three different stability chambers. The log time (log t). appearance of MUPS tablets were found to be unchanged CONCLUSION even at the end of 3 months in all stability conditions except 40°C/75%RH, where the color of tablets becomes slightly yellowish, which is negligible. The color change might be Oxycodone pellets coated with aqueous EC dispersion related to the excipients, as after 3 months at 40°C/75%RH, (Surelease E-7-19050) were incorporated into a multiple- the assay of oxycodone was found 97.2%, which is close unit pellet system providing consistent drug release profiles. to the initial value (Table 4). The LOD value was increased Inclusion of 70% cushioning plastically deforming excipient slightly from its initial value in all stability conditions (Table microcrystalline cellulose (Comprecel M102) into the MUPS 4). No significant change in the assay of oxycodone was tablets and application of compression force between 3 observed from the storage conditions ( Table 4), which reflects and 6 kN resulted in similar dissolution of active substance that the formulated MUPS tablets are stable. In each month, in comparison with reference matrix tablets. The physical the dissolution of oxycodone MUPS tablets was performed and chemical parameters of the oxycodone MUPS tablets for the samples stored in three different conditions. The t , were found consistent over the stability period. The results 50% t , Q , release rate constant (k), and diffusion exponent ( n) generated in this study showed that the selected excipients 80% 8 at different time intervals showed no major difference over and manufacturing process is suitable to design a new, stable, the stability period (Table 4). The calculation was performed oxycodone, MUPS, extended-release formulation. based on the following equations: ACKNOWLEDGMENT 1/n t = (0.5/k) 50% 1/n t = (0.8/k) The study was supported by the Ministry of Education, 80% Science, Research and Sport of the Slovak Republic within where k  is the release rate constant and n is the diffusion project No. Req-00357-0001 „Research and development of exponent. The values of k and n were determined graphically active pharmaceuticals ingredients by stereoselective processes from the following equation (Siepmann & Peppas, 2001): including development of finished dosage forms .“ Qt /Q = k.tn where Qt /Q is the fraction of drug released at time t, log (Qt /Q∞) = log k + n.log t. 9 10 Eur. Pharm. J. 2019, 66(2), 4-10 Formulation and evaluation of new oxycodone extended release multiple unit pellet system Husár Š. et al. References [1] Dey NS, Majumdar S, Rao MEB. Multiparticulate drug delivery systems for controlled release. Trop J Pharm Res. 2008; 7: 1067- [2] Uros K, Sasa B, Igor L et al. Determining the polymer threshold amount for achieving robust drug release from HPMC and HPC matrix tablets containing a high dose BCS class 1 model drug: in vitro and in vivo studies. AAPS PharmSciTech. 2014; 16: 398-406. [3] Jedinger N, Khinast J, Roblegg E et al. The design of controlled release formulations resistant to alcohol induced dose dumping-a review. Eur J Pharm Biopharm. 2014; 87: 217-226. [4] Dashevsky A, Koller K, Bodmeier R. Compression of pellets coated with various aqueous polymer dispersions. Int J Pharm. 2004; 279: 19-26. [5] Fukui S, Yano H, Yada S, Mikkaichi T, Minami H. Design and evaluation of an extended release matrix tablet formulation, the combination of Hypromellose acetate succinate and hydroxypropylcellulose. Asian J Pharm Sci. 2017; 12: 149-156. [6] Rajabi SAR, Farrel TP. Aqueous polymeric coatings for pharmaceutical dosage forms. Eds McGinity J.W. and Feton LA; [7] Bhad ME, Abdul S, Jaiswal SB, Chandewar AV, Jain JM, Sakarkar M. Int J PharmTechRes. 2010; 2: 847-855. [8] Vetchý D, Kopecká M, Vetchá M, Franc A. Modely in vitro-in vivo vo vývoji liečiv. Chem Listy. 2014; 108: 32-39. [9] Al-Hashimi N, Begg N, Alany RG, Hassanin H, Elshaer A. Oral modified release multiple unit particulate systems: Compressed pellets, microparticles and nanoparticles. Pharmaceutics. 2018; 10 (1-23). [10] Siepmann J., Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Delivery Rev. 2001; 48: 139-157. 9 10 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Facultatis Pharmaceuticae Universitatis Comenianae de Gruyter

