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

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Table 1.2: Different hot-melt extruded films comprising of different polymeric materials,plasticisers and active ingredients for various indications.Main polymer(s) Plasticiser/additive Main activeingredient(s)Types of filmsAcrylicEudragit[60, 61]- Triacetin- TriethylcitrateClotrimazoleBioadhesiveControl releaseHydroxypropylcellulose [60]Polyethylene oxideHydroxypropylcellulose [62]HydroxypropylmethylcelluloseN/A Ketoconazole Bioadhesive filmsfor OnychomyosisFast releasePolyethylene glycol 3350 Lidocaine Water solubleBioadhesivePolyethylene oxideHydroxypropylcellulose [65] Polyethylene glycol 400 HydrocortisoneChlorpheniramine maleateHydrophillicBioadhesiveHydroxypropylcellulose [58]PolycarbophilPolyethylene glycol 3350 Clotrimazole BioadhesiveFast releasePolyethylene oxide [59] N/A Ketoprofen BioadhesiveAntifungalRepka and co-workers have conducted extensive research on the use of HME for themanufacture of mucoadhesive buccal films. They successfully evaluated different matrixformers and additives for the processing of the blend prior to extrusion [61, 62, 63, 64] . In an earlyinvestigation, it was found that even though films containing exclusively HPC could not beobtained, the addition of plasticizers, such as triethyl citrate, PEG 2000/8000, or acetyltributylcitrate, allowed for the manufacture of thin, flexible, and stable HPC films [65] . It has also beenfound that increasing the molecular weight of HPC decreased the release of drugs from hot-meltextruded films which resulted in dissolution profiles exhibiting zero-order drug release.According to the models applied in the research, the drug release was solely determined byerosion of the buccal film [66, 67, 68] .Development of films by HME may present future opportunities to develop gastroretentivefilms for prolonged drug delivery and multi-layer films to modulate drug release for11 | P a g e
oral and transdermal applications. The growing market in medical devices, includingincorporating drugs into devices such as biodegradable stents and drug-loaded catheters willundoubtedly require HME manufacturing processes. These are required to be commercialisedand perhaps may lead to new areas of collaboration across pharmaceutical, medical device andbiotechnology research.1.6 HME in commercial productsHME related patents which have been issued for pharmaceutical systems have steadilyincreased since the early 1980‘s [69] . So far, the USA and Germany hold approximately morethan half (56%) of all issued patents for HME in the market. Despite this increased interest, onlya handful of commercialized HME pharmaceutical products are currently marketed. Severalcompanies have been recognized to specialize in the use of HME as a drug delivery technology,such as PharmaForm and SOLIQS (Abbott). Recently, SOLIQS has developed a proprietaryformulation which is known as Meltrex® and re-developed a protease-inhibitor combinationproduct, Kaletra®. Kaletra is mainly used for the treatment of human immunodeficiency virus(HIV) infections. The formulated, melt extruded product was shown to have a significantenhancement in the bioavailability of active substances [70] . Furthermore, HME Kaletra® tabletswere shown to have significant advantages for patient compliance (i.e. reduced dosing frequencyand improved stability) compared to the previous soft-gel capsule formulation as recognized bythe FDA decision to fast-track approval. Additionally, Nurofen (Meltlets® lemon) is available inthe market as a fast dissolving tablet prepared by similar technique to HME [42] . Ibuprofen hasbeen used as active substance in the Meltlets® tablets. Moreover, SOLIQS has also developed afast-onset ibuprofen system and a sustained-release formulation of verapamil (Isoptin® SR-E)through a HME related technology called ‗Calendaring‘ that was the first directly shaped HMEproduct in the market.1.7 SummaryHME has proven to be a robust method of producing numerous drug delivery systemsand therefore it has been found to be useful in the pharmaceutical industry enlarging the scope toinclude a range of polymers and APIs that can be processed with or without plasticizers. It hasalso been documented that HME is a solvent-free, robust, quick and economy favouredmanufacturing process for the production of a large variety of pharmaceutical dosage forms.12 | 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 40 and 41: properties of polymers and excipien
Page 42 and 43: particles‘ wettability [46] . A v
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
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v2d 2p(4.1)Table 4.1: Calculated so
Page 104 and 105:
The observed melting peaks are shif
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Fig. 4.2a: Powder XRPD patterns of
Page 108 and 109:
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
Page 130 and 131:
masking effect for active concentra
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Fig. 5.5b: Distance and discriminat
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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
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scale or lower. XPS is more accurat
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patterns were identified after ener
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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
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at ~533.01 eV is the combination of
Page 154 and 155:
Finally, the XPS analysis confirmed
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Fig. 6.6b: 1 H NMR spectra of all P
Page 158 and 159:
6) Bonferoni, M.C.; Rossi, S.; Ferr
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26) Vandencasteele, N.; Reniers, F.
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Gibbs free energy change before and
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2.5 Hot-melt extrusion (HME) proces
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2.11 X-ray photoelectron spectrosco
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Table 7.2: DSC findings of all APIs
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3.4 In vivo and in vitro taste mask
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Fig. 7.3c: Normalised DI (%) of all
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Table 7.4: Binding energy calculati
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PRP/ polymers extruded in compariso
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atom as NH + 4 . This observed N 1s
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8.0 ConclusionsThe presence of inte
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20. Davies MC, Wilding IR, Short RD
Page 184 and 185:
CHAPTER 8: SUSTAINED RELEASE HYDROC
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2.3 Preparation of formulation blen
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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
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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
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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
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N = 55000/ 219.2 = 250.912Density:
Page 218 and 219:
(4) Eudragit L100, N = (125000/202
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