Development of hot-melt extrusion as a novel technique for the ...

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CHAPTER 8: SUSTAINED RELEASE HYDROCORTISONE TABLETSPROCESSED BY HOT-MELT EXTRUSION (HME)1.0 IntroductionAs noted previously, hot-melt extrusion (HME) has been developed as a novel techniquefor the formulation of oral solid dosage forms in pharmaceutical industries in recent years[1] . A wide variety of downstream processing equipment allows the manufacture of varioussolid dosage forms including pellets, granules, tablets, capsules and films with differentpharmaceutical applications. These solid dosage forms can provide sustained, modified ortargeted release by controlling both formulation and processing parameters. Despite the factthat initial research developments have focused on the effects of formulation and processingvariables on the properties of final dosage forms, [2-5] more recent investigations have focusedon the use of HME as a novel manufacturing technology of solid molecular dispersionsthrough to the development of sustained release formulations as well as paediatricformulations [6,7] . Early studies through HME processing have described the preparation ofmatrix mini-tablets which was followed by further investigations into the properties ofsustained release mini-matrices manufactured from ethyl cellulose, HPMC and ibuprofen[8,9] . Extruded mini tablets showed minimized risk of dose dumping and reduced inter- andintra-subject variability. Very recently, vegetable calcium stearate (CaSt) was reported to beused in the development of retarded release pellets using as a thermoplastic excipientprocessed through HME, where pellets with a paracetamol loading of 20% released only11.54% of the drug after 8 hours due to the significant densification of the pellets. Asexpected, the drug release was influenced by the pellet size and the drug loading [10] . Amicrobicide intravaginal ring (IVRs) IVR was prepared and developed from polyetherurethane (PU) elastomers for the sustained delivery of UC781 (a highly potent non-nucleosidereverse transcriptase inhibitor of HIV-1). PU IVRs containing UC781 were fabricated using ahot-melt extrusion process [11] .Chrono-pharmaceutical dosage forms are designed to release the drug at the desired timeand improve therapeutic efficacy and patient compliance. Time-release formulations could bea useful tool in effecting chrono-pharmacotherapy because their unique drug release propertiescould take advantage of circadian rhythms in physiologic and pathologic functions. HMEtechnique could be applied as a robust tool to formulate sustained release formulations[12, 13] . Cortisol is normally produced by the adrenal glands which regulated by the brain‘shypothalamus and the pituitary gland. The hypothalamus sends "releasing hormones" to thepituitary gland which responds by secreting other hormones that regulate growth, thyroid,151 | P a g e
testosterone and adrenal function. One of the pituitary gland's main functions is to secreteACTH (adrenocorticotropin), a hormone that stimulates the adrenal glands. When the adrenalsreceive the pituitary‘s signal in the form of ACTH, they respond by producing cortisol.Completing the cycle, cortisol then signals the pituitary to lower secretion of ACTH.Hydrocortisone (HCS) is a synthetic form of corticosteroid administrated when the body isdeficient in the natural hormone. It is used to treat allergy, inflammation, asthma, collagendiseases, adrenocortical deficiency, shock and some neoplastic conditions including acutelymphoblastic leukaemia. It generally possesses low bioavailability when they are orallyadministrated and topically applied whereas some patients are found to have severe allergicresponse towards intravenous injection [14] .The drug release rate is difficult to control in all existing conventional sustained-releasetablets as drug absorption is influenced heavily by its transition rate in the gastrointestinaltract, resulting in wide variations in the oral bioavailability [15] . It has been reported that amultiple-unit dosage form can overcome this problem to a certain extent; however, it requiresa primitive manufacturing technology [16, 17] . It is therefore the purpose of this study toimplement HME to develop a new dosage form that overcomes these biological andtechnological problems. A formulation development study on the novel HCS sustained-releasetablets is hereby reported along with the analysis of the release mechanism of all preparedsustained-release tablets.2.0 Materials and methods2.1 MaterialsHydrocortisone (HCS) was purchased from Sigma Aldrich (London, UK). EthylCellulose N10 (EC N10) and Ethyl Cellulose EP7 (EC P7) were kindly donated by Harceulis(Darmstadt, Germany) and Colorcon Ltd respectively. Eudragit S100 (S100) was provided byEvonik Industries (Darmstadt, Germany). SiO 2 and MgSt were purchased from SigmaAldrich, UK. The HPLC solvents were of analytical grade and purchased from FisherChemicals (UK). All materials were used as received.2.2 Calculation of solubility parameters[Please see Chapter 7, Section 2.2 for details].152 | P a g e
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DECLARATION“I certify that this w
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taste masking effect of the process
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CHAPTER 2: DISSOLUTION ENHANCEMENT
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3.2 Powder and ODT characterization
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3.7 In vitro drug release profiles
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3.1 Solubility parameters and extru
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polymers.7.2 DSC findings of all AP
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2.4b Diffractograms of FMT formulat
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4.3 Schematic representation of the
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55 exrudates (b) DPD/L100-55 PM (c)
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8.5d A plot of the logarithm of HCS
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L100Eudragit L100L100-55 Eudragit L
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Maniruzzaman M, Rai D, Boateng JS.