Formulation and evaluation of new oxycodone extended release multiple unit pellet system

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de Gruyter
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© 2019 Š. Husár et al., published by Sciendo
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1338-6786
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2453-6725
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10.2478/afpuc-2019-0019
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Abstract

The goal of the present study is to prepare a stable, multiple-unit, extended-release dosage form containing oxycodone pellets coated with aqueous ethylcellulose (EC) dispersion, Surelease E-7-19050. The application of 18% w/w of EC leads to the similar drug release with the hydrophobic, non-swelling, matrix reference product containing 20 mg of oxycodone. Increasing the compression force to 9 kN and including more than 50% w/w of oxycodone pellets into the formulation resulted in faster drug release, indicating the damaging to the EC film coating. The physical appearance of the final formulation, assay of oxycodone, moisture content, and dissolution data over the stability period showed that the multiple-unit pellet system (MUPS) is efficient for the production of highly stable product. Keywords Opioids – Oxycodone - Dissolution – Extended release - Pellets INTRODUCTION Coated pellets are frequently used for oral, controlled-release, most recent and challenging technologies that combine drug delivery. The recent trends indicate that multiparticulate the advantages of both tablets and pellet-filled capsules in drug delivery systems are especially suitable for achieving one dosage form. The multiparticulates spread uniformly controlled- or delayed-release oral formulations with throughout the gastrointestinal tract, resulting in less variable low risk of dose dumping, flexibility of blending to attain bioavailability and a  reduced risk of local irritation. Various different release patterns, as well as reproducible and short drug release profiles can be obtained by simply mixing pellets gastric residence time (Dey et al., 2008). Controlled-release with different release characteristics or incompatible drugs drug delivery systems provide a uniform concentration at can be easily separated (Dashevsky et al., 2004). absorption site, maintain plasma concentration within a Oxycodone hydrochloride is a semisynthetic opioid agonist therapeutic range, reduce the frequency of administration, that provides effective relief for moderate to severe pain in and minimizes the side effects. It is also important to avoid cancer and postoperative patients. The pharmacokinetic and dose dumping after the oral administration of ER dosage steady-state pharmacodynamic studies with immediate- forms, especially for drugs that possess the characteristics of a release (IR) oxycodone have shown it to be well tolerated, higher solubility, higher dose, or a fatal side effect (Uros et al., with adverse effects similar to those of other opioids. The 2014). Furthermore, an alcohol-induced dose dumping effect bioavailability of oral oxycodone in humans is 60% (range: 50– in oral ER dosage forms has gained increased attention in the 87%). The terminal elimination half-life is independent of dose, recent years (Jedinger et al., 2014). with modest interindividual differences (Fukui et al., 2017). Compaction of multiparticulates, commonly called MUPS Ethylcellulose (EC) has been widely used as a barrier (abbreviation for multiple-unit pellet system), is one of the membrane or binder to prepare pharmaceutical, oral, * E-mail: husar.stefan26@gmail.com © European Pharmaceutical Journal OR 4 Eur. Pharm. J. 2019, 66(2), 4-10 Formulation and evaluation of new oxycodone extended release multiple unit pellet system Husár Š. et al. Table 1. Formulation of oxycodone MUPS tablets F1–F3 (weights in mg/tablet) Formulation code Process step Material F1 F2 F3 Oxycodone hydrochloride 20.0 20.0 20.0 Hypromellose (Methocel E5) 1.2 1.2 1.2 Oxycodone drug Polysorbate 80 1.2 1.2 1.2 layered pellets Talc 0.5 0.5 0.5 Sugar spheres with a diameter of 355–425 50.0 50.0 50.0 µm * * * Release modifying 11.7 21.0 30.4 Surelease clear E-7-19050 polymer (7.3 mg EC) (13.1 mg EC) (19.0 mg EC) Microcrystalline cellulose (Comprecel M102) 124.1 137.5 150.8 Compression