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

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properties of polymers and excipients required and not suitable for relatively high heat sensitivemolecules such as microbial species, proteins etc [20, 21] .1.4 Applications of HMEExtrusion technology is one of the most important fabrication processes in the plastic andrubber industries. Products made from melt extruded polymers range from pipes to hosesthrough to the insulated wires, cables, rubber sheeting and polystyrene tiles. Plastics that arecommonly processed by HME technique include acrylics and cellulosics, polyethylene, polypropylene, polystyrene and vinyl plastics [9, 22] . In the food industry, extrusion has been utilizedfor pasta production with a widely used multitalented technique combining cooking andextrusion in a self-styled extrusion cooker [23] . In the animal feed industry and veterinary science,extrusion is commonly applied as a means of producing pelletized feeds, implants or injectionmoulding [24] . HME has successfully been applied in the formulation of fast dispersing PVP meltextrudates of poorly soluble active agents as solid molecular dispersions in the crop protectionfield [25] .HME technology has already achieved a strong place in the pharmaceutical industry andacademia due to several advantages over traditional processing methods such as roll spinningand grinding [18] . In addition to being an efficient manufacturing process, HME enhances thequality and efficacy of manufactured products and therefore over the past few years HME hasemerged as a novel technique in pharmaceutical applications [15, 28] . The main use of HME is todisperse active pharmaceutical ingredients (APIs) in a matrix at the molecular level, thusforming solid dispersions [1, 26] . In the pharmaceutical industry, HME has been used for variousapplications, such as i) enhancing the dissolution rate and bioavailability of poorly soluble drugsby forming a solid dispersion or solid solution, ii) controlling or modifying the release of thedrug, iii) taste masking of bitter APIs, and iv) formulation of various thin films [27] .The bioavailability of an active ingredient is controlled by its aqueous solubility.Therefore, increasing the solubility of water insoluble drugs is still a real challenge in theformulation development process [26] . Due to the advent of high throughput screening (HTS) inthe drug discovery process, the resultant compounds are often high molecular weight and highlylipophilic and therefore exhibit poor solubility [29] . Scientists have already tried to addresssolubility issues by various pharmaceutical interventions. Among the many methods available toimprove solubility and dissolution rate, preparation of solid dispersions and solid solutions hasgained vast attention. For that reason, HME has been successfully applied to prepare solidmolecular dispersion of APIs into different hydrophilic polymer matrices [26, 29] .7 | P a g e
1.5 Formulation research and developments to dateDespite the fact that initial research developments have focused on the effects offormulation and processing variables on the properties of the final dosage forms,[9, 30, 31, 34, 35]more recent investigations have focused on the use of HME as a novel manufacturingtechnology of solid molecular dispersions through to the development of mini-matrices, tastemasked formulations and also sustained release formulations as well as paediatric formulations[26, 48] . Early work by De Brabander et al. (2000) described the preparation of matrix mini-tabletswhich was followed by further investigations into the properties of sustained release minimatricesmanufactured from ethyl cellulose, HPMC and ibuprofen [32, 33] . Extruded mini tabletsshowed minimised risk of dose dumping, reduced inter- and intra-subject variability. Recently,Roblegg et al. (2011) reported the development of retarded release pellets using vegetablecalcium stearate (CaSt) as a thermoplastic excipient processed through HME, where pellets witha drug loading of 20% paracetamol released only 11.54% of the drug after 8 hours due to thesignificant densification of the pellets. As expected, the drug release was influenced by the pelletsize and the drug loading [36] . A microbicide intravaginal ring (IVR) IVR was prepared anddeveloped from polyether urethane (PU) elastomers for the sustained delivery of UC781 (ahighly potent nonnucleoside reverse transcriptase inhibitor of HIV-1). PU IVRs containingUC781 were fabricated using a hot-melt extrusion process [37] .Moreover, a fourfold increase in the availability of propanolol in the systemic circulationwas observed when the HME formulation was compared with a commercially availableformulation (Inderal®). Over the last five years HME has been used largely to manufacturegranules, pellets, immediate and modified release tablets, transmucosal/ transdermal films andimplantable reservoir devices [3, 4, 9, 35, 38] . For instance, with respect to drug administrationthrough the oral route, molecular solid dispersions of nifedipine [38] , nimodipine [29] anditraconazole [39, 40, 41] have been successfully produced using HME technology. Amorphousindomethacin dispersions have been manufactured using pharmaceutically acceptablehydrophilic polymers by using HME technology [26, 42, 43] .Furthermore, HME research developments have driven targeted drug delivery systemsincluding enteric matrix tablets and capsule systems over the last few years [44, 45] . Miller et al.(2007) have demonstrated the ability of HME to act as an efficient dispersive process foraggregated, fine engineering particles to improve dissolution rate properties by enhancing8 | P a g e
Page 3 and 4: DECLARATION“I certify that this w
Page 6 and 7: taste masking effect of the process
Page 8 and 9: CHAPTER 2: DISSOLUTION ENHANCEMENT
Page 10 and 11: 3.2 Powder and ODT characterization
Page 12 and 13: 3.7 In vitro drug release profiles
Page 15: 3.1 Solubility parameters and extru
Page 18 and 19: polymers.7.2 DSC findings of all AP
Page 20 and 21: 2.4b Diffractograms of FMT formulat
Page 22 and 23: 4.3 Schematic representation of the
Page 24 and 25: 55 exrudates (b) DPD/L100-55 PM (c)
Page 26 and 27: 8.5d A plot of the logarithm of HCS
Page 28 and 29: L100Eudragit L100L100-55 Eudragit L
Page 30 and 31: Maniruzzaman M, Rai D, Boateng JS.