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Maniruzzaman M, Boateng JS, Bonnefi
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CHAPTER 1: INTRODUCTION1.0 Backgrou
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Table 1.1: HME and other convention
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homogenize but also compress the ex
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properties of polymers and excipien
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particles‘ wettability [46] . A v
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Table 1.2: Different hot-melt extru
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1.8 Aims and objectivesThe purpose
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29. Zheng X, Yang R, Tang X and Zhe
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56. International Conference on Har
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CHAPTER 2: DISSOLUTION ENHANCEMENT
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Fdid ,Vi F2pip , p( Ehi/ ViVi )i =
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used. Each sample was scanned from
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Furthermore, by means of thermodyna
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3.2 Particle size morphology and pa
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Fig. 2.4a: Diffractograms of INM fo
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However, the DSC thermograms of the
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Fig. 2.5b: DSC thermograms of INM a
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Fig. 2.5e: DSC thermograms of FMT a
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Nevertheless, more than 80% FMT was
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6. Caron V, Tajber L, Corrigan OI,
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CHAPTER 3: DEVELOPMENT AND EVALUATI
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2.2 Hot-Melt extrusionHot-melt extr
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Committee of the University of Gree
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The PM of formulation II (40% IBU)
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Fig. 3.3: DSC thermograms of pure I
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As a general rule, the powder compr
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Fig. 3.4: Schematic diagram of ODT
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Fig. 3.5: Schematic diagram of ODTs
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Fig. 3.7: Schematic diagram of ODTs
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F2 0 0.5 0 1 0 1F6 0 0.5 0 1 0 2F7
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6. M.F. Al-Omran, S.A. Al-Suwayeh,
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30. L. Saerens, L. Dierickx, B. Len
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leading to significant variations w
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2.6. In vitro drug release studiesI
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v2d 2p(4.1)Table 4.1: Calculated so
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The observed melting peaks are shif
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Fig. 4.2a: Powder XRPD patterns of
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Interestingly, no difference was ob
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7 Astree sensors Taste masking effi
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The in vitro e-tongue evaluation wa
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3. K. Woertz, C. Tissen, P. Kleineb
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25. B.C. Hancock, P. York, R.C. Row
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CHAPTER 5: AN IN VIVO AND IN VITRO
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(dispersion forces and polarization
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Table 5.1: Sample preparation for t
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Table 5.2: Solubility parameters ca
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Physical mixtures (PM) and extruded
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Fig. 5.2c: Thermograms of CTZ and V
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masking effect for active concentra
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Fig. 5.5b: Distance and discriminat
Page 134 and 135: Table 5.4: Mean standard deviation
Page 136 and 137: Fig. 5.6b: Release profiles of VRP
Page 138 and 139: 17. Woertz K,Tissen C, Kleinebudde
Page 140 and 141: scale or lower. XPS is more accurat
Page 142 and 143: patterns were identified after ener
Page 144 and 145: 3.3 Differential scanning calorimet
Page 146 and 147: Fig. 6.3a: Diffractograms of PRP fo
Page 148 and 149: good agreement with the anticipated
Page 150 and 151: Since L100 contained higher proport
Page 152 and 153: at ~533.01 eV is the combination of
Page 154 and 155: Finally, the XPS analysis confirmed
Page 156 and 157: Fig. 6.6b: 1 H NMR spectra of all P
Page 158 and 159: 6) Bonferoni, M.C.; Rossi, S.; Ferr
Page 160 and 161: 26) Vandencasteele, N.; Reniers, F.
Page 162 and 163: Gibbs free energy change before and
Page 164 and 165: 2.5 Hot-melt extrusion (HME) proces
Page 166 and 167: 2.11 X-ray photoelectron spectrosco
Page 168 and 169: Table 7.2: DSC findings of all APIs
Page 170 and 171: 3.4 In vivo and in vitro taste mask
Page 172 and 173: Fig. 7.3c: Normalised DI (%) of all
Page 174 and 175: Table 7.4: Binding energy calculati
Page 176 and 177: PRP/ polymers extruded in compariso
Page 178 and 179: atom as NH + 4 . This observed N 1s
Page 180 and 181: 8.0 ConclusionsThe presence of inte
Page 182 and 183: 20. Davies MC, Wilding IR, Short RD
Page 186 and 187: 2.3 Preparation of formulation blen
Page 188 and 189: medium pH was maintained as 1.2 by
Page 190 and 191: Fig. 8.1: SEM images of [(a), (b)]
Page 192 and 193: Fig. 8.2b: DSC transitions of HCS/E
Page 194 and 195: in the range of 10-12 kP. However,
Page 196 and 197: ate and time on the basis of Eq. (8
Page 198 and 199: Fig. 8.5c: A plot of the cubic root
Page 200 and 201: when n > 0.89. From the results of
Page 202 and 203: 14. Lam PL, Lee KKH,Wong RSM, Cheng
Page 204 and 205: Furthermore, HME has successfully b
Page 206 and 207: Supp. Fig. 2: XPS O 1s peaks for PR
Page 208 and 209: Supp. Fig. 4: O 1s BE peaks for L10
Page 210 and 211: 8.2 s 6.2 s 3.8 s 1.8 s 200 msS
Page 212 and 213: 12.2 s 9.0 s 6.2 s 3.8 s 1.8 s
Page 214 and 215: Supplementary table 1: Solubility p
Page 216 and 217: N = 55000/ 219.2 = 250.912Density:
Page 218 and 219: (4) Eudragit L100, N = (125000/202
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