into Magnesium stearate 2.2 2.4 2.6 MUPS Silica dioxide 1.1 1.2 1.3 MUPS tablet weight in mg 212.0 235.0 258.0 * Surelease clear E-7-19050 contains 62.4% w/w of EC. EC, ethylcellulose. modified-release dosage forms. The aqueous dispersion of to the dispersion and mixed for another 45 min. The required EC, for example, Surelease, has been used to manufacture quantity of Talc was added at the end of oxycodone dispersion modified-release multiparticulates for filling into capsules preparation and mixed for 20 min. Required amount of sugar and single-unit tablets or soft-gel capsules through film- spheres with a  diameter of 355–425 µm was loaded into coating applications. In addition, the use of aqueous EC a  fluidized bed coater Glatt GPCG-2 equipped with a 3.0-L dispersion as a release retardant binder for the manufacture Wurster container, air distribution plate type A, and filter bags of inert matrices has been reported. Surelease enhanced with a porosity of below 20 μm (Glatt GmbH, Germany) and the compaction characteristics of the drug, and the drug preheated to a product temperature of 34–36°C. The layering was released from those inert porous matrices by diffusion conditions were given as follows: batch size, 400 g; inlet air (Rajabi-Siahboomi & Farrell, 2008). temperature, 45°C; product temperature, 33°C; air flow, 120 m /h; nozzle diameter, 1.2 mm; atomizing air pressure, 1.5 bar; MATERIALS AND METHODS spray rate, 5 g/min; final drying at 40°C for 20 min. Materials Coating of drug-layered pellets The materials used in this study were oxycodone hydrochloride The oxycodone drug-layered pellets were coated with aqueous (Saneca Pharmaceuticals, Slovakia), sugar spheres with water dispersion of Surelease E-7-19050 (15% w/w solid a diameter of 355–425 µm (Hanns G. Werner, Germany), talc content) using the fluidized bed coater Glatt GPCG-2 (Glatt (Luzenac, China), hypromellose (HPMC, Methocel E5, Dow GmbH, Germany) and preheated to a  product temperature Chemicals, GB), polysorbate 80 (Centralchem, Slovakia), of 36–48°C. Three different quantities of Surelease E-7-19050 Surelease clear E-7-19050 (Colorcon, USA), microcrystalline were applied onto oxycodone pellets (formulations F1–F3, cellulose (Comprecel M102, Mingtai, China), silica dioxide Table 1). The layering conditions were given as follows: batch (Grace GmbH, GB), and magnesium stearate (Faci SPA, Italia). size, 400 g; inlet air temperature, 50°C; product temperature, 35°C; air flow, 140 m /h; nozzle diameter, 1.2 mm; atomizing METHODS air pressure, 1.5 bar; spray rate, 8 g/min; final drying at 45°C for 30 min. Preparation of opiate pellets Compression of coated pellets The spraying of water dispersion method was chosen to prepare the opioid analgesic pellets. The required quantities The composition of MUPS tablets F1–F3 is presented in Table of hypromellose and polysorbate 80 were dispersed in water, 1. Coated pellets were mixed in a slow speed blender RV1 purified to prepare binding suspension, and mixed until clear (Kovymont, Slovakia) for 15 min at 13 rpm with different solution is achieved. Oxycodone HCl powder was then added amounts of microcrystalline cellulose (Comprecel M102). 5 6 Eur. Pharm. J. 2019, 66(2), 4-10 Formulation and evaluation of new oxycodone extended release multiple unit pellet system Husár Š. et al. Table 2. Formulation of oxycodone MUPS tablets F4–F6 (weights in mg/tablet) Formulation code Process step Material F4 F5 F6 Oxycodone hydrochloride 20.0 20.0 20.0 Hypromellose (Methocel E5) 1.2 1.2 1.2 Oxycodone drug Polysorbate 80 1.2 1.2 1.2 layered pellets Talc 0.5 0.5 0.5 Sugar spheres with a diameter of 355–425 50.0 50.0 50.0 µm * * * Release modifying 21.0 21.0 21.0 Surelease clear E-7-19050 polymer (13.1 mg EC) (13.1 mg EC) (13.1 mg EC) Microcrystalline cellulose 214.4 91.3 38.1 (Comprecel M102) Compression into MUPS Magnesium stearate 3.1 1.9 1.3 Silica dioxide 1.6 0.9 0.7 MUPS tablet weight in mg 313.0 188.0 134.0 Surelease clear E-7-19050 contains 62.4% w/w of EC. EC, ethylcellulose. After that 1.0% of magnesium stearate and 0.5% of silica chambers SC-12 Plus (REMI Laboratory Instruments, India): dioxide were added as a  lubricant/glidant (Table 2) and 25°C/60%, 30°C/65%, and 40°C/75%. After each month, mixed in the slow speed blender RV1 for 5 min at 13 rpm. The