Page 32 and 33: Maniruzzaman M, Boateng JS, Bonnefi
Page 34 and 35: CHAPTER 1: INTRODUCTION1.0 Backgrou
Page 36 and 37: Table 1.1: HME and other convention
Page 38 and 39: homogenize but also compress the ex
Page 42 and 43: particles‘ wettability [46] . A v
Page 44 and 45: Table 1.2: Different hot-melt extru
Page 46 and 47: 1.8 Aims and objectivesThe purpose
Page 48 and 49: 29. Zheng X, Yang R, Tang X and Zhe
Page 50 and 51: 56. International Conference on Har
Page 52 and 53: CHAPTER 2: DISSOLUTION ENHANCEMENT
Page 54 and 55: Fdid ,Vi F2pip , p( Ehi/ ViVi )i =
Page 56 and 57: used. Each sample was scanned from
Page 58 and 59: Furthermore, by means of thermodyna
Page 60 and 61: 3.2 Particle size morphology and pa
Page 62 and 63: Fig. 2.4a: Diffractograms of INM fo
Page 64 and 65: However, the DSC thermograms of the
Page 66 and 67: Fig. 2.5b: DSC thermograms of INM a
Page 68 and 69: Fig. 2.5e: DSC thermograms of FMT a
Page 70 and 71: Nevertheless, more than 80% FMT was
Page 72 and 73: 6. Caron V, Tajber L, Corrigan OI,
Page 74 and 75: CHAPTER 3: DEVELOPMENT AND EVALUATI
Page 76 and 77: 2.2 Hot-Melt extrusionHot-melt extr
Page 78 and 79: Committee of the University of Gree
Page 80 and 81: The PM of formulation II (40% IBU)
Page 82 and 83: Fig. 3.3: DSC thermograms of pure I
Page 84 and 85: As a general rule, the powder compr
Page 86 and 87: Fig. 3.4: Schematic diagram of ODT
Page 88 and 89: Fig. 3.5: Schematic diagram of ODTs
Page 90 and 91:
Fig. 3.7: Schematic diagram of ODTs
Page 92 and 93:
F2 0 0.5 0 1 0 1F6 0 0.5 0 1 0 2F7
Page 94 and 95:
6. M.F. Al-Omran, S.A. Al-Suwayeh,
Page 96 and 97:
30. L. Saerens, L. Dierickx, B. Len
Page 98 and 99:
leading to significant variations w
Page 100 and 101:
2.6. In vitro drug release studiesI
Page 102 and 103:
v2d 2p(4.1)Table 4.1: Calculated so
Page 104 and 105:
The observed melting peaks are shif
Page 106 and 107:
Fig. 4.2a: Powder XRPD patterns of
Page 108 and 109:
Interestingly, no difference was ob
Page 110 and 111:
7 Astree sensors Taste masking effi
Page 112 and 113:
The in vitro e-tongue evaluation wa
Page 114 and 115:
3. K. Woertz, C. Tissen, P. Kleineb
Page 116 and 117:
25. B.C. Hancock, P. York, R.C. Row
Page 118 and 119:
CHAPTER 5: AN IN VIVO AND IN VITRO
Page 120 and 121:
(dispersion forces and polarization
Page 122 and 123:
Table 5.1: Sample preparation for t
Page 124 and 125:
Table 5.2: Solubility parameters ca
Page 126 and 127:
Physical mixtures (PM) and extruded
Page 128 and 129:
Fig. 5.2c: Thermograms of CTZ and V
Page 130 and 131:
masking effect for active concentra
Page 132 and 133:
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
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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 184 and 185:
CHAPTER 8: SUSTAINED RELEASE HYDROC
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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