dissolution, appearance, assay, and LOD (halogen analyser tablets were compressed on a  rotary tablet press Pressima Mettler Toledo HF63, 10 min at 105°C, 5-g samples of crushed AX8 (IMA Pharma, Italy) with different compression forces; tablets) were performed and evaluated. the composition and tablet weight of formulations F1–F6 RESULTS AND DISCUSSION are presented in Tables 1 and 2. The hardness of tablets was tested using a  hardness tester Sotax Tester 8M (Sotax AG, Switzerland), and the disintegration of 6 MUPS tablets in water Compaction of multiparticulates, commonly called MUPS, is (temperature 35–39°C) was performed using a disintegration one of the most recent and challenging technologies that tester Sotax DT2 (Sotax AG, Switzerland). The friability of 6.5g combine the advantages of both tablets and pellet-filled of MUPS tablets was tested using a Sotax friability tester capsules in one dosage form. Ideally, the compacted pellets (Sotax AG, Switzerland) and evaluated after 100 rotations of should not fuse into a nondisintegrating matrix during the drum. The physical characteristics of MUPS fromulations compression and should disintegrate rapidly into individual F1–F6 are reported in Table 3. pellets in gastrointestinal fluids. Importantly, the drug release should not be affected by the compaction process and the In vitro dissolution study polymer coating must be able to resist to the compression force; it can deform, but it should not rupture (Bhad et al., The drug release from the coated and compressed pellets 2010). Most studies on the compression of pellets with was investigated using a  paddle apparatus Sotax AT7 Smart EC revealed damage to the coating layer with a loss of the (Sotax AG, Switzerland) in 900 mL of 0.1N HCl at 75 rpm at extended-release properties. The mechanical properties of 37 ± 0.5°C, n = 6. Samples were withdrawn at predetermined the particular Surelease E-7-19050 polymer coating were time points (sample volume: 1.5 mL) and measured using determined in order to investigate its suitability for the UV spectrophotometer (Cary 50 UV-VIS spectrophotometer, coating of oxycodone pellets, which are intended to be Agilent technologies) at 230 nm. compressed into tablets. Figure 1 shows drug release profiles of MUPS compressed Tablets bulk stability testing using oxycodone coated pellets with different concentration of retarding agent Surelease E-7-19050: 10% w/w (referring to The final formulation of oxycodone MUPS tablets was set the active oxycodone pellets, see composition in Table 1) of for stability study in double PE bags with a dessicant placed EC (EC, Formulation F1), 18% w/w of EC (F2), and 26% w/w of between them and closed in a nontransparent plastic EC (F3). The formulations F1–F3 were compressed at the same container for 3 months at a relative temperature (RT) and main compression force of 4.5 kN. The dissolution profiles relative humidity (RH) conditions in 3 different stability are compared with the commercially available reference 5 6 Eur. Pharm. J. 2019, 66(2), 4-10 Formulation and evaluation of new oxycodone extended release multiple unit pellet system Husár Š. et al. Table 3. Physical characteristics of oxycodone MUPS tablets F1–F6 Formulation Average weight [mg], Hardness [N], Friability Disintegration [s], code n = 20 n = 10 [25 rpm, 4 min, %], n = 3 n = 6 F1 212.2 ± 2.9 51 ± 5.4 0.51 ± 0.08 31 ± 5.8 F2 235.2 ± 2.7 52 ± 6.3 0.47 ± 0.10 24 ± 7.5 F3 258.8 ± 3.6 54 ± 5.8 0.56 ± 0.06 42 ± 4.2 F4 313.0 ± 2.4 76 ± 5.0 0.50 ± 0.07 35 ± 2.8 F5 188.6 ± 2.2 41 ± 4.2 0.35 ± 0.06 161 ± 12.1 F6 134.7 ± 2.9 43 ± 3.6 0.28 ± 0.04 987 ± 9.9 F4 (3 kN) 313.6 ± 3.8 38 ± 4.1 0.91 ± 0.06 24 ± 1.8 F4 (6 kN) 314.2 ± 2.1 54 ± 3.0 0.65 ± 0.02 124 ± 8.2 F4 (9 kN) 313.4 ± 1.2 78 ± 2.6 0.04 ± 0.01 997 ± 13.4 Figure 1. Influence of Ethyl celullose content on oxycodone drug release from MUPS tablets F1-F3 product, Targin (Mundipharma, Austria), containing 20 mg compression. It has been reported that plastically deforming of oxycodone hydrochloride in a hydrophobic, non-swellable excipients are more effective in protecting the coated pellets matrix tablets. As it can be seen, the release decreased with during compression; therefore, the microcrystalline cellulose increasing EC content and the similar dissolution profile (Comprecel M102) was selected to provide a better protective (similarity factor f2 = 84) was achieved with formulation F2 effect to the oxycodone-coated pellets. Figure 2 shows that containing 18% w/w of EC (Surelease E-7-19050). Following increasing the protective excipient to 70% w/w (30% pellet this observation, the effect of filler/pellet content was further content, formulation F4) minimized the damage to the investigated with this concentration of EC. compressed drug pellets, with the f2 between compressed Three formulations, F4, F5, and F6 (containing 18% w/w of and uncompressed pellets being 61. Values for f2 (similarity EC, see composition in Table 2), were prepared with different factor) between 50 and 100 indicate that the two profiles are oxycodone pellet content, 30%, 50% and 70% w/w, mixed similar (Vetchý et al., 2014). Compressing coated pellets with with extragranular excipients and compressed at the same 30% of protective excipient (formulation F6) resulted in the main compression force of 4.5 kN. The oxycodone release loss of their extended-release properties. This is explained from compressed pellets was significantly faster compared by the lower yield pressure of the MCC filler that absorbs with that from the original pellets coated with 18% of EC the energy of compaction and preferentially deforms under as shown in Figure 2. This could be explained by the weak pressure, thus protecting the pellets. A higher level of the mechanical properties of EC films, which ruptured during cushioning excipient also reduces the number of oxycodone 7 8 Eur. Pharm. J. 2019, 66(2), 4-10 Formulation and evaluation of new oxycodone extended release multiple unit pellet system Husár Š. et al. Figure 2. Influence of proportion of coated pellets on oxycodone drug release from MUPS tablets F4-F6 Figure 3. Influence of compression force on oxycodone drug release from MUPS tablets containing 30% w/w proportion of coated pellets pellets coming in direct contact with each other or with the a compression force of 3 and 6 kN were 71 and 62, respectively, punch surface during the compression cycle, which can cause compared with the matrix reference tablets, Targin. Increasing pellets to rupture (Al-Hashimi et al., 2018). the tablet compression force to 9 kN leads to MUPS tablets of Figure 3 shows drug release profile of MUPS compressed greater strength; however, an increase in tablet disintegration at different compression forces using 30% w/w oxycodone time to more than 15 min was also observed (Table 3). Higher pellets content in the formulation. Increasing compression disintegration time could be attributed to a lower penetration force resulted in faster drug release, indicating the damaging of the disintegration test media into the tablet because of the to the EC film coating. The f2 values for tablets compressed at creation of undesirable matrix structure. 7 8 Eur. Pharm. J. 2019, 66(2), 4-10 Formulation and evaluation of new oxycodone extended release multiple unit pellet system Husár Š. et al. Table 4. Stability data* of oxycodone MUPS tablets at different time intervals in three different conditions (formulation F4) 25°C/60% RH 30°C/65% RH 40°C/75% RH Parameters Initial 1M 2M 3M 1M 2M 3M 1M 2M 3M Assay % 98.7 98.4 98.0 97.7 98.2 98.4 98.0 97.4 97.0 97.2 Appearance (white to off- Slightly Comply Comply Comply Comply Comply Comply Comply Comply Comply white, round, yellowish biconvex tablets) Loss on drying % 2.8 3.5 3.8 3.8 3.8 3.8 3.9 4.0 4.2 4.4 Q8 85.91 84.24 84.65 82.17 82.01 82.53 79.85 83.08 81.24 78.66 t 2.14 1.98 2.02 1.89 2.01 2.14 1.80 1.99 1.96 1.78 50% t 6.30 6.14 6.28 6.02 6.24 6.34 5.98 6.27 6.24 5.90 80% r 0.995 0.990 0.997 0.989 0.991 0.994 0.994 0.984 0.986 0.994 k 2.362 2.512 2.378 2.156 2.318 2.305 2.224 1.214 1.105 1.064 n 0.656 0.641 0.652 0.671 0.661 0.663 0.658 0.726 0.741 0.735 Q indicates percentage of oxycodone drug release at 8 h; t , time required for 50% drug release; t , time required for 80% drug 8 50% 80% release; r , correlation coefficient; k, release rate constant; n, diffusion exponent; M, month. MUPS tablets of the formulation F4 (18% EC, 30% oxycodone To study release kinetics, a graph is plotted between log pellets content) compressed at 6 kN were set for the stability cummulative percentage of drug release (log (Qt /Q∞)) versus for 3 months in three different stability chambers. The log time (log t). appearance of MUPS tablets were found to be unchanged CONCLUSION even at the end of 3 months in all stability conditions except 40°C/75%RH, where the color of tablets becomes slightly yellowish, which is negligible. The color change might be Oxycodone pellets coated with aqueous EC dispersion related to the excipients, as after 3 months at 40°C/75%RH, (Surelease E-7-19050) were incorporated into a multiple- the assay of oxycodone was found 97.2%, which is close unit pellet system providing consistent drug release profiles. to the initial value (Table 4). The LOD value was increased Inclusion of 70% cushioning plastically deforming excipient slightly from its initial value in all stability conditions (Table microcrystalline cellulose (Comprecel M102) into the MUPS 4). No significant change in the assay of oxycodone was tablets and application of compression force between 3 observed from the storage conditions ( Table 4), which reflects and 6 kN resulted in similar dissolution of active substance that the formulated MUPS tablets are stable. In each month, in comparison with reference matrix tablets. The physical the dissolution of oxycodone MUPS tablets was performed and chemical parameters of the oxycodone MUPS tablets for the samples stored in three different conditions. The t , were found consistent over the stability period. The results 50% t , Q , release rate constant (k), and diffusion exponent ( n) generated in this study showed that the selected excipients 80% 8 at different time intervals showed no major difference over and manufacturing process is suitable to design a new, stable, the stability period (Table 4). The calculation was performed oxycodone, MUPS, extended-release formulation. based on the following equations: ACKNOWLEDGMENT 1/n t = (0.5/k) 50% 1/n t = (0.8/k) The study was supported by the Ministry of Education, 80% Science, Research and Sport of the Slovak Republic within where k  is the release rate constant and n is the diffusion project No. Req-00357-0001 „Research and development of exponent. The values of k and n were determined graphically active pharmaceuticals ingredients by stereoselective processes from the following equation (Siepmann & Peppas, 2001): including development of finished dosage forms .“ Qt /Q = k.tn where Qt /Q is the fraction of drug released at time t, log (Qt /Q∞) = log k + n.log t. 9 10 Eur. Pharm. J. 2019, 66(2), 4-10 Formulation and evaluation of new oxycodone extended release multiple unit pellet system Husár Š. et al. References [1] Dey NS, Majumdar S, Rao MEB. Multiparticulate drug delivery systems for controlled release. Trop J Pharm Res. 2008; 7: 1067- [2] Uros K, Sasa B, Igor L et al. Determining the polymer threshold amount for achieving robust drug release from HPMC and HPC matrix tablets containing a high dose BCS class 1 model drug: in vitro and in vivo studies. AAPS PharmSciTech. 2014; 16: 398-406. [3] Jedinger N, Khinast J, Roblegg E et al. The design of controlled release formulations resistant to alcohol induced dose dumping-a review. Eur J Pharm Biopharm. 2014; 87: 217-226. [4] Dashevsky A, Koller K, Bodmeier R. Compression of pellets coated with various aqueous polymer dispersions. Int J Pharm. 2004; 279: 19-26. [5] Fukui S, Yano H, Yada S, Mikkaichi T, Minami H. Design and evaluation of an extended release matrix tablet formulation, the combination of Hypromellose acetate succinate and hydroxypropylcellulose. Asian J Pharm Sci. 2017; 12: 149-156. [6] Rajabi SAR, Farrel TP. Aqueous polymeric coatings for pharmaceutical dosage forms. Eds McGinity J.W. and Feton LA; [7] Bhad ME, Abdul S, Jaiswal SB, Chandewar AV, Jain JM, Sakarkar M. Int J PharmTechRes. 2010; 2: 847-855. [8] Vetchý D, Kopecká M, Vetchá M, Franc A. Modely in vitro-in vivo vo vývoji liečiv. Chem Listy. 2014; 108: 32-39. [9] Al-Hashimi N, Begg N, Alany RG, Hassanin H, Elshaer A. Oral modified release multiple unit particulate systems: Compressed pellets, microparticles and nanoparticles. Pharmaceutics. 2018; 10 (1-23). [10] Siepmann J., Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Delivery Rev. 2001; 48: 139-157. 9 10

Journal

Acta Facultatis Pharmaceuticae Universitatis Comenianaede Gruyter

Published: Nov 1, 2019

Keywords: Opioids; Oxycodone; Dissolution; Extended release; Pellets

References